BF3·OEt2-Catalyzed Vinyl Azide Addition to in Situ Generated N-Acyl Iminium Salts: Synthesis of 3-Oxoisoindoline-1-acetamides

Article abstract of DOI:10.1021/acs.joc.9b02127

BF₃·OEt₂-catalyzed nucleophilic addition of vinyl azides to in situ generated N-acyl iminium salts obtained from 3-hydroxyisoindolinones is described in this article. The procedure is operationally simple, mild, additive, and metal-free. The reaction proceeds smoothly at ambient temperature with a wide range of 3-hydroxyisoindol-1-ones and vinyl azides to afford 3-oxoisoindoline-1-acetamides (32 examples) in high yields (up to 97%). Furthermore, the synthetic utility of this methodology is depicted by exploiting the reactivity of an amide functionality in the products.

Full text of DOI:10.1021/acs.joc.9b02127

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Article
BF3·OEt2 Catalyzed Vinyl Azides Addition to in situ Generated N-
Acyl Iminium Salts: Synthesis of 3-Oxoisoindoline-1-acetamides
Deb K. Das, Vinod Kumar Kannaujiya, Milon Mohan Sadhu, Sumit Kumar Ray, and Vinod K. Singh
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02127 • Publication Date (Web): 19 Nov 2019
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BF3·OEt2 Catalyzed Vinyl Azides Addition to in situ Generated N-Acyl Iminium Salts:
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Synthesis of 3-Oxoisoindoline-1-acetamides
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Deb Kumar Das,a Vinod Kumar Kannaujiya,§,a Milon M. Sadhu,§,a Sumit Kumar Raya and
Vinod K. Singh*b
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aDepartment of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal,
MP - 462 066, India
bDepartment of Chemistry, Indian Institute of Technology Kanpur, Kanpur, UP - 208 016, India
Corresponding Author
*E-mail: vinodks@iitk.ac.in
§ These authors contributed equally.
Abstract
BF3·OEt2 catalyzed nucleophilic addition of vinyl azide towards in situ generated N-acyl
iminium salts obtained from 3-hydroxyisoindolinones has been described in this manuscript. The
procedure is operationally simple, mild, additive and metal free. The reaction proceeds smoothly
at ambient temperature with a wide range of 3-hydroxyisoindol-1-ones and vinyl azides, to
afford 3-oxoisoindoline-1-acetamides (32 examples) in high yields (up to 97%). Furthermore, the
synthetic utility of this methodology has been depicted by exploiting the reactivity of an amide
functionality in the products.
Introduction
The amide functionality is omnipresent in many modern pharmaceuticals and biologically active
compounds.1 It has also been found that small organic molecules containing methylene amide
linkages exist in numerous bio-active compounds, chemical probes and drug leads.2 Significant
properties of amides, such as high polarity, stability and conformational diversity, make them of
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great importance in contemporary chemistry. Amide functional group can serve as an important
surrogate for the synthesis of various nitrogen-containing heterocycles.3 Thus, installation of the
amide functionality into organic molecule is highly desirable.4
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On the other hand, isoindolinones have been found as key structural unit present in many
naturally or synthetically useful bio-active compounds as shown in Figure 1.5 In particular, 3-
substituted isoindolinones bearing methylene amide linkage have received considerable
attention since they represent the core unit of a broad range of medicinally important
compounds.6 For examples, JM-12326a (sedative and hypnotic drug) and Pazinaclone6b (sedative
and anxiolytic drug) consist of the similar core in their structures. Therefore, the synthesis of 3-
substituted isoindolinones bearing methylene amide linkage is interesting in the context of drug
discovery. Towards this, our group has already developed a number of novel and efficient
methodologies for the synthesis of 3-substituted isoindolinones.6c-f
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Figure 1. Some biologically active isoindolinone derivatives.
Amide moiety could be installed in organic molecules by nucleophilic addition of amide enolates
to appropriate carbon electrophiles via carbon-carbon bond formation.7 In recent times, vinyl
azides have attracted a great deal of interest among synthetic chemists for being used as an
alternative to amide enolates.8 Vinyl azides display similar nucleophilic reactivity like enamines.8
These have been successfully employed as nucleophiles with a variety of electrophiles such as
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aldehydes, imines, and carbocations obtained from alcohols to provide amides (Scheme 1a and
1b).9 Cui’s group has reported nucleophilic addition reaction of vinyl azides with p-quinone
methides (p-QMs) to furnish amides and nitriles.10 Later on, this strategy was applied for the
reaction of glycols with vinyl azides to access α-C-glycosyl amides.11 These reports reveal that
these can serve as good amide precursors under various reaction conditions.
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3-Aryl-3-hydroxyisoindolinones can be readily dehydrated to generate cyclic N-acyl iminium
salts in the presence of Brønsted acids (Scheme 1c).12 This reactive N-acyl iminium salt
intermediate has been successfully used in various asymmetric reactions such as arylation,13
annulation reactions,14 hydrogenolysis,15 hydrophosphonylation,16 nucleophilic addition of N-
tert-butyl hydrazones,17 indoles,18 thiols19 and alcohols.20 Very recently our group has used this
substrate for enantioselective Mannich-type reaction of α-diazo esters catalyzed by chiral
Brønsted acid.21 Inspired by these aforementioned strategies, we envisaged that under Lewis acid
activation, in situ generated N-acyl iminium salts resulting from 3-aryl-3-hydroxyisoindolinone
might act as an electrophile which can be trapped by vinyl azide. This would provide 3-
oxoisoindoline tethered imino diazonium ion intermediate, which might further undergo a
Schmidt-type 1,2-migration to furnish nitrilium ion intermediate. Finally, hydrolysis of this
intermediate will generate 3-oxoisoindoline-1-acetamide derivative bearing methylene amide
linkages. Herein, we have reported a BF3·OEt2 catalyzed reaction of vinyl azides with a variety
of 3-hydroxyisoindolinones for the synthesis of 3-oxoisoindoline-1-acetamides comprising of a
quaternary carbon center as shown in Scheme 1d.
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Scheme 1. Synthesis of Amide Functionality by Nucleophilic Addition of Vinyl Azides
Result and discussion
To determine the optimized conditions, a model reaction was carried out using 3-hydroxy-3-
phenylisoindolin-1-one (1a) and (1-azidovinyl)benzene (2a) in the presence of 20 mol % of
Cu(OTf)2 in dichloromethane at room temperature. Delightfully, the desired product 2-(3-oxo-1-
phenylisoindolin-1-yl)-N-phenylacetamide (3aa) was obtained in 46% yield (entry 1, Table 1).
Encouraged by this initial result, efforts were given to further improve the yield of 3aa. A series
of Lewis acid catalysts such as (CuOTf)2·C6H6, Sc(OTf)3, InCl3, In(OTf)3 were investigated in
our reaction (entries 2-5, Table 1). Among all, In(OTf)3 was found to be effective catalyst
providing the desired product 3aa in 69% yield. To our delight, when the reaction was conducted
by employing BF3·OEt2 as a catalyst, the reaction proceeded well, affording the desired product
3aa in an excellent level of yield (92%, Table 1, entry 6) in a shorter reaction time (3 h).
Brønsted acid catalysts such as CF3CO2H, CF3SO3H and p-toluenesulfonic acid monohydrate (p-
TsOH·H2O) also afforded the isoindolinone derivative 3aa in moderate to good yields (up to
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74% yield). Notably, it was found that there was no product formation in the absence of catalyst
even after 3 days and only the starting materials were recovered (Table 1, entry 10).
Subsequently, the effect of solvents on the product formation was screened (Table 1, entries 6
and 11-15). It was observed that dichloromethane was the best solvent to furnish the desired
product 3aa in excellent yields (Table 1, entry 6). In contrast, comparatively lower yields were
obtained when the reaction was performed in other solvents such as acetonitrile and toluene
(Table 1, entries 13-14). THF turned out to be ineffective as a solvent for this reaction, and only
a trace amount of 3aa was observed (Table 1, entry 15). Afterward, the effect of catalyst loading
was investigated. It was found that decreasing the amount of BF3·OEt2 from 20 mol % to 10 mol
% showed little impact on the outcome of the reaction (Table 1, entry 16) whereas increasing the
amount of catalyst loading to 50 mol % gave 3-oxoisoindoline-1-acetamides product in lower
yield (78% yield, Table 1, entry 17). This drop in the yield of the product was attributed to the
fact that phenyl vinyl azide (2a) was decomposed to acetanilide (isolated as a by-product), when
higher concentration of BF3·OEt2 was used. Extensive optimization of the reaction conditions
revealed that 20 mol % of BF3·OEt2 as catalyst and CH2Cl2 as a solvent were optimal for the
addition reaction of vinyl azides to 3-aryl-3-hydroxyisoindolinones at ambient temperature.
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Table 1. Optimization of the reaction conditionsa
entry
catalyst
Cu(OTf)2
(CuOTf)2.C6H6
Sc(OTf)3
InCl3
amount (equiv.)
solvent time (h) yieldb(%)
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0.2
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CH2Cl2
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CH2Cl2
CH2Cl2
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CH2Cl2
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In(OTf)3
BF3·OEt2
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CF3CO₂H
CF3SO3H
p-TsOH, H2O
none
0.2
0.2
0.2
-
CH2Cl2
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3
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CH2Cl2
CH2Cl2
CH2Cl2
DCE
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n.r
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BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
0.2
0.2
0.2
0.2
0.2
0.1
0.5
CHCl3
CH3CN
toluene
THF
3
76
12
12
24
3
52
32
Trace
89
CH2Cl2
CH2Cl2
3
78
aIn all cases, reactions were performed using 1a (1.0 equiv , 0.20 mmol, 45.0 mg) and vinyl azide 2a (1.1 equiv ,
0.22 mmol, 32.0 mg) in 2.0 mL of CH2Cl2 at room temperature. bIsolated yield, n.r = no reaction.
Having identified the optimal reaction conditions for this transformation, the substrate scope and
reaction limitations were explored. At first, a variety of differently substituted 3-aryl 3-
hydroxyisoindolinones were screened with the reaction of (1-azidovinyl)benzene (2a), affording
an array of functionalized 3-oxoisoindoline-1-acetamides in good to excellent level of yields.
