Radical on Water Addition to the C=N Bond of Hydrazones: A Synthesis of Isoindolinone Derivatives

Article abstract of DOI:10.1021/acs.joc.7b03193

A radical on water addition to the C=N bond of hydrazones has been described. Hydrazone, diphenylsilane, alkyl iodide, and triethylborane afforded the corresponding addition products on water in good yields. A significant solvent effect was observed from the water. The developed protocol can be applied to the synthesis of 3-substituted isoindolinone derivatives. Moreover, the process offers environmentally benign tin-free radical reaction conditions.

Full text of DOI:10.1021/acs.joc.7b03193

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Article
Radical “on water” addition to C=N bond of
hydrazones: a synthesis of isoindolinone derivatives
Tae Kyu Nam, and Doo Ok Jang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03193 • Publication Date (Web): 02 Mar 2018
Downloaded from http://pubs.acs.org on March 2, 2018
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Radical “on water” addition to C=N bond of hydrazones: a synthesis
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of isoindolinone derivatives
Tae Kyu Nam and Doo Ok Jang*
Department of Chemistry, Yonsei University, Wonju 26493, Republic of Korea
Supporting Information Placeholder
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ABSTRACT: A radical “on water” addition to the C=N bond of hydrazones has been described.
Hydrazone, diphenylsilane, alkyl iodide, and triethylborane afforded the corresponding addition
products “on water” in good yields. A significant solvent effect was observed from water. The developed
protocol can be applied to the synthesis of 3ꢀsubstituted isoindolinone derivatives. Moreover, the
process offers environmentally benign tinꢀfree radical reaction conditions.
INTRODUCTION
Water is an ideal solvent from economic and environmental points of view because it is cheap, readily
available, nonꢀflammable, and nonꢀtoxic. Since the successful use of water as a solvent in organic
synthesis by Breslow,1 several reactions using water as the reaction medium have been reported. As a
solvent in organic synthesis, water has drawn significant attention owing to the “on water” concept
reported by Sharpless,2 which refers to reactions where insoluble reactants react in an aqueous
suspension with accelerated reaction rate and improved selectivity compared to reactions in organic
solvents. Several reactions using onꢀwater conditions have been reported.3
Solvent effects are in radical reactions.4 Thus, water has been generally employed as a reaction
medium in radical reactions without any expectations of solvent effects.5 Research on employing water
in radical reactions has been focused on increasing the solubility of the components. Towards that end,
reactions employing water and organic solvents6 and/or high reaction temperatures with vigorous
stirring7 have been developed. Waterꢀsoluble initiators8 and chain carriers9 have been developed to use
water the reaction medium in radical reactions.
Oshima and coworkers10 reported that halide atom transfer radical reactions with insoluble
substrates took place “on water” at room temperature with a significantly higher reaction rate than
reactions in organic solvents. Most recently, Lipshutz and coworkers11 reported the copperꢀcatalyzed
trimethylation of acrylamides “on water”.
Herein, we wish to report an “on water” radical addition reaction to C=N bonds at room
temperature, wherein a significant solvent effect was observed. Et3B and Ph2SiH2 were used as radical
initiator and radical chain carrier, respectively, as they are stable in water.
RESULTS and DISCUSSION
Benzaldehydeꢀderived phenyl hydrazone 1 was chosen as a model substrate. A heterogeneous
mixture of 1 (0.45 mmol), isopropyl iodide (5 equiv), Ph2SiH2 (1 equiv), and water (15 mL) was treated
with 0.5 equiv of Et3B (1 M solution in THF) at room temperature every 3 h for 24 h. The reaction was
monitored by TLC. The reaction afforded the isopropylꢀadded product 1a in 83% yield (Table 1, entry
1). The same reaction was performed in THF, and resulted in a 63% yield of addition product 1a along
with recovered starting material 1 (20%) and a small quantity of ethyl addition product (10%) (entry 2).
Similarly, reactions performed in organic solvents such as MeOH, acetone, and THF/(CH2Cl)2 (1/1, v/v)
gave low yields of addition product 1a (entries 3ꢀ5). This indicated that the reaction proceeded more
efficiently “on water” than in organic solvents. The reactions that were carried out in water and THF
were less effective than in water only (entries 6 and 7). The reaction performed at 75 °C was not
efficient, giving a 35% yield of isopropyl added product 1a with an increased amount of the Etꢀaddition
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product (entry 8). Sonication was not suitable for promoting the reaction, as it gave product 1a in 53%
yield (entry 9). The reaction without Ph2SiH2 gave a 32% yield of the isopropylꢀadded product with a
considerable amount of the Etꢀaddition adduct (entry 10). The reaction was carried out “on D2O” in
order to determine the hydrogen source. No Dꢀincorporated product was obtained (entry 11), indicating
that H2O and D2O do not act as hydrogen sources in the reaction.12 The reaction was also performed in
the presence of Ph2SiD2, affording 1a in 73% yield with ~20% Dꢀincorporation (entry 12). The reaction
mixture of 1, Ph2SiH2, isopropyl iodide, and Et3B in H2O was analyzed by GCꢀMS, and the observed
intermediate was converted into 1a after silica gel treatment. These observations indicate that the final
step of the reaction is not a radical process, and that Ph2SiH2 is not a major hydrogen source for the
reaction, although it contributes to increase the yield of the desired product. When the reaction was
carried out with neat Et3B, addition products were obtained in 85% yield with an increase in the amount
of the Etꢀaddition adduct due to the high concentration of Et3B (entry 13), proving that a diluted Et3B
solution is required to obtain a high yield of the desired product. The highest yield was attained with a 1
M solution of Et3B in hexanes (92%) (entry 14). The reaction that was carried out in a large volume of
water (50 mL) gave a 94% yield (compared with entry 1), indicating that lower reactant concentrations
increased the yield of the desired product. The reaction was performed in a suspension. After
completion of the reaction, the suspension state was maintained because of the insolubility of the
product. These observations reveal that as a reaction medium, water plays a significant role in
accelerating the reaction rate and selectivity. The solvent effect might be attributed to reduction of
reactant volumes by hydrophobic effects and/or hydrogen bonding between the substrate and free –OH
of interfacial water molecules.13
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Table 1. Screening reaction conditions.a
entry solvent
yield (%)b
83
1
H2O
2
THF
63 (10)
35 (46)
41 (14)
3
MeOH
Acetone
4
5
THF/(CH2Cl)2 (1/1, v/v) 46 (12)
6
THF/H2O (7/3, v/v)
35 (15)
48 (13)
34 (52)c
53 (32)d
32 (45)e
80f
7
THF/H2O (1/1, v/v)
8
H2O
H2O
H2O
D2O
H2O
H2O
H2O
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14
73g
45 (40)h
92i
a0.45 mmol of the substrate was used. Et3B (0.5 equiv, 1 M solution in THF) was added every 3 h
b
until the reaction was complete. Isolated yield. The yield of the Etꢀadduct is given in parenthesis.
d
e
f
cConducted at 75 °C. With sonication. Without Ph2SiH2. Dꢀincorporated product was not observed.
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gWith Ph2SiD2 17% Dꢀincorporated product was observed. hNeat Et3B was used. Et3B (1 M solution in
hexanes) was used.
