Application of the mild-condition phthalimidine synthesis with use of 1,2,3-1h-benzotriazole and 2-mercaptoethanol as dual synthetic auxiliaries. Effective synthesis of phthalimidines possessing a variety of substituents at 2-position

Article abstract of DOI:10.3987/COM-15-S(T)38

The mild-condition phthalimidine synthesis based on Mannich type 1:1 condensation reaction between o-phthalaldehyde with a variety of primary amines in the presence of excess 2-mercaptoethanol and 1,2,3-1H-benzotriazole as "dual synthetic auxiliaries" in MeCN for 13 h at room temperature afford 2-substituted phthalimidines (2,3-dihydroisoindol-1-one) in fair to good isolated yields.

Full text of DOI:10.3987/COM-15-S(T)38

HETEROCYCLES, Vol. 93, No. 2, 2016
557
HETEROCYCLES, Vol. 93, No. 2, 2016, pp. 557 - 571. © 2016 The Japan Institute of Heterocyclic Chemistry
Received, 31st August, 2015, Accepted, 24th December, 2015, Published online, 7th January, 2016
DOI: 10.3987/COM-15-S(T)38
APPLICATION OF THE MILD-CONDITION PHTHALIMIDINE
SYNTHESIS WITH USE OF 1,2,3-1H-BENZOTRIAZOLE AND
2-MERCAPTOETHANOL AS DUAL SYNTHETIC AUXILIARIES.
EFFECTIVE SYNTHESIS OF PHTHALIMIDINES POSSESSING A
VARIETY OF SUBSTITUENTS AT 2-POSITION†
Ichiro Takahashi,1,* Teruki Kawakami,1 Etsushi Hirano,1 Mako Kimino,1
Shigeki Kamimura,1 Takayuki Miwa,1 Takanori Tamura,1 Ryo Tazaki,1
Hidehiko Kitajima,1 Minoru Hatanaka,1 Kimio Isa, 1 and Shinzo Hosoi2
1Department of Applied Chemistry and Biotechnology, Faculty of Engineering,
University of Fukui, Bunkyo, Fukui 910-8507, Japan; 2The Research Center
for Pharmacy Education, Kyoto Pharmaceutical University, 5 Nakauchi-cho,
Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
E-mail: ichiro@u-fukui.ac.jp; shosoi@mb.kyoto-phu.ac.jp
Abstract — The mild-condition phthalimidine synthesis based on Mannich type
1:1 condensation reaction between o-phthalaldehyde with a variety of primary
amines in the presence of excess 2-mercaptoethanol and 1,2,3-1H-benzotriazole
as “dual synthetic auxiliaries” in MeCN for 13 h at room temperature afford
2-substituted phthalimidines (2,3-dihydroisoindol-1-one) in fair to good isolated
yields.
INTRODUCTION
Heterocyclic compounds containing phthalimidine (2,3-dihydroisoindol-1-one) skeletons have attracted a
considerable interest in recent years, because a number of fascinating natural/artificial bioactive
compound have shown clinical utility.1
In the preceding paper,2 we demonstrated the first possibility to “regulate” the double Mannich
condensation-based mild condition phthalimidine synthesis between o-phthalaldehyde (OPT) and a
primary amine (known as Thiele’s method3-5) in the presence of 1,2,3-1H-benzotriazole and 2-mercapto-
___________________________________________________________________________________
†Dedicated to Professor Lutz F. Tietze on his 75th birthday

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ethanol as dual synthetic auxiliaries. Roles of two auxiliaries interpreted in the present stage are as
follows: 2H-isoindole intermediate was first formed by assistance of excessive amount of MET, followed
by the rearrangement of the intermediate via a tethered ion pair, which was assisted by stoichiometric
amount of Bt-H. Optimized reaction condition utilizing p-toluidine as a primary amine is shown as
Scheme 1.
Substituent R
Me
Substituent R
N
Me
MET (9 equiv.)
Bt-H (1 equiv.)
CHO
CHO
H2N
+
MeCN
pH 9.6 buffer
rt, 13 h, 68%
O
(OPT)
Scheme 1
In this paper, we wish to describe the scope of this promising phthalimidine synthesis when a variety of
primary amines are adopted.6
RESULTS AND DISCUSSION
A number of commercially available primary amines were utilized to run the reaction exemplified as
Scheme 1. Both aromatic and aliphatic primary amines were tested. The results are summarized as
Table 1.
As we reported in the preceding papers,6 in order at once to avoid the polymerization of intermediate
2H-isoindoles and facilitate the isolation of phthalimidines, we carried out reaction work-ups based on
filtrations whenever products were solids. Therefore, isolated yields do not necessarily reflect reaction
conversions. However, the alternative work-up procedure, extractions, for compound 4 showed that the
isolated yields may be improved from the results in Table 1, but in 10% or so (see EXPERIMENTAL).
Therefore, we wish to evaluate the scope of our novel phthalimidine synthesis based on the isolated yields
in Table 1.
When p-substituted anilines were used as primary amines, except for some compounds prepared in fair
yields, the electronic effect of substituents (electron-donating or electron-withdrawal) did not greatly
affect yields of products (compounds 1-11). Further elongation of reaction time did not necessarily
improve isolated yields because this factor would compete with polymerization of intermediate or product
(compounds 8, 11, 18 and 19). Similar tendencies were observed in cases of m-substituted anilines,
where electronic effects were not likely to effect much on the nucleophilicity of amino groups
(compounds 12-15).