The results are summarized in Table 2. Substrates (1b and 1c) bearing halogen as a substituent
on the para-position of the aromatic ring at the C-3 position of 3-aryl-3-hydroxyisoindolinones
smoothly reacted to afford the corresponding 3-oxoisoindoline-1-acetamide (3ba and 3ca) with
95% and 97% yields, respectively. Substrates (1d-1h) having electron rich alkyl or alkoxy group
as substituent on the aromatic ring at C-3 position reacted well and furnished products 3da-3ha
in good yields (up to 86%). Noticeably, 3-hydoxy-isoindolinones having electron donating
substituents on the 3-aryl ring took comparably a longer reaction time for completion of the
reaction and also gave lower yield than 3-hydoxy-isoindolines bearing electron withdrawing
substituents on the 3-aryl ring (3da-ha vs. 3ba-ca). Substrate 1i containing a heteroaryl moiety
(thiophene) at C-3 position, affording the desired product 3ia in 84% yield. Isoindolinones with
different substituents on the phthalimide aromatic ring were also examined. The reaction of 3-
hydroxy-isoindolinone derivative 1j with vinyl azide (2a) provided 3-oxoisoindoline-1-
acetamide 3ja in 89% yield (Table 2). Phthalimide aromatic moiety bearing a 5,6-dimethyl or
5,6-dichloro substituents were compatible under the present reaction conditions and furnished
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products 3ka-3pa in good yields. In addition, substrates 1q tethered with a naphthyl ring took a
longer time for completion of the reaction to afford the corresponding product 3qa in 73% yield.
The protocol was successful in producing 3-oxoisoindoline-1-acetamide 3ra in 81% yield when
3-hydroxyisoindolin-1-one 1r was used.
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Table 2. Scope of various 3-hydroxy-3-arylisoindolinones for the synthesis of 3-oxoisoindoline-
1-acetamidesa,b
aIn all cases, reactions were performed using 1 (1.0 equiv, 0.20 mmol), vinyl azide 2 (1.1 equiv, 0.22 mmol) and
BF3·Et2O (0.20 equiv, 0.04 mmol) in 2 mL of CH2Cl2 at room temperature. bIsolated yield
However, 3-hydroxyisoindolinone 1s and 1t bearing a methyl and vinyl group respectively at the
C-3 position failed to give the desired 3-oxoisoindoline-1-acetamide 3sa and 3ta under the
current protocol. The reaction of 3-hydroxy-2,3-diphenylisoindolin-1-one 1u with vinyl azide 2a
did not proceed at all under standard conditions. This control experiment clearly suggests that the
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free NH group in 3-hydroxy isoindolinones is essential for the present transformation. An X-ray
crystal structure analysis of compound 3ba (CCDC No. 1919472) unambiguously confirmed the
proposed structure (please see SI for more details).
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Subsequently, the substrate generality of this reaction was further explored by the reaction of 3-
hydroxy-3-phenylisoindolin-1-one (1a) with a broad range of vinyl azides (2b-n) under
optimized conditions. A variety of vinyl azides having functionalized aromatic ring as
substituents were tested, affording corresponding 3-oxoisoindoline-1-acetamides derivative 3ab-
am in synthetically viable yields (67% - 94% yields).
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Table 3. Scope of various vinyl azides for the synthesis of 3-Oxoisoindoline-1-acetamidesa,b
aIn all cases, reactions were performed using 1 (1.0 equiv, 0.20 mmol), vinyl azide 2 (1.1 equiv, 0.22 mmol) and
BF3·Et2O (0.20 equiv, 0.04 mmol) in 2 mL of CH2Cl2 at room temperature. bIsolated yield
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The halide-containing vinyl azides (2b-d) were well tolerated, generating the halo-substituted 3-
oxoisoindoline-1-acetamides (entries 3ab-ad, Table 3) in good yields. The intact halogen atom in
the products offers an opportunity for further cross-coupling reactions. The reaction efficiencies
remain the same when meta-substituted aromatic vinyl azide 2d was used. Vinyl azides 2e and 2f
t
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bearing an electron-rich alkyl substituent (Me, Bu) readily reacts with 3-hydroxyisoindolinone
1a to afford the corresponding oxoisoindoline-1-acetamide (3ae and 3af) with excellent yields
(up to 94%). The reaction with sterically hindered 1-(1-azidovinyl)-2-methylbenzene 2g was
comparatively slow, resulting 3-oxoisoindoline-1-acetamide 3ag in a moderate yield (67%). The
slow reactivity of sterically hindered vinyl azide is might be due to the increased steric barrier for
Schmidt-type 1,2-migration to furnish nitrilium ion intermediate (See reaction mechanism in
Scheme 3). Para-methoxy substituted vinyl azide (2h) reacted well with 3-hydroxy-
isoindolinone 1a to produce 3ah in 90% yield. The reactions of aryl vinyl azides (2i-k) bearing
strong electron-deficient substituents (CN, CF3, NO2) were sluggish, requiring a longer reaction
time to afford the products (3ai-ak) in moderate yields. Aryl rings having electron-donating
groups provided the desired products in comparatively better yields than the substrates having
electron-withdrawing groups for the present protocol. Furthermore, vinyl azide 2l tethered with
thiophene moiety was amenable to this protocol, affording product 3al in 81% yield. The fused
aryl vinyl azide (2m) also worked smoothly to furnish 3am in excellent yield. Interestingly,
when methyl substitution was introduced at β-position of the vinyl azide 2n (R = Ph, R1 = Me),
the reaction proceeded smoothly and provided 3an in 88% yield with 1:1 dr. To validate the
practical usefulness of this methodology, a gram scale reaction of 1a (5 mmol, 1.12 g) with 1-(1-
azidovinyl)-4-methoxybenzene 2h (5.5 mmol, 0.96 g) was performed under optimized
conditions, furnishing the desired product 3ah in 84% yield (1.56 g)
This transformation may be rationalized with a plausible mechanism as shown in Scheme 2.11, 22
Initially, N-acyl iminium salt intermediate I will be generated from 3-aryl-3-
hydroxyisoindolinones 1 in the presence of BF3·Et2O. The nucleophilic addition of vinyl azide 2
to intermediate I will provide iminodiazonium intermediate II. Next, this iminodiazonium
intermediate (II) will undergo Schmidt-type 1,2-migration (migratory aptitude aryl>alkyl), with
extrusion of dinitrogen (N2) to furnish the nitrilium ion intermediate III. Finally, hydrolysis of
this intermediate III will provide oxoisoindoline-1-acetamides 3 (Scheme 2).
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Scheme 2. Possible reaction mechanism for the synthesis of oxoisoindoline-1-acetamides 3
To unravel the potential utility of this method in organic synthesis, a variety of synthetic
transformations were carried out using oxoisoindoline-1-acetamides 3 (Scheme 3).
Scheme 3. Synthetic transformation of functionalized 3-Oxoisoindoline-1-acetamides 3.
Compound 3aa was effectively hydrolyzed with 20% H2SO4 to furnish acid derivative 4 under
reflux condition. The primary amide bond in compound 3aa was selectively reduced with lithium
aluminum hydride to afford secondary amine derivative 5 in good yields. PMP group of 3ah was
oxidatively cleaved using ceric ammonium nitrate (CAN) to furnish amide derivative 6 in 90%
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yield. In addition, compound 3ra was hydrolyzed with 20% H2SO4 to afford 2-(3-oxoisoindolin-
1-yl)acetic acid 7 which could be easily transformed into bioactive compounds Pazinaclone and
Pagoclone by literature know procedure.23 These results demonstrate the usefulness of 3-
Oxoisoindoline-1-acetamides as synthetic intermediates.
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Conclusion
In summary, we have reported BF3.OEt2 catalyzed vinyl azides addition to in situ generated N-
acyl iminium salt derived from 3-aryl-3-hydroxyisoindolinones, enabling the straightforward
synthesis of 3-oxoisoindoline-1-acetamides derivatives. A variety of vinyl azides were used to
access biologically interesting 3-oxoisoindoline-1-acetamides derivatives with remarkable high
yields (up to 97%). This methodology is equally efficient in gram-scale. The synthetic utility of
this protocol was demonstrated by transforming oxoisoindoline-1-acetamides derivatives into a
variety of advanced synthetic intermediates. Salient features of this protocol are (i) metal and
additive free, (ii) mild reaction conditions (iii) generation of a quaternary carbon centre having
methylene amide linkage, (iv) broad substrates scope.
Experimental Section
Materials and Methods
All reactions were carried out in oven-dried glassware with magnetic stirring. All solvents were
purified and dried according to standard methods prior to use. 1H NMR spectra were recorded on
400 MHz or 500 MHz in CDCl3 and DMSO-d6. C{1H}NMR spectra were recorded on 100 or
13
125 MHz in CDCl3 and DMSO-d6 using TMS or residual solvent signals as internal standard.
Data for 1H NMR are recorded as follows: chemical shift (δ, ppm), multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet or unresolved, coupling constant (s) in Hz,
integration). Data for 13C{1H}NMR are reported in terms of chemical shift (δ, ppm). High
resolution mass spectra (HRMS) were obtained by the ESI (Q-TOF) ionization sources. IR
spectra were measured with FT/IR Vector22 spectrometer. Routine monitoring of reactions was
performed using precoated silica gel TLC plates. All the chromatographic separations were
carried out by using silica gel (100-200 mesh). Melting points were recorded by using a melting
point apparatus and are uncorrected.
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Ethyl acetate (EA), petroleum ether (PE), BF3·OEt2, and dichloromethane (DCM) are
commercially available. All 3-aryl-3-hydroxyisoindolinones and vinyl azides were known
compounds and prepared according to reported procedures.16, 23, 24 Organic azides are potentially
explosive. Proper safety precautions were utilized while performing the reactions.
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General Procedure and characterization data for the Synthesis of 3-hydroxy-3-aryl
isoindolin-1-one:
Characterization data for compounds (1b,16 1f,24a 1g,16 1p,16 1q16) Compounds (1a, 1c, 1d, 1h,
1i, 1k, 1s) 24a and compound (1e,24b 1l,24c 1r24d-e and 1u 24f) are reported in literature.
3-hydroxy-3-aryl isoindolin-1-one 1j, 1m, 1n, 1o, 1t were synthesized according to modified
literature procedure16.
To a solution of aryl bromide/vinyl bromide (4.0 equiv) in THF (20 mL) cooled at –78 °C
temperature, n-butyllithium solution (4.0 equiv, 1.6 M in hexane) was slowly added and stirred
for 30 min at the same temperature. Further, a solution of phthalimide (1.0 equiv, 3.4 mmol) in
THF (15 mL) was added in one portion and stirred for another 30 min at –78 °C. The reaction
mixture was brought to room temperature and stirred until the completion of the reaction
(monitored by TLC) the reaction mixture was then quenched with saturated NH4Cl solution and
acidified with 1N HCl till it reached pH 5.0. The aqueous solution was extracted with ethyl
acetate (thrice). The combined organic layers were washed with brine and dried over anhydrous
Na2SO4, and concentrated in vacuo. The pure product was obtained after washing the crude
product with CH2Cl2/hexane (1:2, v/v) as a solvent.