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The scope and limitations of the reaction were investigated using various alkyl iodides. The
results are presented in Table 2. With secondary alkyl halides, the reactions proceeded smoothly to give
the addition product in high yields (Table 2, entries 1ꢀ2). The reaction with 1ꢀadamantyl iodide, which
cannot be hydrolyzed, gave a high yield of the product (entry 3). However, the reaction with tertꢀbutyl
iodide gave a poor yield of the addition product because this substrate readily hydrolyzed under the
reaction conditions (entry 4). The reaction with primary radical, nꢀoctyl radical, afforded a low yield of
the addition product (entry 5). This was attributed to the competition between the primary nꢀoctyl and
ethyl radicals for the addition to the C=N bond. This problem was resolved by employing
trialkylboranes that have the same alkyl group as the alkyl halide. Thus, when nꢀbutyl iodide was used
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as radical source, tributylborane was employed as radical initiator, affording a high yield of the Buꢀ
added product (entry 6). Similarly, the Etꢀadded product was obtained in a high yield (entry 7).
Table 2. Various alkyl radical additions to C=N bond “on water”.a
Et3B
(equiv)
entry R
time (h) yield (%)b
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2
3
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5
6
7
cꢀHexyl, 1b
cꢀDodecyl, 1c
3
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18
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48
42
36
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79
68
1ꢀAdamantyl, 1d 8
84
tꢀButyl, 1e
nꢀOctyl, 1f
nꢀButyl, 1g
Ethyl, 1h
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34 (53)
55 (34)
92c
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92
a0.45 mmol of the substrate was used. Et3B (0.5 equiv, 1 M solution in hexanes) was added every 3 h
until the reaction was complete. bIsolated yield. The yield of the Etꢀadduct is given in parenthesis. cBu3B
(1 M solution in THF) was used.
Next, we investigated the substrate generality of the reaction (Table 3). Various hydrazone derivatives
were used as substrates in the presence of isopropyl iodide under the optimized “on water” conditions.
Aromatic aldehydeꢀderived hydrazone derivatives with electronꢀwithdrawing groups underwent the
reaction smoothly to produce the corresponding addition product in higher yields (Table 3, entries 1ꢀ7)
than hydrazones with electroꢀdonating groups (entries 8ꢀ10). A heteroaromatic aldehydeꢀderived
hydrazone afforded the addition product in moderate yield (entry 11). An aliphatic aldehydeꢀderived
hydrazone reacted with lower efficiency than aromatic aldehydeꢀderived hydrazones (entry 12). A
hydrazone with a long aliphatic chain gave a poor yield (entry 13), due to the hindrance caused by the
folding of the long chain.
Table 3. Isopropyl radical addition to various hydrazones “on water”.a
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Et3B
(equiv)
entry R
time (h) yield (%)b
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4ꢀFꢀC6H4, 2a
4
24
30
15
36
36
24
12
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48
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92
90
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81
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41
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3ꢀFꢀC6H4, 3a
4ꢀClꢀC6H4, 4a
3ꢀClꢀC6H4, 5a
2ꢀClꢀC6H4, 6a
2ꢀBrꢀC6H4, 7a
4ꢀCF3ꢀC6H4, 8a
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4ꢀMeOꢀC6H4, 9a 2
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4ꢀEtꢀC6H4, 10a
2ꢀMeꢀC6H4, 11a
2ꢀFuryl, 12a
Me, 13a
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nꢀHeptyl, 14a
aEt3B (0.5 equiv, 1 M solution in hexanes) was added every 3 h until the reaction was complete.
bIsolated yield.
A plausible mechanism for the alkyl radical addition to the C=N bond of hydrazone is depicted in
Scheme 1. The interaction of Et3B with oxygen generates an ethyl radical, which reacts with the alkyl
halide to give the alkyl radical. The resulting alkyl radical adds to the C=N bond of hydrazone, resulting
in the formation of radical intermediate I. This intermediate can abstract a hydrogen from Ph2SiH2
through a minor pathway (path a) to form the addition product and diphenylsilyl radical, which sustains
the radical chain. Alternatively, intermediate I reacts with Et3B, via the dominant pathway, to form
intermediate II, which undergoes hydrolysis on silica gel, finally affording the addition product (path b).
Scheme 1. Proposed mechanism for alkyl radical addition to C=N bond.
Many biologically important heterocyclic compounds contain an isoindolinone moiety.14 The 3ꢀ
substituted isoindolinone skeleton has drawn considerable attention due to its wide range of therapeutic
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activities.15 As such, the present process was applied to the synthesis of 3ꢀsubstituted isoindolinone
derivatives. The addition of isopropyl radical to substrate 15 was carried out under the optimized
reaction conditions, resulting in 75% yield of 3ꢀisopropyl substituted isoindolinone 15a (Table 4, entry
1). Interestingly, the reaction without Ph2SiH2 also proceeded smoothly, affording an even higher yield
of the isoindolinone derivative (entry 2). Upon increasing the amount of Ph2SiH2, the yield of the
product decreased (entry 3). These results indicate that the hydrogen radical source is not required for
the reaction. The reaction might proceed via intermediate II in Scheme 1, which is more reactive in the
intramolecular cyclization than intermediate I. The reaction with a large excess of Ph2SiH2 gave a lower
yield of the product, supporting that the intermediate of the reaction is II.
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Table 4. Effect of amount of Ph2SiH2 on the addition reaction.a
entry Ph2SiH2 (equiv) yield (%)b
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2
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1
0
4
75
91
46
a0.45 mmol of the substrate was used. Et3B (0.5 equiv, 1 M solution in hexanes) was added every 3 h
until the reaction was complete. bIsolated yield.
Next, the scope of the reaction was investigated with various alkyl iodides as radical precursors
(Table 5). Reactions with secondary alkyl iodides gave the corresponding 3ꢀsubstituted isoindolinones
in high yields (Table 5, entries 1ꢀ2). The reaction with 1ꢀadamantyl iodide exhibited high efficiency,
whereas tꢀbutyl iodide afforded the Etꢀadded product as the major product, due to the hydrolysis of tꢀ
butyl iodide (entries 3 and 4). Moderateꢀtoꢀlow yields were observed in the reaction with primary alkyl
iodides due to the competitive addition of the ethyl radical generated from triethylborane (entries 5 and
6). When primary alkyl halides with the same alkyl group as the trialkylborane were employed, there
was no complication in the reaction, and products were obtained in excellent yields (entries 7 and 8).
Table 5. “On water” synthesis of 3-alkyl isoindolinone with various alkyl groups.a
Et3B
(equiv)
entry R
time (h) yield (%)b
1
2
3
cꢀHexyl, 15b
cꢀDodecyl, 15c
4
4
24
24
24
84
89
90
1ꢀAdamantyl, 15d 4
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5
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8
tꢀButyl, 15e
nꢀOctyl, 15f
iꢀButyl, 15g
nꢀButyl, 15h
Ethyl, 15i
5
4
4
4
4
30
15 (74)
55 (32)
27 (60)
95c
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8
24
24
24
24
94
a0.45 mmol of the substrate was used. Et3B (0.5 equiv, 1 M solution in hexanes) was added every 3 h
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until the reaction was complete. bIsolated yield. The yield of the Etꢀadduct is given in parenthesis. cBu3B
(1 M solution in THF) was used.
