The behavior of 2-substituted-3-hydroxyisoindolinones in the reaction with sec-butyllithium

Article abstract of DOI:10.1002/jhet.1636

This paper presents a dualistic behavior of 2-substituted-3- hydroxyisoindolones in reactions with sec-butyllithium (sec-BuLi). 2-tert-Butyl-3-hydroxy-2,3-dihydro-1H-isoindol-1-one (1a) treated with sec-BuLi undergoes metalation at position 7. On the other hand, the reaction between 3-hydroxy-2-phenyl-2,3-dihydroxyisoindol-1-one (1j) and sec-BuLi results in 3-sec-butyl-2-phenyl-2,3-dihydroisiondol-1-one (3j).

Full text of DOI:10.1002/jhet.1636

March 2014
The Behavior of 2-Substituted-3-hydroxyisoindolinones in the Reaction
with sec-Butyllithium
357
A. Jóźwiak* and M. Ciechańska
Department of Organic Chemistry, Faculty of Chemistry, University of Łódź, Tamka 1291-403 Łódź, Poland
*
E-mail: ajozwiak@uni.lodz.pl
Received July 28, 2011
DOI 10.1002/jhet.1636
Published online 12 November 2013 in Wiley Online Library (wileyonlinelibrary.com).
Me
Me
SiMe3
O
O
1) sec-BuLi
1) sec-BuLi
2
) SiMe Cl
2) SiMe Cl
3
3
N R1
N R1
OH
N R1
o
o
-78 C
-
78 C
OH
R = t-Bu
O
1
1
R = Ph
This paper presents a dualistic behavior of 2-substituted-3-hydroxyisoindolones in reactions with
sec-butyllithium (sec-BuLi). 2-tert-Butyl-3-hydroxy-2,3-dihydro-1H-isoindol-1-one (1a) treated with
sec-BuLi undergoes metalation at position 7. On the other hand, the reaction between 3-hydroxy-2-
phenyl-2,3-dihydroxyisoindol-1-one (1j) and sec-BuLi results in 3-sec-butyl-2-phenyl-2,3-dihydroisiondol-
1-one (3j).
J. Heterocyclic Chem., 51, 357 (2014).
INTRODUCTION
,3-Dihydroisoindol-1-ones (phtalimidinones) constitute
active functions that control ortho-lithiation processes [5].
It is also known that a small dihedral angle between the
ortho-hydrogen and the amide oxygen increases the effec-
tiveness of ortho-lithiation of amides [4a, 5c]. On the other
hand, the carbon–oxygen double bond of amide group
can be also subject to attach organolithium compounds [6].
2
a central structural block in a large number of biologically
active substances, and therefore, considerable efforts have
been directed toward the synthesis and modifications of their
structure [1]. As shown in Figure 1, the action of organo-
lithium compounds or lithium amides on phthalimidinones
A may lead to the formation of isoindoles (path I) [2] or
lithiation at position 3 (path II) [3] as well as to lithiation of
isoindolinone species at position 7 (path III) [4].
Data available in literature indicate that 3-hydroxy-2,3-
dihydroisoindol-1-ones can be successfully lithiated by
sec-butyllithium (sec-BuLi) at position 7 [4]. This paper
discusses the range and limitations of this method.
3
-Hydroxyisoindoles 1e–i undergo these conversions to a
large extent. These compounds form products of type 2 as
well as mixtures of diastereoisomers 3 and isoindolinones
1
j,k that form only products of type 3. In this case, the
addition of organolithium reagent leads to the formation of
salts 5, whose acidification results in the formation of deriva-
tives substituted with sec-butyl group of type 3 [7].
The intermediate formation of salts 5 allows one to
explain the formation of 3-sec-butyl-6-chloro-2-phenyl-
2
,3-dihydroisoindol-1-one 3f, the product with amide
group and chlorine atoms in changed positions in relation
to the substrate. Alkyl substituents at position 2 of isoindi-
linone facilitate the matalation at position 7. A similar
effect is observed in the case of derivatives substituted with
methoxy group or chlorine atom at position 5. Apparently,
in these cases, the electron-donating effect is sufficient to
discourage substitution at the amide carbonyl.
Siliceous derivative 2a in the presence of air shows a
high tendency to change into 2-tert-butyl-4-trimethylsila-
nyl-isoindole-1,3-dione (6) (see the Experimental section).
RESULTS AND DISCUSSION
The silylation process was selected as the way for
determining the ortho-metalation of compound 1 with
organolithium reagent. The detailed results of the reaction
of sec-BuLi with 3-hydroxyisoindolinones 1 and then with
chlorotrimethylsilane (Scheme 1) are listed in Table 1.
These results show that the way of substitution of 3-
hydroxyisoindolinone system affects the type and mutual
quantitative proportions of products 2 and 3.
Compounds 1a–d form only appropriate siliceous pro-
ducts 2a–d, which indicates that the isoindole system in
the ortho-lithiation process is metalated at position 7 to
form dilithium derivatives of type 4 (Fig. 2). The conver-
sion direction observed is connected with the fact that the
amide group in the structure of substrate is one of the most
CONCLUSIONS
To sum up, one can state that the use of sec-BuLi for an
effective functionalization of 3-hydroxyisoindolinones at
position 7 is considerably restricted by the competitive
©
2013 HeteroCorporation

3
58
A. Jóźwiak and M. Ciechańska
Vol 51
1
2
3
R = t-Bu, R = R = Me, (s-BuLi/TMEDA) [4a]
1
2
3
R = C(Me) Ph, R = H, R = OH, (s-BuLi/TMEDA) [4b]
2
1
2
3
R = Me, R = H, R = OH, (s-BuLi/TMEDA) [4c]
iii
O
i
1
2
3
R = Me, R = R = H, (PhCH Li) [2a]; (PhLi) [2b]; (MeLi) [2e]
2
N R1
R2
1
2
3
R = Me, R = Ph, R = H, (PhLi) [2c]
R = R = Ph, R3 = H, (PhLi) [2d]
1
2
R3
A
ii
1
= Me, R2 = R = H, (LDA) [3a]; (t-BuLi) [3b]; (LHMDS) [3f]
3
R
1
1
1
2
3
R
R
R
= N(Me) , R = R = H, (LHMDS) [3c]
2
= 4-methoxybenzyl, R = R = H, (LHMDS) [3d, 3f]
= 2-hydroxy-1-phenylethyl, R = R = H, (LDA, LHMDS)[3e]
2
3
2
3
Figure 1. The possible reactive site of phthalimidinones in reactions with organolithium compounds and lithium amides.