3-hydroxy-6-methyl-3-phenylisoindolin-1-one (1j): White solid, 617.76 mg, 76% yield. Rf=
0.38 (50% EtOAc in hexanes). MP: 151−153 °C. 1H NMR (500 MHz, DMSO-d6) δ 9.13 (s, 1H),
7.53 (d, J = 7.7 Hz, 1H), 7.49 (d, J = 7.2 Hz, 2H), 7.35 (dd, J = 8.4, 6.7 Hz, 2H), 7.31 – 7.27 (m,
2H), 7.11 (s, 1H), 6.86 (s, 1H), 2.34 (s, 3H). 13C{1H}NMR(125 MHz, DMSO-d6) δ 168.9, 151.8,
143.0, 142.8, 130.1, 128.7, 128.6, 128.2, 125.9, 123.5, 122.9, 87.6, 21.8. IR (film) νmax 2079,
1655, 1445, 1344, 1180, 1050 cm-1; HRMS (ESI-TOF) m/z : Exact mass calcd for
C15H13NO2Na, [M+Na]+ : 262.0838; Found 262.0837.
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3-hydroxy-5,6-dimethyl-3-phenylisoindolin-1-one (1m): White solid, 689.18 mg, 80% yield.
Rf= 0.40 (50% EtOAc in hexanes). MP: 158−160 °C.1H NMR (500 MHz, CDCl3+DMSO-d6)δ
8.91 (s, 1H), 7.48 (d, J = 7.2 Hz, 2H), 7.38 (s, 1H), 7.28 (s, 2H), 7.23 (d, J = 7.0 Hz, 1H), 7.02 (s,
1H), 6.64 (d, J = 14.4 Hz, 1H), 2.27 (s, 3H), 2.23 (s, 3H). 13C{1H}NMR(125 MHz,
CDCl3+DMSO-d6) δ 169.3, 149.3, 142.7, 141.4, 137.5, 128.9, 128.3, 127.8, 125.8, 123.8, 123.5,
87.5, 20.5, 20.0. IR (film) νmax 2840, 2127, 1660, 1450, 1402, 1203, 1111, 1015 cm-1; HRMS
(ESI-TOF) m/z : Exact mass calcd for C16H15NO2Na [M+Na]+ : 276.0995; Found 276.1013.
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3-(4-fluorophenyl)-3-hydroxy-5,6-dimethylisoindolin-1-one (1n): White solid, 691.25 mg,
75% yield. Rf= 0.36 (50% EtOAc in hexanes). MP: 142−146 °C.1H NMR (500 MHz, DMSO-
d6) δ 9.08 (s, 1H), 7.49 (dd, J = 8.7, 5.6 Hz, 2H), 7.42 (s, 1H), 7.16 (t, J = 8.7 Hz, 2H), 7.08 (s,
1H), 6.85 (s, 1H), 2.28 (s, 3H), 2.24 (s, 3H). 13C{1H}NMR (125 MHz, DMSO-d6) δ 169.0, 162.1
(d, J = 243.5 Hz), 149.2, 141.9, 139.2 (d, J = 2.8 Hz), 137.9, 128.9, 128.1 (d, J = 8.6 Hz), 123.9,
123.6, 115.3 (d,
J
=
21.4 Hz), 87.2, 20.4, 19.9. IR (film) νmax
2132,1710,1649,1511,1339,1222,1020 cm-1; HRMS (ESI-TOF) m/z : Exact mass calcd for
C16H15FNO2, [M+H]+ : 272.1081; Found 272.1096.
3-hydroxy-5,6-dimethyl-3-(p-tolyl)isoindolin-1-one (1o): White solid, 763.69 mg, 84% yield.
Rf= 0.40 (50% EtOAc in hexanes). MP: 156−158 °C. 1H NMR (500 MHz, DMSO-d6) δ 8.99 (s,
1H), 7.38 (s, 1H), 7.35 – 7.29 (m, 2H), 7.12 (d, J = 7.9 Hz, 2H), 7.03 (s, 1H), 6.69 (s, 1H), 2.26
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(s, 6H), 2.22 (s, 3H). C{1H}NMR (125 MHz, DMSO-d6) δ 168.6, 149.1, 141.2, 139.5, 137.2,
136.7, 128.6, 128.5, 125.4, 123.4, 123.0, 87.0, 20.6, 19.9, 19.4. IR (film) νmax 2909, 1673, 1625,
1426, 1331, 1201, 1050 cm-1; HRMS (ESI-TOF) m/z : Exact mass calcd for C17H17NO2Na
[M+Na]+ : 290.1151; Found 290.1176.
3-hydroxy-3-vinylisoindolin-1-one (1t): White solid, 476 mg, 80% yield. Rf= 0.38 (60% EtOAc
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in hexanes). MP: 96-98 °C. H NMR (500 MHz, DMSO-d6) δ 9.00 (d, J = 3.0 Hz, 1H), 7.66 –
7.56 (m, 2H), 7.56 – 7.43 (m, 2H), 6.52 (d, J = 3.1 Hz, 1H), 6.03 (dd, J = 17.1, 10.4 Hz, 1H),
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5.47 (d, J = 17.1 Hz, 1H), 5.17 (d, J = 10.4 Hz, 1H). C{1H}NMR (100 MHz, Chloroform-d) δ
170.0, 148.3, 136.5, 133.1, 130.0, 129.7, 123.7, 122.8, 116.5, 87.0. IR (film) νmax 2918, 1711,
1665, 1466, 1352, 1206,1066, 995,755,609,694 cm-1; HRMS (ESI-TOF) m/z : Exact mass calcd
for C10H9NO2Na [M+Na]+ : 198.0525; Found 198.0520.
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General Procedure and characterization data for the Synthesis of Vinyl azide:
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Characterization data for compounds (2a, 2b, 2c, 2e, 2f and 2g)25a, Compounds (2h and 2i)25b
and compounds (2j,25c 2n25c and 2k25d) are reported in literature.
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Vinyl azide derivatives 2d, 2l and 2m were synthesized according to the modified literature
procedure25d
A mixture of aryl acetylene (1.0 equiv, 2.0 mmol), TMS-N3 (2.0 equiv, 4.0 mmol) and H2O (1.5
equiv, 3.0 mmol) was taken in 10 mL DMSO solvent. Then Ag2CO3 (0.1 equiv, 0.2 mmol) was
added to the reaction mixture and heated at 80 ºC in oil bath. The mixture was then stirred at the
same temperature for 2 h until the starting material consumed (monitored by TLC). The reaction
mixture was cooled down to room temperature then concentrated and extracted with
dichloromethane (3 × 30 mL). The combined organic layer was washed with brine (2 × 60 mL)
and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo and the crude product
was purified over silica gel by column chromatography (5-10% EtOAc in Hexane) to afford
vinyl azide.
Note: Proper safety precautions were utilized while performing the reactions as explosive AgN3
was precipitated as by-product.
1-(1-azidovinyl)-3-fluorobenzene (2d): Colorless viscous liquid, 189.25 mg, 58% yield. Rf=
0.46 (10% EtOAc in hexanes).1H (500 MHz, CDCl3) δ 7.40 (dd, J = 7.9, 1.4 Hz, 1H), 7.37 –
7.30 (m, 2H), 7.11 – 7.05 (m, 1H), 5.51 (d, J = 2.8 Hz, 1H), 5.04 (d, J = 2.7 Hz, 1H).
13C{1H}NMR (125 MHz, Chloroform-d) δ 162.9 (d, J = 245.7 Hz), 144.0 (d, J = 2.8 Hz), 136.5
(d, J = 8.0 Hz), 129.9 (d, J = 8.3 Hz), 121.1 (d, J = 2.8 Hz), 115.9 (d, J = 21.3 Hz), 112.6 (d, J =
23.5 Hz), 98.6. IR (film) νmax 2925, 2106, 1583, 1490, 1310, 1180, 922 cm-1; HRMS (ESI-TOF)
m/z: Exact mass calcd for C8H7FN3 [M+H]+: 164.0619; Found 164.0631.
2-(1-azidovinyl)thiophene (2l): Yellow viscous liquid, 160.06 mg, 53% yield. Rf= 0.40 (10%
EtOAc in hexanes). 1H NMR (500 MHz, CDCl3) δ 7.49 (dd, J = 3.1, 1.4 Hz, 1H), 7.33 (dd, J =
5.1, 3.0 Hz, 1H), 7.29 (dd, J = 5.1, 1.4 Hz, 1H), 5.39 (d, J = 2.5 Hz, 1H), 4.96 (d, J = 2.5 Hz,
1H). 13C{1H}NMR(125 MHz, CDCl3) δ 141.0, 136.6, 126.5, 125.0, 122.8, 96.9. IR (film) νmax
3117, 2930, 2111, 1604, 1400, 1288, 935 cm-1; HRMS (ESI-TOF) m/z : Exact mass calcd for
C6H6N3S, [M+H]+: 152.0277; Found 152.0284.
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5-(1-azidovinyl)benzo[d][1,3]dioxole (2m): colorless viscous liquid, 241.92 mg, 64% yield.
Rf= 0.38 (10% EtOAc in hexanes). 1H NMR (500 MHz, CDCl3) δ 7.12 (dd, J = 8.2, 1.9 Hz, 1H),
7.07 (d, J = 1.9 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 5.98 (s, 2H), 5.33 (d, J = 2.5 Hz, 1H), 4.89 (d,
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J = 2.5 Hz, 1H). C{1H}NMR(125 MHz, CDCl3) δ 148.4, 147.9, 144.6, 128.5, 119.7, 108.0,
106.1, 101.4, 96.6. IR (film) νmax 3297, 2893, 2111, 1737, 1445, 1209, 930 cm-1; HRMS (ESI-
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TOF) m/z : Exact mass calcd for C9H8N3O2, [M+H]+: 190.0611; Found 190.0633.
General Procedure and characterization data for the Synthesis of 3-Oxoisoindoline-1-
acetamides, 3.
In a round bottomed flask, 3-aryl-3-hydroxyisoindolinones 1 (0.2 mmol, 1 equiv) and BF3-Et2O
(2.4 μL, 0.02 mmol) were taken in 2.0 mL CH2Cl2 solvent. The mixture was stirred at room
temperature (25 °C) for 10 minutes under nitrogen atmosphere. Then vinyl azide 2 (0.22 mmol,
1.1 equiv) was added dropwise. The reaction mixture was allowed to stir at room temperature.
After completion of reaction as indicated by TLC, the reaction was quenched with saturated
NaHCO3 (aq) and warmed to room temperature. The resulting mixture was extracted three times
with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4 and
concentrated under vacuum. The resulting crude mixture was purified over silica gel by
chromatography using petroleum ether/ethyl acetate (PE/EA = 4/1 to 1/1) as the eluent to give
the corresponding products 3.