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559
Table 1. Yields and Physical Properties of Phthalimidines
Compound
R-NH2
Yield (%) mp (oC)/lit. mp (oC)g
149-152/180-182
191-191.5/-----
136-139/134
140-141.5/139-140
162-164.5/160
180-183/184-185
181-182/183
196-198/200-201
237-239/243-244
214-217/-----
1
2
3
4
5
6
7
8
9
p-NEt2-C6H4-NH2
p-NMe2-C6H4-NH2
p-OMe-C6H4-NH2
p-Me-C6H4-NH2
C6H5-NH2
p-Cl-C6H4-NH2
p-Br-C6H4-NH2
p-I-C6H4-NH2
72
73
70
68e
66
72
62
34(44)f
84
80
39(28)f
77
60
44
p-COMe-C6H4-NH2
10 p-CO2Me-C6H4-NH2
11 p-NO2-C6H4-NH2
12 m-OMe-C6H4-NH2
13 m-Me-C6H4-NH2
14 m-Cl-C6H4-NH2
15 m-NO2-C6H4-NH2
234-236/236
129-130/130-131
148.5-149.5/145
186/185.5
231-233/237-238
169-171/-----
59
49
a
16 3-C5H4-NH2
98-99/97.5-98
125/172-173
161-162/164
125-126.5/124-124.5
104-106/-----
190-191/194-195
102-105/-----
17 o-Me-C6H4-NH2
18 o-Cl-C6H4-NH2
54
27(12)f
18(33)f
80
19 o-NO2-C6H4-NH2
20 2,6-Me2-C6H3-NH2
21 2,4,6-Me3-C6H2-NH2
49
62
72
75
47
67
76
66
68
60
53
70
b
22 1-C10H7-NH2
23 p-OMe-C6H4CH2-NH2
24 C6H5CH2-NH2
25 Me-NH2
92-95/90-91
112.5-114/116-117
oil/(bp2=120-121)
oil/33.1-34.7
oil/(bp3=280-285)
107-111/-----
109-110.5/107-109
60/53.5-54
142-148/150(dec)
188-190/-----
26 MeCH2-NH2
27 MeCH2CH2-NH2
c
28 C18H36-NH2
29 rac-C6H5-CH(Me)-NH2
30 cyclo-C6H11-NH2
31 t-C4H9-NH2
32 NH3
33 C6H5-NHNH2
d
21
(a) 3-aminopyridine. (b) 1-naphthylamine. (c) oleylamine.
(d) cyclohexylamine. (e) see preceding paper. (f) 49 h-mode reaction.
(g) see experimental section for references.
When o-substituted anilines were used, they were likely to retard the reaction process itself, which was
not necessarily improved by elongated reaction periods (compounds 16-22). In turn, use of
2,6-dimethylated anilines (compounds 20 and 21) did not show as much yield decrements as those

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observed in cases of o-chloro and o-nitroanilines (compounds 18 and 19), suggesting that some specific
conformational orientation reported in cases of 2-substituted phthalimidines may possibly become
obstacles during phthalimidine-forming transition states, too.7,8
When aliphatic amines were used, isolated yields dropped more or less irrespective of alkyl groups,
although oily phthalimidines required extractions and column chromatography during isolation
(compounds 23-31).
Interestingly, the use of ammonia as a source of “primary amine” gave 2-unsubstituted phthalimidine (32)
in good isolated yields, although reaction media was alkaline.6 Even with the use of phenylhydrazine,
apparently competing hydrazone-forming reaction paths, gave desired phthalimidine (33) but in low
yield.
13
1H and C NMR spectra (see EXPERIMENTAL for those of new compounds) showed typical signal
patterns of phthalimidine derivatives, of which diagnostic chemical shifts (ppm) variations can be
interpreted in terms of substituents’ inductive effects (including spectra of known compounds, of course),
as had been reported in our previous work concerning benzotriazole (Bt)-substituted isoindolines.9 As
for electron-donating abilities, alkylamines would be likely to react faster than arylamines, although in
terms of isolated yields, significant differences were not observed. Considering that nucleophilicity do
not effect on the reaction velocity, some reaction mechanism similar to SN1 format is to be assumed.
Thus, when intermediate 2H-isoindole is formed, excessive amount of MET would work as a synthetic
auxiliary to form an immonium cation (hard) via slow process, which is followed by the immediate attack
of a nucleophile (Scheme 2).
OH
- H2O
OH
S
S
OPT + MET
O
X-
CHO
OH
II
I
H+ (from Bt-H or MET)
RNH2
OH
OH
S
O
N R
S
N R
OH
N R
H
V
III
IV
Scheme 2. Supplementary Plausible Reaction Mechanism
The present results are compared with formerly reported ones (ascertained as Thiele’s method) in Table 2.

HETEROCYCLES, Vol. 93, No. 2, 2016
561
Table 2. Comparison of Isolated Yields
Yield (%)
This Work Thiele's Methoda
Compound
R-NH2
3
4
5
6
7
p-MeO-C6H4-NH2
p-Me-C6H4-NH2
C6H5-NH2
p-Cl-C6H4-NH2
p-Br-C6H4-NH2
p-I-C6H4-NH2
p-NO2-C6H4-NH2
m-MeO-C6H4-NH2
m-Me-C6H4-NH2
m-Cl-C6H4-NH2
m-NO2-C6H4-NH2
o-Cl-C6H4-NH2
o-NO2-C6H4-NH2
1-C10H7-NH2
70
68
66
72
62
44
39
77
60
44
59
27
33
62
68
13
16
79
6
57
37
5
8
11
12
13
14
15
18
19
22
29
3
9
27
10
10
12
11
21
rac-C6H5-CH(Me)-NH2
(a) Based on ref. 4 except for 5 (ref. 3) and 29 (ref.5).
Our method as a whole provides phthalimidines in fair to good isolated yields based on facile and reliable
procedures. In addition, our method is tolerant to the synthesis of 2-alkylphthalimidines, some of which
have formerly been prepared but via methods other than Thiele’s (see EXPERIMENTAL). These
results proved that the Mannich-based synthetic method originated some 100 years ago was able to be
regulated for the first time.
It had long been known that 2-phenylphthalimidine (5) was able to be prepared by Thiele’s method in
exceptionally high isolated yield. Therefore, phthalimidines possessing substituents on aromatic ring at
2-position had formerly been prepared from 5, for which multistep procedure was indispensable. For
example, industrial synthetic schemes of anti-inflammatory agent Indoprofen required more than 10 steps
when started from 5 or 2-(4-acetylphenyl)phthalimidine (9).10,11 Our method is tolerate to the structures
of primary amines, and therefore, preparation of the amine sector in advance to phthalimidine-forming
step would abate the number of reaction steps in the procedure. Based on this idea, we planned a
short-step synthesis targeting indoprofen (Scheme 3).