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The results of the addition of isopropyl group to various hydrazone derivatives are summarized in
Table 6. Substrates with both electronꢀwithdrawing and electronꢀdonating groups underwent the
addition reaction “on water” to afford high yields of the corresponding 3ꢀisopropyl isoindolinone
derivatives.
Table 6. Synthesis of 3-isopropyl isoindolinone derivatives using on-water conditions.a
Et3B
time yield
entry R1, R2
(equiv) (h) (%)b
R1= H, R2 = Cl,
16a
1
2
3
5
6
6
30
36
36
78
83
83
R1= H, R2 =
OEt, 17a
R1, R2 = OMe,
18a
a0.45 mmol of the substrate was used. Et3B (0.5 equiv, 1 M solution in hexanes) was added every 3 h
until the reaction was complete. bIsolated yield. The yield of the Etꢀadduct is given in parenthesis.
In conclusion, we have developed an “on water” radical addition reaction to the C=N bond of
hydrazones. The reaction was faster “on water” than in organic solvents. The radical addition/reduction
reaction shows a significant solvent effect of water. The established process is a tinꢀfree radical reaction
using nonꢀtoxic diphenyl silane as the radical chain carrier and hydrogen source. The process could be
applied to the synthesis of 3ꢀsubstituted isoindolinone derivatives with high efficiencies. The advantages
of the present process include high yields, the use of a green solvent, tinꢀfree conditions, and an easy
workꢀup.
EXPERIMENTAL SECTION
General information.
Unless otherwise specified, chemicals were purchased from SigmaꢀAldrich Co. and used without further
purification. Column chromatography was performed on silica gel (230–400 mesh, Merck). TLC was
performed on glass sheets preꢀcoated with silica gel (Kieselgel 60 PF254, Merck). Hꢀ and CꢀNMR
1
13
1
spectra were recorded on a Bruker 400 NMR spectrometer, which operated at 400 MHz for H and 100
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MHz for 13C nuclei and are internally referenced to residual proton solvent signals. Chemical shifts are
reported in parts per million (ppm). IR spectra were recorded on a Perkin–Elmer 16 PC FTIR
spectrometer. Microanalyses were performed on a CE instrument EA1110 elemental analyzer. Highꢀ
resolution mass spectra (HRMS) were recorded on ThermoFisher Scientific LTQ Orbitrap XL (ESI).
Typical experimental procedure.
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A heterogeneous mixture of hydrazone (0.45 mmol), alkyl iodide (2.23 mmol), Ph2SiH2 (82.8 ꢁL, 0.45
mmol), and water (15 mL) was purged with argon for 10 min. Et3B (220 ꢁL, 0.22 mmol, 1 M solution in
hexanes) was added every 3 h to the suspension via syringe with the needle directly above the
suspension until the reaction was complete. When the reaction was complete, the reaction mixture was
extracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4. After filtration, the residue
was purified by flash column chromatography on silica gel.
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N'-(2-Methyl-1-phenylpropyl)benzohydrazide (1a): Purified by column chromatography on silica gel
(hexanes/EtOAc, 9:1). White solid; 92% yield (110 mg); mp 97ꢀ99 °C;; IR (KBr) ν 3235, 1633, 1604,
1463 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.72 (d, J = 6.8 Hz, 3H), 1.03 (d, J = 6.7 Hz, 3H), 1.91ꢀ2.01
(m, 1H), 3.79 (d, J = 7.3 Hz, 1H), 4.55 (brs, 1H), 7.17ꢀ7.23 (m, 1H), 7.23ꢀ7.32 (m, 6H), 7.33ꢀ7.41 (m,
13
1H), 7.44ꢀ7.49 (m, 2H); C NMR (100 MHz, CDCl3) δ 19.2, 19.8, 32.6, 71.5, 127.0, 127.7, 128.5,
–
128.7, 128.8, 131.9, 133.0, 140.5, 167.2; HRMS (ESIꢀMS) calc. (m/z) for C17H19N2O (M–H) :
267.1497, found: 267.1502.
N'-(Cyclohexyl(phenyl)methyl)benzohydrazide (1b): Purified by column chromatography on silica
gel (hexanes/EtOAc, 9:1). White solid; 79% yield (108 mg); mp 146ꢀ148 °C; IR (KBr) ν 3234, 1625,
1
1602, 1459 cm–1; H NMR (400 MHz, CDCl3) δ 0.81ꢀ0.93 (m, 1H), 1.02ꢀ1.18 (m, 3H), 1.18ꢀ1.33 (m,
1H), 1.39ꢀ1.49 (m, 1H), 1.56ꢀ1.67 (m, 2H), 1.67ꢀ1.82 (m, 2H), 1.98ꢀ2.07 (m, 1H), 3.84 (dd, J = 7.5, 2.5
Hz, 1H), 5.27 (brs, 1H), 7.22ꢀ7.29 (m, 1H), 7.29ꢀ7.35 (m, 6H), 7.40ꢀ7.45 (m, 1H), 7.50ꢀ7.54 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 26.1 (2), 26.4, 29.3, 30.1, 42.2, 70.6, 126.9, 127.5, 128.3, 128.6, 131.7,
132.8, 140.7, 166.9; HRMS (ESIꢀMS) calc. (m/z) for C20H25N2O (M+H)+: 309.1967, found: 309.1958.
N'-(Cyclododecyl(phenyl)methyl)benzohydrazide (1c): Purified by column chromatography on silica
gel (hexanes/EtOAc, 9:1). Colorless oil; 68% yield (119 mg); IR (KBr) ν 3285, 2931, 1638, 1578 cmꢀ1;
1H NMR (400 MHz, CDCl3) δ 1.07ꢀ1.52 (m, 23H), 4.13 (d, J = 8.3 Hz, 1H), 7.28ꢀ7.35 (m, 4H), 7.35ꢀ
7.41 (m, 3H), 7.41ꢀ7.49 (m, 2H), 7.50ꢀ7.57 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 21.5, 22.0, 23.2 (2),
23.5, 23.6, 24.8, 25.3 (2), 26.3, 39.7, 68.0, 126.9, 127.6, 128.5, 128.8 (2), 131.9, 133.2, 141.7, 167.1;
HRMS (ESIꢀMS) calc. (m/z) for C26H35N2O (M–H)–: 391.2749, found: 391.2755.
N'-(1-Adamantyl(phenyl)methyl)benzohydrazide (1d): Purified by column chromatography on silica
gel (hexanes/EtOAc, 9:1). White solid; 84% yield (135 mg); mp 180ꢀ183 °C; IR (KBr) ν 3252, 1625,
1
1469, 1643 cm–1; H NMR (400 MHz, CDCl3) δ 1.57ꢀ1.85 (m, 12H), 2.00 (s, 3H), 3.74 (s, 1H), 7.29ꢀ
13
7.41 (m, 6H), 7.42ꢀ7.58 (m, 4H); C NMR (100 MHz, CDCl3) δ 28.6, 36.4, 37.2, 39.2, 75.3, 126.9,
127.5, 128.0, 128.8, 129.7, 131.8, 133.1, 138.9, 167.0; HRMS (ESIꢀMS) calc. (m/z) for C24H29N2O
(M+H)+: 361.2280, found: 361.2263.