2-(3-oxo-1-phenylisoindolin-1-yl)-N-phenylacetamide (3aa): White solid, 62.92 mg, 92%
yield. Rf= 0.32 (30% EtOAc in hexanes).MP: 107−109 °C.1H NMR (500 MHz, DMSO-d6) δ
9.92 (s, 1H), 8.95 (s, 1H), 7.64 (t, J = 5.6 Hz, 2H), 7.61 – 7.52 (m, 3H), 7.45 – 7.38 (m, 3H), 7.35
(t, J = 7.7 Hz, 2H), 7.27 – 7.21 (m, 3H), 7.00 (t, J = 7.2 Hz, 1H), 3.57 (d, J = 14.8 Hz, 1H), 3.40
(s, 1H). 13C{1H}NMR(125 MHz, DMSO-d6) δ 168.8, 167.2, 150.7, 142.5, 138.7, 131.8, 130.8,
128.6, 128.5, 128.1, 127.3, 125.1, 123.3, 123.0, 123.0, 119.2, 64.7, 44.9. IR (film) νmax 3377,
3280, 2129, 1010, 1654, 817 cm-1; HRMS (ESI-TOF) m/z : Exact mass calcd for C22H18N2O2Na
[M+Na]+: 365.1260; Found 365.1262.
N-(4-bromophenyl)-2-(3-oxo-1-phenylisoindolin-1-yl)acetamide (3ba): White solid,80.04 mg,
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95% yield. Rf= 0.33 (30% EtOAc in hexanes). MP: 228-230 °C. H NMR (500 MHz, DMSO-
d6) δ 9.92 (s, 1H), 9.00 (s, 1H), 7.64 (dd, J = 7.6, 4.7 Hz, 2H), 7.54 (s, 5H), 7.43 (dd, J = 13.4,
7.5 Hz, 3H), 7.24 (t, J = 7.9 Hz, 2H), 7.00 (t, J = 7.4 Hz, 1H), 3.56 (d, J = 15.6 Hz, 1H), 3.28 (d,
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J = 15.1 Hz, 1H).13C{1H}NMR(125 MHz, DMSO-d6) δ 168.8, 167.1, 150.3, 142.0, 138.7, 132.0,
131.4, 130.7, 128.7, 128.3, 127.6, 123.3, 123.1, 123.0, 120.6, 119.2, 64.4, 44.7. IR (film) νmax
3368, 3220, 2241, 1655, 827 cm-1; HRMS (ESI-TOF) m/z : Exact mass calcd for
C22H17BrN2O2Na [M+Na]+: 443.0366. Found: 443.0339.
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N-(4-fluorophenyl)-2-(3-oxo-1-phenylisoindolin-1-yl)acetamide (3ca): White solid, 69.91 mg,
97% yield. Rf = 0.32 (30% EtOAc in hexanes).MP: 238-240 °C. 1H NMR (500 MHz, DMSO-d6)
δ 9.92 (s, 1H), 9.00 (s, 1H), 7.65 (d, J = 7.7 Hz, 2H), 7.61 (d, J = 5.2 Hz, 2H), 7.56 (t, J = 7.6 Hz,
1H), 7.42 (d, J = 8.3 Hz, 3H), 7.24 (t, J = 7.7 Hz, 2H), 7.18 (t, J = 8.6 Hz, 2H), 7.00 (t, J = 7.4
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Hz, 1H), 3.55 (d, J = 15.1 Hz, 1H), 3.31 (d, J = 15.1 Hz, 1H). C{1H}NMR (125 MHz,
Chloroform-d) δ 168.8, 167.1, 161.4 (d, J = 243.9 Hz), 150.6, 138.7, 138.7 (d, J = 3.1 Hz),
132.0, 130.8, 128.7, 128.2, 127.4 (d, J = 8.0 Hz), 123.3, 123.0, 119.2, 115.2 (d, J = 21.4 Hz),
64.4, 45.0. IR (film) νmax 3412, 3368, 2130, 1646, 1006 cm-1; HRMS (ESI-TOF) m/z : Exact
mass calcd for C22H18FN2O2 [M+H]+ : 361.1347. Found: 361.1326.
2-(3-oxo-1-(p-tolyl)isoindolin-1-yl)-N-phenylacetamide (3da): White solid, 61.23 mg, 86%
yield. Rf= 0.38 (30% EtOAc in hexanes). MP: 118-120 °C.1H NMR (500 MHz, DMSO-d6) δ
9.03 (s, 1H), 7.99 (s, 1H), 6.77 – 6.72 (m, 2H), 6.66 (t, J = 6.9 Hz, 1H), 6.58 (d, J = 8.3 Hz, 2H),
6.55 (dd, J = 7.3, 3.1 Hz, 3H), 6.38 – 6.34 (m, 2H), 6.27 (d, J = 8.1 Hz, 2H), 6.12 (t, J = 7.4 Hz,
1H), 2.66 (d, J = 15.0 Hz, 1H), 2.40 (d, J = 15.0 Hz, 1H), 1.37 (s, 3H).13C{1H}NMR(125 MHz,
DMSO-d6) δ 168.8, 167.3, 150.9, 139.4, 138.8, 136.5, 131.8, 130.8, 129.1, 128.6, 128.0, 125.1,
123.3, 122.9, 119.2, 64.5, 44.8, 20.5. IR (film) νmax 3278, 3266, 2132, 1659, 1022, 822 cm-1;
HRMS (ESI-TOF) m/z : Exact mass calcd for C23H20N2O2Na [M+Na]+ : 379.1417. Found:
379.1423.
2-(1-(3,5-dimethylphenyl)-3-oxoisoindolin-1-yl)-N-phenylacetamide (3ea): White solid, 59.94
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mg, 81% yield. Rf= 0.40 (40% EtOAc in hexanes).MP: 204-206 °C. H NMR (500 MHz,
DMSO-d6) δ 9.89 (s, 1H), 8.81 (s, 1H), 7.62 (d, J = 7.8 Hz, 2H), 7.54 (t, J = 8.0 Hz, 1H), 7.41
(dd, J = 7.4, 5.2 Hz, 3H), 7.23 (t, J = 7.8 Hz, 2H), 7.20 (s, 2H), 6.99 (t, J = 7.4 Hz, 1H), 6.87 (s,
1H), 3.51 (d, J = 15.0 Hz, 1H), 3.28 (d, J = 15.0 Hz, 1H), 2.24 (s, 6H). 13C{1H}NMR (125 MHz,
DMSO-d6) δ 168.8, 167.2, 150.8, 142.4, 138.7, 137.5, 131.7, 130.8, 128.7, 128.6, 128.0, 123.2,
122.9, 122.9, 122.8, 119.2, 64.6, 44.8, 21.1. IR (film) νmax 3404, 2936, 2261, 1655, 1022, 828
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cm-1; HRMS (ESI-TOF) m/z : Exact mass calcd for C24H23N2O2 [M+H]+ : 371.1754. Found:
371.1746
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2-(1-(4-methoxyphenyl)-3-oxoisoindolin-1-yl)-N-phenylacetamide (3fa): White solid, 55.80
mg, 75% yield. Rf= 0.20 (30% EtOAc in hexanes). MP: 64-66 °C. 1H NMR (500 MHz, DMSO-
d6) δ 9.88 (s, 1H), 8.86 (s, 1H), 7.61 (t, J = 7.7 Hz, 2H), 7.54 (t, J = 7.5 Hz, 1H), 7.46 (d, J = 8.9
Hz, 2H), 7.41 (t, J = 7.8 Hz, 3H), 7.26 – 7.21 (m, 2H), 6.99 (t, J = 7.3 Hz, 1H), 6.90 (d, J = 8.9
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Hz, 2H), 3.71 (s, 3H), 3.49 (d, J = 15.0 Hz, 1H), 3.27 (d, J = 14.9 Hz, 1H). C{1H}NMR (125
MHz, DMSO-d6) δ 168.7, 167.2, 158.4, 151.1, 138.7, 134.3, 131.8, 130.8, 128.6, 127.9, 126.4,
123.2, 122.9, 122.9, 119.2, 113.8, 64.3, 55.1, 44.9. IR (film) νmax 3382, 2944, 1659, 1015, 828
cm-1; HRMS (ESI-TOF) m/z : Exact mass calcd for C23H21N2O3 [M+H]+ : 373.1547. Found:
373.1543.
2-(1-(4-ethoxyphenyl)-3-oxoisoindolin-1-yl)-N-phenylacetamide (3ga): White solid, 55.58
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mg, 72% yield. Rf= 0.22 (30% EtOAc in hexanes).MP: 170-172 °C. H NMR (500 MHz,
DMSO-d6) δ 9.88 (s, 1H), 8.86 (s, 1H), 7.61 (t, J = 7.4 Hz, 2H), 7.54 (t, J = 7.5 Hz, 1H), 7.45 (d,
J = 8.9 Hz, 2H), 7.42 (dd, J = 7.3, 5.7 Hz, 3H), 7.26 – 7.21 (m, 2H), 6.99 (t, J = 7.3 Hz, 1H),
6.88 (d, J = 8.9 Hz, 2H), 3.97 (q, J = 7.0 Hz, 2H), 3.49 (d, J = 14.9 Hz, 1H), 3.27 (d, J = 14.9 Hz,
1H), 1.28 (t, J = 7.0 Hz, 3H).13C{1H}NMR (125 MHz, DMSO-d6) δ 168.7, 167.3, 157.7, 151.1,
138.8, 134.1, 131.8, 130.8, 128.6, 127.9, 126.4, 123.3, 122.9, 122.9, 119.2, 114.3, 64.3, 63.0,
44.9, 14.6. IR (film) νmax 3359, 3357, 2126, 1646, 1001, 819 cm-1; HRMS (ESI-TOF) m/z :
Exact mass calcd for C24H23N2O3 [M+H]+ : 387.1703. Found: 387.1692.
2-(1-(3-methoxyphenyl)-3-oxoisoindolin-1-yl)-N-phenylacetamide(3ha): White solid, 61.01
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mg, 82% yield. Rf= 0.31 (30% EtOAc in hexanes).MP: 180-182 °C. H NMR (500 MHz,
DMSO-d6) δ 9.17 (s, 1H), 8.16 (s, 1H), 6.89 (t, J = 7.7 Hz, 2H), 6.78 (t, J = 6.9 Hz, 1H), 6.66
(dd, J = 7.5, 4.5 Hz, 3H), 6.52 – 6.45 (m, 3H), 6.38 (d, J = 6.0 Hz, 2H), 6.23 (t, J = 7.3 Hz, 1H),
6.06 (d, J = 7.0 Hz, 1H), 2.96 (s, 3H), 2.80 (d, J = 15.1 Hz, 1H), 2.51 (d, J = 15.0 Hz,
1H).13C{1H}NMR(125 MHz, DMSO-d6) δ 169.3, 167.7, 159.8, 151.1, 144.5, 139.2, 132.3,
131.2, 130.2, 129.1, 128.6, 123.8, 123.5, 119.6, 117.8, 112.7, 111.9, 65.2, 55.6, 45.3. IR (film)
νmax 3412, 3396, 2126, 1659, 1006, 828 cm-1; HRMS (ESI-TOF) m/z : Exact mass calcd for
C23H21N2O3 [M+H]+ : 373.1547. Found: 373.1537.