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HETEROCYCLES, Vol. 93, No. 2, 2016
b
O2N
CH CO2H
O2N
CH CO2C2H5
90%
Me
Me
34
36
67%
a
80%
a
b
H2N
CH CO2H
H2N
CH CO2C2H5
42%
Me
Me
35
37
62%
O
c
O
d
N
CHCO2C2H5
Me
N
CHCO2H
Me
83%
38
39 (Indoprofen)
a) H2 (50 kg/cm2), 5% Pd-C, EtOH, rt, 45 min; b) EtOH, toluene,
p-TsOH, reflux, 12 h; c) OPT (1 eq.), Bt-H (1 eq.), MET (9 eq.), MeCN,
borate buffer (pH 9.6), rt, 13 h; d) KOH, 95% EtOH, reflux, 3 h.
Scheme 3. Short-Step Synthesis of rac-Indoprofen
First, aiming at shortest total synthesis (2 steps) from commercially available starting material, we
reduced nitro group of 34 to give primary amine 35. However, attempted phthalimidine synthesis using
above obtained 35 to give indoprofen (39) was unsuccessful. Then 35 was converted into ester 37,
which was subjected to our phthalimidine synthesis to give indoprofen ethyl ester (38) of which isolated
yield was consistent with the data shown in Table 1. Hydrolysis of 38 gave indoprofen (39). In
addition, access to 38 was improved via ester (36) in view of chemical yield. These results proved that
Indoprofen (39) can be prepared from commercially available 36 in as few as 4 steps (37% in total),
exhibiting the utility of the “dual auxiliary assisted” Mannich condensation-based phthalimidine synthesis
established by us.
CONCLUSION
Utility of dual synthetic auxiliaries (Bt-H and MET) in Mannich type condensation reaction between OPT
and primary amine exhibited that famous method originated by Thiele and co-workers became tacit and
reliable phthalimidine-forming procedure for the first time. Further exploitation along this line is now
underway in these laboratories.
EXPERIMENTAL
General Information. All melting points are uncorrected. Infrared (ir) spectra were measured with a
Shimadzu IR-430 grating infrared spectrophotometer and a JASCO FT/IR-8000 Fourier transform

HETEROCYCLES, Vol. 93, No. 2, 2016
563
13
infrared spectrometer. 1H (270 MHz) and C (67.5 MHz) nuclear magnetic resonance (nmr) spectral
measurements were carried out with a JEOL JNM-GX200 Fourier transform NMR spectrometer. All
signals are expressed as ppm downfield from tetramethylsilane (TMS) used as an internal reference (
value). The following abbreviations are used: singlet(s), doublet(d), triplet(t), quartet(q), multiplet(m),
broad(b). Positional numbers are assembled as follows: no prime, isoindole ring; single prime,
substituent at 2-position. Mass spectra (ms; EI and FAB modes) were taken with a JEOL JMS DX-303
mass spectrometer, where mass numbers of local maxima (relative intensities in parentheses) are
recorded.
Typical Experimental Procedure for the Preparation of Phthalimidine (2,3-Dihydroisoindol-1-one).
Method A. Preparation of 2-[p-(N,N-Diethylamino)phenyl]phthalimidine (1).
To a solution of o-phthaldehyde (OPT; 1.341 g, 10 mmol) in MeCN (30 mL) was added successively (i) a
solution of 2-mercaptoethanol (MET; 6.0 mL, 86 mmol) in MeCN (10 mL) over 3 min, (ii) a solution of
N,N-diethylphenylenediamine (1.720 g, 10 mmol) in MeCN (10 mL) over 2 min, (iii)
1,2,3-1H-benzotriazole (1.191 g, 10 mmol) portionwise over 2 min, and (iv) pH 9.6 buffer (0.05 M
H3BO3-KCl-NaOH; 5 mL) over 3 min with stirring at room temperature. After the additions were
complete, the mixture was further stirred at room temperature for 13 h under N2., and then evaporated.
After storage in refrigerator for 3 h, the resulting solids were filtered, washed successively with ice-cold
o
Et2O and water, and then dried in vacuo to give crude phthalimidine (1.956 g, mp 145-206 C). The
filtrate was evaporated and diluted with water (100 mL). The further resulting solids were filtered,
washed successively with ice-cold Et2O and water, and then dried in vacuo to give another crop of crude
o
product (0.376 g, mp 142-224 C). Both of the crude samples were combined (2.432 g, 87%) and
subjected to recrystallization from MeOH to give the analytically pure sample of
o
2-[4-(N,N-diethylamino)phenyl]phthalimidine (1; 2.094 g, 72%, mp 149-152 C) as lemon-yellow
needles.
Compounds 3-7, 9-16, 21, 22, 24, and 30 were also prepared from the corresponding primary amines
using the similar procedure to that described above. In cases of compounds 2 and 8, precipitates
appeared during 13 h reaction time, so the reaction mixture was first filtered to collect crude
phthalimidine, followed by the work-up described above.
Typical Experimental Procedure for the Preparation of Phthalimidine.
Method B. Preparation of 2-(o-chlorophenyl)phthalimidine (18).
To a solution of o-phthaldehyde (OPT; 1.341 g, 10 mmol) in MeCN (30 mL) was added successively (i) a
solution of 2-mercaptoethanol (MET; 6.0 mL, 86 mmol) in MeCN (10 mL) over 5 min, (ii) a solution of