N'-(2,2-Dimethyl-1-phenylpropyl)benzohydrazide (1e): Purified by column chromatography on silica
gel (hexanes/EtOAc, 9:1). White solid; 34% yield (43 mg); mp 112ꢀ114 °C; IR (KBr) ν 3218, 1622,
1576, 1451 cm–1; 1H NMR (400 MHz, CDCl3) δ 1.01 (s, 9H), 3.89 (s, 1H), 7.25ꢀ7.34 (m, 6H), 7.34ꢀ7.42
(m, 3H), 7.44ꢀ7.50 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 27.1, 34.6, 74.4, 127.0, 127.6, 128.1, 128.8,
129.5, 131.9, 133.0, 139.6, 167.1; HRMS (ESIꢀMS) calc. (m/z) for C18H21N2O (M–H)–: 281.1654,
found: 281.1657.
N'-(1-Phenylnonyl)benzohydrazide (1f): Purified by column chromatography on silica gel
1
(hexanes/EtOAc, 9:1). Yellow oil; 55% yield (83 mg); IR (KBr) ν 3282, 1635, 1603, 1455 cm–1; H
NMR (400 MHz, CDCl3) δ 0.89 (t, J = 6.9 Hz, 3H), 1.15ꢀ1.40 (m, 12H), 1.65ꢀ1.78 (m, 1H), 1.80ꢀ1.92
(m, 1H), 4.08 (dd, J = 8.3, 5.8 Hz, 1H), 7.27ꢀ7.35 (m, 1H), 7.35ꢀ7.45 (m, 6H), 7.46ꢀ7.53 (m, 1H), 7.60ꢀ
7.65 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 14.3, 22.8, 26.2, 29.4, 29.6, 29.8, 32.0, 35.4, 65.6, 127.4,
127.8, 128.1, 128.7, 128.8, 131.9, 133.1, 142.1, 167.3; HRMS (ESIꢀMS) calc. (m/z) for C22H31N2O
(M+H)+: 339.2436, found: 339.2425.
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N'-(1-Phenylpentyl)benzohydrazide (1g): Purified by column chromatography on silica gel
(hexanes/EtOAc, 7:3). Colorless oil; 92% yield (116 mg); IR (KBr) ν 3282, 1637, 1534, 1459 cm–1; 1H
NMR (400 MHz, CDCl3) δ 0.83 (t, J = 7.0 Hz, 3H), 1.12ꢀ1.22 (m, 1H), 1.22ꢀ1.36 (m, 3H), 1.60ꢀ1.72 (m,
1H), 1.76ꢀ1.86 (m, 1H), 4.03 (dd, J = 8.2, 5.90 Hz, 1H), 5.17 (s, 1H), 7.25ꢀ7.31 (m, 1H), 7.30ꢀ7.40 (m,
1
2
3
4
13
6H), 7.41ꢀ7.48 (m, 2H), 7.54ꢀ7.59 (m, 2H); C NMR (100 MHz, CDCl3) δ 13.9, 22.7, 28.1, 34.8, 65.5,
5
6
7
8
9
126.9, 127.7, 127.9, 128.6, 128.6, 131.8, 132.7, 141.6, 167.2; HRMS (ESIꢀMS) calc. (m/z) for
C18H21N2O (M–H)–: 281.1654, found: 281.1658.
N'-(1-Phenylpropyl)benzohydrazide (1h):16 Purified by column chromatography on silica gel
(hexanes/EtOAc, 7:3). White solid; 92% yield (104 mg); mp 90ꢀ92 °C; IR (KBr) ν 3271, 1640, 1601,
10
11
12
13
14
15
16
17
18
19
20
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22
23
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1
1476 cm–1; H NMR (400 MHz, CDCl3) δ 0.84 (t, J = 7.6 Hz, 3H), 1.64ꢀ1.80 (m, 1H), 1.80ꢀ1.95 (m,
1H), 3.99 (dd, J = 8.4, 5.6 Hz, 1H), 7.25ꢀ7.31 (m, 1H), 7.31ꢀ7.42 (m, 6H), 7.42ꢀ7.51 (m, 2H), 7.56ꢀ7.67
13
(m, 2H); C NMR (100 MHz, CDCl3) δ 10.6, 28.2, 67.0, 127.0, 127.8, 128.7, 128.8, 132.0, 133.0,
141.6, 167.4; HRMS (ESIꢀMS) calc. (m/z) for C16H19N2O (M+H)+: 255.1497, found: 255.1490.
N'-(1-(4-Fluorophenyl)-2-methylpropyl)benzohydrazide (2a): Purified by column chromatography
on silica gel (hexanes/EtOAc, 9:1). White solid; 92% yield (117 mg); mp 116ꢀ118 °C; IR (KBr) ν 3228,
1638, 1604, 1463 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.79 (d, J = 6.8 Hz, 3H), 1.09 (d, J = 6.7 Hz, 3H),
1.92ꢀ2.09 (m, 1H), 3.84 (d, J = 7.2 Hz, 1H), 3.93 (brs, 1H), 7.14ꢀ7.22 (m, 1H), 7.22ꢀ7.29 (m, 2H), 7.29ꢀ
13
7.40 (m, 3H), 7.40ꢀ7.49 (m, 2H), 7.49ꢀ7.65 (m, 2H); C NMR (100 MHz, CDCl3) δ 19.1, 19.8, 32.8,
2
3
4
70.6, 115.3 (d, JCꢀ1F = 21.2 Hz), 126.9, 128.9, 130.1, (d, JCꢀF = 7.9 Hz), 132.0, 133.1, 136.7 (d, JCꢀF
=
3.0 Hz), 162.4 (d, JCꢀF = 245.3 Hz), 167.3; Elem. Anal. Calcd for C17H19FN2O: C, 71.31; H, 6.69; N,
9.78. Found: C, 71.28; H, 6.73; N, 9.74.
N'-(1-(3-Fluorophenyl)-2-methylpropyl)benzohydrazide (3a): Purified by column chromatography
on silica gel (hexanes/EtOAc, 9:1). White solid; 90% yield (115 mg); mp 117ꢀ119 °C; IR (KBr) ν 3252,
1
1626, 1591, 1449 cm–1; H NMR (400 MHz, CDCl3) δ 0.81 (d, J = 6.8 Hz, 3H), 1.09 (d, J = 6.7 Hz,
3H), 1.96ꢀ2.07 (m, 1H), 3.87 (d, J = 7.0 Hz, 1H), 4.80 (brs, 1H), 6.93ꢀ7.02 (m, 1H), 7.07ꢀ7.15 (m, 2H),
13
7.25ꢀ7.32 (m, 1H), 7.33ꢀ7.40 (m, 2H), 7.44ꢀ7.50 (m, 1H), 7.56ꢀ7.62 (m, 2H), 7.64 (brs, 1H); C NMR
2
2
(100 MHz, CDCl3) δ 19.0, 19.7, 32.7, 70.7, 114.4 (d, JCꢀF = 21.2 Hz), 115.2 (d, JCꢀF = 21.4 Hz), 124.5
4
3
3
(d, JCꢀF = 2.7 Hz), 127.0, 128.7, 129.7 (d, JCꢀF = 8.2 Hz), 131.9, 132.9, 143.7 (d, JCꢀF = 6.7 Hz), 163.0
(d, JCꢀF = 245.4 Hz), 167.5; HRMS (ESIꢀMS) calc. (m/z) for C17H20FN2O (M+H)+: 287.1560, found:
1
287.1552.
