Application of phthalimidine synthesis with use of 1,2,3-1H-benzotriazole and 2-mercaptoethanol as dual synthetic auxiliaries. 2.1 Effective synthesis of phthalimidines possessing bulky group at 2-position

Article abstract of DOI:10.3987/COM-00-S(I)104

Potentially bioactive phthalimidines are prepared in fair to good isolated yields by the 1:1 condensation reaction of o-phthalaldehyde with a variety of sterically-hindered primary alkyl amines in the presence of 1,2,3-1H-benzotriazole and 2-mercaptoethan

Full text of DOI:10.3987/COM-00-S(I)104

HETEROCYCLES, Vol. 54, No. 2, pp. 635-638, Received, 8th November, 2000
APPLICATION OF PHTHALIMIDINE SYNTHESIS WITH USE
OF 1,2,3-1H-BENZOTRIAZOLE AND 2-MERCAPTOETHANOL
1
AS DUAL SYNTHETIC AUXILIARIES.
2.
EFFECTIVE
SYNTHESIS OF PHTHALIMIDINES POSSESSING BULKY
†
GROUP AT 2-POSITION
,
a
a
a
a
Ichiro Takahashi,* Teruki Kawakami, Mako Kimino, Etsushi Hirano,
Shigeki Kamimura,a Takanori Tamura,a Hidehiko Kitajima,a Minoru
a
a
a
b
Hatanaka, Hiroyuki Uchida, Akihiko Nomura, and Motohiro Tanaka
a
Dep artment of Ap plied C hemistr y and B iotechn olo gy, Faculty o f
Engineering, Fukui University, Bunkyo, Fukui 910-8507, Japan
b
Can cer Research Ins titute, K anazawa Un iversity, Tak ara-machi,
Kanazawa 920-0934, Japan
Abs tract
-
Potentially bioactive phthalimidines are prepared in fair to
g o o d is o lated y ield s b y th e 1 :1 co n d en s atio n r eactio n o f o -
phthalaldehyde with a variety of sterically-hindered primary alkyl amines
in the pr esence o f 1, 2, 3- 1H-benzo triazole and 2-mercaptoethanol as
dual synthetic auxiliaries.
Heterocyclic compounds containing phthalimidine (2, 3-dihydroisoindol-1-one) skeletons
hav e attr acted co ns iderable sy nthetic in ter es t in r ecen t year s, becaus e a nu mb er o f
fascinating natural/artificial bioactive compounds such as staurosporine (protein kinase C
inhibitor), indoprofen (antiinflammatory agent) , and DN-2327 (also known as pazinaclone;
2
anxiolytic agent) have been found to have clinical utilities.
Me
O
X
Z
R1
C R2
R3
Me
Me
Q
N C
Y
N
Me
O
1
2
X, Y, Z, Q = H, F, Cl, Br, OMe
_____________________________________
_
†
th
Dedicated to Professor Shô Itô on his 77 birthday.