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o-chloroaniline (1.276 g, 10 mmol) in MeCN (10 mL) over 5 min, (iii) 1,2,3-1H-benzotriazole (1.191 g,
10 mmol) portionwise over 4 min, and (iv) pH 9.6 buffer (0.05 M H3BO3-KCl-NaOH; 5 mL) over 1 min
with stirring at room temperature. After the additions were complete, the mixture was further stirred at
room temperature for 13 h under N2., and then evaporated. After storage in refrigerator for 1 h (no
precipitates appeared), the residue was dissolved in CHCl3, washed successively with 2 N HCl, sat.aq.
NaHCO3, and then dried over anhyd. Na2SO4. Filtration followed by evaporation in vacuo gave crude
o
phthalimidine (1.72 g, 80%, mp 85-93 C), which was recrystallized from Et2O to give the analytically
o
pure sample of 2-(o-chlorophenyl)phthalimidine (18; 1.248 g, 60%, mp 109-110 C) as colorless cubic
prisms.
Compounds 8 (49 h-mode), 11 (49 h-mode), 17, 18 (49 h-mode), 19 (both 13 h- & 49 h-modes), 20, 23,
29, and 31-33 were also prepared from the corresponding primary amines using the similar procedure to
that described above.
Typical Experimental Procedure for the Preparation of Phthalimidine.
Method C. Preparation of 2-(1-propyl)phthalimidine (27).
To a solution of o-phthaldehyde (OPT; 1.341 g, 10 mmol) in MeCN (30 mL) was added successively (i) a
solution of 2-mercaptoethanol (MET; 6.0 mL, 86 mmol) in MeCN (10 mL) over 2 min, (ii) a solution of
n-propylamine (0.591 g, 10 mmol) in MeCN (10 mL) over 1 min, (iii) 1,2,3-1H-benzotriazole (1.191 g,
10 mmol) portionwise over 1 min, and (iv) pH 9.6 buffer (0.05 M H3BO3-KCl-NaOH; 5 mL) over 1 min
with stirring at room temperature. After the additions were complete, the mixture was further stirred at
room temperature for 13 h under N2., and then evaporated.
The crude material (3.60 g) was subjected to column chromatographic purifications (silica gel,
C6H6-AcOEt = 4:1 in the first column; C6H6-AcOEt = 6:1 in the second column) to give the crude
1
phthalimidine (0.687 g, lemon-yellow oil; pure from H NMR spectra) and a mixture of phthalimidine
and recovered Bt-H (2.183 g), the latter of which was washed with sat. a.q. NaHCO3 to give another
portion of phthalimidine (0.371 g, lemon-yellow oil; pure from 1H NMR spectra). Total yield was 60%.
Compounds 25, 26, and 28 were also prepared from the corresponding primary amines using the similar
procedure to that described above.
1H NMR spectral and combustion analytical data were recorded for compounds 1 and 18 (known),
because our melting points were apart from those previously reported. Physical data of phthalimidines
(1-33) are as follows.
2-[p-(N,N-Diethylamino)phenyl]phthalimidine (1). Lemon-yellow needles from MeOH; mp 149-152

