Superelectrophiles in Synthesis: Preparation of Aromatic Imides

Article abstract of DOI:10.1021/acs.joc.9b01437

Aromatic carboxylic acids are found to undergo reactions with isocyanates, wherein triflic acid promotes the formation of aromatic imide products in fair to good yields. It is proposed that the carboxylic acid group directs the isocyanate electrophile to

Full text of DOI:10.1021/acs.joc.9b01437

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Note
Superelectrophiles in synthesis: preparation of aromatic imides
Sean H Kennedy, Mark N. Schaeff, and Douglas A. Klumpp
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01437 • Publication Date (Web): 01 Oct 2019
Downloaded from pubs.acs.org on October 6, 2019
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Superelectrophiles in synthesis: preparation of aromatic imides.
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Sean H. Kennedy, Mark N. Schaeff, and Douglas A. Klumpp*
Department of Chemistry and Biochemistry
Northern Illinois University
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DeKalb, Illinois 60115
Abstract. Aromatic carboxylic acids are found to undergo reactions with isocyanates wherein
triflic acid promotes formation of aromatic imide products in fair to good yields. It is proposed
that the carboxylic acid group directs the isocyanate electrophile to the ortho position. This is
thought to occur by formation of a temporary carbamic acid anhydride group, which cleaves
upon ortho functionalization. A series of imide products are synthesized, as well as the
synthesis of a potential selective inhibitor of tyrosyl DNA phosphodiesterase II.
Functionalized aromatic compounds are important building blocks for a wide variety of fine
chemicals, pharmaceutical intermediates, and commodity chemicals.1 An important strategy for
the synthesis of functionalized arenes has involved the use of ortho directing groups (eq 1).2
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This may involve the metalation of the ortho-position on the arene through the use of strongly
basic reagents, such as butyllithium, or through the use of catalytic transition metals3 The
metallated ortho-position may then be reacted with an electrophilic or nucleophilic reagent,
depending on the nature of the coordinating metal. Recently, we reported the superacid-
promoted reactions of ferrocenes with isocyanates.4 When ferrocene carboxylic acids are used,
the corresponding ferrocenyl imides are formed in good yields (eq 2). This result suggested to
us a potentially new method of directing incoming electrophilic groups to the ortho position of
an aromatic carboxylic acid: temporary covalent attachment of an electrophile. In the following
Note, we describe our efforts to extend this chemistry to aromatic substrates beyond the
ferrocene derivatives.
The studies were initiated using phenylacetic acid and phenyl isocycanate. We sought to
optimize the conversion to an imide by varying the ratio of carboxylic acid and isocyanate, the
reaction time and temperature, the type of acid promoter, and the quantity of acid promoter.
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In general, the best conversion to an imide product was obtained by reacting phenylacetic acid
(3) and phenyl isocycanate – in a 1:1.5 mol ratio – for 30 minutes at 0 °C in CH2Cl2 and then
adding 10 equivalents of CF3SO3H, triflic acid (eq 3). With these reaction conditions, the imide 4
is isolated in 62% yield, but it is also accompanied by ca. 20% of aniline. When only 2
equivalents of triflic acid is used, imide 4 and amide 5 are formed in roughly equal amounts
with some aniline formed as a coproduct. With even less triflic acid, no imide is formed and
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only the amide 5 is observed. If a weaker acid is used, such as H2SO4, neither the imide or amide
are formed as a major product. Primarily aniline is found in the product mixture.
In order to evaluate the scope of this reaction, a variety of arylacetic acids and
isocyanates were subjected to the optimum reaction conditions (Table 1). Using phenylacetic
acid, aryl isocyanates or aliphatic isocyanates, the respective aromatic imides (6-11) are formed
in good yields. The chemistry tolerates substituents on the arylacetic acid. This includes
halogens (16-18), alkyl groups (21), aryl groups (19 and 22), ether groups (20), and ring-fused
derivatives (23). When a strongly deactivating substituent is present, however, the chemistry
does not proceed to the imide product. For example, 4-nitrophenyl acetic acid was reacted with
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Table 1. Products and yields from the reactions of arylacetic acid derivatives, isocyanates, and
triflic acid.
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cyclohexyl isocyanate and a complex product mixture was obtained. In some cases, the Friedel-
Crafts chemistry was observed at the carboxylic acid group. For example, 3-phenylpropionic
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acid leads to 1-indanone as product. It was alsoobserved that other nucleophilic groups may
react with the carboxylic acid group. Thus, 2-(2-hydroxyphenyl)acetic acid leads to formation of
benzofuran-2(3H)-one (eq 4).
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Aromatic imides similar to those obtained (Table 1) have shown biological activities. For
example, compound 24 has been examined for its activity as a selective inhibitor
of tyrosyl DNA phosphodiesterase II (TDP2).5 Using the biaryl substrate 25, the analog 26 is
prepared in good yield by reaction with the isocyanate and triflic acid (eq 5).
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Benzoic acid derivatives provide phthalimides upon reactions with isocyanates and triflic
acid (Table 2). With aryl isocyanates, phthalimides (27-32) are formed in fair to good yields. It
was observed that some of these conversions often give significant amounts of the
corresponding benzamide products. For example, product 40 is generated from the reaction of
3,5-dimethylbenzoic acid and 3-trifluoromethylphenylisocyanate. The crude product mixture is
found to contain phthalimide (30) and benzamide (40) in a 73:23 ratio.
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Unfortunately, compounds 30 and 40 are difficult to separate using chromatography, so the
phthalimide 30 could only be isolated in 32% yield. Likewise, product 31 also had to be
separated from an amide contaminant and as a result, the isolated yield of 31 is low. These
coproducts are not entirely unexpected, as carboxylic acids and isocyanates are known to
provide good yields of amides by decarboxylation of carbamic acid anhydride intermediates
(vide infra).6 In addition to the aryl isocyanates, aliphatic-type isocyanates provided the
phthalimide products (33-39). Phthalimide 34 is isolated in 67% yield as the product from 2,5-
dimethoxybenzoic acid. Evidently, one of the methoxy groups is demethylated in the superacid
and the phthalimide 34 is formed. A similar process is envisaged to occur to provide compound
39 from 1-methoxynaphthoic acid.
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Table 2. Products and isolated yields from the reactions of benzoic acid derivative, isocyanates,
and triflic acid.
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Given the synthetic value of aromatic imides, we sought to determine if products could
be formed with protected and deprotected (unsubstituted) nitrogen centers. Two strategies
were attempted: use of trimethylsilylisocyanate and p-toluenesulfonyl isocyanate in the
cyclization strategy. Using phenylacetic acid, p-toluenesulfonyl isocyanate did not provide the
desired imide (42) but instead the primary amide (41) was formed (eq 6). The same type of
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outcome was observed with 2,5-dimethylbenzoic acid – exclusive formation of the benzamide.
With phenylacetic acid and trimethylsilylisocyanate, the unsubstituted aromatic imide (43) is
isolated in 50% yield (eq 7). Evidently, the silyl group cleaves off in the superacidic media (eq 7).