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2-(3-oxo-1-(thiophen-2-yl)isoindolin-1-yl)-N-phenylacetamide (3ia): Yellow solid, 58.54 mg,
84% yield. Rf = 0.40 (30% EtOAc in hexanes).MP: 208-210 °C. 1H NMR (500 MHz, DMSO-d6)
δ 9.91 (s, 1H), 9.06 (s, 1H), 7.65 – 7.62 (m, 2H), 7.60 – 7.56 (m, 1H), 7.45 (t, J = 7.5 Hz, 1H),
7.40 (d, J = 8.7 Hz, 2H), 7.36 (dd, J = 5.1, 1.2 Hz, 1H), 7.31 (dd, J = 3.6, 1.3 Hz, 1H), 7.26 –
7.22 (m, 2H), 7.02 – 6.99 (m, 2H), 3.48 (d, J = 14.9 Hz, 1H), 3.40 (s, 1H).13C{1H}NMR(125
MHz, DMSO-d6) δ 168.5, 166.6, 150.3, 147.6, 138.7, 132.0, 130.5, 128.7, 128.4, 127.5, 124.8,
124.0, 123.3, 123.0, 122.9, 119.2, 62.9, 45.3. IR (film) νmax 3375,3102,2128,1652,1015,822 cm-
1; HRMS (ESI-TOF) m/z : Exact mass calcd for C20H17N2O2S [M+H]+ : 349.1005. Found:
349.0981.
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2-(5-methyl-3-oxo-1-phenylisoindolin-1-yl)-N-phenylacetamide (3ja): White solid, 63.44 mg,
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89% yield. Rf= 0.32 (20% EtOAc in hexanes).MP: 220-222 °C. H NMR (500 MHz, DMSO-
d6) δ 9.90 (s, 1H), 8.80 (s, 1H), 7.57 (t, J = 6.7 Hz, 2H), 7.52 (d, J = 7.7 Hz, 1H), 7.43 (d, J = 7.4
Hz, 3H), 7.35 (t, J = 7.8 Hz, 2H), 7.24 (t, J = 8.0 Hz, 4H), 7.00 (t, J = 7.3 Hz, 1H), 3.56 (d, J =
15.0 Hz, 1H), 3.28 (d, J = 15.0 Hz, 1H), 2.35 (s, 3H).13C{1H}NMR(125 MHz, DMSO-d6) δ
168.9, 167.3, 151.3, 148.1, 142.6, 142.0, 138.8, 137.7, 132.7, 128.9, 128.6, 127.2, 125.2, 123.3,
122.8, 119.2, 64.5, 44.9, 21.5. IR (film) νmax 3391, 2940, 2129, 1652, 1014, 760 cm-1; HRMS
(ESI-TOF) m/z : Exact mass calcd for C23H21N2O2 [M+H]+ : 357.1598. Found: 357.1574.
2-(5,6-dichloro-3-oxo-1-phenylisoindolin-1-yl)-N-phenylacetamide (3ka): Yellow solid,
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75.44 mg, 93% yield. Rf = 0.36 (30% EtOAc in hexanes).MP: 246-248°C. H NMR (500 MHz,
DMSO-d6) δ 9.9 (s, 1H), 9.4 (s, 1H), 8.0 (s, 1H), 7.8 (s, 1H), 7.6 (d, J = 7.8 Hz, 2H), 7.4 (d, J =
8.0 Hz, 2H), 7.4 (t, J = 7.6 Hz, 2H), 7.3 (t, J = 7.3 Hz, 1H), 7.2 (t, J = 7.8 Hz, 2H), 7.0 (t, J = 7.3
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Hz, 1H), 3.7 (d, J = 15.0 Hz, 1H), 3.4 (s, 1H). C{1H}NMR(125 MHz, DMSO-d6) δ 167.4,
167.2, 151.3, 142.2, 139.1, 134.9, 132.3, 131.7, 129.2, 129.1, 128.2, 126.0, 125.6, 125.1, 123.8,
119.6, 64.9, 44.6. IR (film) νmax 3399, 3262, 2121, 1648, 1014, 821 cm-1; HRMS (ESI-TOF) m/z
: Exact mass calcd for C22H16Cl2N2O2Na [M+Na]+ : 433.0481. Found: 433.0477.
2-(5,6-dichloro-3-oxo-1-(p-tolyl)isoindolin-1-yl)-N-phenylacetamide (3la): White
solid,
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76.50 mg, 90% yield.Rf= 0.30 (30% EtOAc in hexanes).MP: 238-240 °C. HNMR (500 MHz,
DMSO-d6) δ 9.92 (s, 1H), 9.29 (s, 1H), 7.99 (s, 1H), 7.80 (s, 1H), 7.43 (dd, J = 14.8, 7.9 Hz,
4H), 7.24 (t, J = 7.8 Hz, 2H), 7.17 (d, J = 7.9 Hz, 2H), 7.00 (t, J = 7.3 Hz, 1H), 3.64 (d, J = 15.0
Hz, 1H), 3.34 (d, J = 6.2 Hz, 1H), 2.25 (s, 3H). 13C{1H}NMR(125 MHz, DMSO-d6) δ 166.9,
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166.8, 151.0, 138.8, 138.7, 137.0, 134.4, 131.8, 131.1, 129.3, 128.7, 125.5, 125.1, 124.6, 123.3,
119.2, 64.3, 44.1, 20.5. IR (film) νmax 3388, 3218, 2126, 1651, 1030, 824 cm-1; HRMS (ESI-
TOF) m/z : Exact mass calcd for C23H19Cl2N2O2 [M+H]+ : 425.0818. Found: 425.0831.
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2-(5,6-dimethyl-3-oxo-1-phenylisoindolin-1-yl)-N-phenylacetamide (3ma): White solid,
67.42 mg, 91% yield.Rf= 0.26 (30% EtOAc in hexanes).MP: 240-242 °C. 1H NMR (500 MHz,
DMSO-d6) δ 9.95 (s, 1H), 8.69 (s, 1H), 7.52 (d, J = 7.3 Hz, 2H), 7.39 (d, J = 6.6 Hz, 3H), 7.33
(dd, J = 15.0, 7.3 Hz, 3H), 7.25 – 7.20 (m, 3H), 6.99 (t, J = 7.4 Hz, 1H), 3.53 (s, 1H), 3.17 (d, J =
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15.1 Hz, 1H), 2.24 (s, 3H), 2.22 (s, 3H). C{1H}NMR(125 MHz, DMSO-d6) δ 169.7, 167.8,
149.2, 142.7, 141.5, 138.9, 137.0, 129.0, 128.9, 128.6, 127.6, 125.3, 123.9, 123.8, 123.8, 119.6,
64.7, 45.1, 20.5, 19.7. IR (film) νmax 3418, 3329, 2121, 1648, 821 cm-1; HRMS (ESI-TOF) m/z :
Exact mass calcd for C24H23N2O2 [M+H]+ : 371.1754. Found: 371.1726.
2-(1-(4-fluorophenyl)-5,6-dimethyl-3-oxoisoindolin-1-yl)-N-phenylacetamide (3na): White
solid, 73.02 mg, 94% yield. Rf= 0.22 (30% EtOAc in hexanes).MP: 238-240 °C. 1H NMR (500
MHz, DMSO-d6) δ 9.88 (s, 1H), 8.76 (s, 1H), 7.58 (dd, J = 8.9, 5.4 Hz, 2H), 7.40 (dd, J = 15.8,
7.7 Hz, 4H), 7.27 – 7.21 (m, 2H), 7.16 (t, J = 8.9 Hz, 2H), 7.00 (t, J = 7.3 Hz, 1H), 3.52 (d, J =
13
15.0 Hz, 1H), 3.21 (d, J = 15.1 Hz, 1H), 2.26 (d, J = 6.4 Hz, 6H). C{1H}NMR (125 MHz,
DMSO-d6) δ 168.9, 167.2, 161.3 (d, J = 243.8 Hz), 148.8, 141.0, 138.9 (d, J = 3.2 Hz), 138.7,
136.6, 128.6, 128.6, 127.3 (d, J = 8.1 Hz), 123.6, 123.5, 123.3, 119.2, 115.1 (d, J = 21.2 Hz),
63.9, 45.1, 20.2, 19.4. IR (film) νmax 3432, 3312, 2127, 1647, 1004, 821 cm-1; HRMS (ESI-TOF)
m/z : Exact mass calcd for C24H22FN2O2 [M+H]+ : 389.1660. Found: 389.1653.
2-(5,6-dimethyl-3-oxo-1-(p-tolyl)isoindolin-1-yl)-N-phenylacetamide (3oa): White solid,
67.40 mg, 89% yield. Rf= 0.36 (30% EtOAc in hexanes).MP: 212-214 °C. 1H NMR (500 MHz,
DMSO-d6) δ 9.92 (s, 1H), 8.64 (s, 1H), 7.45 – 7.41 (m, 4H), 7.39 (s, 1H), 7.33 (s, 1H), 7.24 (t, J
= 7.9 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 7.00 (t, J = 7.4 Hz, 1H), 3.54 (d, J = 15.0 Hz, 1H), 3.17
(d, J = 14.9 Hz, 1H), 2.25 (s, 3H), 2.23 (d, J = 3.1 Hz, 6H).13C{1H}NMR(125 MHz, DMSO-d6)
δ 169.1, 167.5, 149.2, 140.9, 139.7, 138.8, 136.5, 136.4, 129.1, 128.7, 128.6, 125.0, 123.6, 123.5,
123.3, 119.2, 64.2, 45.0, 20.5, 20.2, 19.4. IR (film) νmax 3345, 2948, 2886, 1652, 1022, 760 cm-1;
HRMS (ESI-TOF) m/z : Exact mass calcd for C25H24N2O2Na [M+Na]+ : 407.1730. Found:
407.1748
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2-(1-(4-methoxyphenyl)-5,6-dimethyl-3-oxoisoindolin-1-yl)-N-phenylacetamide (3pa): White
solid, 59.20 mg, 74% yield. Rf= 0.22 (30% EtOAc in hexanes). MP: 264-266 °C. 1H NMR (500
MHz, DMSO-d6) δ 9.88 (s, 1H), 8.63 (s, 1H), 7.45 – 7.41 (m, 4H), 7.38 (s, 1H), 7.33 (s, 1H),
7.26 – 7.22 (m, 2H), 7.00 (t, J = 7.3 Hz, 1H), 6.88 (d, J = 8.9 Hz, 2H), 3.70 (s, 3H), 3.50 (d, J =
15.0 Hz, 1H), 3.17 (d, J = 14.9 Hz, 1H), 2.25 (d, J = 6.0 Hz, 6H).13C{1H}NMR(125 MHz,
DMSO-d6) δ 169.0, 167.5, 158.3, 149.3, 140.8, 138.8, 136.4, 134.5, 128.7, 128.6, 126.4, 123.5,
123.5, 123.3, 119.2, 113.8, 64.0, 55.1, 45.1, 20.2, 19.4. IR (film) νmax 3408, 3375, 2126, 1656,
1024, 824 cm-1; HRMS (ESI-TOF) m/z : Exact mass calcd for C25H25N2O3 [M+H]+ : 401.1860.