HETEROCYCLES, Vol. 93, No. 2, 2016
565
oC (lit.,12 mp 180-182 oC). 1H NMR (CDCl3) 7.90 (1H, dd, J = 7 Hz and 1 Hz, H-7), 7.60 (2H, d, J = 9
Hz, H-2’ and 6’), 7.54 (1H, ddd, J = 7 Hz, 7 Hz, and 1 Hz, H-5), 7.52-7.40 (2H, m, H-4 and 6), 6.72 (2H,
d, J = 9 Hz, H-3’ and 5’), 4.76 (2H, s, H-3), 3.35 (4H, q, J = 7 Hz, NCH2), 1.16 (6H, t, J = 7 Hz, NCH3).
Anal. Calcd for C18H20N2O: C, 77.11; H, 7.19; N, 9.99. Found: C, 77.06; H, 7.41; N, 10.02.
2-[p-(N,N-Dimethylamino)phenyl]phthalimidine (2).
Lemon-yellow needles from MeOH; mp
191-191.5 oC. 1H NMR (CDCl3) 7.90 (1H, dd, J = 8 Hz and 1 Hz, H-7), 7.65 (2H, d, J = 9 Hz, H-2’
and 6’), 7.55 (1H, ddd, J = 7 Hz, 7 Hz, and 1 Hz, H-5), 7.51-7.43 (2H, m, H-4 and 6), 6.78 (2H, d, J = 9
Hz, H-3’ and 5’), 4.76 (2H, s, H-3), 2.94 (6H, s, NCH3). 13C NMR (CDCl3) 166.8 (C=O), 147.7
(C-4’), 140.1 (C-3a), 133.3 (C-7a), 131.3 (C-5), 129.0 (C-1’), 127.9 (C-7), 123.5 (C-4), 122.3 (C-6),
121.1 (C-2’ and 6’), 112.7 (C-3’ and 5’), 50.9 (C-3), 40.5 (NCH3). IR (KBr): max (cm-1) 1676 (C=O),
1618, 816, 731. MS (EI): m/z (rel. intensities) 252 (M+, 29), 239 (100), 224 (69), 211 (6), 196 (14), 165
(32), 149 (13), 137 (9), 103 (12), 89 (16), 69 (33), 59 (52), 45 (31). Anal. Calcd for C16H16N2O: C,
76.16; H, 5.99 N, 11.10. Found: C, 76.32; H, 6.29; N, 11.15.
o
2-(p-Methoxyphenyl)phthalimidine (3). White leaflets from MeOH; mp 136-139 C (lit.,13 mp 134
oC).
o
2-(p-Methylphenyl)phthalimidine (4). White crystalline solids from MeOH; mp 140-141.5 C.2
Preparation using the procedure similar to that of method C raised the isolated yield of 4 upto 82%.
2-Phenylphthalimidine (5). White small leaflets from dioxane; mp 162-164.5 oC (lit.,13 mp 160 oC).
o
2-(p-Chlorophenyl)phthalimidine (6). White small leaflets from dioxane; mp 180-183 C (lit.,4 mp
184-185 oC).
o
2-(p-Bromophenyl)phthalimidine (7). White small leaflets from dioxane; mp 181-182 C (lit.,4 mp
183 oC).
o
2-(p-Iodophenyl)phthalimidine (8). White small leaflets from dioxane; mp 196-198 C (lit.,4 mp
200-201 oC).
o
2-(p-Acetylphenyl)phthalimidine (9). Lemon-yellow leaflets from dioxane; mp 237-239 C (lit.,10 mp
243-244 oC).
2-(p-Methoxycarbonylphenyl)phthalimidine (10). Slightly lemon-yellow small leaflets from dioxane;
mp 215-217 oC. 1H NMR (CDCl3)  8.08 (2H, d, J = 9 Hz, H-3’ and 5’), 7.98 (2H, d, J = 9 Hz, H-2’
and 6’), 7.91 (1H, d, J = 7 Hz, H-7), 7.62 (1H, ddd, J = 7 Hz, 7 Hz, and 1 Hz, H- 5), 7.52 (1H, d, J = 8 Hz,
H-4), 7.51 (1H, dd, J = 8 Hz and 7 Hz, H-6), 4.87 (2H, s, H-3), 3.91 (3H, s, CO2CH3). 13C NMR
(DMSO-d6) 166.7 (C=O of C-1), 165.6 (C=O of ester), 143.4 (C-1’), 140.7 (C-1’), 132.1 (C-5), 132.0
(C-7a), 129.8 (C-3’ and 5’), 127.9 (C-7), 125.0 (C-4’), 123.1 (C-4), 122.9 (C-6), 118.3 (C-2’ and 6’), 51.2
(CO2CH3), 50.2 (C-3). IR (KBr): max (cm-1) 1714 (C=O), 1603, 857, 772, 737. MS (EI): m/z (rel.

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intensities) 267 (M+, 100), 236 (77), 208 (16), 180 (4), 152 (4), 104 (8), 90 (11), 76 (9), 63 (4), 51 (3).
Anal. Calcd for C16H13NO3: C, 71.90; H, 4.96; N, 5.24. Found: C, 71.76; H, 4.82; N, 5.04.
o
2-(p-Nitrophenyl)phthalimidine (11). Lemon-yellow small leaflets from dioxane; mp 234-236 C
(lit.,4 mp 236 oC).
2-(m-Methoxyphenyl)phthalimidine (12). Beige crystalline solids from dioxane; mp 129-130 oC (lit.,4
mp 130-131 oC).
o
2-(m-Methylphenyl)phthalimidine (13). White crystalline solids from dioxane; mp 148.5-149.5 C
(lit.,4 mp 145 oC).
2-(m-Chlorophenyl)phthalimidine (14). White small needles from dioxane; mp 186 oC (lit.,4 mp 185.5
oC).
o
2-(m-Nitrophenyl)phthalimidine (15). Lemon-yellow prisms from dioxane; mp 231-232 C (lit.,4 mp
237-238 oC).
o
2-(3-Pyridyl)phthalimidine (16). Beige powders from dioxane; mp 169-171 C. 1H NMR (CDCl3)
8.94 (1H, d, J = 3 Hz, H-2’), 8.46 (1H, ddd, J = 7 Hz, 3 Hz, and 2 Hz, H-4’), 8.40 (1H, dd, J = 5 Hz and
1 Hz, H-6’), 7.88 (1H, d, J = 8 Hz, H-7), 7.61 (1H, ddd, J = 8 Hz, 8 Hz, and 6 Hz, H-5), 7.53 (1H, d, J = 7
Hz, H-4), 7.49 (1H, dd, J = 7 Hz and 7 Hz, H-6), 7.33 (1H, dd, J = 8Hz and 5 Hz, H-5’), 4.85 (2H, s, H-3).
13C NMR (CDCl3) 167.8 (C=O), 145.3 (C-4’), 140.0 (C-3a), 139.9 (C-2’), 136.2 (C-1’), 132.5 (C-5),
132.3 (C-7a), 128.5 (C-7), 126.3 (C-6’), 124.1 (C-5’), 123.6 (C-4), 122.7 (C-6), 49.9 (C-3). IR (KBr):