With benzoic acid derivatives, only benzamide products are obtained from
trimethylsilylisocyanate.
To explain the transformations in Tables 1 and 2, it is suggested that the isocyanates and
carboxylic acids react to provide the carbamic acid anhydrides as the initial intermediate
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(Scheme 1). For example, phenylacetic acid reacts with phenyl isocyanate to give the adduct 44.
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Previously, this type of species has been proposed as the key intermediate in synthetic
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Scheme 1. Proposed mechanism for imide formation.
methodologies leading to amide products.7 Amides are thought to arise from decarboxylation
of carbamic acid anhydrides (such as 44).6,7 The results from our study indicate that another
reaction manifold is possible with the carbamic acid anhydrides. Protonation leads to the
cationic structure 45. With the need for excess triflic acid in the conversions, this is consistent
with the formation of diprotonated, superelectrophilic species (46).8 In several previous studies,
doubly protonated species have been proposed with dicarbonyl compounds in triflic acid-
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promoted reactions.9 Superelectrophile 46 should be capable of undergoing the intramolecular
Friedel-Crafts-type reaction, leading to intermediate 47. Ring-opening to 48 then provides the
observed product 4 by dehydration. The proposed mechanism may suggest why excess
superacid is necessary for the conversion. First, the protonated carbamic acid anhydrides may
be less prone to undergo decarboxylations to form the amides. Secondly, the superacid is likely
needed to generate the reactive, diprotonated species 46.
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In summary, we have found that aromatic carboxylic acids undergo reactions with
isocyanates - and with the addition of triflic acid - aromatic imides are directly formed. Aryl
acetic acids and benzoic acids have been found to produce the aromatic imides by this
chemistry. We believe the conversion involves formation of a carbamic acid anhydride
intermediate which then undergoes a superelectrophilic C-C bond formation. The overall
transformation represents the use of a temporary covalent attachment of two functional
groups – the carboxylic acid and isocyanate – to effect ortho-functionalization on the arene.
EXPERIMENTAL SECTION
General. All reactions were performed under an argon atmosphere using oven dried glassware.
Trifluoromethanesulfonic acid (triflic acid) was freshly distilled prior to use. All commercially
available compounds and solvents were used as received. 1H and 13C{1H} NMR were done using
either 300 MHz or 500 MHz spectrometers. Low-resolution mass spectra were obtained from a
gas chromatography instrument quipped with a mass-selective detector and electron impact
ionization. High resolution mass spectra were obtained on a Bruker maXis II Q-TOF LC/MS.
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General procedure for the synthesis of aromatic imides. The carboxylic acid (0.5 mmol) is
dissolved in 5 mL CH2Cl2 at room temperature under an N2 atmosphere. The isocyanate ( 0.75
mmol, 1.5 equiv.) is added via syringe and the reaction is stirred for 30 minutes.
Trifluoromethanesulfonic acid (0.5 mL, 0.44 mmol, approx. 10 eq) is then added and the
solution is stirred for 2 hours. The mixture is quenched by pouring the solution onto 20 g of ice
and the resulting biphasic mixture is adjusted to pH 10-11 with saturated Na2CO3(aq). After
transferring to a separatory funnel, the organic layer is separated and the aqueous layer is
extracted with CH2Cl2 (2 x 10 mL). The combined organic extracts are subsequently washed with
deionized water (15 mL) and brine (15 mL), dried over anhydrous sodium sulfate, and filtered.
The solvent is removed by rotary evaporation and the crude product purified by flash
chromatography on silica gel.
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2-Phenylisoquinoline-1,3(2H,4H)-dione (4).10 Using the general procedure, phenylacetic acid
(68 mg, 0.5 mmol) and phenylisocyanate (0.082 mL, 89 mg, 0.75 mmol) provide imide 4 as a
white solid (73 mg, 0.31 mmol, 62%), Rf = 0.47 (2:1 hexanes/ethyl acetate), mp 179 - 181 C. 1H
NMR (500 MHz, CDCl3): δ 8.26 (d, J = 8.0 Hz, 1H), 7.68 – 7.65 (m, 1H), 7.55 – 7.50 (m, 4H), 7.37
(d, J = 7.0 Hz, 1H), 7.24 – 7.22 (m, 2H), 4.24 (s, 2H); 13C{1H} NMR (125 MHz, CDCl3): δ 170.0,
165.1, 135.1, 134.2, 134.0, 129.5, 129.4, 128.7, 128.5, 127.9, 127.3, 125.5, 37.0. HRMS (ESI):
Calcd. for C15H12NO2 ([M+H]+) m/z 238.0868, found m/z 238.0872.
2-(4-ethylphenyl)isoquinoline-1,3(2H,4H)-dione (6).11 Using the general procedure,
phenylacetic acid (68 mg, 0.5 mmol) and 4-ethylphenyl isocyanate (0.108 mL,110 mg, 0.75
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mmol) provide imide 6 as a white solid (81 mg, 0.31 mmol, 61%), Rf = 0.66 (75:25 hexanes/ethyl
acetate), mp 129 – 131 C. 1H NMR (500 MHz, CDCl3): δ 8.25 (d, J = 8.1 Hz, 1H), 7.64 (m, 1H),
7.48 (t, J = 7.6 Hz, 1H), 7.38 – 7.32 (m, 3H), 7.13 (d, J = 8.2 Hz, 2H), 4.22 (s, 2H), 2.74 (q, J = 7.7
Hz, 2H), 1.30 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 170.0, 165.1, 144.7, 134.2,
133.9, 132.5, 129.5, 128.8, 128.2, 127.8, 127.3, 125.5, 36.9, 28.6, 15.2; HRMS (ESI): Calcd. for
C17H15NO2Na ([M+Na]+) m/z 288.1000, found m/z 288.0999.
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2-(3-Chlorophenyl)isoquinoline-1,3(2H,4H)-dione (7).11 Using the general procedure,
phenylacetic acid (68 mg, 0.5 mmol) and 3-chlorophenyl isocyanate (0.091 mL, 115 mg, 0.75
mmol) provides imide 7 as a white solid (64 mg, 0.24 mmol, 47%), Rf = 0.25 (75:25
hexanes/ethyl acetate), mp 156 – 158 C. 1H NMR (500 MHz, CDCl3): δ 8.26 (d, J = 7.9 Hz, 1H),
7.67 (ddd, J = 7.6, 7.5, 1.0 Hz, 1H), 7.53 – 7.48 (m, 1H), 7.47 – 7.43 (m, 2H), 7.37 (d, J = 7.7 Hz,
1H), 7.26 (s, 1H), 7.16 – 7.12 (m, 1H), 4.23 (s, 2H); 13C{1H} NMR (125 MHz, CDCl3): δ 169.7,
164.8, 136.2, 134.8, 134.2, 134.1, 130.2, 129.5, 129.1, 129.0, 128.0, 127.4, 127.0, 125.2, 36.9;
HRMS (ESI): Calcd. for C15H10ClNO2Na ([M+Na]+) m/z 294.0298, found m/z 294.0293.