Scheme 1. The products isolated upon the treatment of 3-hydroxyisoindolinones 1 with sec-BuLi followed with chlorotrimethylsilane.
Me
Me
O
1) sec-BuLi / THF
) SiMe Cl
SiMe
3
O
2
3
N R1
OH
N R1
OH
N R1
+
R3
R3
R3
R2
R2
R2
O
1
2
3
Table 1
The products isolated upon the treatment of 3-hydroxyisoindolinones 1 with sec-BuLi followed with chlorotrimethylsilane.
Products, % yield
%
Yield recovered
1
2
3
Entry
R
R
R
Substrate 1
2
3
a
b
a
a
a
a
c
a
b
c
d
e
f
g
h
i
tBu
H
H
H
H
H
H
H
H
OMe
H
H
H
OMe
OMe
H
Cl
H
H
OMe
H
80 (98)
75
65
85
66
75
70
40
C(Me)
Me
2
Ph
19
18
6
Ph
Me
Ph
25
a
10
27
30
25
75
90
a
3,4,5-(MeO)
3
C
6
H
2
4-MeOC
Ph
6
H
4
15
10
17
5
45
a
j
k
Ph
Ph
a
OMe
H
a
Not detected.
b
c
2-tert-Butyl-4-trimethylsilanylisoindole-1,3-dione (6) was also separated after column chromatography; see the Experimental section.
Product is formed in trace amounts.
commercially available materials were used without purification
unless otherwise stated. Butyllithium (2.5 M solution in hexanes)
and sec-BuLi (1.4 M solution in cyclohexane) were obtained from
addition process, whose products, after acidifcation, lead to
the formation of isoindoles 3.
0
0
Aldrich and were titrated before use. N,N,N ,N -Tetramethylethy-
lenediamine (TMEDA) (99.5%) from Aldrich was distilled before
use and stored over potassium hydroxide pellets. Chlorotri-
methylsilane was obtained from Fluka. Tetrahydrofuran (THF)
(pure) was obtained from POCh and freshly distilled from sodium
benzophenone ketyl. Air-sensitive reactions were carried out un-
der an argon atmosphere. Thin-layer chromatography was carried
out on Merck silica-gel plates (Kiselgel 60 F254, layer thickness
EXPERIMENTAL
Melting points were determined using a Boetius hot stage
apparatus and were uncorrected. IR spectra were recorded on an
1
13
FT-IR Nexus. H and C NMR spectra were recorded at 200
and 50 MHz, respectively, by using a Varian Gemini 200 or
Bruker Avance III 600 MHz spectrometer. All reagents and
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2014
The Behavior of 2-Substituted-3-hydroxyisoindolinones in the Reaction with sec-Butyllithium
359
Me
ꢀ1
1
Li
O
SiMe3
O
(KBr): 1702 cm
d =7.80–7.55 (m, 4H, Ar–H), 7.09 (s, 2H, Ar–H), 6.92 (d,
(C═O); H NMR (200 MHz, DMSO-d6):
LiO
Me
N
R1
N R1
N
tBu
0
0
J= 8.8 Hz, 1H, 3-H), 6.52 (d, J= 8.8 Hz, 1H, OH), 3.79 (s, 6H, 3 ,5 -
R3
R3
0
13
OMe), 3.68 (s, 3H, 4 -OMe); C NMR (50 MHz, CDCl
d =166.72 (C═O); 152.81, 142.84, 132.95, 132.59, 130.96, 129.66,
23.36, 123.00, 100.33, 83.42, 60.66, 55.83. Anal. Calcd for
C H NO : C, 64.75; H, 5.43; N, 4.44. Found: C, 64.7; H, 5.2; N, 4.5.
3
):
R2
OLi
R2
OLi
O
4
5
6
1
17
17
5
Figure 2. Dilithium derivatives and product oxidation of siliceous deriva-
tives 2a in the presence of air.
3
-Hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1H-isoindol-
ꢁ
1
[
-one (1h). Yield (6.43 g; 60%); mp 161–163 C (methanol)
ꢁ
lit [13] mp 156 C].
0
.2 mm) and visualized using a UV lamp at 254 nm. Column
3-Hydroxy-4,5-dimethoxy-2-phenyl-2,3-dihydro-1H-isoindol-1-
ꢁ
chromatography separations and purifications were performed
on silica gel 60 (0.063–0.100 mm) from Merck. 3-Hydroxy-2,3-
dihydro-1H-isoindol-1-ones
one (1i). Yield (9.59 g; 80%); mp 167–169 C (toluene); IR (KBr):
ꢀ
1
1
1682 cm (C═O); H NMR (200 MHz, DMSO-d ): d = 7.84–
6
1
were prepared according to
7.10 (m, 7H, H–Ar), 6.64 (br s, 1H, 3-H), 3.94 (s, 3H, OMe),
1
3
previously used procedures [8–10].
3.90 (s, 3H, OMe); C NMR (50 MHz, DMSO-d ): d = 165.15
6
General procedure for the preparation of 3-hydroxy-2,3-
(C═O), 155.87, 144.53, 137.81, 134.99, 128.79, 124.88,
124.57, 122.15, 118.86, 114.26, 80.55, 60.22, 56.48. Anal.