max (cm-1) 1701 (C=O), 1599, 804, 733, 702. MS (EI): m/z (rel. intensities) 211 [(M+1)+, 100], 210 (M+,
29), 183 (25), 168 (3), 155 (4), 133 (4), 119 (3), 105 (21), 89 (15), 78 (26), 63 (9), 51 (15). Anal. Calcd
for C13H10N2O: C, 74.27 H, 4.79; N, 13.32. Found: C, 74.07; H, 4.87; N, 13.42.
o
2-(o-Methylphenyl)phthalimidine (17). Slightly yellow prisms from Et2O; mp 98-99 C (lit.,8 mp
97.5-98 oC).
o
2-(o-Chlorophenyl)phthalimidine (18). White crystalline solids from dioxane; mp 125 C (lit.,4 mp
172-173 oC). 1H NMR (acetone-d6) 7.90 (1H, dd, J = 7 Hz and 1 Hz, H-7), 7.63 (1H, ddd, J = 7 Hz, 6
Hz, and 2 Hz, H-5), 7.53 (1H, ddd, J = 7 Hz, 7 Hz, and 2 Hz, H-6), 7.52 (1H, d, J = 7 Hz, H-4), 7.43 (1H,
ddd, J = 7 Hz, 7 Hz, and 2 Hz, H-5’), 7.40-7.30 (3H, m, H-3’, 4’ and 6’), 4.82 (2H, s, H-3). Anal. Calcd
for C14H10ClNO: C, 69.00; H, 4.14; N, 5.75. Found: C, 69.15; H, 4.05; N, 5.55.
o
2-(o-Nitrophenyl)phthalimidine (19). Yellow powders from dioxane; mp 161-162 C (lit.,4 mp 164
oC).
2-(2,6-Dimethylphenyl)phthalimidine (20). White needles from hexane-AcOEt (2:1); mp 125-126.5
oC (lit.,8 mp 124-124.5 oC).
o
2-(2,4,6-Trimethylphenyl)phthalimidine (21). Slightly yellow prisms from Et2O; mp 104-106 C.

HETEROCYCLES, Vol. 93, No. 2, 2016
567
1H NMR (CDCl3) 7.94 (1H, dd, J = 8 Hz and 1 Hz, H-7), 7.58 (1H, ddd, J = 8 Hz, 8 Hz, and 1 Hz, H-5),
7.50 (1H, d, J = 7 Hz, H-4), 7.49 (1H, dd, J = 7 Hz and 7 Hz, H-6), 6.96 (2H, s, H-3’ and 5’), 4.56 (2H, s,
H-3), 2.30 (3H, s, CH3-4’), 2.13 (6H, s, CH3-3’ and 5’). 13C NMR (CDCl3)  167.8 (C=O), 141.6
(C-3a), 138.1 (C-4’), 136.3 (C-2’and 6’), 132.8 (C-4’), 132.3 (C-7a), 131.5 (C-5), 129.2 (C-3’ and 5’),
128.0 (C-7), 124.1 (C-4), 122.8 (C-6), 51.2 (C-3), 20.9 (ArCH3-4’), 17.8 (ArCH3-2’ and 6’). IR (KBr):
max (cm-1) 1694 (C=O), 1608, 852, 736. MS (EI): m/z (rel. intensities) 252 [(M+1)+, 76], 251 (M+, 5),
235 (5), 207 (5), 180 (2), 133 (37), 121 (99), 106 (19), 97 (4), 90 (13), 77 (10), 63 (5), 51 (4), 39 (6), [28
(100) = N2]. Anal. Calcd for C17H17NO: C, 81.24; H, 6.82; N, 5.57. Found: C, 81.24; H, 6.79; N, 5.29.
o
2-(1-Naphthyl)phthalimidine (22). Slightly beige prisms from dioxane; mp 190-191 C (lit.,4 mp
194-195 oC).
2-[(p-Methoxyphenyl)methyl]phthalimidine (23). Slightly gray small needles from AcOEt; mp
102-105 oC. 1H NMR (CDCl3)  7.86 (1H, d, J = 7 Hz, H-7), 7.48 (1H, ddd, J = 7 Hz, 6 Hz and 1 Hz,
H-5), 7.42 (1H, dd, J = 8 Hz and 7 Hz, H-6), 7.35 (1H, d, J = 7 Hz, H-4), 7.23 (2H, d, J = 8 Hz, H-2’ and
6’), 6.84 (2H, d, J = 8 Hz, H-3’ and 5’), 4.72 (2H, s, H-3), 4.21 (2H, s, ArCH2), 3.76 (3H, s, OCH3). 13C
NMR (CDCl3) 168.3 (C=O), 159.0 (C-4’), 141.1 (C-3a), 132.7 (C-7a), 131.2 (C-5), 129.4 (C-2’ and 6’),
129.1 (C-1’), 127.9 (C-7), 123.7 (C-4), 122.6 (C-6), 114.0 (C-3’ and 5’), 55.2 (OCH3), 49.2 (C-3), 45.7
(C-). IR (KBr): max (cm-1) 1672 (C=O), 1585, 1242, 1028, 833, 814, 733. MS (EI): m/z (rel.
intensities) 254 [(M+1)+, 100], 253 (M+, 47), 239 (6), 223 (7), 211 (2), 195 (2), 169 (2), 146 (12), 122
(67), 110 (9), 91 (31), 77 (19), 70 (4), 65 (9), 51 (9), 43 (48). Anal. Calcd for C16H15NO2: C, 75.87; H,
5.97; N, 5.53. Found: C, 75.77; H,5.94; N, 5.25.
o
2-(Phenylmethyl)phthalimidine (24). White crystalline solids from AcOEt; mp 92-95 C (lit.,14 mp
90-91 oC).
2-Methylphthalimidine (25).
White crystalline solids from chromatographic purification; mp
112.5-114 oC (lit.,15 mp 116-117 oC).
2-Ethylphthalimidine (26). Slightly yellow oil from chromatographic purification (lit.,15 bp2 120-121
oC).
2-Propylphthalimidine (27). Lemon-yellow oil from chromatographic purification (lit.,16 mp 33.1-34.7
oC).
2-Oleylphthalimidine (28). Lemon-yellow oil from chromatographic purification (lit.,17 bp3 280-285
oC).
2-(rac--Phenethyl)phthalimidine (29). White small prisms from AcOEt-hexane (1:1); mp 107-111
oC (lit.,5,18 no mp data indicated).
2-Cyclohexylphthalimidine (30). Colorless cubic prisms fron Et2O; mp 109-110 oC (lit.,17 mp 107-109