N'-(1-(4-Chlorophenyl)-2-methylpropyl)benzohydrazide (4a): Purified by column chromatography
on silica gel (hexanes/EtOAc, 9:1). White solid; 90% yield (122 mg); mp 115ꢀ117 °C; IR (KBr) ν 3229,
1
1634, 1603, 1463 cm–1; H NMR (400 MHz, CDCl3) δ 0.77 (d, J = 6.8 Hz, 3H), 1.07 (d, J = 6.8 Hz,
3H), 1.91ꢀ2.03 (m, 1H), 3.83 (d, J = 7.0 Hz, 1H), 5.24ꢀ5.33 (m, 1H), 7.22ꢀ7.32 (m, 4H), 7.35 (t, J = 15.2
13
Hz, 2H), 7.38ꢀ7.49 (m, 2H), 7.79ꢀ7.57 (m, 2H); C NMR (100 MHz, CDCl3) δ 19.0, 19.8, 32.7, 70.8,
127.0, 128.7, 128.9, 130.1, 132.1, 132.8, 133.4, 139.2, 167.4; HRMS (ESIꢀMS) calc. (m/z) for
C17H20ClN2O (M+H)+: 303.1264, found: 303.1257.
N'-(1-(3-Chlorophenyl)-2-methylpropyl)benzohydrazide (5a): Purified by column chromatography
on silica gel (hexanes/EtOAc, 9:1). White solid; 81% yield (123 mg); mp 117ꢀ119 °C; IR (KBr) 3249,
ν
1
1629, 1601, 1463 cm–1; H NMR (400 MHz, CDCl3) δ 0.82 (d, J = 6.8 Hz, 3H), 1.10 (d, J = 6.6 Hz,
3H), 1.91ꢀ2.08 (m, 1H), 3.84 (d, J = 6.4 Hz, 1H), 5.33 (brs, 1H), 7.17ꢀ7.23 (m, 1H), 7.23ꢀ7.30 (m, 2H),
13
7.33ꢀ7.43 (m, 4H), 7.43ꢀ7.51 (m, 1H), 7.53ꢀ7.60 (m, 2H); C NMR (100 MHz, CDCl3) δ 19.1, 19.7,
32.7, 71.0, 127.0, 127.1, 127.9, 128.6, 128.9, 129.7, 132.1, 132.8, 134.4, 143.1, 167.5; HRMS (ESIꢀMS)
calc. (m/z) for C17H20ClN2O (M+H)+: 303.1264, found: 303.1254.
N'-(1-(2-Chlorophenyl)-2-methylpropyl)benzohydrazide (6a): Purified by column chromatography
on silica gel (hexanes/EtOAc, 9:1). White solid; 83% yield (112 mg); mp 118ꢀ119 °C; IR (KBr) ν 3235,
1
1633, 1581, 1459 cm–1; H NMR (400 MHz, CDCl3) δ 0.88 (d, J = 6.9 Hz, 3H), 1.13 (d, J = 6.7 Hz,
3H), 1.92ꢀ2.18 (m, 1H), 4.47 (d, J = 7.4 Hz, 1H), 5.39 (brs, 1H), 7.13ꢀ7.20 (m, 1H), 7.22ꢀ7.38 (m, 4H),
13
7.38ꢀ7.46 (m, 1H), 7.51ꢀ7.63 (m, 4H); C NMR (100 MHz, CDCl3) δ 19.0, 19.5, 32.6, 66.5, 127.0,
128.4, 128.7, 129.1, 129.6, 131.7, 133.1, 134.5, 135.2, 139.2, 167.3; HRMS (ESIꢀMS) calc. (m/z) for
C17H20ClN2O (M+H)+: 303.1264, found: 303.1251.
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N'-(1-(2-Bromophenyl)-2-methylpropyl)benzohydrazide (7a): Purified by column chromatography
on silica gel (hexanes/EtOAc, 9:1). Pale yellow solid; 81% yield (126 mg); mp 97ꢀ100 °C; IR (KBr) ν
3286, 1634, 1603, 1467 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.88 (d, J = 6.9 Hz, 3H), 1.13 (d, J = 6.7
Hz, 3H), 1.96ꢀ2.10 (m, 1H), 4.42 (d, J = 7.4 Hz, 1H), 7.01ꢀ7.12 (m, 1H), 7.28ꢀ7.39 (m, 4H), 7.39ꢀ7.45
1
2
3
4
13
(m, 1H), 7.49ꢀ7.55 (m, 3H), 7.55ꢀ7.60 (m, 1H); C NMR (100 MHz, CDCl3) δ 18.9, 19.7, 32.7, 69.0,
5
6
7
8
9
125.9, 127.0, 127.6, 128.7 (2), 129.3, 131.7, 132.9, 133.1, 140.8, 167.3; HRMS (ESIꢀMS) calc. (m/z)
for C17H20BrN2O (M+H)+: 347.0759, found: 347.0745.
N'-(2-Methyl-1-(4-(trifluoromethyl)phenyl)propyl)benzohydrazide (8a): Purified by column
chromatography on silica gel (hexanes/EtOAc, 9:1). White solid; 83% yield (125 mg); mp 120ꢀ123 °C;
IR (KBr) ν 3244, 1624, 1544, 1463 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.77 (d, J = 6.8 Hz, 3H), 1.06
(d, J = 6.7 Hz, 3H), 1.95ꢀ2.11 (m, 1H), 3.94 (d, J = 7.0 Hz, 1H), 5.27 (brs, 1H), 7.29ꢀ7.36 (m, 2H), 7.41ꢀ
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7.47 (m, 3H), 7.51ꢀ7.59 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 18.9, 19.6, 32.7, 70.8, 124.4 (q, 1JCꢀF
=
272.0 Hz), 125.2 (q, 3JCꢀF = 3.7 Hz), 127.0, 128.8, 129.0, 129.7 (q, 2JCꢀF = 32.2 Hz), 132.0, 132.7, 145.1,
167.6; HRMS (ESIꢀMS) calc. (m/z) for C18H20F3N2O (M+H)+: 337.1528, found: 337.1519.
N'-(1-(4-Methoxyphenyl)-2-methylpropyl)benzohydrazide (9a): Purified by column chromatography
on silica gel (hexanes/EtOAc, 9:1). White solid; 75% yield (100 mg); mp 130ꢀ134 °C; IR (KBr) ν 3235,
1
1633, 1581, 1459 cm–1; H NMR (400 MHz, CDCl3) δ 0.81 (d, J = 6.8 Hz, 3H), 1.12 (d, J = 6.6 Hz,
3H), 1.97ꢀ2.09 (m, 1H), 3.81 (d, J = 7.6 Hz, 1H), 3.83 (s, 3H), 6.90 (d, J = 8.6 Hz, 2H), 7.25ꢀ7.31 (m,
13
2H), 7.34ꢀ7.42 (m, 2H), 7.44ꢀ7.51 (m, 1H), 7.54ꢀ7.60 (m, 2H); C NMR (100 MHz, CDCl3) δ 19.2,
19.9, 32.7, 55.4, 70.9, 113.8, 127.0, 128.8, 129.7, 131.9, 132.7, 133.1, 159.2, 167.1; HRMS (ESIꢀMS)
calc. (m/z) for C18H21N2O2 (M–H)–: 297.1603, found: 297.1607.