Calcd for C H NO : C, 67.36; H, 5.30; N, 4.91. Found: C,
dihydro-1H-isoindol-1-ones 1.
The appropriate benzanilide
ꢁ
(
42.0 mmol) [11] stirred in THF (110 mL) at ꢀ78 C under argon
1
6
15
4
ꢁ
was added BuLi (85.0 mmol). The solution was held at ꢀ78 C for
67.4; H, 5.1; N, 5.0.
ꢁ
ꢁ
0
.5 h, allowed to warm to 0 C, and then kept at 0 C for 0.1h. The
3-Hydroxy–2-phenyl-2,3-dihydro-1H-isoindol-1-one (1j).
(8.99 g; 95%); mp 171–172 C (methanol) [lit [9] mp 167–168 C].
Yield
ꢁ
ꢁ
ꢁ
whole lot was cooled to ꢀ78 C, and DMF (85.0 mmol) was
ꢁ
added. The reaction mixture after 1 h at ꢀ78 C was warmed to
3-Hydroxy-4-methoxy-2-phenyl-2,3-dihydro-1H-isoindol-1-
ꢁ
room temperature, kept for 1 h, and then added with water. The
mixture was adjusted to pH ~2 with hydrochloric acid, and the
organic layer was separated. The water layer was extracted with
one (1k). Yield (7.50 g; 70%); mp 157–159 C (ethyl acetate) [lit
[8] mp 167–169 C].
ꢁ
3-Hydroxy-4,5,6-trimethoxy-2-(4-methoxyphenyl)-2,3-dihydro-
ꢁ
3
CHCl . The combined organic solutions were dried with
1H-isoindol-1-one (1l).
Yield (7.40 g; 51%); mp 142–144 C
ꢀ
1
1
magnesium sulfate(VI) and evaporated to give the crude products.
The products were purified by crystallization.
(ethyl acetate : hexane 8:2); IR (KBr): 1676 cm (C═O); H NMR
(200 MHz, CDCl ): d = 7.60 (d, J =9.0 Hz, 2H, Ar–H), 7.11
3
2
-tert-Butyl-3-hydroxy-2,3-dihydro-1H-isoindol-1-one
(s, 1H, H–Ar), 6.96 (d, J = 9.1 Hz, 2H, Ar–H), 4.10 (s, 3H,
ꢁ
(
1
1a). Yield (5.17 g; 60%); mp 136–138 C (toluene) [lit [12] mp
39–140 C].
OMe), 3.93 (s, 3H, OMe), 3.91 (s, 3H, OMe), 3.83 (s, 3H,
ꢁ
13
OMe), 2.95 (br s, 1H, OH); C NMR (50 MHz, CDCl3):
3
-Hydroxy-2-(1- methyl-1-phenylethyl)-2,3-dihydro-1H-
d = 165.90 (C═O), 156.63, 155.33, 148.88, 146.64, 129.96,
126.86, 126.30, 123.15, 113.76, 101.23, 81.59, 60.81, 60.50,
55.81, 55.15. Anal. Calcd for C H NO : C, 62.60; H, 5.55;
ꢁ
isoindol-1-one (1b). Yield (6.11 g; 54%); mp 214–217 C
ꢀ
1
1
(
(
7
benzene); IR (KBr): 1666 cm
200 MHz, DMSO-d ): d = 7.70–7.44 (m, 4H, 4,5,6,7-H),
.43–7.32 (m, 2H, 2,6-Ph-H), 7.31–7.07 (m, 3H, 3,4,5-Ph-
H), 6.61 (d, J = 9.1 Hz, 1H, OH), 6.33 (d, J = 9.1 Hz, 1H, 3-
H), 1.82 and 1.89 (two overlapping s, 6H, Me); C NMR
50 MHz, DMSO-d ) d = 166.4, 148.51, 145.43, 132.06,
29.30, 127.97, 125.84, 125.07, 123.55, 122.12, 81.64,
8.49, 28.86, 27.91. Anal. Calcd for C17 : C, 76.39;
H, 6.41; N, 5.24. Found: C, 76.3; H, 6.4; N, 5.4.
3
-one (1c). Yield (6.57 g; 81%); mp 166–167 C (methanol);
IR (KBr): 1663cm
d = 7.46 (d, J = 8.3 Hz, 1H, H–Ar), 7.08 (br s, 1H, H–Ar), 6.95–
.85 (dd, J = 2.3 and 2.2 Hz, 1H, H–Ar), 5.23 (d, J = 11.5 Hz, 1H,
-H), 3.88 (s, 3H, OMe), 3.65 (d, J = 11.5Hz, 1H, OH), 2.92 (s,
H, N–Me); C NMR (50 MHz, CDCl
63.18, 146.14, 128.53, 124.37, 115.91, 108.06, 83.19, 55.64,
6.07. Anal. Calcd for C H NO : C, 62.17; H, 5.74; N, 7.25.
(C═O);
H
NMR
1
8
19
6
6
N, 4.06. Found: C, 62.7; H, 5.6; N, 4.1.
Reactions of isoindol-1-ones 1 with sec-butyllithium and next
with chlorotrimethylsilane. sec-Butyllithium (7.0mmol) was
added to a stirred solution of appropriate compound 1 (2.0 mmol)
1
3
0 0
and N,N,N ,N -tetramethylethylenediamine (7.0 mmol) in THF
(
1
5
6
ꢁ
ꢁ
(70 mL) at ꢀ78 C. The solution was kept at ꢀ78 C for 1.5 h and
ꢁ
H
17NO
2
added with SiMe Cl (7.0 mmol). Stirring at ꢀ78 C was
3
continued for another 0.1 h, and then the reaction mixture was
warmed up to room temperature and added with water (20 mL).