Found: 401.1846.
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2-(1-(4-methoxyphenyl)-3-oxo-2,3-dihydro-1H-benzo[f]isoindol-1-yl)-N-
phenylacetamide(3qa): White solid, 61.61 mg, 73% yield. Rf = 0.23 (30% EtOAc in
hexanes).MP: 256-258 °C. 1H NMR (500 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.01 (s, 1H), 8.26 (s,
1H), 8.11 (d, J = 8.1 Hz, 1H), 8.07 (s, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.59 (t, J = 7.5 Hz, 1H),
7.54 (d, J = 8.8 Hz, 3H), 7.40 (d, J = 7.4 Hz, 2H), 7.23 – 7.18 (m, 2H), 6.98 (t, J = 7.4 Hz, 1H),
6.92 (d, J = 8.9 Hz, 2H), 3.71 (s, 3H), 3.56 (d, J = 15.1 Hz, 1H), 3.47 (d, J = 15.1 Hz, 1H).
13C{1H}NMR (125 MHz, DMSO-d6) δ 168.4, 167.3, 158.4, 146.6, 138.8, 135.1, 134.8, 132.4,
129.6, 129.3, 128.6, 128.1, 127.6, 126.4, 126.2, 123.2, 123.0, 121.5, 119.1, 113.9, 64.1, 55.1,
45.4. IR (film) νmax 3406, 3396, 2126, 1659, 1006, 828, 764 cm-1; HRMS (ESI-TOF) m/z :
Exact mass calcd for C27H22N2O3Na [M+Na]+ : 445.1523. Found: 445.1528.
2-(3-oxoisoindolin-1-yl)-N-phenylacetamide (3ra):White solid, 43.09 mg, 81% yield. Rf = 0.42
(30% EtOAc in hexanes)MP: 146-148 °C.1H NMR (500 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.68
(s, 1H), 7.67 (d, J = 7.5 Hz, 1H), 7.63 – 7.57 (m, 4H), 7.49 (td, J = 7.0, 6.6, 1.9 Hz, 1H), 7.35 –
7.30 (m, 2H), 7.09 – 7.04 (m, 1H), 5.00 (t, J = 6.9 Hz, 1H), 2.83 (dd, J = 15.0, 6.3 Hz, 1H), 2.66
(dd, J = 15.0, 7.7 Hz, 1H).13C{1H}NMR(125 MHz, DMSO-d6) δ 169.0, 168.2, 147.2, 138.9,
132.2, 131.6, 128.7, 128.2, 123.4, 123.1, 122.9, 119.4, 53.1, 41.8. IR (film) νmax 3380, 3308,
2126, 1664, 824 cm-1; HRMS (ESI-TOF) m/z : Exact mass calcd for C16H15N2O2 [M+H]+ :
267.1128. Found: 267.1125
N-(4-chlorophenyl)-2-(3-oxo-1-phenylisoindolin-1-yl)acetamide (3ab): White solid, 67.68
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mg, 90% yield. Rf= 0.26 (30% EtOAc in hexanes). MP: 217-219 °C. H NMR (500 MHz,
DMSO-d6) δ 10.06 (s, 1H), 8.98 (s, 1H), 7.65 (d, J = 7.6 Hz, 2H), 7.58 (d, J = 7.8 Hz, 2H), 7.54
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(t, J = 7.7 Hz, 1H), 7.46 (d, J = 8.9 Hz, 2H), 7.42 (t, J = 7.4 Hz, 1H), 7.34 (t, J = 7.8 Hz, 2H),
7.29 (d, J = 8.7 Hz, 2H), 7.24 (t, J = 7.3 Hz, 1H), 3.55 (d, J = 15.1 Hz, 1H), 3.35 (d, J = 15.0 Hz,
1H).13C{1H}NMR(125 MHz, DMSO-d6) δ 168.9, 167.3, 150.7, 142.4, 137.7, 131.8, 130.9,
128.6, 128.1, 127.3, 126.8, 125.2, 123.0, 120.7, 64.7, 44.9. IR (film) νmax 3411, 3380, 2124,
1657, 1018, 824cm-1; HRMS (ESI-TOF) m/z : Exact mass calcd for C22H17ClN2O2Na [M+Na]+ :
399.0871. Found: 399.0879.
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N-(4-fluorophenyl)-2-(3-oxo-1-phenylisoindolin-1-yl)acetamide (3ac): White solid, 63.36 mg,
88% yield. Rf= 0.32 (30% EtOAc in hexanes).MP: 178-180 °C. 1H NMR (500 MHz, DMSO-d6)
δ 9.99 (s, 1H), 8.96 (s, 1H), 7.65 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 7.2 Hz, 2H), 7.54 (t, J = 7.8 Hz,
1H), 7.45 – 7.40 (m, 3H), 7.34 (t, J = 7.8 Hz, 2H), 7.24 (t, J = 7.3 Hz, 1H), 7.08 (t, J = 8.9 Hz,
2H), 3.54 (d, J = 15.0 Hz, 1H), 3.32 (d, J = 15.0 Hz, 1H). 13C{1H}NMR (125 MHz, DMSO-d6) δ
168.9, 167.2, 158.0 (d, J = 239.9 Hz), 150.8, 142.4, 135.1 (d, J = 2.6 Hz), 131.9, 130.9, 128.6,
128.1, 127.4, 125.2, 123.1, 123.0, 121.0 (d, J = 7.8 Hz), 115.2 (d, J = 22.2 Hz), 64.8, 44.8. IR
(film) νmax 3354, 3276, 2120, 1647, 987, 822 cm-1; HRMS (ESI-TOF) m/z : Exact mass calcd for
C22H18FN2O2 [M+H]+ : 361.1347. Found: 361.1324.
N-(3-fluorophenyl)-2-(3-oxo-1-phenylisoindolin-1-yl)acetamide (3ad): White solid, 65.52 mg,
91% yield. Rf = 0.38 (30% EtOAc in hexanes).MP: 118-120 °C. 1H NMR (500 MHz, DMSO-d6)
δ 10.14 (s, 1H), 8.99 (s, 1H), 7.65 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 7.8 Hz, 2H), 7.55 (t, J = 7.7
Hz, 1H), 7.42 (dd, J = 9.2, 5.5 Hz, 2H), 7.35 (t, J = 7.7 Hz, 2H), 7.31 – 7.23 (m, 2H), 7.14 (d, J =
9.9 Hz, 1H), 6.83 (td, J = 8.5, 2.6 Hz, 1H), 3.56 (d, J = 15.1 Hz, 1H), 3.36 (d, J = 15.1 Hz, 1H).
13C{1H}NMR (125 MHz, DMSO-d6) δ 168.9, 167.6, 162.1 (d, J = 241.2 Hz), 150.7, 142.4,
140.5 (d, J = 11.1 Hz), 131.9, 130.8, 130.3 (d, J = 9.5 Hz), 128.6, 128.1, 127.3, 125.1, 123.0,
114.8 (d, J = 2.6 Hz), 109.7 (d, J = 21.1 Hz), 106.0, 105.8, 64.6, 44.9. IR (film) νmax 3425, 3318,
2120, 1657, 1006, 825 cm-1; HRMS (ESI-TOF) m/z : Exact mass calcd for C22H18FN2O2
[M+H]+ : 361.1347. Found: 361.1328.
2-(3-oxo-1-phenylisoindolin-1-yl)-N-(p-tolyl)acetamide (3ae):White solid, 66.93 mg, 94%
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yield. Rf= 0.32 (30% EtOAc in hexanes). MP: 106-108 °C. H NMR (500 MHz, DMSO-d6) δ
9.83 (s, 1H), 8.93 (s, 1H), 7.64 (d, J = 7.9 Hz, 2H), 7.58 (d, J = 7.3 Hz, 2H), 7.54 (t, J = 7.6 Hz,
1H), 7.44 – 7.40 (m, 1H), 7.34 (t, J = 7.8 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 7.24 (t, J = 7.4 Hz,
1H), 7.04 (d, J = 8.2 Hz, 2H), 3.54 (d, J = 15.1 Hz, 1H), 3.30 (d, J = 15.0 Hz, 1H), 2.20 (s,
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3H).13C{1H}NMR (125 MHz, DMSO-d6) δ 168.8, 167.0, 150.8, 142.5, 136.2, 132.2, 131.8,
130.9, 129.0, 128.5, 128.1, 127.3, 125.2, 123.0, 123.0, 119.2, 64.7, 44.8, 20.4. IR (film) νmax
3382, 3279, 2124, 1646, 944, 821 cm-1; HRMS (ESI-TOF) m/z : Exact mass calcd for
C23H21N2O2 [M+H]+ : 357.1598. Found: 357.1573.
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N-(4-(tert-butyl)phenyl)-2-(3-oxo-1-phenylisoindolin-1-yl)acetamide (3af): White solid,
70.94mg, 89% yield. Rf = 0.42 (30% EtOAc in hexanes).MP: 186-188 °C. 1H NMR (500 MHz,
DMSO-d6) δ 9.84 (s, 1H), 8.91 (s, 1H), 7.64 (d, J = 8.6 Hz, 2H), 7.58 (d, J = 7.2 Hz, 2H), 7.57 –
7.52 (m, 1H), 7.45 – 7.40 (m, 1H), 7.37 – 7.31 (m, 4H), 7.27 – 7.22 (m, 3H), 3.54 (d, J = 14.9
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Hz, 1H), 3.28 (d, J = 14.9 Hz, 1H), 1.22 (s, 9H). C{1H}NMR (125 MHz, DMSO-d6) δ 168.7,
167.0, 150.7, 145.6, 142.4, 136.2, 131.8, 130.8, 128.5, 128.1, 127.3, 125.2, 125.2, 123.0, 123.0,
119.0, 64.7, 44.9, 34.0, 31.2. IR (film) νmax 3418, 3308, 2259, 1656, 1014, 824 cm-1; HRMS
(ESI-TOF) m/z : Exact mass calcd for C26H26N2O2Na [M+Na]+ : 421.1886. Found: 421.1874.