568
HETEROCYCLES, Vol. 93, No. 2, 2016
oC).
o
2-(tert-Butyl)phthalimidine (31). Colorless thin needles from dioxane; mp 60 C (lit.,15 mp 53.5-54
oC).
o
Phthalimidine (32). White crystalline solids fron chromatographic purification; mp 142-148 C (dec.)
[lit.,19 150 oC (dec.)].
o
2-(Phenylamino)phthalimidine (33). Lemon-yellow powders from dioxane; mp 188-190 C. 1H
NMR (CDCl3) 7.85 (1H, d, J = 7 Hz, H-7), 7.70 (1H, s, NH), 7.63 (1H, dd, J = 8 Hz and 7 Hz, H-5),
7.58-7.48 (2H, m, H-4 and 6), 7.19 (2H, dd, J = 8 Hz and 7 Hz, H-3’ and 5’), 6.82 (1H, t, J = 7 Hz, H-4’),
6.71 (2H, d, J = 7 Hz, H-2’ and 6’), 4.63 (2H, s, H-3). 13C NMR (CDCl3) 167.7 (C=O), 146.5 (C-1’),
139.8 (C-3a), 132.0 (C-5), 131.0 (C-7a), 129.2 (C-3’ and 5’), 128.2 (C-7), 124.1 (C-4), 123.0 (C-6), 121.0
(C-4’), 113.3 (C-2’ and 6’), 51.1 (C-3). IR (KBr): max (cm-1) 1691 (C=O), 1523, 1496, 1173, 736.
MS (EI): m/z (rel. intensities) 224 (M+, 100), 132 (35), 104 (37), 90 (58), 77 (89), 65 (60), 51 (56), 39
(37). Anal. Calcd for C14H12N2O: C, 74.98; H, 5.39; N, 12.49. Found: C, 74.68; H, 5.37; N, 12.38.
Preparation of rac-2-(4-aminophenyl)propanoic acid (35) from 34.
A solution of 2-(4-nitrophenyl)propanoic acid (34; 5.00 g, 25 mmol) in EtOH (100 mL) was poured into
an autoclave. After the suspension of 5% Pd-C (0.625 g), the apparatus was sealed and filled with H2
(50kg/cm2). The mixture was stirred at room temperature for 45 min. The reaction mixture was
o
1
filtered and evaporated in vacuo to give the crude product (4.21 g, 100%, mp 131-132 C; pure from H
NMR spectra). Recrystallization from dioxane gave the analytically pure sample of aminoacid (35;
3.96 g, 93%, mp 133-134 oC) (lit.,20 no mp data indicated) as beige granules.
Preparation of ethyl rac-2-(4-nitrophenyl)propanoate (36) from 34.
Acid (34; 3.90 g, 20 mmol) and p-toluenesulfonic acid monohydrate (3.44 g, 20 mmol) were dissolved in
anhyd. EtOH (80 mL) and the mixture was heated at reflux for 24 h with stirring, eliminating water by
use of a Dean-Stark apparatus filled with molecular sieves (4A). After cooled to room temperature, the
reaction mixture was evaporated in vacuo, and the residue was dissolved in AcOEt, washed successively
with sat. aq. NaHCO3 and sat. a.q. NaCl, and then dried over anhyd. MgSO4. Filtration followed by
evaporation in vacuo gave the crude product as a yellow oil (5.30 g), which was further purified by
column chromatography (silica gel, C6H6-AcOEt = 6:1) to give analytically pure sample of ethyl ester
(36; 4.02 g, 90%) as a lemon-yellow oil.
Physical properties of compound 36 were as follows: 1H NMR (CDCl3) 8.19 (2H, d, J = 9 Hz, H-3 and
5), 7.49 (2H, d, J = 9 Hz, H-2 and 6), 4.15 (2H, AB-quartet type m, CH2CH3), 3.84 (1H, q, J = 7 Hz,

HETEROCYCLES, Vol. 93, No. 2, 2016
569
H-2’), 1.55 (3H, d, J = 7 Hz, H-3’), 1.22 (3H, t, J = 7 Hz, CH2CH3). 13C NMR (CDCl3) 173.0 (C=O),
147.8 (C-1), 146.8 (C-4), 128.4 (C-2), 123.6 (C-3), 61.0 (OCH2), 45.2 (C-2’), 18.2 (C-3’), 13.8 (CH2CH3).
IR (neat): max (cm-1) 2984, 1732, 1625, 1522, 1348, 1178, 1072, 1024, 858, 741, 698. MS (EI): m/z (rel.
intensities) 223 (M+, 15), 193 (4), 178 (6), 150 (41), 134 (12), 120 (15), 103 (60), 91 (100), 77 (33), 63 (7),
51 (9), 39 (10). Anal. Calcd for C11H13NO4: C, 59.19; H, 5.87; N, 6.27. Found: C, 58.96; H, 5.73; N,
5.99.
Preparation of ethyl rac-2-(4-aminophenyl)propanoate (37) from 35.
Aminoacid (35; 0.352 g, 2.09 mmol) and p-toluenesulfonic acid monohydrate (0.405 g, 2.13 mmol) were
dissolved in anhyd. EtOH (30 mL) and the mixture was heated at reflux for 18 h with stirring, eliminating
water by use of a Dean-Stark apparatus filled with molecular sieves (4A). After cooled to room
temperature, the reaction mixture was evaporated in vacuo, and the residue was dissolved in AcOEt,
washed successively with conc. NH4OH, sat. aq. NaHCO3 and sat. a.q. NaCl, and then dried over anhyd.
Na2SO4. Filtration followed by evaporation in vacuo gave the crude product (37; 0.386 g, 96%; pure
1
o
from H NMR spectra) as a red viscous oil (lit.,21 bp0.8 120-122 C). This sample was subjected to the
reaction (preliminary) with OPT without further purification.
Preparation of ester (37) from 36.
A solution of ethyl 2-(4-nitrophenyl)propanoate (36; 3.35 g, 15 mmol) in EtOH (80 mL) was poured into
an autoclave. After the suspension of 5% Pd-C (0.5 g), the apparatus was sealed and filled with H2
(50kg/cm2). The mixture was stirred at room temperature for 45 min. The reaction mixture was
filtered and evaporated in vacuo to give the crude product (3.82 g), which was washed with AcOEt.
o
After the removal of insoluble material (0.40 g, mp > 260 C), purification by column chromatography
(silica gel, C6H6-AcOEt = 4:1) gave the analytically pure sample of aminoester (37; 2.33 g, 80%) as a
yellow oil. This sample was subjected to the reaction with OPT without further purification.
Preparation of rac-Indoprofen ethyl ester (38) from 37.
To a solution of o-phthalaldehyde (OPT; 1.340 g, 10 mmol) in MeCN (30 mL) was added successively (i)
a solution of 2-mercaptoethanol (MET; 6.0 mL, 86 mmol) in MeCN (10 mL) over 2 min, (ii) a solution of
ethyl ester (37; 1.930 g, 10 mmol) in MeCN (10 mL) over 2 min, (iii) 1,2,3-1H-benzotriazole (Bt-H;
1.191 g, 10 mmol) portionwise over 2 min, and (iv) pH 9.6 borate buffer (0.05 M H3BO3-KCl-NaOH; 5
mL) over 2 min with stirring at room temperature. After the additions were complete, the mixture was
further stirred at room temperature for 13 h under N2, and then evaporated. The residue was dissolved in
CHCl3, washed successively with sat. a.q. NaHCO3, 2N HCl, and sat. a.q. NaCl, and then dried over