The mixture was adjusted to pH ~2 with hydrochloric acid, and
the organic layer was separated. The combined organic solutions
were dried with magnesium sulfate(VI). Products were separated
by column chromatography.
-Hydroxy-5-methoxy-2-methyl-2,3-dihydro-1H-isoindol-
ꢁ
1
ꢀ
1
1
3
(C═O); H NMR (200MHz, CDCl ):
6
3
3
1
2
Reaction of 2-tert-butyl-3-hydroxy-2,3-dihydro-1H-isoindol-1-
13
3
): d = 167.48 (C═O),
one (1a).
Analysis (TLC, toluene) of organic layer indicated
the presence of two compounds (R = 0.54 and 0.15). The first
f
1
0
11
3
eluted fraction (R = 0.54) was identified as 2-tert-butyl-4-
f
Found: C, 62.4; H, 5.9; N, 7.6.
trimethylsilanyl-isoindole-1,3-dione (6) (0.10 g; yield 18%); mp
96–98 C; IR (KBr): 1766, 1749, 1706cm (C═O); H NMR
ꢁ
ꢀ1
1
3
-Hydroxy-5-methoxy-2-phenyl-2,3-dihydro-1H-isoindol-1-
ꢁ
one (1d). Yield (8.58 g; 80%); mp 201–202 C (toluene) [lit [8]
(600MHz, CDCl ): d = 7.82 (dd, J = 7.2 and 0.6Hz, 1H, 5-H),
3
ꢁ
mp 194–196 C].
7.78 (dd, J = 7.2 and 0.6 Hz, 1H, 7-H), 7.64–7.60 (m, 1H, 6-H),
13
3
-Hydroxy-2-methyl-2,3-dihydro-1H-isoindol-1-one (1e).
Yield
1.13 (s, 9H, tert-butyl), 0.42 (s, 9H, SiMe3); C NMR (150MHz,
ꢁ
ꢁ
(
6.10 g; 89%); mp 135–138 C (toluene) [lit [9] mp 133 C].
CDCl ): d = 170.69, 170.04 (C═O), 139.51, 138.72, 136.62,
3
5
-Chloro-3-hydroxy-2-phenyl-2,3-dihydro-1H-isoindol-1-
132.31, 132.29, 122.94, 57.60, 29.14, ꢀ1.12. Anal. Calcd for
ꢁ
one (1f).
Yield (10.69 g; 98%); mp 198–200 C (methanol)
C H NO Si: C, 65.41; H, 7.69; N, 5.09. Found: C, 65.3; H, 7.6;
15
21
2
ꢁ
[
lit [10] mp 196–198 C].
N, 5.0. Compound 6 was formed by oxidation of 2-tert-butyl-3-
hydroxy-7-trimethylsilanyl-2,3-dihydro-1H-isoindol-1-one (2a),
3-Hydroxy-2-(3,4,5-trimethoxyphenyl)-2,3-dihydro-1H-isoindol-1-
ꢁ
one (1g). Yield (10.06 g; 76%); mp 179–180 C (ethyl acetate); IR
which was a component of the second eluated fraction (R = 0.15)
f
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

3
60
A. Jóźwiak and M. Ciechańska
Vol 51
ꢁ
ꢀ1
1
(
0.44 g; yield 80%); mp 95–97 C; IR (KBr): 1697 cm (C═O); H
ꢀ0.70 (SiMe ). Anal. Calcd for C H NO Si: C, 61.24; H,
3
12 17
2
NMR (200 MHz, CDCl ): d = 7.65–7.42 (m, 3H, H–Ar), 5.94 (br s,
7.28; N, 5.95. Found: C, 61.3; H, 7.2; N, 6.0. The second eluted
3
1
H, 3-H), 2.22 (br s, 1H, OH), 1.60 (s, 9H, tert-butyl), 0.34 (s, 9H,
fraction (R
diastereoisomers
3
isoindol-1-one (3e) (trace); oil; H NMR (200 MHz, CDCl ):
f
= 0.32) appeared to be the mixture of two
13
SiMe
1
3 3
); C NMR (50MHz, CDCl ): d = 168.71 (C═O), 143.37,
of 3-sec-butyl-2-methyl-2,3-dihydro-1H-
1
38.51, 137.24, 135.94, 130.77, 123.32, 81.99, 54.47, 28.56,
ꢀ
0.61. Anal. Calcd for C H NO Si: C, 64.94; H, 8.36; N, 5.05.
Found: C, 64.9; H, 8.4; N 5.0.
d = 7.86–7.76 (1H, m, 7-H), 7.75–7.33 (3H, m, 4,5,6-H), 4.44–
4.36 (1H, m, 3-H), 3.10 and 3.08 (3H, two overlapping s, Me),
2.26–1.96 (1H, m, 1-(1-methylpropyl)-H), 1.80–0.35 (8H, m,
2,3-(1-methylpropyl)-H and Me). The third eluted fraction
1
5
23
2
Reaction of 3-hydroxy-2-(1-methyl-1-phenylethyl)-2,3-dihydro-
H-isoindol-1-one (1b). Analysis (TLC, hexane : ethyl acetate
:1) of organic layer indicated the presence of two compounds
1
9
(R = 0.06) turned out to be the starting material 1e (0.08 g; yield
f
(
R = 0.36 and 0.20). The first eluated fraction (R =0.36) was
25%).
f
f
identified as 3-hydroxy-2-(1-methyl-1-phenylethyl-7-trimethylsilanyl-
,3-dihydro-1H-isoindol-1-one (2b) (0.51 g, yield 75%); oil; IR
Reaction of 5-chloro-3-hydroxy-2-phenyl-2,3-dihydro-1H-
2
isoindol-1-one (1f).