2-(3-oxo-1-phenylisoindolin-1-yl)-N-(o-tolyl)acetamide (3ag): White solid, 47.76 mg, 67%
1
yield. Rf= 0.32 (30% EtOAc in hexanes).MP: 210-212 °C. H NMR (500 MHz, DMSO-d6) δ
9.25 (s, 1H), 8.90 (s, 1H), 7.70 – 7.60 (m, 4H), 7.57 (t, J = 7.5 Hz, 1H), 7.44 (t, J = 7.4 Hz, 1H),
7.37 (t, J = 7.8 Hz, 2H), 7.27 (t, J = 7.3 Hz, 1H), 7.14 (t, J = 8.0 Hz, 2H), 7.07 (t, J = 6.7 Hz,
1H), 7.04 – 6.99 (m, 1H), 3.60 (d, J = 14.5 Hz, 1H), 3.34 (d, J = 14.5 Hz, 1H), 2.00 (s,
3H).13C{1H}NMR(125 MHz, DMSO-d6) δ 168.7, 167.2, 150.5, 142.5, 135.9, 131.8, 131.6,
130.9, 130.2, 128.6, 128.1, 127.3, 125.8, 125.2, 125.1, 124.7, 123.2, 123.0, 64.8, 44.5, 17.6. IR
(film) νmax 3378, 3352, 2126, 1648, 998 cm-1; HRMS (ESI-TOF) m/z : Exact mass calcd for
C23H21N2O2 [M+H]+ : 357.1598. Found: 357.1588.
N-(4-methoxyphenyl)-2-(3-oxo-1-phenylisoindolin-1-yl)acetamide (3ah): White solid, 66.96
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mg, 90% yield. Rf= 0.26 (30% EtOAc in hexanes).MP: 188-190 °C. H NMR (500 MHz,
DMSO-d6) δ 9.77 (s, 1H), 8.91 (s, 1H), 7.66 – 7.62 (m, 2H), 7.58 (d, J = 7.3 Hz, 2H), 7.55 (t, J =
7.6 Hz, 1H), 7.42 (t, J = 7.4 Hz, 1H), 7.36 – 7.30 (m, 4H), 7.25 (t, J = 7.3 Hz, 1H), 6.81 (d, J =
9.0 Hz, 2H), 3.68 (s, 3H), 3.52 (d, J = 14.9 Hz, 1H), 3.27 (d, J = 14.9 Hz, 1H).13C{1H}NMR
(125 MHz, DMSO-d6) δ 168.8, 166.8, 155.3, 150.8, 142.5, 131.9, 131.8, 130.9, 128.5, 128.1,
127.3, 125.2, 123.0, 123.0, 120.8, 113.8, 64.8, 55.1, 44.8. IR (film) νmax 3389, 3216, 2134, 1640,
1027 cm-1; HRMS (ESI-TOF) m/z : Exact mass calcd for C23H20N2O3Na [M+Na]+ : 395.1366.
Found: 395.1337.
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N-(4-cyanophenyl)-2-(3-oxo-1-phenylisoindolin-1-yl)acetamide (3ai): White solid, 55.74 mg,
76% yield. Rf = 0.20 (30% EtOAc in hexanes).MP: 144−145 °C.1H NMR (500 MHz, DMSO-d6)
δ 10.35 (s, 1H), 9.00 (s, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.66 – 7.59 (m, 4H), 7.58 – 7.52 (m, 3H),
7.42 (t, J = 7.4 Hz, 1H), 7.35 (t, J = 7.6 Hz, 2H), 7.25 (t, J = 7.4 Hz, 1H), 3.56 (d, J = 15.0 Hz,
1H), 3.42 (d, J = 15.3 Hz, 1H).13C{1H}NMR(125 MHz, DMSO-d6) δ 168.9, 167.9, 150.6, 142.9,
142.4, 133.2, 131.8, 130.9, 128.6, 128.1, 127.3, 125.1, 123.0, 123.0, 119.1, 119.0, 105.0, 64.6,
45.0. IR (film) νmax 3416, 3380, 2234, 2128, 1655, 1020, 818 cm-1; HRMS (ESI-TOF) m/z :
Exact mass calcd for C23H18N3O2 [M+H] +: 368.1394. Found: 368.1403.
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2-(3-oxo-1-phenylisoindolin-1-yl)-N-(4-(trifluoromethyl)phenyl)acetamide (3aj): White
solid, 60.68 mg, 74% yield. Rf = 0.21 (30% EtOAc in hexanes). MP: 254-256 °C. 1H NMR (500
MHz, DMSO-d6) δ 10.28 (s, 1H), 8.99 (s, 1H), 7.66 – 7.59 (m, 6H), 7.58 – 7.52 (m, 3H), 7.42 (t,
J = 7.9 Hz, 1H), 7.35 (t, J = 7.8 Hz, 2H), 7.25 (t, J = 7.3 Hz, 1H), 3.56 (d, J = 15.1 Hz, 1H), 3.37
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(d, J = 10.5 Hz, 1H). C{1H}NMR (125 MHz, DMSO-d6) δ 169.0, 167.8, 150.6, 142.4, 142.3,
131.9, 130.9, 128.6, 128.2, 127.4, 126.1, 126.0, 126.0, 125.2, 123.1, 123.0, 119.0, 64.7, 45.0. IR
(film) νmax 3368, 3221, 2252, 1659, 1031, 824 cm-1; HRMS (ESI-TOF) m/z : Exact mass calcd
for C23H17F3N2O2Na[M+Na]+ : 433.1134. Found: 433.1120.
N-(4-nitrophenyl)-2-(3-oxo-1-phenylisoindolin-1-yl)acetamide(3ak): Yellow solid, 54.95 mg,
71% yield. Rf = 0.20 (30% EtOAc in hexanes).MP: 252-254 °C. 1H NMR (500 MHz, DMSO-d6)
δ 10.54 (s, 1H), 9.05 (s, 1H), 8.16 (d, J = 8.7 Hz, 2H), 7.72 – 7.63 (m, 4H), 7.59 (d, J = 7.6 Hz,
2H), 7.54 (t, J = 7.7 Hz, 1H), 7.42 (t, J = 7.7 Hz, 1H), 7.35 (t, J = 7.9 Hz, 2H), 7.26 (d, J = 7.6
Hz, 1H), 3.61 (d, J = 15.5 Hz, 1H), 3.39 (d, J = 16.6 Hz, 1H).13C{1H}NMR(125 MHz, DMSO-
d6) δ 169.0, 168.1, 150.6, 144.9, 142.4, 142.2, 131.9, 130.9, 128.6, 128.1, 127.4, 125.1, 124.9,
123.0, 118.7, 64.6, 45.0. IR (film) νmax 3396, 3361, 2119, 1648, 2246, 759 cm-1; HRMS (ESI-
TOF) m/z : Exact mass calcd for C22H17N3O4Na [M+Na]+ : 410.1111. Found: 410.1134.
2-(3-oxo-1-phenylisoindolin-1-yl)-N-(thiophen-2-yl)acetamide (3al): Yellow solid, 56.44 mg,
81% yield. Rf = 0.32 (20% EtOAc in hexanes).MP: 82-84 °C. 1H NMR (500 MHz, DMSO-d6) δ
10.33 (s, 1H), 8.92 (s, 1H), 7.66 – 7.61 (m, 2H), 7.55 (dd, J = 13.4, 7.4 Hz, 3H), 7.43 (t, J = 7.4
Hz, 1H), 7.39 (dd, J = 5.1, 3.2 Hz, 1H), 7.37 (dd, J = 3.3, 1.4 Hz, 1H), 7.34 (t, J = 7.8 Hz, 2H),
7.24 (t, J = 7.3 Hz, 1H), 6.97 (dd, J = 5.1, 1.4 Hz, 1H), 3.52 (d, J = 15.1 Hz, 1H), 3.28 (d, J =
15.2 Hz, 1H). 13C{1H}NMR (125 MHz, DMSO-d6) δ 168.8, 166.3, 150.8, 142.4, 136.4, 131.9,
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130.8, 128.5, 128.1, 127.3, 125.1, 124.6, 123.0, 123.0, 121.2, 108.6, 64.6, 44.3. IR (film) νmax
3375, 3318, 2117, 1654, 1006, 824,762 cm-1; HRMS (ESI-TOF) m/z : Exact mass calcd for
C20H17N2O2S [M+H]+ : 349.1005. Found: 349.0996.
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N-(benzo[d][1,3]dioxol-5-yl)-2-(3-oxo-1-phenylisoindolin-1-yl)acetamide (3am): White solid,
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69.55 mg, 90% yield.Rf= 0.34 (30% EtOAc in hexanes).MP: 218-220 °C. H NMR (500 MHz,
DMSO-d6) δ 9.82 (s, 1H), 8.92 (s, 1H), 7.63 (d, J = 9.0 Hz, 2H), 7.55 (dd, J = 17.3, 8.1 Hz, 3H),
7.43 (t, J = 6.9 Hz, 1H), 7.35 (t, J = 7.8 Hz, 2H), 7.25 (t, J = 7.4 Hz, 1H), 7.09 (d, J = 1.8 Hz,
1H), 6.82 – 6.73 (m, 2H), 5.94 (s, 2H), 3.50 (d, J = 14.9 Hz, 1H), 3.27 (d, J = 14.9 Hz, 1H).
13C{1H}NMR (125 MHz, DMSO-d6) δ 168.8, 166.8, 150.7, 146.9, 142.9, 142.4, 133.1, 131.8,
130.8, 128.5, 128.1, 127.3, 125.2, 123.0, 123.0, 112.1, 107.9, 101.4, 100.9, 64.7, 44.8. IR (film)
νmax 3405, 2939, 2245, 1652, 1014, 821 cm-1; HRMS (ESI-TOF) m/z : Exact mass calcd for
C23H19N2O4 [M+H]+ : 387.1339. Found: 387.1335.