N'-(1-(4-Ethylphenyl)-2-methylpropyl)benzohydrazide (10a): Purified by column chromatography
on silica gel (hexanes/EtOAc, 9:1). White solid; 71% yield (94 mg); mp 125ꢀ127 °C; IR (KBr) ν 3284,
1
1637, 1601, 1459 cm–1; H NMR (400 MHz, CDCl3) δ 0.77 (d, J = 6.8 Hz, 3H), 1.08 (d, J = 6.7 Hz,
3H), 1.22 (t, J = 7.6 Hz, 3H), 1.93ꢀ2.07 (m, 1H), 2.63 (q, J = 7.6 Hz, 2H), 3.79 (d, J = 7.3 Hz, 1H), 4.25
(brs, 1H), 7.12ꢀ7.18 (m, 2H), 7.20ꢀ7.26 (m, 2H), 7.30ꢀ7.37 (m, 2H), 7.41ꢀ7.47 (m, 1H), 7.50ꢀ7.56 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 15.7, 19.3, 19.8, 28.7, 32.7, 71.2, 127.0, 127.9, 128.6, 128.8, 131.9,
133.1, 137.8, 143.6, 167.1; HRMS (ESIꢀMS) calc. (m/z) for C19H25N2O (M+H)+: 297.1967, found:
297.1960.
N'-(2-Methyl-1-o-tolylpropyl)benzohydrazide (11a): Purified by column chromatography on silica
gel (hexanes/EtOAc, 9:1). White solid; 62% yield (78 mg); mp 123ꢀ126 °C; IR (KBr) ν 3285, 2962,
1638, 1532, 1464 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.80 (d, J = 6.9 Hz, 3H), 1.6 (d, J = 6.6 Hz, 3H),
1.95ꢀ2.06 (m, 1H), 2.25 (s, 3H), 4.18 (d, J = 7.9 Hz, 1H), 4.90 (brs, 1H), 7.08ꢀ7.17 (m, 2H), 7.18ꢀ7.24
(m, 1H), 7.29ꢀ7.36 (m, 2H), 7.40ꢀ7.46 (m, 1H), 7.46ꢀ7.55 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 19.5,
19.7, 20.0, 33.2, 66.0, 126.3, 126.9, 127.0, 127.3, 128.7, 130.5, 131.8, 133.1, 137.4, 139.7, 167.3;
HRMS (ESIꢀMS) calc. (m/z) for C18H23N2O (M+H)+: 283.1810, found: 283.1808.
N'-(1-(Furan-2-yl)-2-methylpropyl)benzohydrazide (12a): Purified by column chromatography on
silica gel (hexanes/EtOAc, 9:1). Yellow oil; 70% yield (81 mg); IR (KBr) ν 3302, 2873, 1646, 1544 cm–
1; 1H NMR (400 MHz, CDCl3) δ 0.85 (d, J = 6.8 Hz, 3H), 1.07 (d, J = 6.7 Hz, 3H), 2.07ꢀ2.17 (m, 1H),
3.91 (dd, J = 7.2, 2.8 Hz, 1H), 5.16ꢀ5.23 (m, 1H), 6.20ꢀ6.23 (m,1H), 6.31 (dd, J = 3.0, 1.8 Hz, 1H),
13
7.35ꢀ7.41 (m, 3H), 7.44ꢀ7.52 (m, 2H), 7.61 (d, J = 7.4 Hz, 2H); C NMR (100 MHz, CDCl3) δ 19.1,
19.8, 30.9, 65.1, 109.2, 110.3, 127.1, 128.9, 132.2, 132.6, 142.4, 153.3, 167.2; HRMS (ESIꢀMS) calc.
(m/z) for C15H19N2O2 (M+H)+: 259.1447, found: 259.1430.
N'-(3-Methylbutan-2-yl)benzohydrazide (13a):16 Purified by column chromatography on silica gel
(hexanes/EtOAc, 9:1). White solid; 76% yield (70 mg); mp 80ꢀ83 °C; IR (KBr) ν 3282, 1634, 1539,
1463 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.92 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.9 Hz, 3H), 1.01 (d, J =
6.5 Hz, 3H), 1.72ꢀ1.89 (m, 1H), 2.90ꢀ2.98 (m, 1H), 5.77 (brs, 1H), 7.37ꢀ7.45 (m, 2H), 7.45ꢀ7.57 (m,
1H), 7.72ꢀ7.82 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 14.3, 17.2, 19.5, 31.0, 61.1, 127.1, 128.8, 132.0,
133.1, 167.5; HRMS (ESIꢀMS) calc. (m/z) for C12H19N2O (M+H)+: 207.1497, found: 207.1490.
N'-(2-Methyldecan-3-yl)benzohydrazide (14a): Purified by column chromatography on silica gel
1
(hexanes/EtOAc, 9:1). Yellow oil; 41% yield (52 mg); IR (KBr) ν 3284, 1637, 1601, 1459 cm–1; H
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NMR (400 MHz, CDCl3) δ 0.85 (t, J = 6.8 Hz, 3H), 0.92 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 6.9 Hz, 3H),
1
2
3
4
5
6
7
8
1.17ꢀ1.35 (m, 8H), 1.35ꢀ1.52 (m, 3H), 1.79ꢀ1.92 (m, 1H), 2.70ꢀ2.75 (m, 1H), 4.90 (brs, 1H), 7.38ꢀ7.44
13
(m, 2H), 7.46ꢀ7.52 (m, 1H), 7.57 (brs, 1H), 7.69ꢀ7.75 (m, 2H); C NMR (100 MHz, CDCl3) δ 14.3,
17.9, 18.7, 22.9, 26.8, 29.0, 29.5 (2), 30.2, 32.1, 65.9, 127.0, 128.9, 131.9, 133.3, 167.3; Elem. Anal.
Calcd for C18H30N2O: C, 74.44; H, 10.41; N, 9.65. Found: C, 74.40; H, 10.44; N, 9.61.
N-(1-Isopropyl-3-oxoisoindolin-2-yl)benzamide (15a):6b Purified by column chromatography on silica
gel (hexanes/EtOAc, 8:2). White solid; yield 91% (119 mg); mp 217ꢀ218 °C; IR (KBr) ν 3222, 2961,
1
1722, 1659, 1296 cm–1; H NMR (400 MHz, CDCl3) δ 0.71 (d, J = 6.9 Hz, 3H), 1.06 (d, J = 7.1 Hz,
9
3H), 2.44ꢀ2.54 (m, 1H), 4.99 (d, J= 2.6 Hz, 1H), 7.21ꢀ7.27 (m, 2H), 7.34ꢀ7.40 (m, 1H), 7.42ꢀ7.48 (m,
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2H), 7.53ꢀ7.59 (m, 1H), 7.81ꢀ7.87 (m, 3H), 10.87 (s, 1H); C NMR (100 MHz, CDCl3) δ 16.7, 18.1,
29.6, 66.6, 123.3, 124.2, 127.7, 128.3, 128.6, 130.7, 131.1, 132.2, 132.4, 143.8, 166.4, 168.8; HRMS
(ESIꢀMS) calc. (m/z) for C18H19N2O2 (M+H)+: 295.1447, found: 295.1437.