Synth etic 1-sub stitu ted 3 -phen ylpyr rolid inon es (1 ), wh ich h ave r ecently been us ed as
herbicides in Chinese soils, can be character ized by sterically-hindered alkyl group at 2 -
3
pos ition .
S ince the s tru cture o f p hthalimidine is dedu ced as b en zop yr rolid ino ne,
phthalimidine counterpart (2 ) of these pyrrolidinone herbicides attract our attention as clues
to highly bioactive skeletons.
In general, past phthalimidine syntheses have largely depended on the Clemmensen-typ e
4
reduction of corresponding phthalimide, where 2- tert-butylph thalimidine was the only
example known in literature to date; it is anticipated that severe acidic conditions may not be
tolerant to tertiary alkyl groups. On the other hand, present pyrrolidinone syntheses involve
3
the aldol-type condensation to form C3-C4 linkage as key steps, which are not applicable to
the formation of phthalimidine skeletons.
In this communication, we describe the effective preparation of phthalimidine derivatives
having sterically-hindered alkyl group at 2-position, applying the recently unveiled mild-
condition method based on the double Mannich reaction mediated by weak protonic acids as
1
,5
synthetic auxiliary.
Bt-H (1 eq.)
MET (9 eq.)
CHO
CHO
+
N R
H N R
2
pH 9.6 buffer
MeCN, rt
O
3
(OPT)
4
2
Sterically-hindered primary alkyl amines are either availed co mmercially o r prepared b y
6
means of the Ritter reaction from corresponding alcohols. The standard experimental
procedure is as follows. To a solution of o-phthalaldehyde (3 ; OPT; 5 mmol) and 2-
mercaptoethanol (MET; 43 mmol) in MeCN (15 mL) are added successively a solution of
primary amine (4; 5 mmol) in MeCN (5 mL), 1,2, 3-1H-benzotriazole (Bt-H; 5 mmol), and pH
9
. 6 buffer (0. 05 M H BO -KCl-NaOH, 3 mL) for over 1 min each. The mixture is stirred at
3 3
room temperature for 13 h. In the case where an intermediate precipitate is formed in course
of reaction, the reaction time is prolonged until the reaction mixture becomes a clear solution
and no starting material (3 ) is detected. After evaporation of solvent, the residue is dissolved
in CHCl (30 mL), then the organic layer is washed successively with 2 M HCl and satd. aq.
3
NaHCO , and then dried over Na SO . Filtration followed by evaporation of solvent gives a
3
2
4
crude product, which is subjected to column chromatography (silica gel) for purification.
Results are summarized in Table 1.
Aqueous washings during work-ups are indispensable if crude phthalimidine is "reluctant" to
solidify, which may reduce isolated yields when hydrophobic group is relatively small (Runs
2
and 5). Wh en trity lamine is used as the primary amine, the y ield is lowered by an
unexpected formation of ditritylamine (Run 10). Otherwise, the isolated y ields of 2 -

Table 1. Results Using Sterically-Hindered Primary Amines.
Run
R
Time/h Yield/%
Mp/°C
CH3
1
CH C CH
16
13
13
13
13
20
13
13
13
16
76
53
74
68
50
80
68
65
59
30
72-75
2
3
CH3
CH3
C CH3
2
60a
CH3
CH3
3
C CH CH
120-125
150-154
oil
2
3
CH3
CH3
4
C C CH
CH3
CH3
5
6
219-220
107-111
semisolid
semisolid
amorphousb
H
(
RS)
7
C CH3
Ph
CH3
8
C CH3
Ph
CH3
C Ph
Ph
9
Ph
C Ph
Ph
1
0
(a) 53.5-54 °C (ref. 4). (b) Ditritylamine (49%) is also formed.

substituted phthalimidines (2 ) are close to those in which aniline or simple aliphatic amine is
1
,5
used, as we reported previously.
Preliminary bioassays of thus obtained phthalimidines show that 2-trityl derivative exhibits
quite strong inhibitions on the in vitro grouth of L1210 and KB cells, with IC values of <4. 0
5
0
and 6.3 mg/mL, respectively. These values are comparable to those by 6-mercaptopurine (6-
MP; IC = 2.6 and 11.0 mg/mL, respectively), encouraging further intensive studies.
5
0
Unexpectedly, treatments of crude phthalimidines (from Runs 5, 8, 9, 10) with 25% ammonia
kick out" bu lky substitu ents, giving 2-unsubstitu ted phthalimidines in ca . 50% yields . In
addition, the treatment of 2-tritylphthalimidine with tritylamine under standard phthalimidine-
"
1
, 5
forming reaction conditions
forms ditritylamine in ca. 50% yield. These features may
represent the "tethered ion pair" of tertiary alkyl cation with a phthalimidin-2-ide anion in
polar solvent systems, as has often been reported for Schiff base-benzotriazole adducts by
7
Katritzky and coworkers.
from this point of view, too.
Further exploitation on this class of compounds must be sought
In summary, our phthalimidine synthesis is tolerated by bulky alkyl amines, and allows the
obtention of promising bioactive phthalimidines in fair to good isolated yields. Further
exploitation along this line is now underway.
ACKNOWLEDGMENT
This work was suppo rted in p art by Grant-in-Aid for Scientific Res earch (A1 ) from th e
Research Found ation for the Electrotechno logy of Chubu . We thank Pr of. Kenji Kog a
(NAIST) for microanalyses.
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