2-(3-(Trifluoromethyl)phenyl)isoquinoline-1,3(2H,4H)-dione (8). Using the general procedure,
phenylacetic acid (68 mg, 0.5 mmol) and 3-(trifluoromethyl)phenyl isocyanate (0.103 mL, 140
mg, 0.75 mmol) provide imide 8 as a white solid (79 mg, 0.26 mmol, 52%), Rf = 0.44 (75:25
hexanes/ethyl acetate), mp 131 – 133 C. 1H NMR (500 MHz, CDCl3): δ 8.26 (d, J = 7.8 Hz, 1H),
7.73 (d, J = 7.8 Hz, 1H), 7.71 – 7.63 (m, 2H), 7.55 – 7.49 (m, 2H), 7.44 (d, 7.8 Hz, 1H), 7.37 (d, J =
7.7 Hz, 1H), 4.24 (s, 2H). 13C{1H} NMR (125 MHz, CDCl3): δ 169.7, 164.9, 135.6, 134.3, 134.1,
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132.3, 131.8 (q, J = 33.0 Hz), 129.9, 129.5, 128.0, 127.4, 125.9 (q, J = 3.7 Hz), 125.6 (q, J = 3.6
Hz), 125.1, 123.7 (q, J = 271.8 Hz), 36.9. HRMS (ESI): Calcd. for C16H10F3NO2Na ([M+Na]+) m/z
328.0562, found m/z 328.0561.
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2-(o-Tolyl)isoquinoline-1,3(2H,4H)-dione (9). Using the general procedure, phenylacetic acid
(68 mg, 0.5 mmol) and o-tolyl isocyanate (0.093 mL, 100 mg, 0.75 mmol) provide imide 9 as a
light brown oil (37.6 mg, 0.15 mmol, 30%), Rf = 0.37 (75:25 hexanes/ethyl acetate). 1H NMR
(500 MHz, CDCl3): δ 8.29 (d, J = 7.9 Hz, 1H), 7.68 (ddd, J = 7.8, 7.6, 1.2 Hz, 1H), 7.54 – 7.49 (m,
1H), 7.41 – 7.34 (m, 4H), 7.14 (d, J = 7.5 Hz, 1H), 4.25 (s, 2H), 2.18 (s, 3H). 13C{1H} NMR (125
MHz, CDCl3): δ 169.6, 164.7, 135.8, 134.4, 134.0, 131.0, 129.5, 129.1, 128.5, 127.9, 127.4, 127.1,
125.4, 36.9, 17.6. HRMS (ESI): Calcd. for C16H14NO2 ([M+H]+) m/z 252.1024, found m/z
252.1016.
2-(4-Methoxyphenyl)isoquinoline-1,3(2H,4H)-dione (10).12 Using the general procedure,
phenylacetic acid (68 mg, 0.5 mmol) and 4-methoxyphenyl isocyanate (0.097 mL, 112 mg, 0.75
mmol) provide imide 10 as a white solid (91 mg, 0.34 mmol, 68%), Rf = 0.32 (2:1 hexanes/ethyl
acetate), mp 175 - 177 C. 1H NMR (500 MHz, CDCl3): δ 8.27 (dd, J = 7.9, 0.9 Hz, 1H), 7.66 (ddd, J
= 7.6, 7.5, 1.3 Hz, 1H), 7.52 – 7.47 (m, 1H), 7.38 – 7.34 (m, 1H), 7.16 – 7.12 (m, 2H), 7.06 – 7.02
(m, 2H), 4.24 (s, 2H), 3.87 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 170.2, 165.2, 159.6, 134.2,
133.9, 129.5, 129.4, 127.9, 127.5, 127.3, 125.5, 114.7, 55.5, 37.0; HRMS (ESI): Calcd. for
C16H14NO3 ([M + H]+) m/z 268.0973, found m/z 268.0971.
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2-(2,4-Dichlorophenyl)isoquinoline-1,3(2H,4H)-dione (11).13 Using the general procedure,
phenylacetic acid (68 mg, 0.5 mmol) and 2,4-dichlorophenyl isocyanate (141 mg, 0.75 mmol)
provide imide 11 as a white solid (78 mg, 0.26 mmol, 51%), Rf = 0.40 (75:25 hexanes/ethyl
acetate), 165 – 167 mp C. 1H NMR (500 MHz, CDCl3): δ 8.27 (d, J = 7.8 Hz, 1H), 7.69 (ddd, J =
7.6, 7.5, 1.2 Hz, 1H), 7.59 (d, J = 2.1 Hz, 1H), 7.54 – 7.50 (m, 1H), 7.43 – 7.37 (m, 2H), 7.23 (d, J =
8.4 Hz, 1H), 4.33 – 4.20 (m, 2H); 13C{1H} NMR (125 MHz, CDCl3): δ 169.1, 164.1, 135.6, 134.3,
134.2, 133.7, 131.9, 131.3, 130.2, 129.6, 128.2, 128.0, 127.5, 124.9, 36.8; HRMS (ESI): Calcd. for
C15H10Cl2NO2 ([M + H]+) m/z 306.0088, found m/z 306.0083.
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2-Benzylisoquinoline-1,3(2H,4H)-dione (12).14 Using the general procedure, phenylacetic acid
(68 mg, 0.5 mmol) and benzyl isocyanate (0.093 mL, 100 mg, 0.75 mmol) provides imide 12 as a
white solid (87 mg, 0.35 mmol, 69%), Rf = 0.33 (80:20 hexanes/ethyl acetate), mp 118 - 120 C.
1H NMR (300 MHz, CDCl3): δ 8.21 (d, J = 7.83, 1H), 7.56 (ddd, J = 7.6, 7.5, 0.9 Hz, 1H), 7.50 – 7.40
(m, 3H), 7.34 – 7.21 (m, 4H), 5.18 (s, 2H), 4.04 (s, 2H); 13C{1H} NMR (75 MHz, CDCl3): δ 169.8,
164.8, 137.1, 134.1, 133.6, 129.2, 128.9, 128.4, 127.7, 127.5, 127.1, 125.4, 43.3, 36.5; HRMS
(ESI): Calcd. for C16H14NO2 ([M + H]+) m/z 252.1024, found m/z 252.1022.
2-Dodecylisoquinoline-1,3(2H,4H)-dione (13). Using the general procedure, phenylacetic acid
(68 mg, 0.5 mmol) and dodecyl isocyanate (0.181 mL, 159 mg, 0.75 mmol) provide imide 13 as a
colorless oil (105 mg, 0.32 mmol, 64%), Rf = 0.80 (80:20 hexanes/ethyl acetate), mp 52 - 54 C.