3
Analysis (TLC, CHCl : toluene : acetone
ꢀ
1
1
(
7
6
film): 1707 cm (C═O); H NMR (200 MHz, CDCl
.54 (m, 1H, 4,5,6-H), 7.37–7.08 (m, 5H, Ph–H), 6.74 (s, 1H, 3-OH),
.04 (s, 1H, 3-H), 1.96 and 1.84 (two overlapping s, 6H, Me), 0.31
3
): d =7.62–
80:18:2) of organic layer indicated the presence of two
compounds (R = 0.63 and 0.36). The first eluted fraction
f
(R = 0.63) was identified as 5-chloro-3-hydroxy-2-phenyl-7-
f
13
(
1
1
s, 9H, SiMe
47.05, 143.32, 138.81, 136.87, 132.18, 130.88, 129.86, 128.27,
26.39, 125.05, 82.15, 59.03, 28.64, ꢀ0.74 (SiMe ). The second
eluted fraction (R = 0.02) turned out to be the starting material (1b)
3
); C NMR (50MHz, CDCl
3
): d = 167.45, (C═O),
trimethylsilanyl-2,3-dihydro-1H-isoindol-1-one (2f) (0.50 g; yield
ꢁ
ꢀ1
75%); mp 195–197 C (decomposition); IR (KBr): 1684 cm
1
3
(C═O); H NMR (200 MHz, CDCl
3
): d =7.80–7.11 (m, 7H, Ar–
H), 6.34 (br s, 1H, 3-H), 2.70 (br s, 1H, OH), 0.39 (s, 9H,
f
13
(
0.10 g; 19%).
Reaction of 3-hydroxy-5-methoxy-2-methyl-2,3-dihydro-1H-
isoindol-1-one (1c). Analysis (TLC, CHCl : acetone 9:1) of
organic layer indicated the presence of two compounds
R = 0.56 and 0.10). The first eluted fraction (R = 0.56) was
SiMe3); C NMR (50MHz, CDCl ): d = 166.27 (C═O), 144.7,
3
138.5, 136.2, 131.87, 129.2, 129.0, 125.4, 124.5, 124.1, 122.5,
3
81.6, ꢀ0. 9 (SiMe
3 2
). Anal. Calcd for C17H18ClNO Si: C, 61.53;
H, 5.47; N, 4.22. Found: C, 61.4; H, 5.5; N, 4.2. The second
(
eluted fraction (R = 0.36) appeared to be the mixture of two
f
f
f
identified as 3-hydroxy-5-methoxy-2-methyl-7-trimethylsilanyl-
diastereoisomers of 3-sec-butyl-6-chloro-2-phenyl-2,3-dihydro-1H-
ꢁ
2
1
,3-dihydro-1H-isoindol-1-one (2c) (0.35 g; yield 65%); mp
23–125 C; IR (KBr): 1662 cm (C═O); H NMR (200 MHz,
isoindol-1-one (3f) (0.06 g; yield 10%); mp 158–161 C (hexane);
ꢁ
ꢀ1
1
ꢀ1
1
3
IR (KBr): 1686 cm (C═O); H NMR (600 MHz, CDCl ) 7.91
CDCl ): d = 7.17–7.10 (br s, 1H, H–Ar), 7.07–7.02 (br s, 1H,
and 7.90 (two overlapping d, J = 1.8 and 2.2 Hz, 1H, 7-H,
both of diastereoisomers), 7.57–7.41 (m, 6H, 4,5-H and
2,3,5,6-Ph–H, both of diastereoisomers), 7.30–7.23 (m, 1H, 4-
Ph–H, both of diastereoisomers), 5.21 (d, J = 3.0 Hz, 1H, 3-H of
minor diastereoisomer), 5.15 (d, J = 3.0 Hz, 1H, 3-H of major
diastereoisomer), 2.03–1.93 (m, 1H, 1-(1-methylpropyl)-H, both
of diastereoisomers), 1.76–1.65 (m, 1H, 2-(1-methylpropyl)-H) of
minor diastereoisomer), 1.58–1.47 (m, 1H, 2-(1-methylpropyl)-H)
of minor diastereoisomer), 1.13–1.00 (m, 1H, 2-(1-methylpropyl)-
H) and Me of major diastereoisomer) and 3-(1-methylpropyl)-H)
of minor diastereoisomer), 0.67 (t, J = 7.2 Hz, 3H, 3-(1-
methylpropyl)-H) of major diastereoisomer), 0.56–0.45 (m, 1H, 2-
(1-methylpropyl)-H) of major diastereoisomer), 0.38 (d,
3
H–Ar), 5.58 (d, J = 9.5 Hz, 1H, 3H), 3.87 (s, 3H, OMe), 3.06
1
3
(
s, 3H, N–Me), 0.36 (s, 9H, SiMe
CDCl ): d = 168.03 (C═O), 161.84, 146.28, 140.57, 128.39,
22.69, 107.68, 82.93, 55.46, 26.27, ꢀ0.76 (SiMe ). Anal.
Calcd for C H NO Si: C, 58.94; H, 7.22; N, 5.28. Found: C,
3
); C NMR (50 MHz,
3
1
3
13
19
3
5
8.9; H, 7.3; N, 5.3. The second eluted fraction (R = 0.10)
f
turned out to be the starting material 1c (0.07g; yield 18%).
Reaction of 3-hydroxy-5-methoxy-2-phenyl-2,3-dihydro-1H-
isoindol-1-one (1d).
:2) of organic layer indicated the presence of two compounds
R = 0.58 and 0.33). The first eluted fraction (R = 0.58) was
3
Analysis (TLC, CHCl : ethyl acetate
8
(
f
f
identified as 3-hydroxy-5-methoxy-2-phenyl-7-trimethylsilanyl-
1
2
1
,3-dihydro-1H-isoindol-1-one (2d) (0.56 g; yield 85%); mp
90–192 C (toluene); IR (KBr): 1672 cm (C═O); H NMR
J = 6.6Hz, 1H, Me of minor diastereoisomer). The exact H NMR
ꢁ
ꢀ1
1
1
1
assignment of proton was extracted from the H– H COSY plot.