2-(3-oxo-1-phenylisoindolin-1-yl)-N-phenylpropanamide (3an-upper spot): White solid,
31.32 mg, 88% overall yield. Rf = 0.32 (30% EtOAc in hexanes).MP: 146−148 °C.1H NMR
(500 MHz, Chloroform-d) δ 8.81 (s, 1H), 7.99 (s, 1H), 7.72 (d, J = 7.5 Hz, 1H), 7.60 (d, J = 7.6
Hz, 2H), 7.39 – 7.34 (m, 2H), 7.32 – 7.27 (m, 3H), 7.21 – 7.17 (m, 2H), 7.16 – 7.09 (m, 3H),
6.96 (t, J = 7.4 Hz, 1H), 3.90 (q, J = 6.8 Hz, 1H), 0.95 (d, J = 6.9 Hz, 3H).13C{1H}NMR(125
MHz, Chloroform-d) δ 173.1, 170.9, 149.9, 141.3, 137.7, 132.9, 131.0, 129.1, 129.0, 128.7,
128.0, 124.9, 124.7, 124.1, 122.2, 120.6, 68.8, 47.9, 13.4. IR (film) νmax 3306, 3138, 2354,
1664, 1041, 696 cm-1; HRMS (ESI-TOF) m/z : Exact mass calcd for C23H20N2O2Na [M+Na]+ :
379.1417. Found: 379.1426.
2-(3-oxo-1-phenylisoindolin-1-yl)-N-phenylpropanamide (3an-lower spot): White solid,
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31.32 mg, 88% overall yield. Rf= 0.42 (20% EtOAc in hexanes). MP: 196−198 °C. H NMR
(500 MHz, Chloroform-d) δ 8.86 (s, 1H), 7.78 – 7.75 (m, 2H), 7.64 (d, J = 7.2 Hz, 3H), 7.57 (t, J
= 7.6 Hz, 1H), 7.42 (d, J = 7.2 Hz, 1H), 7.37 (t, J = 7.6 Hz, 2H), 7.30 (t, J = 7.3 Hz, 1H), 7.14 –
7.09 (m, 2H), 7.03 (d, J = 7.3 Hz, 2H), 6.99 (t, J = 7.3 Hz, 1H), 3.72 (q, J = 7.1 Hz, 1H), 1.33 (d,
J = 7.1 Hz, 3H).13C{1H}NMR(125 MHz, DMSO-d6) δ 170.0, 169.0, 148.6, 141.9, 138.4, 131.5,
131.1, 128.6, 128.4, 128.1, 127.4, 125.5, 124.2, 123.2, 122.5, 119.4, 68.7, 47.2, 13.5. IR (film)
νmax 3391, 3328, 2256, 1658, 991, 828 cm-1; HRMS (ESI-TOF) m/z : Exact mass calcd for
C23H21N2O2 [M+H]+ : 357.1598. Found: 357.1571.
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General Procedure for the Synthesis of 2-(3-oxoisoindolin-1-yl)acetic acid (4/7):
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A solution of 3-Oxoisoindoline-1-acetamide 3aa(1.0 equiv, 0.2 mmol, 68.48 mg ) or 3ra (1.0
equiv, 0.2 mmol, 53.26 mg ) in 4 mL 20% H2SO4 were reflux at 110°C in oil bath for 10 h. Upon
completion of reaction (monitored by TLC) the reaction was quenched with a saturated aqueous
solution of NaHCO3 and extracted with EtOAc (3x10 mL). The organic was dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by
column chromatography using EtOAc/Hexane as eluent to afford the product 4/7.
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2-(3-oxo-1-phenylisoindolin-1-yl)acetic acid (4):Yellow solid, 50.2 mg, 94% yield. Rf = 0.24
(50% EtOAc in hexanes). MP: 158−160 °C.1H NMR (500 MHz, Chloroform-d) δ 10.68 (s,
1H), 8.91 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.42 (t, J = 7.0 Hz, 1H), 7.36 – 7.31 (m, 3H), 7.26 (d,
J = 7.7 Hz, 1H), 7.20 – 7.12 (m, 3H), 3.75 (d, J = 17.1 Hz, 1H), 2.69 (d, J = 17.1 Hz,
1H).13C{1H}NMR(125 MHz, Chloroform-d) δ 173.7, 171.8, 151.2, 139.7, 133.2, 129.3, 129.1,
128.8, 128.0, 124.9, 124.5, 122.3, 65.6, 43.4.IR (film) νmax 3398, 2932, 1678, 1029 cm-1;
HRMS (ESI-TOF) m/z : Exact mass calcd for C16H14NO3 [M+H]+ : 268.0968. Found: 268.0948.
2-(3-oxoisoindolin-1-yl)acetic acid (7):White solid, 31.70 mg, 83% yield. Rf = 0.20 (50%
EtOAc in hexanes).MP: 148−152 °C. 1H NMR (500 MHz, DMSO-d6) δ 8.6 (s, 1H), 7.6 (d, J =
7.5 Hz, 1H), 7.6 (d, J = 5.9 Hz, 2H), 7.5 (t, J = 7.9 Hz, 1H), 4.8 (t, J = 6.6 Hz, 1H), 3.4 (s, 1H),
2.8 (dd, J = 16.4, 5.7 Hz, 1H), 2.5 (dd, J = 16.3, 7.5 Hz, 1H).13C{1H}NMR(125 MHz,
Chloroform-d) δ 174.9, 172.2, 146.1, 132.5, 131.4, 128.8, 124.2, 122.4, 53.9, 39.1.IR (film) νmax
3351, 2925, 1761, 1283, 1066, 750 cm-1;HRMS (ESI-TOF) m/z : Exact mass calcd for
C10H10NO3, [M+H]+ :192.0655. Found: 192.0637.
General Procedure for the Synthesis of 3-phenyl-3-(2-(phenylamino)ethyl)isoindolin-1-one
(5): LiAlH4 (1.5 equiv, 0.3 mmol, 11.38 mg) was added to a solution of 2-(3-oxo-1-
phenylisoindolin-1-yl)-N-phenylacetamide 3aa (1.0 equiv, 0.2 mmol, 68.48 mg) in dry THF (4
mL) at room temperature. The reaction mixture was heated at 70°C in sealed tube in oil bath for
10 h, upon completion of reaction (monitored by TLC), the reaction mixture was quenched with
a saturated aqueous solution of NH4Cl and extracted with EtOAc (3x10 mL). The organic was
dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was
purified by column chromatography using EtOAc/Hexane as eluent to afford the product 5.
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3-phenyl-3-(2-(phenylamino)ethyl)isoindolin-1-one (5): White solid, 56.41 mg, 86% yield.Rf=
0.40 (20% EtOAc in hexanes).MP: 109−111 °C. 1H NMR (500 MHz, Chloroform-d)δ 7.88 (d, J
= 7.5 Hz, 1H), 7.56 (td, J = 7.5, 1.2 Hz, 2H), 7.52 (dd, J = 8.4, 1.3 Hz, 2H), 7.48 (td, J = 7.5, 0.9
Hz, 1H), 7.43 (d, J = 7.7 Hz, 1H), 7.39 – 7.36 (m, 2H), 7.33 – 7.29 (m, 1H), 7.13 (dd, J = 8.6, 7.2
Hz, 2H), 6.74 – 6.67 (m, 1H), 6.48 (d, J = 7.4 Hz, 2H), 3.61 (bs, 1H), 3.24 (td, J = 8.1, 4.0 Hz,
1H), 3.04 (dt, J = 13.2, 7.4 Hz, 1H), 2.80 (ddd, J = 13.4, 7.9, 5.0 Hz, 1H), 2.54 (ddd, J = 14.5,
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8.0, 6.9 Hz, 1H). C{1H}NMR (125 MHz, Chloroform-d) δ 170.5, 151.1, 147.5, 141.2, 132.6,
130.3, 129.3, 129.1, 128.5, 127.9, 125.2, 124.2, 122.2, 117.9, 113.1, 66.3, 39.9, 38.4. IR (film)
νmax 3212, 2920, 1692, 1318, 1182, 747 cm-1; HRMS (ESI-TOF) m/z : Exact mass calcd for
C22H21N2O, [M+H]+ : 329.1648. Found: 329.1638.
General Procedure for the Synthesis of (3-oxo-1-phenylisoindolin-1-yl)acetamide(6):
A solution of N-(4-methoxyphenyl)-2-(3-oxo-1-phenylisoindolin-1-yl)acetamide 3ah (1.0 equiv,
, 0.2 mmol, 74.48 mg) in CH3CN (4 mL) was cooled at -5 °C using ice-salt water bath. An
aqueous solution of CAN (2.5 equiv, 0.5 mmol, 274.11 mg dissolved in 1.0 mL H2O) and H2SO4
(1.0 equiv, 0.2 mmol) were added dropwise sequentially. The mixture was stirred at room
temperature for 2 h, upon completion of reaction (monitored by TLC), the reaction was quenched
with a saturated aqueous solution of NaHCO3 and extracted with EtOAc (3x10 mL). The organic
was dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude product
was purified by column chromatography using EtOAc/Hexane as eluent to afford the product 6.
2-(3-oxo-1-phenylisoindolin-1-yl)acetamide (6):White solid, 74.80 mg, 90% yield.Rf = 0.32
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(50% EtOAc in hexanes). MP: 182−184 °C. H NMR (500 MHz, DMSO-d6) δ 8.69 (s, 1H),
7.63 (d, J = 7.5 Hz, 1H), 7.56 – 7.50 (m, 4H), 7.45 – 7.40 (m, 1H), 7.35 – 7.30 (m, 3H), 7.24 (t, J
= 7.3 Hz, 1H), 6.89 (s, 1H), 3.39 (d, J = 15.0 Hz, 1H), 2.89 (d, J = 15.0 Hz,
1H).13C{1H}NMR(125 MHz, DMSO-d6) δ 170.7, 168.6, 151.0, 142.4, 131.9, 130.7, 128.5,
128.0, 127.2, 125.1, 123.0, 122.9, 64.5, 43.5. IR (film) νmax 2927, 2095, 1694, 1301 cm-1;
HRMS (ESI-TOF) m/z : Exact mass calcd for C16H15N2O2 [M+H]+ : 267.1128. Found:
267.1106.
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AUTHOR INFORMATION
Corresponding Author
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*E-mail: vinodks@iitk.ac.in
Author Contributions
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aBoth the authors contributed equally
Notes
The authors declare no competing financial interest.
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at
http://pubs.acs.org.
Crystallographic data for compound 3ba.
1H, 13C{1H}NMR spectra for all isolated compounds.
ACKNOWLEDGMENT
V.K.S. acknowledges DST/SERB, India for a J. C. Bose fellowship (SR/S2/JCB-17/2008) and
SERB (CRG/2018/ 000552) for the financial support. D. K. D. thanks to IISERB for Institute
postdoctoral fellowship. V. K. K. is thankful to IISERB for Project fellowship. S. K. R. thanks
DST for an INSPIRE Faculty award (DST/INSPIRE/04/2016001704). M. M. S. thanks DST-
Inspire for fellowship. Facilities from the Department of Chemistry, IISER Bhopal are gratefully
acknowledged. We thank CIF, XRD facility, IISER Bhopal and Dr. Syed Meheboob Elahi from
Nanjing University, Department of Chemistry for the help in structure determination and data
analysis.
References
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towards Organometallic Reagents: An Overview. Adv. Synth. Catal. 2014, 356, 3697-3736.
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4. (a) Pattabiraman, V. J.; Bode, J. W. Rethinking amide bond synthesis. Nature 2011, 480, 471-
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