570
HETEROCYCLES, Vol. 93, No. 2, 2016
anhyd. Na2SO4. Filtration followed by evaporation gave the crude material (3.40 g), which was purified
by column chromatography (silica gel, C6H6-AcOEt = 5:1) to give the crude phthalimidine (38; 1.91 g,
62%, 105-107 oC; pure from 1H NMR spectra) as beige crystalline solids. Chromatographically-purified
sample was immediately subjected to combustion analyses.
Physical properties of compound 38 were as follows: 1H NMR (CDCl3) 7.92 (1H, dd, J = 7 Hz and 1 Hz,
H-7), 7.82 (2H, d, J = 8 Hz, H-2’), 7.60 (1H, ddd, J = 7 Hz, 7 Hz, and 1 Hz, H-5), 7.52 (1H, d, J = 8 Hz,
H-4’), 7.50 (1H, dd, J = 8 Hz and 8 Hz, H-6), 7.37 (2H, d, J = 8 Hz, H-3’), 4.85 (2H, s, H-3), 4.22-4.04
(2H, AB-quartet type m, CH2CH3), 3.72 (1H, q, J = 7 Hz, CHCH3), 1.51 (3H, d, J = 7 Hz, CHCH3), 1.22
(3H, t, J = 7 Hz, CH2CH3). 13C NMR (CDCl3) 174.5 (C=O of ester), 167.5 (C=O of C-1), 140.1
(C-3a), 138.4 (C-4’), 136.8 (C-1’), 133.2 (C-7a), 132.1 (C-5), 128.4 (C-7), 128.2 (C-3’ and 5’), 124.2
(C-4), 122.6 (C-6), 119.6 (C-2’ and 6’), 60.8 (OCH2), 50.7 (C-3), 45.0 (CHCH3), 18.5 (CHCH3), 14.1
(CH2CH3). IR (KBr): max (cm-1) 3337, 2976, 2934, 1676 (C=O), 1516, 1385, 1205, 1172, 1055, 787,
747, 691. MS (EI): m/z (rel. intensities) 309 (M+, 36), 279 (18), 236 (100), 218 (25), 192 (15), 167 (38),
149 (54), 104 (50), 90 (39), 77 (44), 65 (34), 57 (52), 41 (71). Anal. Calcd for C19H19NO3: C, 73.77; H,
4.53; N, 6.19. Found: C, 73.47; H, 6.17; N, 4.39.
Preparation of rac-Indoprofen (39) from 38.
To a solution of ester (38; 100 mg, 0.32 mmol) in EtOH (19 mL) was added 10% KOH (1 mL), and the
mixture was heated at reflux for 3 h. After cooled to room temperature, the reaction mixture was
evaporated in vacuo, and the residue was dissolved in cold water (10 mL). Acidification of aqueous
solution gave precipitates, which were collected by filtration. Since the crude material was very
hygroscopic, it was immediately recrystallized from EtOH to give the analytically pure sample of
o
o
1
rac-indoprofen [39; 78 mg, 83%, mp 205-207 C (lit.,10 213-214 C); pure from H NMR spectra] as
slightly yellow crystalline solids.
The result of combustion analyses proved that our sample was hydrated: Anal. Calcd for
C17H15NO3+1/3H2O: C, 71.07; H, 5.50; N, 4.87. Found: C, 71.01; H, 5.44; N, 4.63.
ACKNOWLEDGMENTS
This work was supported in part by Grant-in-Aid for Scientific Research (A1) from the Research
Foundation for the Electrotechnology of Chubu. Authors are grateful to the central laboratory of
analysis in the department of pharmaceutical sciences (University of Tokyo) and Dr. Shingo Yasuda
(Fukuju Pharmaceutical Co. Ltd.) for the courtesy of microanalysis. We thank Dr. Makoto Nakajima
(University of Kumamoto) for some old liretature searches. We are also indebted to Dr. Alan R.
Katritzky (University of Florida) for useful discussions.

HETEROCYCLES, Vol. 93, No. 2, 2016
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