1H NMR (500 MHz, CDCl3): δ 8.21 (dd, J = 7.8, 0.5 Hz, 1H), 7.58 (td, J = 7.5, 1.2 Hz, 1H), 7.44 (t, J
= 7.5 Hz, 1H), 7.27 (d, J = 7.7 Hz, 1H), 4.03 (s, 2H), 3.98 (t, J = 7.7 Hz, 2H), 1.62 (p, J = 7.5 Hz, 2H),
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1.40 – 1.22 (m, 18H), 0.89 (t, J = 7.0 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 169.9, 164.8,
134.1, 133.5, 129.1, 127.6, 127.1, 125.5, 40.3, 36.4, 31.9, 29.63, 29.61, 29.58, 29.53, 29.32,
28.0, 27.1, 22.7, 14.1. HRMS (ESI): Calcd. for C21H32NO2 ([M + H]+) m/z 330.2433, found m/z
330.2430.
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2-Ethylisoquinoline-1,3(2H,4H)-dione (14).15 Using the general procedure, phenylacetic acid
(68 mg, 0.5 mmol) and ethyl isocyanate (0.059 mL, 53 mg, 0.75 mmol) provide imide 14 as a
white solid (61 mg, 0.33 mmol, 65%), Rf = 0.57 (75:25 hexanes/ethyl acetate), mp 100 – 102 C.
1H NMR (300 MHz, CDCl3): δ 8.16 (d, J = 7.8Hz, 1H), 7.54 (ddd, J = 7.5, 7.4, 1.3 Hz, 1H), 7.42 –
7.36 (m, 1H), 7.23 (d, J = 7.6 Hz, 1H), 4.04 – 3.95 (m, 4H, 2 CH2), 1.19 (t, J = 7.1 Hz, 3H); 13C{1H}
NMR (75 MHz, CDCl3): δ 169.7, 164.5, 134.1, 133.4, 129.0, 127.6, 127.0, 125.5, 36.4, 35.2, 13.2;
HRMS (ESI): Calcd. for C11H12NO2 ([M + H]+) m/z 190.0868, found m/z 190.0864.
2-Cyclohexylisoquinoline-1,3(2H,4H)-dione (15).16 Phenylacetic acid (680 mg, 5 mmol) is
dissolved in 50 mL CH2Cl2 and cyclohexyl isocyanate (0.96 mL, 7.5 mmol, 1.5 eq) is added via
syringe. The solution is stirred for 30 min at 25 °C. Trifluoromethanesulfonic acid (3 mL, 33
mmol, 6.6 eq) is slowly added, and after 2 h, the mixture is quenched by pouring it over20 g of
ice. The resulting biphasic mixture is adjusted to pH 10-11 with saturated Na2CO3 and extracted
with CH2Cl2 (2 x 10 mL). The combined organic extracts are subsequently washed with water (15
mL) and brine (15 mL), dried over anhydrous sodium sulfate, and then filtered. The solvent is
removed by rotary evaporation and the crude product is purified by flash chromatography on
silica gel to afford a white solid (706 mg, 2.9 mmol, 58%), Rf = 0.8 (80:20 hexanes/ethyl
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acetate), mp 157 – 159 C. 1H NMR (500 MHz, CDCl3): δ 8.19 (dd, J = 7.9, 0.9 Hz, 1H), 7.57 (ddd,
J = 7.6, 7.6, 1.3 Hz, 1H), 7.44 (ddd, J = 7.6, 7.5, 0.8 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H), 4.80 (tt, J =
12.3, 3.7 Hz, 1H), 4.01 (s, 2H), 2.41 (qd, J = 12.7, 3.6 Hz, 2H), 1.89 – 1.82 (m, 2H), 1.73 – 1.61 (m,
3H), 1.40 (qt, J = 13.3, 3.3 Hz, 2H), 1.28 (qt, J = 13.0, 3.5 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3):
δ 170.5, 165.3, 134.1, 133.3, 129.1, 127.6, 126.8, 126.1, 53.7, 37.2, 29.1, 26.5, 25.4; HRMS (ESI):
Calcd. for C15H18NO2 ([M + H]+) m/z 244.1337, found m/z 244.1335.
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7-Bromo-2-cyclohexylisoquinoline-1,3(2H,4H)-dione (16). Using the general procedure, 4-
bromophenyl acetic acid (108 mg, 0.5 mmol) and cyclohexyl isocyanate (0.096 mL, 93.9 mg,
0.75 mmol) provide imide 16 as a white solid (106 mg, 0.33 mmol, 66%), Rf = 0.66 (75:25
hexanes/ethyl acetate), mp 103 - 105 C. 1H NMR (500 MHz, CDCl3): δ 8.28 (d, J = 2.1 Hz, 1H),
7.65 (dd, J = 8.1, 2.1 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 4.75 (tt, J = 12.3, 3.7 Hz, 1H), 3.94 (s, 2H),
2.36 (dq, J = 12.3, 3.5 Hz, 2H), 1.87 – 1.80 (m, 2H), 1.70 – 1.59 (m, 3H), 1.37 (qt, J = 13.2, 3.3 Hz,
2H), 1.30 – 1.20 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ 169.8, 164.0, 136.2, 132.8, 131.9,
128.5, 127.8, 121.5, 53.9, 36.8, 29.0, 26.4, 25.3. HRMS (ESI): Calcd. for C16H18BrNO4Na([M +
H][CHOONa]+) m/z 390.0317, found m/z 390.0310.
7-Chloro-2-cyclohexylisoquinoline-1,3(2H,4H)-dione (17). Using the general procedure, 4-
chlorophenyl acetic acid (85 mg, 0.5 mmol) and cyclohexyl isocyanate (0.096 mL, 93.9 mg, 0.75
mmol) provide imide 17 as a white solid (76 mg, 0.275 mmol, 55%), Rf = 0.45 (80:20
hexanes/ethyl acetate), mp 107 - 109 C. 1H NMR (500 MHz, CDCl3): δ 8.14 (d, J = 2.2 Hz, 1H),
7.51 (dd, J = 8.2, 2.2 Hz, 1H), 7.19 (d, J = 8.2 Hz, 1H), 4.77 (tt, J = 12.3, 3.7 Hz, 1H), 3.97 (s, 2H),
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2.37 (qd, J = 12.4, 3.7 Hz, 2H), 1.88 – 1.81 (m, 2H), 1.71 – 1.60 (m, 3H), 1.38 (qt, J = 13.1, 3.1 Hz,
2H), 1.30 – 1.23 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ 169.8, 164.1, 133.8, 133.4, 132.3,
128.9, 128.3, 127.6, 53.9, 36.7, 28.9, 26.4, 25.3. HRMS (ESI): Calcd. for C15H16ClNO2Na ([M +
Na]+) m/z 300.0767, found m/z 300.0754.