(
200 MHz, CDCl3): d =7.83–7.02 (m, 7H, Ar–H), 6.29
Ratio of diastereoisomers 3:7 (the composition of diastereisomers
was measured by integrating the 3H-proton signal). C NMR
13
(d, J =9.62 Hz, 1H, 3-H), 3.91 (s, 3H, OMe), 2.70 (d, J = 10.4Hz,
1
3
1
H, OH), 0.41 (s, 9H, SiMe
3
); C NMR (50 MHz, CDCl
3
):
(50 MHz, CDCl ): d = 154.40, 141.79, 140.87, 137.08, 134.62,
3
d = 167.07 (C═O), 162.71, 145.55, 144.84, 137.45, 129.21,
25.11, 123.77, 122.04, 107.53, 81.94, 55.59, 0.93. Anal. Calcd
for C H NO Si: C, 66.02; H, 6.46; N, 4.28. Found: C, 66.0; H,
131.73, 131.73, 131.64, 129.19, 126.11, 125.88, 124.41, 65.96,
64.56, 36.68, 36.06, 23.08, 15.76, 12.41, 11.82. Anal. Calcd for
C18H18ClNO: C, 72.11; H, 6.05; N, 4.67. Found: C, 72.4; H, 6.1;
N, 4.7.
Reaction of 3-hydroxy-2-(3,4,5-methoxyphenyl)-2,3-dihydro-
3
1H-isoindol-1-one (1g). Analysis (TLC, CHCl : acetone : hexane
1
18
21
3
6
.4; N, 4.3. The second eluted fraction (R
be the starting material 1d (0.03 g; yield 6%).
Reaction of 3-hydroxy-2-methyl-2,3-dihydro-1H-isoindol-1-
f
= 0.33) turned out to
one (1e).
Analysis (TLC, CHCl : acetone 9:1) of organic
7:1:2) of organic layer indicated the presence of two compounds
3
layer indicated the presence of three compounds (R = 0.54,
(R = 0.34 and 0.27). The first eluted fraction (R = 0.34) appeared to
f
f
f
0
.32, and 0.06). The first eluted fraction (R
f
= 0.54) was
be the mixture of two diastereoisomers of 3-sec-butyl-2-(3,4,5-
trimethoxyphenyl)-2,3-dihydro-1H-isoindol-1-one (3g) (0.19 g; yield
27%); mp 132–135 C (hexane); IR (KBr): 1686 cm (C═O); H
identified as 3-hydroxy-2-methyl-7-trimethylsilanyl-2,3-dihydro-
ꢁ
ꢁ
ꢀ1
1
1H-isoindol-1-one (2e) (0.31 g; yield 66%); mp 126–130 C; IR
ꢀ
1
1
(
KBr): 1693 cm
(C═O);
H
NMR (200 MHz, CDCl3):
NMR (200 MHz, CDCl ): d =7.97–7.84 (m, 1H, 7-H), both of
3
d = 7.72–7.46 (m, 3H, 4,5,6-H), 5.66 (d, J = 11.5 Hz, 1H, 3-H),
diastereoisomers 7.64–7.40 (m, 3H, 4,5,6,-H), both of
diastereoisomers 6.77 and 6.71 (two overlapping s, 2H, Ar–H),
5.15 (d, J = 2.7 Hz, 1H, 3-H of minor diastereoisomer), 5.07
(d, J = 2.5 Hz, 1H, 3-H of major diastereoisomer), 3.87–3.82
3
.12 (s, 3H, Me), 2.21 (d, J = 11.5 Hz, 1H, OH), 0.39 (s, 9H,
13
SiMe
3
);
3
C NMR (50 MHz, CDCl ); d = 168.26 (C═O),
1
43.53, 138.71, 136.18, 135.88, 130.87, 123.68, 83.19, 26.19,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2014
The Behavior of 2-Substituted-3-hydroxyisoindolinones in the Reaction with sec-Butyllithium
361
13
(three overlapping s, 9H, OMe), 2.14–0.30 (m, 9H, (1-
SiMe3); C NMR (50 MHz, CDCl ): d =154.79 (C═O), 145.13,
3
methylpropyl)-H, both of diastereoisomers). Ratio of
diastereoisomers 4:6 (the composition of diastereisomers was
135.57, 134.88, 129.19, 126.08, 125.17, 122.98, 121.97, 120.72,
120.35, 80.40, 60.96, 56.11, 0.80. Anal. Calcd for C19
63.84; H,6.49; N, 3.92. Found: C, 63.7; H, 6.6; N, 3.9. The second
eluted fraction (R = 0.11) appeared to be the mixture of two
diastereoisomers of 3-sec-butyl-6,7-dimethoxy-2-phenyl-2,3-dihydro-
4
H23NO Si: C,
13
measured by integrating the 3H-proton signal). C NMR
50 MHz, CDCl ): d = 167.80, 165.50 (C═O), 153.50, 153.30,
43.74, 142.74, 138.9, 133.30, 131.64, 128.50, 128.37, 124.20,
(
3
f
1
1
5
ꢀ
1
24.10, 123.20, 122.95, 102.70, 102.00, 66.60, 65.00, 60.90,
6.20, 36.90, 36.10, 26.60, 23.20, 15.16, 12.50,12.40, 11.80.
1H-isoindol-1-one (3i) (0.16 g; yield 25%); oil; IR (film): 1690 cm
1
3
(C═O); H NMR (200MHz, CDCl ): d =7.60–7.34 (m, 4H, 2,3,5,6-
Anal. Calcd for C21
Found: C, 70.9; H, 7.0; N, 4.0. The second eluated fraction
Rf = 0.27) was identified as 3-hydroxy-2-(3,4,5-methoxyphenyl)-
-trimethylsilanyl-2,3-dihydro-1H-isoindol-1-one (2g) (0.54 g;
H
25NO
4
: C, 70.96; H, 7.09; N, 3.94.