N-(1-Cyclohexyl-3-oxoisoindolin-2-yl)benzamide (15b):6b Purified by column chromatography on
silica gel (hexanes/EtOAc, 8:2). White solid; 84% yield (125 mg); mp 171ꢀ173 °C; IR (KBr) ν 3205,
1
2931, 1710, 1673, 1529, 1296 cm–1; H NMR (400 MHz, CDCl3) δ 0.64ꢀ0.79 (m, 1H), 1.04ꢀ1.18 (m,
1H), 1.18ꢀ1.34 (m, 2H), 1.34ꢀ1.44 (m, 2H), 1.48ꢀ1.61 (m, 2H), 1.61ꢀ1.75 (m, 2H), 2.08 (td, J = 12.1, 2.6
Hz, 1H), 4.90 (d, J = 2.1 Hz, 1H), 7.17ꢀ7.23 (m, 2H), 7.29ꢀ7.35 (m, 1H), 7.40ꢀ7.46 (m, 2H), 7.50ꢀ7.57
(m, 1H), 7.80 (d, J = 7.5 Hz, 1H), 7.84ꢀ7.90 (m, 2H), 11.03 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 8.0,
26.4 (2), 26.7, 27.3, 28.5, 39.8, 66.3, 123.1, 124.0, 127.6, 127.9, 128.4, 130.3, 131.0, 132.0, 132.3,
143.9, 166.2, 168.8; HRMS (ESIꢀMS) calc. (m/z) for C21H23N2O2 (M+H)+: 335.1760, found: 335.1747.
N-(1-Cyclododecyl-3-oxoisoindolin-2-yl)benzamide (15c): Purified by column chromatography on
silica gel (hexanes/EtOAc, 8:2). Colorless oil; 89% yield (166 mg); IR (KBr) ν 3286, 2862, 1705, 1683
cm–1; 1H NMR (400 MHz, CDCl3) δ 0.98ꢀ1.45 (m, 23H), 5.11 (s, 1H), 7.22ꢀ7.28 (m, 2H), 7.33ꢀ7.40 (m,
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1H), 7.42ꢀ7.49 (m, 2H), 7.52ꢀ7.59 (m, 1H), 7.81 (d, J = 7.40 Hz, 3H), 10.57 (s, 1H); C NMR (100
MHz, CDCl3) δ 22.8, 23.2, 23.3, 23.6, 23.7, 24.0, 24.1, 25.7, 26.4, 35.1, 64.3, 123.1, 124.3, 127.7, 128.1,
128.6, 130.5, 130.5, 131.3, 132.2, 132.5, 145.0, 166.5, 169.2; HRMS (ESIꢀMS) calc. (m/z) for
C27H35N2O2 (M+H)+: 419.2699, found: 419.2687.
N-(1-Adamantyl-3-oxoisoindolin-2-yl)benzamide (15d):6b Purified by column chromatography on
silica gel (hexanes/EtOAc, 8:2). White solid; 90% yield (155 mg); mp 239ꢀ241 °C; IR (KBr) ν 3237,
1
2905, 1700, 1668, 1528, 1292, 757 cm–1; H NMR (400 MHz, CDCl3) δ 1.46ꢀ1.73 (m, 9H), 1.74ꢀ1.91
(m, 3H), 1.91ꢀ2.09 (m, 3H), 4.60 (s, 1H), 7.19ꢀ7.34 (m, 2H), 7.34ꢀ7.43 (m, 1H), 7.43ꢀ7.53 (m, 1H),
13
7.53ꢀ7.71 (m, 2H), 7.80ꢀ7.85 (m, 1H), 7.89 (d, J = 7.5 Hz, 1H), 10.39 (s, 1H); C NMR (100 MHz,
CDCl3) δ 28.3, 36.6, 38.0, 38.6, 71.0, 76.6, 76.9, 77.1, 77.2, 124.1, 124.9, 127.4, 127.9, 128.3, 130.4,
131.2, 131.7, 131.9, 143.7, 165.7, 170.6; HRMS (ESIꢀMS) calc. (m/z) for C25H25N2O2 (M–H)–:
385.1916, found: 385.1921.
N-(1-tert-Butyl-3-oxoisoindolin-2-yl)benzamide (15e):6b Purified by column chromatography on silica
gel (hexanes/EtOAc, 8:2). White solid; 15% yield (21 mg); mp 230ꢀ233 °C; IR (KBr) ν 3268, 2970,
1
1723, 1650, 1293 cm–1; H NMR (400 MHz, CDCl3) δ 1.03 (s, 9H), 4.76 (s, 1H), 7.18ꢀ7.24 (m, 2H),
7.30ꢀ7.36 (m, 1H), 7.41ꢀ7.48 (m, 1H), 7.49ꢀ7.57 (m, 2H), 7.76ꢀ7.83 (m, 2H), 7.84ꢀ7.88 (m, 1H), 10.71
(s, 1H); 13C NMR (100 MHz, CDCl3) δ 27.2, 36.0, 70.7, 124.4, 124.8, 127.7, 128.2, 128.6, 130.6, 131.4,
132.1, 132.2, 144.7, 166.1, 170.5; Elem. Anal. Calcd for C19H20N2O2: C, 74.00; H, 6.54; N, 9.08. Found:
C, 74.04; H, 6.50; N, 9.04.
N-(1-Octyl-3-oxoisoindolin-2-yl)benzamide (15f):6b Purified by column chromatography on silica gel
(hexanes/EtOAc, 8:2). Yellow oil; 55% yield (90 mg); IR (KBr) ν 3235, 2927, 1708, 1664, 1293 cm–1;
1H NMR (400 MHz, CDCl3) δ 0.83 (t, J = 7.1 Hz, 3H), 0.86ꢀ0.96 (m, 1H), 0.98ꢀ1.09 (m, 2H) 1.09ꢀ1.30
(m, 9H), 1.89ꢀ2.00 (m, 2H), 5.05 (t, J = 4.6 Hz, 1H), 7.20ꢀ7.28 (m, 2H), 7.34ꢀ7.47 (m, 3H), 7.53ꢀ7.60
13
(m, 1H), 7.79ꢀ7.87 (m, 3H), 10.69 (s, 1H); C NMR (100 MHz, CDCl3) δ 14.3, 22.8, 23.5, 29.4, 29.6,
29.9, 30.7, 32.0, 61.6, 122.7, 124.2, 127.8, 128.2, 128.6, 130.2, 131.1, 132.2, 132.6, 145.2, 166.5, 168.7;
HRMS (ESIꢀMS) calc. (m/z) for C23H27N2O2 (MꢀH)ꢀ: 363.2073, found: 363.2079.
N-(1-Isobutyl-3-oxoisoindolin-2-yl)benzamide (15g): Purified by column chromatography on silica
gel (hexanes/EtOAc, 8:2). White solid; 27% yield (37 mg); mp 131ꢀ133 °C; IR (KBr) ν 3236, 2958,
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1710, 1674, 1292 cm–1; H NMR (400 MHz, CDCl3) δ 0.87 (d, J = 6.6 Hz, 3H), 0.92 (d, J = 6.6 Hz,
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3H), 1.57ꢀ1.70 (m, 1H), 1.74ꢀ1.89 (m, 1H), 1.89ꢀ2.06 (m, 1H), 5.02 (t, J = 6.2 Hz, 1H), 7.25ꢀ.734 (m,
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2H), 7.36ꢀ7.49 (m, 3H), 7.53ꢀ7.60 (m, 1H), 7.80ꢀ7.91 (m, 3H), 10.30 (s, 1H); C NMR (100 MHz,
CDCl3) δ 23.1, 23.2, 25.1, 41.6, 60.2, 123.0, 124.3, 127.8, 128.2, 128.7, 129.8, 131.3, 132.3, 132.6,
146.0, 166.6, 168.6; HRMS (ESIꢀMS) calc. (m/z) for C19H19N2O2 (M–H)–: 307.1447, found: 307.1451.