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2-Cyclohexyl-7-fluoroisoquinoline-1,3(2H,4H)-dione (18). Using the general procedure, 4-
fluorophenyl acetic acid (77 mg, 0.5 mmol) and cyclohexyl isocyanate (0.096 mL, 93.9 mg, 0.75
mmol) provide imide 18 as a white solid (75 mg, 0.28 mmol, 57%), Rf = 0.45 (80:20
hexanes/ethyl acetate), mp C. 1H NMR (500 MHz, CDCl3): δ 7.84 (dd, J = 9.1, 2.6 Hz, 1H), 7.30 –
7.21 (m, 2H), 4.77 (tt, J = 12.3, 3.7 Hz, 1H), 3.97 (s, 2H), 2.37 (qd, J = 12.4, 3.7 Hz, 2H), 1.88 –
1.81 (m, 2H), 1.71 – 1.60 (m, 3H), 1.38 (qt, J = 13.1, 3.1 Hz, 2H), 1.30 – 1.23 (m, 1H). 13C{1H}
NMR (125 MHz, CDCl3): δ 170.1, 164.28 (d, J = 2.5 Hz), 161.9 (J = 247.3 Hz), 129.76 (J = 3.1 Hz),
128.7 (d, J = 7.4 Hz), 127.9 (d, J = 7.7 Hz), 120.9 (d, J = 22.6 Hz), 115.3 (d, J = 23.5 Hz), 53.9, 36.6,
29.0, 26.4, 25.3. HRMS (ESI): Calcd. for C15H16FNO2Na ([M + Na]+) m/z 284.1063, found m/z
284.1055.
2-Cyclohexyl-4-phenylisoquinoline-1,3(2H,4H)-dione (19). Using the general procedure,
diphenyl acetic acid (106 mg, 0.5 mmol) and cyclohexyl isocyanate (0.096 mL, 93.9 mg, 0.75
mmol) provide imide 19 as a white solid (115 mg, 0.36 mmol, 72%), Rf = 0.5 (90:10
hexanes/ethyl acetate), mp 138 – 140 C. 1H NMR (500 MHz, CDCl3): δ 8.28 (dd, J = 7.8, 1.3 Hz,
1H), 7.55 (ddd, J = 7.5, 7.4, 1.4 Hz, 1H), 7.48 (ddd, J = 7.8, 7.6, 0.9 Hz, 1H), 7.34 – 7.26 (m, 4H),
7.16 – 7.13 (m, 3H), 5.04 (s, 1H), 4.72 (tt, J = 12.3, 3.7 Hz, 1H), 2.39 (dq, J = 12.4, 3.7 Hz, 1H),
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2.26(dq, J = 12.4, 3.7 Hz, 1H), 1.84 – 1.77 (m, 2H), 1.69 – 1.62 (m, 2H), 1.53 – 1.45 (m, 1H), 1.40
– 1.20 (m, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 172.4, 165.2, 139.0, 138.0, 133.6, 129.1, 128.9,
128.1, 127.91, 127.89, 127.88, 126.2, 54.1, 53.6, 29.6, 28.3, 26.5, 26.3, 25.3. HRMS (ESI): Calcd.
for C21H22NO2 ([M + H]+) m/z 320.1650, found m/z 320.1646.
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2-Cyclohexyl-6,7-dimethoxyisoquinoline-1,3(2H,4H)-dione (20). Using the general procedure,
3,4-dimethoxyphenyl acetic acid (98 mg, 0.5 mmol) and cyclohexyl isocyanate (0.096 mL, 93.9
mg, 0.75 mmol) provide imide 20 as a yellow solid (91 mg, 0.3 mmol, 60%), Rf = 0.18 (80:20
hexanes/ethyl acetate), mp 155 – 157 C. 1H NMR (500 MHz, CDCl3): δ 7.56 (s, 1H), 6.61 (s, 1H),
4.75 (tt, J = 12.1, 3.6 Hz, 1H), 3.93 (s, 6H), 3.91 (s, 2H), 2.37 (qd, J = 12.3, 3.5 Hz, 2H), 1.86 – 1.78
(m, 2H), 1.69 – 1.58 (m, 3H), 1.36 (qt, J = 13.1, 3.2 Hz, 2H), 1.28 – 1.20 (m, 1H). 13C{1H} NMR
(125 MHz, CDCl3): δ 170.6, 165.1, 153.7, 148.7, 128.3, 118.7, 110.2, 108.3, 56.2, 56.1, 53.5,
39.9, 29.1, 26.5, 25.4. HRMS (ESI): Calcd. for C17H21NO4Na ([M + Na]+) m/z 326.1368, found m/z
326.1365.
7-Isobutyl-4-methyl-2-phenylisoquinoline-1,3(2H,4H)-dione (21). Using the general procedure,
-methyl-4-(isobutyl)phenyl acetic acid (103 mg, 0.5 mmol) and cyclohexyl isocyanate (0.096
mL, 93.9 mg, 0.75 mmol) provide imide 21 as a white solid (81 mg, 0.27 mmol, 53%), Rf = 0.
(80:20 hexanes/ethyl acetate), mp 133 – 135 C. 1H NMR (500 MHz, CDCl3): δ 8.05 (d, J = 1.6 Hz,
1H), 7.56 – 7.52 (m, 2H), 7. 50 – 7.46 (m, 2H), 7.35 (d, J = 7.9 Hz, 1H), 7.25 – 7.21 (m, 2H), 4.08
(q, J = 7.5 Hz, 1H), 2.61 (d, J = 7.2 Hz, 2H), 1.96 (sept, J = 6.8 Hz, 1H), 1.79 (d, J = 7.5 Hz, 3H), 0.97
(d, J = 6.7 Hz, 6H); 13C{1H} NMR (75 MHz, CDCl3): δ 174.5, 165.0, 141.5, 137.9, 135.5, 135.2,
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129.5, 129.3, 128.6, 128.5, 126.6, 124.4, 44.8, 41.4, 30.1, 22.4, 22.3; HRMS (ESI): Calcd. for
C20H21NO2Na ([M + Na]+) m/z 330.1470, found m/z 330.1465.
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2-Cyclohexyl-7-phenylisoquinoline-1,3(2H,4H)-dione (22). Using the general procedure, 4-
biphenyl acetic acid (106 mg, 0.5 mmol) and cyclohexyl isocyanate (0.096 mL, 93.9 mg, 0.75
mmol) provide imide 22 as a white solid (105 mg, 0.33 mmol, 66%), Rf = 0.38 (90:10
hexanes/ethyl acetate), mp 159 – 161 C. 1H NMR (300 MHz, CDCl3): δ 8.42 (d, J = 1.8 Hz, 1H),
7.77 (dd, J = 8.0, 1.9 Hz, 1H), 7.65 – 7.60 (m, 2H), 7.50 – 7.34 (m, HH), 7.80 (d, J = 8.0 Hz, 1H),
4.82 (tt, J = 12.2, 3.6 Hz, 1H), 4.01 (s, 2H), 2.43 (qd, J = 12.2, 3.1 Hz, 2H), 1.89 – 1.83 (m, 2H),
1.72 – 1.63 (m, 3H), 1.48 – 1.24 (m, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ 170.4, 165.3, 140.7,
139.5, 132.9, 131.9, 129.0, 127.9, 127.4, 127.3, 127.0, 126.5, 53.8, 37.0, 29.0, 26.5, 25.4. HRMS
(ESI): Calcd. for C21H22NO2 ([M + H]+) m/z 320.1650, found m/z 320.1646.