Ar–H), 7.28–7.04 (m, 3H, 4,5-H, and 4-Ar–H), 5.13 (d, J=3.0Hz,
1H, 3-H of minor diastereoisomer), 5.07 (d, J= 2.8 Hz, 1H, 3-H of
major diastereoisomer), 4.07 (s, 3H, OMe) 3.91 (s, 3H, OMe),
2.02–0.37 (m, 9H, 1,2,3-(1-methylpropyl)-H, and Me). Ratio of
diastereoisomers 4:6 (the composition of diastereisomers was
(
7
ꢁ
ꢀ1
yield 70%); mp 133–135 C (hexane); IR (KBr): 1686cm
1
13
(
4
(
C═O); H NMR (200 MHz, CDCl
,6-H), 7.53–7.41 (m, 1H, 5-H), 7.04 (s, 2H, Ar–H), 6.28
d, J = 10.8 Hz, 1H, 3-H), 3.90–3.82 (two overlapping s, 9H,
3
): d = 7.82–7.72 (m, 2H,
measured by integrating the 3H-proton signal). C NMR (50MHz,
CDCl ): d = 165.65, 165.44 (C═O), 152.66, 152.59, 147.74, 147.67,
3
137.56, 137.24, 137.18, 136.22, 129.03, 128.98, 125.71, 125.48,
124.57; 124.09, 118.31, 117.96, 116.59, 116.48, 64.88, 63.49,
62.47, 62.43, 56.75, 37.18, 36.34, 26.47, 23.24, 15.47, 12.35, 12.26,
1
3
OMe), 3.19 (d, J = 10.8 Hz, 1H, OH), 0.44 (s, 9H, SiMe
3
);
C
3
NMR (50 MHz, CDCl ) d = 166.79 (C═O), 153.37, 147.72,
1
6
6
38.95, 136.62, 133.14, 130.67, 129.47, 124.34, 100.69, 84.36,
3
11.85. Anal. Calcd for C20H23NO : C, 73.82; H, 7.12; N, 4.30.
0.91, 56.21, ꢀ0.34 (SiMe ). Anal. Calcd for C H NO Si: C,
Found: C, 73.7; H, 7.1; N, 4.2. The third eluted fraction (R =0.03)
3
20 25
5
f
1.99; H, 6.50; N, 3.61. Found: C, 62.6; H, 6.6; N, 3.7.
turned out to be the starting material (1i) (0.04 g, yield 10%).
Reaction of 3-hydroxy-2-phenyl-2,3-dihydro-1H-isoindol-1-one
Reaction of 3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1H-
isoindol-1-one (1h). Analysis (TLC, CHCl : toluene : acetone
:3:1) of organic layer indicated the presence of three compounds
R = 0.42, 0.39, and 0.20). The first eluated fraction (R =0.42 ) was
3
(1j).
3
Analysis (TLC, CHCl ) of organic layer indicated the
6
(
presence of two compounds (R
f
= 0.15 and 0.03). The first eluted
fraction (R = 0.15) was identified as the mixture of two
f
f
f
identified as 3-hydroxy-2-(4-methoxyphenyl)-7-trimethylsilanyl-2,3-
dihydro-1H-isoindol-1-one (2h) (0.26 g; yield 40%); glass oil; IR
diastereoisomers of 3-sec-butyl-2-phenyl-2,3-dihydro-1H-isoindol-1-
ꢁ
one (3j) (0.40 g; yield 75%); mp 142–144 C (hexane); IR (KBr):
ꢀ
1
1
ꢀ1
1
(
(
2
(
film): 1683 cm (C═O); H NMR (200 MHz, CDCl
dd, J = 5.8 and 2.4 Hz, 1H, 6-H), 7.64–7.43 (m, 4H, 4,5-H, and
,6-Ar–H), 6.98–6.85 (m, 2H, 3,5-Ar–H), 6.17 (s, 1H, 3-H), 3.76
3
): d =7.70
3
1680 cm (C═O); H NMR (200 MHz, CDCl ): d = 8.02–7.85
(m, 1H, 7-H), 7.68–7.38 (m, 7H, 4,5,6-H, and 2,3,5,6-Ar–H), 7.34–
7.18 (m, 1H, 4-Ar–H), 5.25 (d, J= 3.1 Hz, 1H, 3-H of minor
diastereoisomer), 5.19 (d, J= 2.7 Hz, 1H, 3-H of major
diastereoisomer), 2.12–0.32 (m, 9H, 1,2,3-(1-methylpropyl)-H,
and Me). Ratio of diastereoisomers 4:6 (the composition of
diastereisomers was measured by integrating the 3H-proton signal).
13
s, 3H, OMe), 0.41 (s, 9H, SiMe
d = 167.21 (C═O), 157.32, 142.85, 139.33, 136.20, 131.37,
24.79, 123.81, 114.36, 82.72, 55.41, ꢀ0.70 (SiMe ). Anal. Calcd
for C H NO Si: C, 66.02; H, 6.46; N, 4.28. Found: C, 66.1; H,
3 3
); C NMR (50MHz, CDCl ):
1
3
18
21
3
13
6
.5; N, 4.3. The second eluted fraction (R =0.39) appeared to
C NMR (50MHz, CDCl ): d = 167.55, 167.35 (C═O), 143.75,
f
3
be the mixture of two diastereoisomers of 3-sec-butyl-2-(4-
methoxyphenyl)-2,3-dihydro-1H-isoindol-1-one (3h) (0.18g; yield
142.82, 137.54, 137.19, 133.45, 133.03, 131.61, 131.52, 129.14,
128.37, 128.33, 125.83, 125.59, 124.47, 124.19, 124.01, 123.24,
122.95, 66.08, 64.64, 36.71, 36.04, 23.04, 15.62, 12.32, 11.75.