N-(1-Butyl-3-oxoisoindolin-2-yl)benzamide (15h):6b Purified by column chromatography on silica gel
(hexanes/EtOAc, 8:2). White solid; 95% yield (131 mg); mp 131ꢀ133 °C; IR (KBr) ν 3236, 2958, 1710,
1674, 1292 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.73 (t, J = 7.1 Hz, 3H), 0.80ꢀ0.95 (m, 1H), 1.15ꢀ1.35
(m, 3H), 1.91ꢀ2.00 (m, 2H), 5.09 (t, J = 4.6 Hz, 1H), 7.25ꢀ7.31 (m, 2H), 7.38ꢀ7.50 (m, 3H), 7.57ꢀ7.62
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(m, 1H), 7.81ꢀ7.90 (m, 3H), 10.69 (s, 1H); C NMR (100 MHz, CDCl3) δ 14.1, 22.9, 25.5, 30.4, 61.6,
122.7, 124.3, 127.8, 128.2, 128.6, 130.3, 131.2, 132.2, 132.7, 145.2, 166.6, 168.7; HRMS (ESIꢀMS)
calc. (m/z) for C19H19N2O2 (M–H)–: 307.1447, found: 307.1449.
N-(1-Ethyl-3-oxoisoindolin-2-yl)benzamide (15i):6b Purified by column chromatography on silica gel
(hexanes/EtOAc, 8:2). White solid; 94% yield (118 mg); mp 137ꢀ140 °C; IR (KBr) ν 3235, 2970, 1707,
1673, 1526, 1293, 754 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.58 (t, J = 7.3 Hz, 3H), 1.89ꢀ2.07 (m, 2H),
5.03 (t, J = 4.2 Hz, 1H), 7.12ꢀ7.24 (m, 2H), 7.25ꢀ7.45 (m, 3H), 7.45ꢀ7.55 (m, 1H), 7.71ꢀ7.86 (m, 3H),
10.84 (s, 1H); 13C NMR (100 MHz, CD3CN) δ 7.9, 24.1, 63.0, 124.1, 124.4, 128.5, 129.3, 129.8, 131.5,
133.2, 133.4, 133.6, 145.5, 167.5, 168.1; HRMS (ESIꢀMS) calc. (m/z) for C17H15N2O2 (M–H)–:
279.1134, found: 279.1137.
N-(5-Chloro-1-isopropyl-3-oxoisoindolin-2-yl)benzamide
(16a):6b
Purified
by
column
chromatography on silica gel (hexanes/EtOAc, 8:2). White solid; 78% yield (114 mg); mp 172ꢀ173 °C;
IR (KBr) ν 3241, 2966, 1712, 1673, 1293, 755 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.64 (d, J = 6.8 Hz,
3H), 1.00 (d, J = 7.1 Hz, 3H), 2.33ꢀ2.46 (m, 1H), 4.91 (d, J = 2.6 Hz, 1H), 7.15 (t, J = 7.7 Hz, 2H), 7.28ꢀ
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7.38 (m, 2H), 7.45 (dd, J = 8.2, 1.9 Hz, 1H), 7.68ꢀ7.74 (m, 3H), 10.97 (s, 1H); C NMR (100 MHz,
CDCl3) δ 16.5, 18.0, 29.5, 66.4, 124.2, 124.6, 127.7, 128.5, 130.8, 132.3, 132.4, 132.6, 134.6, 141.8,
166.2, 167.6; HRMS (ESIꢀMS) calc. (m/z) for C18H18ClN2O2 (M+H)+: 329.1057, found: 329.1046.
N-(5-Ethoxy-1-isopropyl-3-oxoisoindolin-2-yl)benzamide (17a): Purified by column chromatography
on silica gel (hexanes/EtOAc, 8:2). Pale yellow solid; yield 83% (126 mg); mp 162ꢀ164 °C; IR (KBr) ν
3239, 2915, 1707, 1674, 1493, 1258 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.65 (d, J = 6.8 Hz, 3H), 1.03
(d, J = 7.0 Hz, 3H), 1.40 (t, J = 6.9 Hz, 3H), 2.36ꢀ2.48 (m, 1H), 4.04 (q, J = 6.9 Hz, 2H), 4.88 (d, J = 2.5
Hz, 1H), 7.08 (dd, J = 8.4, 2.4 Hz, 1H), 7.17ꢀ7.23 (m, 2H), 7.26ꢀ7.37 (m, 3H), 7.81 (d, J = 7.6 Hz, 2H),
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10.88 (s, 1H); C NMR (100 MHz, CDCl3) δ 14.9, 16.5, 18.3, 29.5, 64.1, 66.3, 107.6, 121.1, 124.2,
127.7, 128.5, 131.1, 131.8, 132.1, 135.8, 159.3, 166.3, 166.3, 169.0; Elem. Anal. Calcd for C20H22N2O3:
C, 70.99; H, 6.55; N, 8.28. Found: C, 70.96; H, 6.53; N, 8.32.
N-(1-Isopropyl-4,5-dimethoxy-3-oxoisoindolin-2-yl)benzamide (18a):6b Purified by column
chromatography on silica gel (hexanes/EtOAc, 8:2). White solid; 83% yield (131 mg); mp 194ꢀ195 °C;
IR (KBr) ν 3256, 2954, 1733, 1645, 1219 cm–1; 1H NMR (400 MHz, CDCl3) δ 0.71 (d, J = 6.9 Hz, 3H),
0.94 (d, J = 7.0 Hz, 3H), 2.28ꢀ2.37 (m, 1H), 3.82 (s, 3H), 3.98 (s, 3H), 4.83 (d, J = 2.6 Hz, 1H), 7.01ꢀ
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7.05 (m, 2H), 7.13ꢀ7.20 (m, 2H), 7.27ꢀ7.34 (m, 1H), 7.73 (d, J = 7.8 Hz, 2H), 10.69 (s, 1H); C NMR
(100 MHz, CDCl3) δ 16.8, 17.7, 30.0, 56.7, 62.6, 65.2, 117.1, 118.3, 122.9, 127.7, 128.4, 131.1, 132.0,
137.0, 147.7, 152.3, 166.1, 167.2; HRMS (ESIꢀMS) calc. (m/z) for C20H23N2O4 (M+H)+: 355.1658,
found: 355.1645.
ASSOCIATED CONTENT
Supporting Information
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The Supporting Information for copies of H and C NMR spectra of compounds is available free of
charge on the ACS Publications website.
AUTHOR INFORMATION
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Corresponding Author
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*Eꢀmail address: dojang@yonsei.ac.kr
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ACKNOWLEDGMENT
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This research was supported by Basic Science Research Program through the National Research
Foundation of Korea (NRF) funded by the Ministry of Education (NRFꢀ2016R1D1A3B03932348).
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