3-Cyclohexylbenzo[f]isoquinoline-2,4(1H,3H)-dione (23). Using the general procedure, 1-
naphthaleneacetic acid (93 mg, 0.5 mmol) and cyclohexyl isocyanate (0.096 mL, 93.9 mg, 0.75
mmol) provide imide 23 as a white solid (107 mg, 0.37 mmol, 73%), Rf = 0.42 (90:10
hexanes/ethyl acetate), mp 166 - 168 C. 1H NMR (500 MHz, CDCl3): δ 8.18 (d, J = 8.8 Hz, 1H),
7.91 – 7.88 (m, 2H), 7.84 (d, J = 8.8 Hz, 1H), 7.67 – 7.61 (m, 2H), 4.87 (tt, J = 12.3, 3.7 Hz, 1H),
4.27 (s, 2H), 2.47 (dq, J = 12.3, 3.4 Hz, 2H), 1.92 – 1.85 (m, 2H), 1.75 – 1.67 (m, 3H), 1.43 (tq, J =
13.0, 3.1 Hz, 2H), 1.31 (tq, J = 12.8, 3.4 Hz, 1H). 13C{1H} NMR (75 MHz, CDCl3): δ 170.1, 165.6,
135.2, 132.5, 129.3, 128.9, 128.7, 127.9, 127.4, 124.0, 123.7, 123.4, 53.7, 34.8, 29.1, 26.5, 25.4.
HRMS (ESI): Calcd. for C19H20NO2 ([M + H]+) m/z 294.1494, found m/z 294.1489.
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7-(3-Chlorophenyl)-2-(3-(trifluoromethyl)phenyl)isoquinoline-1,3(2H,4H)-dione (26). Using the
general procedure, (3’-chloro[1,1’-biphenyl]-4-yl)acetic acid (123 mg, 0.5 mmol) and 3-
trifluoromethylphenyl isocyanate (0.103 mL, 140 mg, 0.75 mmol) provide imide 26 as a white
solid (108 mg, 52%), Rf = 0.18 (80:20 hexanes/ethyl acetate), mp 150 - 152 C. 1H NMR (500
MHz, CDCl3): δ 8.46 (d, J = 1.9 Hz, 1H), 7.88 (dd, J = 8.0, 2.0 Hz, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.70-
7.65 (m, 1H), 7.65 – 7.63 (m, 1H), 7.56 – 7.52 (m, 2H), 7.49 – 7.39 (m, 4H), 4.30 (s, 2H). 13C{1H}
NMR (125 MHz, CDCl3): δ 169.5, 164.7, 141.0, 139.9, 135.5, 135.0, 133.4, 132.9, 132.7, 132.2
131.8 (q, J = 33 Hz), 130.4, 130.3, 130.0, 129.8, 128.2, 128.1, 127.8, 127.7, 127.3, 127.2, 126.0,
125.9, 125.7, 125.3, 125.25, 125.19, 123.7 (q, J = 272 Hz), 36.7. HRMS (ESI): Calcd. for
C22H13ClF3NO2Na ([M + Na]+) m/z 438.0485, found m/z 438.0482.
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4,6-Dimethyl-2-phenylisoindoline-1,3-dione (27).17 Using the general procedure, 3,5-
dimethylbenzoic acid (75 mg, 0.5 mmol) and phenyl isocyanate (0.082 mL, 89.3 mg, 0.75 mmol)
provide imide 27 as a white solid (83 mg, 0.33 mmol, 66%), Rf = 0.44 (80:20 hexanes/ethyl
acetate), mp 116 - 119 C. 1H NMR (300 MHz, CDCl3): δ 7.60 (s, 1H), 7.54 – 7.49 (m, 2H), 7.47 –
7.43 (m, 2H), 7.41 (tt, J = 7.3, 1.1 Hz, 1H), 7.35 (s, 1H), 2.72 (s, 3H), 2.50 (s, 3H); 13C{1H} NMR
(125 MHz, CDCl3): δ 168.0, 167.5, 145.1, 138.7, 137.2, 132.6, 131.9, 129.0, 127.8, 126.6, 125.9,
122.0, 21.8, 17.6; HRMS (ESI): Calcd. for C16H14NO2 ([M + H]+) m/z 252.1024, found m/z
252.1020.
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2-(4-Ethylphenyl)-4,6-dimethylisoindoline-1,3-dione (28). Using the general procedure, 3,5-
dimethylbenzoic acid (75 mg, 0.5 mmol) and 4-ethylphenyl isocyanate (0.108 mL, 110 mg, 0.75
mmol) provide imide 28 as a white solid (68 mg, 0.25 mmol, 49%), Rf = 0.52 (90:10
hexanes/ethyl acetate), mp 131 – 133 C. 1H NMR (300 MHz, CDCl3): δ 7.57 (s, 1H), 7.36 – 7.29
(m, 5H), 2.71 (q, J = 7.7 Hz, 2H), 2.69 (s, 3H), 2.48 (s, 3H), 1.28 (t, J = 7.6 Hz, 3H). 13C{1H} NMR (75
MHz, CDCl3): δ 168.2, 167.6, 145.0, 144.0, 138.1, 137.1, 132.7, 129.4, 128.5, 126.5, 126.0, 121.9,
28.6, 21.8, 17.6, 15.4. HRMS (ESI): Calcd. for C18H18NO2 ([M + H]+) m/z 280.1337, found m/z
280.1334.
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2-(4-Methoxyphenyl)-4,6-dimethylisoindoline-1,3-dione (29). Using the general procedure,
3,5-dimethylbenzoic acid (75 mg, 0.5 mmol) and 4-methoxyphenyl isocyanate (0.097 mL, 112
mg, 0.75 mmol) provide imide 29 as a white solid (95 mg, 0.34 mmol, 68%), Rf = 0.20 (90:10
hexanes/ethyl acetate), mp 157 - 159 C. 1H NMR (300 MHz, CDCl3): δ 7.58 (s, 1H), 7.35 (s, 1H),
7.33 (d, J = 9.0 Hz, 2H), 7.03 (d, J = 9.0 Hz, 2H), 3.86 (s, 3H), 2.71 (s, 3H), 2.50 (s, 3H). 13C{1H}
NMR (75 MHz, CDCl3): δ 168.3, 167.8, 159.1, 145.0, 138.2, 137.1, 132.7, 128.0, 126.0, 124.6,
121.9, 114.4, 55.5, 21.8, 17.6. HRMS (ESI): Calcd. for C17H16NO3 ([M + H]+) m/z 282.1130, found
m/z 282.1128.
4,6-Dimethyl-2-(3-(trifluoromethyl)phenyl)isoindoline-1,3-dione (30). Using the general
procedure, 3,5-dimethylbenzoic acid (75 mg, 0.5 mmol) and 3-(trifluoromethyl)phenyl
isocyanate (0.103 mL, 140 mg, 0.75 mmol) provide imide 30 as a white solid (51 mg, 0.16 mmol,
32%), Rf = 0.68 (75:25 hexanes/ethyl acetate), mp 111 – 113 C. 1H NMR (500 MHz, CDCl3): δ
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7.80 (s, 1H), 7.72 – 7.68 (m, 1H), 7.68 – 7.63 (m, 2H), 7.62 (s, 1H) 7.38 (s, 1H), 2.73 (s, 3H), 2.53
(s, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 167.6, 167.0, 145.6, 138.6, 137.6, 132.5, 132.3, 131.5
(q, J = 32.9 Hz), 129.7, 129.5, 125.7, 124.4 (q, J = 3.8 Hz), 123.6 (q, J = 272.6 Hz), 123.4 (q, J = 3.9
Hz), 122.2, 21.9, 17.7. HRMS (ESI): Calcd. for C17H13F3NO2 ([M + H]+) m/z 320.0898, found m/z
320.0893. Chromatography purification also provides by-product amide 40.
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2-(3-Chlorophenyl)-4,6-dimethylisoindoline-1,3-dione (31). Using the general procedure, 3,5-
dimethylbenzoic acid (75 mg, 0.5 mmol) and 3-chlorophenyl isocyanate (0.091 mL, 115 mg, 0.75
mmol) provide imide 31 as a white solid (43 mg, 0.15 mmol, 30%), Rf = 0.75 (75:25
hexanes/ethyl acetate), mp 168 – 171 C. 1H NMR (500 MHz, CDCl3): δ 7.61 (s, 1H), 7.52 – 7.50
(m, 1H), 7.47 – 7.42 (m, 1H), 7.40 – 7.35 (m, 3H), 2.72 (s, 3H), 2.52 (s, 3H). 13C{1H} NMR (125
MHz, CDCl3): δ 167.6, 167.1, 145.4, 138.5, 137.5, 134.5, 133.0, 132.4, 129.9, 127.9, 126.7, 125.7,
124.6, 122.2, 21.9, 17.7. HRMS (ESI): Calcd. for C16H13ClNO2 ([M + H]+) m/z 286.0635, found m/z
286.0630.
6-Phenyl-5H-[1,3]dioxolo[4,5-f]isoindole-5,7(6H)-dione (32).17 Using the general procedure,
piperonylic acid (83 mg, 0.5 mmol) and phenyl isocyanate (0.082 mL, 89.3 mg, 0.75 mmol)
provide imide 32 as a white solid (39 mg, 0.15 mmol, 29%), Rf = 0.19 (90:10 hexanes/ethyl
acetate), mp 214 – 217 C. 1H NMR (300 MHz, CDCl3): δ 7.54 – 7.48 (m, 2H), 7.47 – 7.37 (m, 3H),
7.32 (s, 2H), 6.21 (s, 2H); 13C{1H} NMR (75 MHz, CDCl3): δ 166.7, 153.0, 131.9, 129.0, 127.9,
127.3, 126.4, 104.0, 103.1; HRMS (ESI): Calcd. for C15H9NO4Na ([M + Na]+) m/z 290.0429, found
m/z 290.0424.
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6-Ethyl-5H-[1,3]dioxolo[4,5-f]isoindole-5,7(6H)-dione (33). Using the general procedure,
piperonylic acid (83 mg, 0.5 mmol) and ethyl isocyanate (0.059 mL, 53.3 mg, 0.75 mmol)
provide imide 33 as a white solid (51 mg, 0.24 mmol, 47%), Rf = 0.30 (90:10 hexanes/ethyl
acetate), mp 161 – 163 C. 1H NMR (300 MHz, CDCl3): δ 7.15 (s, 2H), 6.14 (s, 2H), 3.65 (q, J = 7.3
Hz, 2H), 1.22 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ 137.6, 152.4, 127.7, 103.6,
102.9, 32.9, 14.0. HRMS (ESI): Calcd. for C11H10NO4 ([M + H]+) m/z 220.0610, found m/z
220.0605.
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2-Cyclohexyl-4-hydroxy-7-methoxyisoindoline-1,3-dione (34). Using the general procedure,
2,5-dimethoxybenzoic acid (91 mg, 0.5 mmol) and cyclohexyl isocyanate (0.096 mL, 93.9 mg,
0.75 mmol) provide imide 34 as a white solid (92 mg, 0.34 mmol, 67%), Rf = 0.20 (2:1
hexanes/ethyl acetate), mp 148 - 150 C. 1H NMR (300 MHz, CDCl3): δ 7.45 (d, J = 3.1 Hz), 7.23
(dd, J = 9.0, 3.1 Hz, 1H), 7.16 (d, J = 9.0 Hz, 1H), 4.82 (tt, J = 12.1, 3.6 Hz, 1H), 3.87 (s, 3H), 2.40
(qd, J = 12.3, 3.7 Hz, 2H), 1.92 – 1.85 (m, 2H), 1.75 – 1.68 (m, 3H), 1.42 (qt, J = 13.2, 3.4 Hz, 2H),
1.27 (qt, J = 13.2, 3.4 Hz, 1H). 13C{1H} NMR (75 MHz, CDCl3): δ 161.1, 156.7, 147.5, 147.0, 124.5,
117.5, 114.8, 108.7, 56.0, 55.3, 28.5, 26.2, 25.1. HRMS (ESI): Calcd. for C15H18NO4 ([M + H]+) m/z
276.1236, found m/z 276.1232.
2-Ethyl-4,6-dimethylisoindoline-1,3-dione (35). Using the general procedure, 3,5-
dimethylbenzoic acid (75 mg, 0.5 mmol) and ethyl isocyanate (0.059 mL, 53.3 mg, 0.75 mmol)
provide imide 35 as a white solid (81 mg, 0.4 mmol, 80%), Rf = 0.50 (90:10 hexanes/ethyl
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acetate), mp 62 – 64 C. 1H NMR (300 MHz, CDCl3): δ 7.42 (s, 1H), 7.20 (s, 1H), 3.67 (q, J = 7.2
Hz, 2H), 2.61 (s, 3H), 2.41 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ 169.0,
168.4, 144.4, 137.5, 136.6, 133.0, 126.4, 121.4, 32.5, 21.7, 17.4, 13.9. HRMS (ESI): Calcd. for
C12H14NO2 ([M + H]+) m/z 204.1024, found m/z 204.1020.
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2-Benzyl-4,6-dimethylisoindoline-1,3-dione (36). Using the general procedure, 3,5-
dimethylbenzoic acid (75 mg, 0.5 mmol) and benzyl isocyanate (0.093 mL, 99.9 mg, 0.75 mmol)
provide imide 36 as a white solid (81 mg, 0.32 mmol, 63%), Rf = 0.35 (90:10 hexanes/ethyl
acetate), mp 126 - 128 C.1H NMR (500 MHz, CDCl3): δ 7.43 (s, 1H), 7.22 (s, 1H), 4.07 (tt, J =
12.3, 3.9 Hz, 1H), 2.63 (s, 3H), 2.43 (s, 3H), 2.20 (qd, J = 12.5, 3.4 Hz, 2H), 1.89 – 1.82 (m, 2H),
1.74 – 1.65 (m, 3H), 1.41 – 1.24 (m, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 169.3, 168.6, 144.2,
137.4, 136.6, 132.9, 126.2, 121.3, 50.6, 29.9, 26.1, 25.2, 21.7, 17.3. HRMS (ESI): Calcd. for
C16H20NO2 ([M + H]+) m/z 258.1494, found m/z 258.1489.
2-Cyclohexyl-4,6-dimethylisoindoline-1,3-dione (37). Using the general procedure, 3,5-
dimethylbenzoic acid (75 mg, 0.5 mmol) and cyclohexyl isocyanate (0.096 mL, 93.9 mg, 0.75
mmol) provide imide 37 as a white solid (81 mg, 0.32 mmol, 63%), Rf = 0.35 (90:10
hexanes/ethyl acetate), mp 126 - 128 C.1H NMR (500 MHz, CDCl3): δ 7.43 (s, 1H), 7.22 (s, 1H),
4.07 (tt, J = 12.3, 3.9 Hz, 1H), 2.63 (s, 3H), 2.43 (s, 3H), 2.20 (qd, J = 12.5, 3.4 Hz, 2H), 1.89 – 1.82
(m, 2H), 1.74 – 1.65 (m, 3H), 1.41 – 1.24 (m, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 169.3, 168.6,
144.2, 137.4, 136.6, 132.9, 126.2, 121.3, 50.6, 29.9, 26.1, 25.2, 21.7, 17.3. HRMS (ESI): Calcd. for
C16H20NO2 ([M + H]+) m/z 258.1494, found m/z 258.1489.
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2-Dodecyl-4,6-dimethylisoindoline-1,3-dione (38). Using the general procedure, 3,5-
dimethylbenzoic acid (75 mg, 0.5 mmol) and dodecyl isocyanate (0.181 mL, 159 mg, 0.75 mmol)
provide imide 38 is isolated as a light brown oil (65 mg, 0.19 mmol, 38%), Rf = 0.5 (95:5
hexanes/ethyl acetate). 1H NMR (500 MHz, CDCl3): δ 7.47 (s, 1H), 7.25 (s, 1H), 3.64 (t, J = 7.3 Hz,
2H), 2.65 (s, 3H), 2.45 (s, 3H), 1.66 (p, J = 7.1 Hz, 2H), 1.38 – 1.21 (m, 18H), 0.89 (t, J = 7.1 Hz,
3H). 13C{1H} NMR (125 MHz, CDCl3): δ 169.3, 168.7, 144.4, 137.5, 136.6, 133.0, 126.4, 121.4,
37.8, 31.9, 29.62, 29.61, 29.56, 29.49, 29.33, 29.21, 28.63, 26.9, 22.7, 21.7, 17.4, 14.1. HRMS
(ESI): Calcd. for C22H33NO2Na ([M + Na]+) m/z 366.2409, found m/z 366.2402.
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2-Cyclohexyl-4-hydroxy-1H-benzo[f]isoindole-1,3(2H)-dione (39). Using the general procedure,
1-methoxy-2-naphthoic acid (101 mg, 0.5 mmol) and ethyl isocyanate (0.096 mL, 93.9 mg, 0.75
mmol) provide imide 39 as a white solid (50 mg, 0.17 mmol, 34%), Rf = 0.61 (80:20
hexanes/ethyl acetate), mp 154 – 156 C. 1H NMR (500 MHz, CDCl3): δ 8.44 (d, J = 8.0 Hz, 1H),
7.97 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.75 – 7.70 (m, 2H), 7.70 – 7.65 (m, 1H), 4.91 (tt,
J = 12.3, 3.7 Hz, 1H), 2.47 (qd, J = 12.6, 3.5 Hz, 2H), 1.96 – 1.88 (m, 2H), 1.82 – 1.70 (m, 3H), 1.46
(qt, J = 13.1, 3.3 Hz, 2H), 1.32(qt, J = 12.9, 3.7 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ 161.5,
150.7, 147.5, 137.0, 130.1, 128.0, 127.5, 125.0, 122.6, 122.0, 121.8, 109.8, 5.2, 28.5, 26.2, 25.1.
HRMS (ESI): Calcd. for C18H17NO3Na ([M + Na]+) m/z 318.1106, found m/z 318.1102.
3,5-Dimethyl-N-(3-(trifluoromethyl)phenyl)benzamide (40). Using the general procedure, 3,5-
dimethylbenzoic acid (75 mg, 0.5 mmol) and 3-(trifluoromethyl)phenyl isocyanate (0.103 mL,
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140 mg, 0.75 mmol) provide a mixture of imide 30 and amide 40. Following chromatographic
separation, amide 40 is isolated as a white solid (18 mg, 0.06 mmol, 12%), Rf = 0.75 (75:25
hexanes/ethyl acetate), mp 134 - 136C. 1H NMR (500 MHz, CDCl3): δ 7.96 – 7.91 (m, 3H), 7.54 –
7.47 (m, 3H), 7.45 – 7.40 (m, 1H), 7.23 (s, 1H). 2.41 (s, 6H). 3C NMR (125 MHz, CDCl3): δ 166.2,
138.7, 138.6, 134.4, 133.8, 131.5 (q, J = 32.3 Hz), 129.6, 124.8, 123.8 (q, J = 273.8 Hz), 120.9 (q, J
= 3.5 Hz), 116.7 (q, J = 3.8 Hz). HRMS (ESI): Calcd. for C16H15F3 NO ([M + H]+) m/z 294.1105,
found m/z 294.1101.
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Isoquinoline-1,3(2H,4H)-dione (43).18 Using a modified general procedure (triflic acid is added
and allowed to react for 5 minutes before quenching), phenylacetic acid (68.1 mg, 0.5 mmol)
and (trimethylsilyl)isocyanate (0.102 mL, 86.4 mg, 0.75 mmol) provide compound 43 as a white
solid (40 mg, 0.25 mmol, 50%). 1H NMR (300 MHz, DMSO-d6): δ 11.28 (s, 1H), 8.02 (dd, J = 7.8,
0.9 Hz, 1H), 7.63 (ddd, J = 7.6, 7.5, 1.3 Hz, 1H), 7.49 – 7.44 (m, 1H), 7.39 (d, J = 7.7 Hz, 1H), 4.03
(s, 2H); 13C{1H} NMR (75 MHz, DMSO-d6): δ 171.4, 165.8, 137.1, 133.9, 128.3, 127.9, 127.6,
125.5, 36.4. HRMS (ESI): Calcd. for C9H8NO2 ([M + H]+) m/z 162.0555, found m/z 162.0556.
Associated Content
Supporting Information. 1H and 13C NMR spectra of prepared compound. Available free of
charge on the ACS Publication website at DOI:
Author Information
Corresponding Author
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*E-mail for D.A.K.: dklumpp@niu.edu
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ORCHID
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Douglas A. Klumpp, ORCHID ID: https://orcid.org/0000-0001-5271-699X
Notes
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The authors declare no competing financial interests.
Acknowledgements. Support from the NIGMS-NIH is gratefully acknowledged (grant number
1R15GM126498-01). Gratitude is also expressed on behalf of an author (SHK) for a Dissertation
Completion Fellowship from Northern Illinois University and to the ACS Division of Organic
Chemistry for an invitation (SHK) to present this work at the 2019 Graduate Research
Symposium.
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