ꢁ
ꢀ1
1
3
0%); mp 80–82 C (hexane); IR (film): 1686 cm (C═O); H
NMR (200 MHz, CDCl ); d =8.00–7.84 (m, 1H, 7-H), 7.80–6.80
Anal. Calcd for C H NO: C, 81.47; H, 7.22; N, 5.28. Found: C,
3
18 19
(m, 7H, 4,5,6-H and Ar–H), 5.14 (d, J = 3.1Hz, 1H, 3-H of minor
81.5; H, 7.3; N, 5.3. The second eluted fraction (R = 0.03) turned
f
diastereoisomer), 5.08 (d, J = 3.0 Hz, 1H, 3-H of major
diastereoisomer), 3.84 (s, 3H, OMe), 2.08–0.30 (m, 9H, 1,2,3-(1-
methylpropyl)-H, and Me). Ratio of diastereoisomers 4:6 (the
composition of diastereisomers was measured by integrating the
out to be the starting material (1j) (0.08 g; yield 17%).
Reaction of 3-hydroxy-4-methoxy-2-phenyl-2,3-dihydro-1H-
isoindol-1-one (1k).
3
Analysis (TLC, CHCl : acetone 95:5) of
organic layer indicated the presence of two compounds (R = 0.31
f
1
3
3
1
1
1
2
H-proton signal). C NMR (50MHz, CDCl ): d = 167.61,
and 0.12). The eluated fraction (R = 0.31) was identified as the
3
f
67.32 (C═O), 157.63, 157.45, 153.46, 153.13, 143.75, 143.11,
42.77, 136.02, 131.38, 131.27, 128.18, 126.17, 125.71, 124.05
23.99, 123.08, 122.76, 114.38, 66.54, 65.23, 55.42, 36.83, 36.10,
6.53, 23.19, 15.47, 12.23. Anal. Calcd for C H NO : C, 77.26;
mixture of two diastereoisomers of 3-sec-butyl-7-methoxy-2-
phenyl-2,3-dihydro-1H-isoindol-1-one (2k) (0.53 g; yield 90%);
ꢁ
ꢀ1
mp 145–146 C (hexane: ethyl acetate 2:8); IR (KBr): 1680 cm
1
(C═O); H NMR (200 MHz, CDCl ): d = 7.60–6.88 (m, 8H,
1
9
21
2
3
H, 7.17; N, 4.74. Found: C, 77.2; H, 7.3; N, 4.8. The third eluted
fraction (R = 0.20) turned out to be the starting material 1h
0.07 g; yield 15%).
Reaction of 3-hydroxy-4,5-dimethoxy-2-phenyl-2,3-dihydro-1H-
isoindol-1-one (1i). Analysis (TLC, hexane : ethyl acetate 8:2) of
organic layer indicated the presence of three compounds (R =0.45,
.11, and 0.03). The first eluated fraction (R = 0.45) was identified as
-hydroxy-4,5-dimethoxy-2-phenyl-7-trimethylsilanyl-2,3-dihydro-1H-
4,5,6-H, and Ar–H), 5.17 (d, 1H, J = 3.0Hz, 3-H of minor
diastereoisomer), 5.12 (d, J = 2.7 Hz, 1H, 3-H of major
diastereoisomer), 3.98 (s, 3H, OMe), 2.04–0.37 (m, 9H, 1,2,3-(1-
methylpropyl)-H, and Me). Ratio of diastereoisomers 3:7 (the
composition of diastereisomers was measured by integrating
f
(
1
3
f
3
the 3H-proton signal). C NMR (50 MHz, CDCl ): d = 166.29
0
3
f
(C═O), 158.06, 157.98, 146.70, 145.71, 137.72, 137.33, 133.18,
133.08, 128.96, 125.45, 125,18, 124.41, 123.87, 115.31, 115.00,
110.33, 65.12, 63.69, 55.77, 37.01, 36.15, 26.35, 23.18, 15.32,
12.19, 11.75. Anal. Calcd for C H NO : C, 77.26; H, 7.17; N,
ꢁ
isoindol-1-one (2i) (0.57 g; yield 45%); mp 121–123 C (hexane : ethyl
ꢀ
1
1
acetate 8:2); IR (KBr): 1700 cm (C═O); H NMR (200 MHz,
CDCl ): d =7.88–7.72 (m, 2H, 2,6-Ar–H), 7.54–7.36 (m, 2H, 3,5-Ar–
H), 7.32–7.14 (m, 2H, 6-H, and 4-Ar–H), 6.52 (br s, 1H, 3-H), 4.06
s, 3H, OMe), 3.98 (s, 3H, OMe), 2.69 (br s, 1H, OH), 0.42 (s, 9H,
19
21
2
3
4.74. Found: C, 77.3; H, 7.0; N, 4.8. The second eluted fraction
(R = 0.12) turned out to be the starting material (1j) (0.03g;
yield 5%).
f
(
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

3
62
A. Jóźwiak and M. Ciechańska
Vol 51
Acknowledgment. This work was supported by Grant-in-Aid
for Scientific Research from the University of Łódź.
J Chem Res Synop 2002, 26, 9; (e) Pérard-Viret, J.; Prangé, T.; Tomas,
A.; Royer, J. Tetrahedron 2002, 58, 5103; (f) Couture, A.; Deniau, E.;
Grandclaudon, P.; Hoarau, C.; Rys, V. Tetrahedron Lett 2002, 43, 2207.
[4] (a) Beak, P.; Kerrick, S. T.; Dallagher, D. J. J Am Chem Soc
1
993, 115, 10628; (b) Metallinos, C.; Nerdinger, S.; Snieckus, V. Org
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1
4
[
(
[
4
[
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(
(
(
(
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet