Synthesis of nitrogen heterocycles by intramolecular cyclization of alkenyl N-acylaminophthalimides using phenyliodine(III) bis(trifluoroacetate) (PIFA)

Article abstract of DOI:10.3987/COM-07-11295

PIFA-mediated intramolecular cyclization of alkenyl N-acylaminophthalimides leads to the formation of a new C-N bond via an N-acyl-N-phthalimidonitrenium ion intermediate. The reaction pathway also results in the introduction of an oxygen function into th

Full text of DOI:10.3987/COM-07-11295

HETEROCYCLES, Vol. 75, No. 5, 2008
1133
HETEROCYCLES, Vol. 75, No. 5, 2008, pp. 1133 - 1149. © The Japan Institute of Heterocyclic Chemistry
Received, 8th December, 2007, Accepted, 22nd January, 2008, Published online, 25th January, 2008. COM-07-11295
SYNTHESIS
OF
NITROGEN
HETEROCYCLES
OF ALKENYL
USING PHENYLIODINE(III)
BY
INTRAMOLECULAR
CYCLIZATION
N-ACYLAMINOPHTHALIMIDES
BIS(TRIFLUOROACETATE) (PIFA)
Masato Tsukamoto, Kousuke Murata, Takeshi Sakamoto, Setsuo Saito,*
and Yasuo Kikugawa*
Faculty of Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, Sakado,
Saitama 350-0295, Japan
E-mail: saitoset@josai.ac.jp
Abstract
–
PIFA-mediated intramolecular cyclization of alkenyl
N-acylaminophthalimides leads to the formation of a new C-N bond via an
N-acyl-N-phthalimidonitrenium ion intermediate. The reaction pathway also
results in the introduction of an oxygen function into the molecule giving added
versatility to this single step procedure.
Nitrogen heterocyclic compounds occur in a large number of natural products and pharmaceutical drugs.
Therefore, development of new routes to this class of compounds continues to be an important area of
synthetic organic chemistry. In our own research to this end we have investigated the synthetic utility of
positively charged nitrogen species (nitrenium ions) and have reported new syntheses of benzene fused
N-heterocycles by intramolecular aromatic substitution with N-methoxy-N-acylnitrenium1 and
N-phthalimido-N-acylnitrenium2 ions (I and II). In the former case we utilized PIFA to generate
N-methoxy-N-acylnitrenium ions directly from the corresponding amides.3
O
O
O
OMe
NPhth
R
N
N
-NPhth =
R
N
I
II
O
Very recently we reported the intermolecular reaction of styrenes with N-acetylaminophthalimide
mediated by PIFA to produce 2-(N-acetylaminophthalimido)aminoethyl trifluoroacetates in high yield.4

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HETEROCYCLES, Vol. 75, No. 5, 2008
We now wish to describe intramolecular ring closure reactions which take place by electrophilic attack of
a nitrogen electrophile (nitrenium ion) on a neighboring double bond. This results in a convenient
synthetic pathway for the preparation of a variety of nitrogen heterocycles.
Reports of ring closure reactions initiated by an internal nitrogen electrophile with formation of a new
carbon-nitrogen bond are rare. Gassman, et al. reported the first example of such an intramolecular
addition of a nitrenium ion to a carbon-carbon double bond.5 Recently Tellitu and Domínguez reported an
intramolecular PIFA mediated alkene amidation through an N-aryl-N-acylnitrenium ion intermediate.6 For
the success of the reaction the generated nitrenium ion should be stabilized such that there is a sufficient
life-time to react with a C-C double bond. Therefore, the selection of the appropriate N-substituent is of
key importance.
Initially, we examined the reaction of N-methoxy(cyclohex-3-ene)carboxamide with PIFA in chloroform.
However, the resulting reaction mixture contained complex mixtures of unidentified products (TLC). In
contrast, when we changed the N-substituent of the starting compound from an N-methoxy to an
N-phthalimido group, the ring closure reaction went smoothly and the reaction mixture contained a single
product (TLC), the structure of which was determined to be 2a. Therefore, we examined in greater detail
of the reaction of N-phthalimido(cyclohex-3-ene)carboxamide (1a) with PIFA in order to optimize the
experimental conditions. The results are presented in Table 1.
Table 1. Reaction of N-phthalimido(cyclohex-3-ene)carboxamide (1a) with
PIFA in various solvents
H
O
N
O
NPhth
NPhth
N
PIFA (1.3 equiv)
solvent
OCOCF3
1a
2a
entry
solvent
CHCl3
CHCl3
CH2Cl2
temp (°C)
r.t.
time (h)
4
yield (%)
89
1a
2
3
4
5
6
7
8
refl.
refl.
refl.
refl.
r.t.
0.5
0.5
0.5
0.5
10b
24
97
97
ClCH2CH2Cl
MeCN
88
19
CF3CO2H
trace
trace
trace
CF3CH2OH
(CF3)2CHOH
r.t.
r.t.
1
a 1.1 Equivalent of PIFA was used. b Minutes.

HETEROCYCLES, Vol. 75, No. 5, 2008
1135
Since halogenated solvents consistently gave good results, the cyclization reactions of other starting
compounds (1b – i) were carried out under the condition of entry 2 (Table1). The results are presented in
Table 2.
Table 2. Intramolecular cyclization of alkenyl N-acylaminophthalimides using PIFA
entry
starting material
time (h)
product yield (%)
O
O
NPhth
N
NPhth
N
1
1
H
1b
2b (56%)
F3CCOO
O
O
O
H
NPhth
2c + 3c (92%)
(2c : 3c = 3 : 1)a
N
N
NPhth
N
NPhth
2
3
0.5
0.5
2c
3c
1c
O
O
CH2OCOCF3
OCOCF3
O
H
NPhth
2d + 3d (93%)
(2d : 3d = 9 : 1)a
N
N
NPhth
N
NPhth
2d
3d
1d
CH2OCOCF3
OCOCF3
O
O
NPhth
H
NPhth
N
2e + 3e (90%)
(2e : 3e = 9 : 1)a
N
N
NPhth
4
5
6
0.5
0.5
0.5
2e
3e
O
O
1e
CH2OCOCF3
OCOCF3
O
H
N
NPhth
N
NPhth
2f (98%)
1f
CH2OCOCF3
O
O
H
NPhth
N
H
N
NPhth
H
1g
2g (79%)
OCOCF3
F3COCO
H
H
F3COCO
CO2Me
CO2Me
CO2Me
7
0.5
N
PhthN
CONHNPhth
N
PhthN
2h (60%)
O
2h' (18%)
O
1h

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HETEROCYCLES, Vol. 75, No. 5, 2008
OCOCF3
1i
N
8
0.5
NPhth
3i (34%)
N
CONHNPhth
NPhth
O
O
2i (60%)
a These product ratios were determined by 1H NMR integration of the C-5 methine protons of 3c-e which
appear at 5.24-5.61 ppm apart from other proton signals.
In this reaction the N-acyl-N-phthalimidonitrenium ion (II) generated by the action of PIFA on the
starting compound can be trapped by the olefin present in the molecule by a 5-exo-trig cyclization mode.
The resulting carbocation can be subsequently captured by a free trifluoroacetate anion to afford the
product. In general, a 5-exo-trig closure rather than a 6-endo-trig path will be more favorable and
formation of a five-membered ring is prefered over a six-membered ring.7 Consistent with this, a
five-membered ring forms preferentially in the above examples (Table 2, entries 1 - 7). On the other hand,
in the case of 2-vinyl-N-phthalimidobenzamide (1i) isoquinolinone derivatives (2i and 3i) were obtained
in quantitative combined yield without formation of a five-membered ring (entry 8).
Formation of 2i and 3i can be explained as follows. The reaction proceeds in an intramolecular
electrophilic attack of the nitrenium ion to the double bond, and the created carbocationic species can be
captured by a free trifluoroacetate anion to afford 2i or quenched by the elimination of an adjacent
hydrogen to afford 3i. Serna et al. reported6c that in the case of 2-vinyl-N-(4-methoxyphenyl)benzamide
the 5-exo-trig cyclization took place to afford the isoindolinone derivative through an aziridinium ion
intermediate.8 Furthermore they reported in the reaction mixture the presence of trace amounts of the
dimeric compound which would be derived from a radical mechanism.6c
In our case, an addition of a radical scavenger N,N-diphenylpicrylhydrazil9 had no affect on the
cyclization reaction. Therefore, a radical mechanism is not supported in our case, although the presence
of an aziridinium ion intermediate is not completely excluded. These defferences suggest the requirement
for a proper electronic environment surrounding the positive nitrogen. Although the reason for this rather
peculiar requirement remains unknown, we suspect that the phthalimido moiety of II assumes a strong
stabilizing role for a nitrenium ion in the reaction. The described transformation exemplified by the
reaction of 1a can be rationalized as depicted in Scheme 1.

HETEROCYCLES, Vol. 75, No. 5, 2008
1137
NPhth
+
N
O
NPhth
NH
-OCOCF3
O
PIFA
NPhth
N
O
O
1a
NPhth
N
OCOCF3
2a
Scheme 1
The trifluoroacetyl groups of 2 and 3 were removed under mildly acidic conditions to afford 4 and 5,
respectively. The two protective groups were removed directly using hydrazine monohydrate in ethanol.
The results are presented in Table 3 and Table 4.
Table 3. Removal of trifluoroacetyl group under acidic conditionsa
entry
starting material
time (min)
product yield (%)
O
NPhth
OH
N
1
2a
30
endo : exo = 2 : 1
4a (81%)
O
O
NPhth
4c + 5c (76%)
(4c : 5c = 3 : 1)
N
NPhth
N
2
3
2c + 3c
2d + 3d
10
10
4c
5c
CH2OH
OH
O
O
NPhth
4d + 5d (84%)
(4d : 5d = 5 : 1)
N
NPhth
N
4d
5d
CH2OH
OH
O
O
NPhth
NPhth
4e + 5e (85%)
(4e : 5e = 6 : 1)
N
N
4
2e + 3e
10
4e
5e
CH2OH
OH

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HETEROCYCLES, Vol. 75, No. 5, 2008
O
NPhth
N
5
6
7
8
2f
2g
2h
2i
60
30
30
15
4f (76%)
4g (87%)
CH2OH
O
H
N
NPhth
H
OH
HO
H
CO2Me
N
PhthN
4h (68%)
O
OH
N
NPhth
O
4i (83%)
a Reaction conditions: in AcOH-THF-H2O (3:1:1) at 70 °C.
Table 4. Removal of phthaloyl group with hydrazine monohydrate
.
starting
material
H2NNH2 H2O
(equiv)
time
entry
1
product yield (%)
(min)
O
NH2
N
2a
5.0
30
30
6a (88%)
OH
O
NH2
N
2
4c
2.5
6c (73%)
CH2OH
O
NH2
N
3
4
4f
2.5
2.5
30
30
6f (75%)
6a (71%)
CH2OH
O
NH2
N
4a
OH

HETEROCYCLES, Vol. 75, No. 5, 2008
1139
In conclusion, intramolecular cyclization of an internal nitrogen electrophile was initiated by the action of
PIFA on precursor alkenyl N-acylaminophthalimides. This provides a facil synthesis of lactams through
5-exo-trig and 6-endo-trig processes. The procedure is operationally extremely simple and offers an easy
access to a wide range of substituted lactams.
EXPERIMENTAL
All melting points were determined on a micro hot-stage apparatus and are uncorrected. 1H and 13C NMR
spectra were recorded on JEOL JNM-EX270 or JNM-A500 spectrometers with tetramethylsilane (MeSi4)
as an internal reference. IR spectra were measured at a JASCO IR 810 spectrophotometer. MS spectra
were obtained with a JEOL JMX-DX 300 spectrometer with a direct inlet system at 70 eV. Elemental
analyses were performed in the Microanalytical Laboratory of this University.
Preparation of N-(1,3-dioxoisoindolin-2-yl)cyclohex-3-enecarboxamide (1a): Typical Procedure for
Starting Materials. EDCI (1973 mg, 10.3 mmol) was added to a solution of cyclohex-3-ene-1-carboxylic
acid (1000 mg, 7.92 mmol) and N-aminophthalimide (1284 mg, 7.92 mmol) in pyridine (50 mL). The
reaction mixture was stirred for 24 h at rt. After the reaction was complete, the solvent was removed in
vacuo and 10% HCl (80 mL) was added. The mixture was extracted with EtOAc (3 x 50 mL) and the
combined organic solvent was washed with 10% aq Na2CO3 (2 x 50 mL), brine (2 x 50 mL), and dried
over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel using
50% EtOAc-hexane to give the product 1a (1817 mg, 85%). 1a: colorless crystals, mp 172-173 °C
1
(EtOAc-hexane); IR (KBr) 3250, 1800, 1750, 1680, 1520, 1205, 880, 705 cm-1; H NMR (270 MHz,
CDCl3) δ 1.77-2.76 (m, 7H), 5.75 (s, 2H), 7.57 (br s, 1H), 7.72-7.98 (m, 4H); 13C NMR (68 MHz, CDCl3)
δ 24.25, 25.53, 27.62, 39.03, 123.85, 124.76, 126.87, 129.89, 134.55, 165.08, 174.46; EIMS m/z 270 (M+,
12.5), 163 (100), 108 (26.0), 81 (64.8). Anal. Calcd for C15H14N2O3: C, 66.66; H, 5.22; N, 10.36. Found:
C, 66.76; H, 5.09; N, 10.26.
The other starting materials 1b-g were prepared following the same procedure described for 1a.
N-(1,3-Dioxoisoindolin-2-yl)but-3-enamide (1b). Yield 60%, colorless crystals, mp 178-183 °C
1
(EtOAc-hexane); IR (KBr) 3270, 3000, 1800 cm-1; H NMR (270 MHz, CDCl3) δ 3.26 (d, J = 6.9 Hz,
13
2H), 5.29-5.50 (m, 2H), 5.95-6.14 (m, 1H), 7.60 (br s, 1H), 7.74-7.99 (m, 4H); C NMR (126 MHz,
CDCl3) δ 38.98, 120.81, 124.26, 129.54, 130.00, 164.42, 169.28; EIMS m/z 230 (M+, 5.7), 162 (100), 104
(19.3), 68 (10.5). Anal. Calcd for C12H10N2O3: C, 62.61; H, 4.38; N, 12.17. Found: C, 62.61; H, 4.19; N,
12.19.
N-(1,3-Dioxoisoindolin-2-yl)pent-4-enamide (1c). Yield 78%, colorless crystals, mp 120-121 °C
1
(EtOAc-hexane); IR (KBr) 3275, 2990, 1800, 1750, 1675, 1515, 1390, 1210, 885, 710 cm-1; H NMR

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HETEROCYCLES, Vol. 75, No. 5, 2008
(270 MHz, CDCl3) δ 2.52 (s, 4H), 4.91-5.24 (m, 2H), 5.72-6.02 (m, 1H), 7.56 (br s, 1H), 7.70-8.02 (m,
4H); 13C NMR (68 MHz, CDCl3) δ 28.95, 33.10, 116.04, 123.87, 129.82, 134.58, 136.09, 165.03, 171.06;
EIMS m/z 244 (M+, 0.3), 214 (4.4), 162 (100), 104 (19.8), 83 (7.2). Anal. Calcd for C13H12N2O3: C,
63.93; H, 4.95; N, 11.47. Found: C, 63.82; H, 4.89; N, 11.42.
N-(1,3-Dioxoisoindolin-2-yl)-3-methylpent-4-enamide (1d). Yield 84%, colorless crystals, mp
136-137 °C (EtOAc-hexane); IR (KBr) 3260, 3000, 2970, 1800, 1750, 1670, 1515, 1210, 885, 710 cm-1;
1H NMR (270 MHz, CDCl3) δ 1.13 (d, J = 7.1 Hz, 3H), 2.26-2.54 (m, 2H), 2.65-2.85 (m, 1H), 4.97-5.17
13
(m, 2H), 5.76-5.93 (m, 1H), 7.71-7.92 (m, 4H), 8.00 (br s, 1H); C NMR (68 MHz, CDCl3) δ 19.24,
34.34, 40.69, 113.80, 123.75, 129.72, 134.45, 141.82, 164.90, 170.40; EIMS m/z 258 (M+, 0.7), 162 (100),
96 (9.0), 69 (21.7). Anal. Calcd for C14H14N2O3: C, 65.11; H, 5.46; N, 10.85. Found: C, 64.89; H, 5.42; N,
10.85.
N-(1,3-Dioxoisoindolin-2-yl)-2-methylpent-4-enamide (1e). Yield 70%, colorless crystals, mp
1
139-140 °C (EtOAc-hexane); IR (KBr) 3230, 3025, 1800, 1745, 1680, 1220, 885, 710 cm-1; H NMR
(270 MHz, CDCl3) δ 1.29 (d, J = 6.8 Hz, 3H), 2.21-2.38 (m, 1H), 2.44-2.67 (m, 2H), 5.05-5.27 (m, 2H),
5.80-5.99 (m, 1H), 7.42 (br s, 1H), 7.74-7.98 (m, 4H, ArH); 13C NMR (68 MHz, CDCl3) δ 16.97, 38.01,
38.73, 117.49, 123.79, 129.84, 134.51, 134.84, 164.98, 174.63; EI-MS m/z 258 (M+, 7.7), 162 (100), 148
(7.8), 96 (42.9), 69 (76.8). Anal. Calcd for C14H14N2O3: C, 65.11; H, 5.46; N, 10.85. Found: C, 64.90; H,
5.42; N, 10.82.
N-(1,3-Dioxoisoindolin-2-yl)-3,3-dimethylpent-4-enamide (1f). Yield 76%, colorless crystals: mp
96-101 °C (EtOAc-hexane); IR (KBr) 3520, 3380, 3170, 2970, 1795, 1730, 1675, 1560, 1415, 1210, 930,
880, 705 cm-1; 1H NMR (270 MHz, CDCl3) δ 1.23 (s, 6H), 2.41 (s, 2H), 5.09 (d, J = 10 Hz, 1H), 5.14 (d,
13
J = 16 Hz, 1H), 6.02 (dd, J = 16, 10 Hz, 1H), 7.72-7.98 (m, 5H); C NMR (68 MHz, CDCl3) δ 26.83,
36.41, 46.78, 112.33, 123.82, 129.89, 134.52, 146.66, 165.03, 169.50; EIMS m/z 272 (M+, 1.7), 257 (5.2),
242 (4.5), 162 (100), 104 (23.6), 69 (54.6). Anal. Calcd for C15H16N2O3: C, 66.16; H, 5.92; N, 10.29.
Found: C, 66.21; H, 5.97, N, 10.33.
2-(Cyclopent-2-enyl)-N-(1,3-dioxoisoindolin-2-yl)acetamide (1g). Yield 89%, colorless crystals: mp
190-192 °C (EtOAc-hexane); IR (KBr) 3250, 1805, 1750, 1670, 1520, 880, 710 cm-1; 1H NMR (270 MHz,
CDCl3) δ 1.47-1.63 (m, 1H), 2.10-2.52 (m, 5H), 3.10-3.23 (m, 1H), 5.74-5.86 (m, 2H), 7.74-7.97 (m,
13
5H); C NMR (68 MHz, CDCl3) δ 29.49, 31.85, 39.90, 42.29, 123.95, 129.98, 132.09, 133.28, 134.67,
165.22, 171.01; EIMS m/z 270 (M+, 1.8), 204 (35.7), 162 (100), 67 (61.8). Anal. Calcd for C15H14N2O3; C,
66.66; H, 5.22; N, 10.36. Found; C, 66.69; H, 5.15; N, 10.34.
Preparation of Methyl 3-endo-(1,3-Dioxoisoindolin-2-ylcarbamoyl)bicyclo[2.2.1]hept-5-ene-2-endo-
carboxylate (1h). To a solution of cis-5-norbornene-endo-2,3-dicarboxylic anhydride (656 mg, 4.00
mmol) in MeOH (10 mL) was added triethylamine (1.0 mL, 8.00 mmol) at rt. After stirring for 10 min,

HETEROCYCLES, Vol. 75, No. 5, 2008
1141
the solvent was removed in vacuo and 10% HCl (10 mL) was added. The acidic mixture was extracted
with EtOAc (2 x 50 mL) and the combined organic solvent was washed with brine (2 x 50 mL) and dried
over Na2SO4. After removal of solvent in vacuo, the crude monomethyl ester was used without further
purification. EDCI (996 mg, 5.20 mmol) was added to a solution of the crude product and
N-aminophthalimide (650 mg, 4.00 mmol) in pyridine (20 mL) and the reaction mixture was stirred for 10
h at rt. After the reaction was complete, the mixture was concentrated in vacuo, acidified with 10% HCl,
and diluted with water (50 mL). The mixture was extracted with EtOAc (2 x 50 mL) and the combined
organic solvent was washed with brine (2 x 40 mL), dried over Na2SO4, and concentrated. The residue
was recrystallized from CH2Cl2-hexane to afford the product 1h (476 mg, 35%). 1h: colorless crystals,
mp 176-178 °C (CH2Cl2-hexane); IR (KBr) 3250, 1800, 1745, 1685, 1210, 885, 710 cm-1; 1H NMR (270
MHz, CDCl3) δ 1.44 (dd, J = 31, 8.3 Hz, 2H), 3.14 (s, 1H), 3.20-3.35 (m, 2H), 3.45-3.56 (m, 1H), 3.60 (s,
13
3H), 6.11-6.30 (m, 1H), 6.42-6.62 (m, 1H), 7.66-7.98 (m, 4H), 8.20 (br s, 1H); C NMR (68 MHz,
CDCl3) δ 19.87, 21.74, 22.33, 23.56, 26.03, 97.99, 104.20, 107.59, 108.73, 111.07, 139.30, 144.98,
147.32; EIMS m/z 340 (M+, 2.2), 243 (18.7), 179 (27.0), 113 (100). Anal. Calcd for C18H16N2O5: C,
63.53; H, 4.74; N, 8.23. Found: C, 63.55; H, 4.52; N, 8.29.
Preparation of N-(1,3-Dioxoisoindolin-2-yl)-2-vinylbenzamide (1i). An ethereal solution of
diazomethane was added droppwise to a solution of phthaladehydic acid (1.0 g, 6.66 mmol) in EtOAc (10
mL). After removal of solvent in vacuo, the residue was purified by short column chromatography using
30% EtOAc-hexane to give the methyl ester (917 mg, 83.9%). The product was converted into the
corresponding methyl o-allylbenzoate by the Wittig reaction according to the previously reported
method.10 Next, to a solution of the o-allylbenzoate (232 mg, 1.432 mmol) in MeOH (5 mL) was added
5% NaOH (20 mL) and the reaction mixture was refluxed for 1 h. After cooling, the mixture was
acidified with 10% HCl and extracted with EtOAc (2 x 40 mL). The combined organic solvent was
washed with brine (2 x 30 mL), dried over Na2SO4, and concentrated. The residue was diluted with
pyridine (10 mL). To the solution were added EDCI (394 mg, 1.862 mmol) and N-aminophthalimide (385
mg, 2.148 mmol) and the reaction mixture was stirred for 24 h at rt. After the reaction was complete, the
solvent was concentrated in vacuo and the residue was diluted with EtOAc (70 mL). The organic solution
was washed with 10% HCl (2 x 25 mL), 10% Na2CO3 (2 x 25 mL), and brine (2 x 30 mL), and dried over
Na2SO4. After removal of solvent in vacuo, the residue was purified by column chromatography on silica
gel using 35% EtOAc-hexane to give the product 1i (134 mg, 32%). 1i: colorless crystals, mp 172-174 °C
1
(EtOAc-hexane); IR (KBr) 3275, 1790, 1720, 1695, 1265, 1210, 880, 710 cm-1; H NMR (270 MHz,
CDCl3) δ 5.44 (d, J = 11 Hz, 1H), 5.78 (d, J = 17 Hz, 1H), 7.26 (dd, J = 17, 11 Hz, 1H), 7.34 (td, J = 7.5,
1.2 Hz, 1H), 7.48 (td, J = 7.4, 1.0 Hz, 1H), 7.61 (dd, J = 7.9, 0.71 Hz, 1H), 7.69 (dd, J = 7.8, 1.0 Hz, 1H),
7.76-8.02 (m, 5H); 13C NMR (68 MHz, CDCl3) δ 117.71, 123.97, 126.38, 127.68, 128.15, 129.97, 130.84,

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HETEROCYCLES, Vol. 75, No. 5, 2008
131.39, 133.91, 134.63, 136.86, 164.92, 167.41; EIMS m/z 292 (M+, 11.7), 131 (100), 103 (31.8). Anal.
Calcd for C17H12N2O3: C, 69.86; H, 4.14; N, 9.58. Found: C, 70.01; H, 3.98; N, 9.58.
Table 1: Product obtained from compound 1a.
Entry 2.
6-(1,3-Dioxoisoindolin-2-yl)-7-oxo-6-azabicyclo[3.2.1]octan-4-yl 2,2,2-Trifluoroacetate (2a): Typical
Procedure for Table 1. PIFA (262 mg, 0.722 mmol) was added to a solution of compound 1a (150 mg,
0.555 mmol) in CHCl3 (10 mL) and the reaction mixture was refluxed for 0.5 h. After the reaction was
complete, the solvent was evaporated in vacuo and the residue was purified by column chromatography
on silica gel using 50% EtOAc-hexane to give the product 2a (206 mg, 97%). 2a: colorless oil; IR (neat)
1785, 1730, 1220, 1160, 880, 710 cm-1; 1H NMR (270 MHz, CDCl3) δ 1.77-2.44 (m, 4.3H), 2.55-2.81 (m,
1.7H), 2.83-2.90 (m, 0.3H), 2.96-3.15 (m, 0.7H), 3.93-4.00 (m, 0.3H), 4.07 (t, J = 4.8 Hz, 0.7H), 5.35 (t, J
= 4.2 Hz, 0.7H), 5.61-5.70 (m, 0.3H), 7.78-7.98 (m, 4H); EIMS m/z 382 (M+, 100), 268 (30.1). HR-EIMS
for C17H13N2O5F3: 382.0777. Found: 382.0778.
Table 2: Products obtained from compounds 1b-i.
Entry 1.
1-(1,3-Dioxoisoindolin-2-yl)-5-oxopyrrolidin-3-yl 2,2,2-Trifluoroacetate (2b): Typical Procedure for
Table 2. PIFA (364 mg, 0.848 mmol) was added to a solution of compound 1b (150 mg, 0.652 mmol) in
CHCl3 (10 mL) and the reaction mixture was refluxed for 1 h. After the reaction was complete, the
solvent was evaporated in vacuo and the residue was purified by column chromatography using 50%
EtOAc-hexane to give the product 2b (125 mg, 56%). 2b: crystals, mp 169.5-173 °C; IR (KBr) 1790,
1730, 1220, 1160, 1130, 875, 705 cm-1; 1H NMR (270 MHz, CDCl3) δ 2.82 (dd, J = 19, 3.1 Hz, 1H), 3.15
(dd, J = 19, 7.8 Hz, 1H), 3.85 (dd, J = 11, 2.2 Hz, 1H), 4.25 (dd, J = 11, 6.1 Hz, 1H), 5.65-5.76 (m, 1H),
7.78-8.00 (m, 4H); EIMS m/z 342 (M+, 1.1), 228 (100), 175 (34.1), 130 (34.0), 104 (51.2); FABMS m/z
343 (M+ + 1, 100).
Entry 2.
Cyclization of N-(1,3-Dioxoisoindolin-2-yl)pent-4-enamide (1c). Following the typical procedure for
the cyclization reaction, compound 1c (150 mg, 0.614 mmol) in CHCl3 (10 mL) was reacted with PIFA
(343 mg, 0.798 mmol). After 0.5 h, workup, and column chromatography (50% EtOAc-hexane) gave a
mixture of compounds 2c + 3c (201 mg, 92%, in a 2c : 3c = 3 : 1 ratio, as determined by 1H NMR). 2c +
1
3c: IR (KBr) 1795, 1740, 1720, 1685, 1210, 1175, 880, 710 cm-1; H NMR (270 MHz, CDCl3) δ
2.00-2.19 (m, 0.75H), 2.30-2.44 (m, 0.40H), 2.46-2.96 (m, 2.85H), 3.91 (dd, J = 13, 3.0 Hz, 0.2H), 4.13
(dd, J = 13, 3.0 Hz, 0.2H), 4.25-4.47 (m, 1.4H), 4.59 (dd, J = 11, 2.3 Hz, 0.7H), 5.49-5.58 (m, 0.2H),

HETEROCYCLES, Vol. 75, No. 5, 2008
1143
7.76-7.98 (m, 4H); EIMS m/z 356 (M+, 0.7), 337 (3.6), 242 (100), 201 (67.3) 130 (33.2).
Entry 3.
Cyclization of N-(1,3-Dioxoisoindolin-2-yl)-3-methylpent-4-enamide (1d). Following the typical
procedure for the cyclization reaction, compound 1d (150 mg, 0.581 mmol) was reacted with PIFA (325
mg, 0.755 mmol). After 0.5 h, workup and column chromatography (50% EtOAc-hexane) gave a mixture
of compounds 2d + 3d (200 mg, 93%, in a 2d : 3d = 5 : 1 ratio, as determined by 1H NMR). 2d + 3d: IR
1
(KBr) 1800, 1745, 1720, 1215, 1170, 880, 715 cm-1; H NMR (270 MHz, CDCl3) δ 1.12-1.45 (m, 3H),
2.18-3.13 (m, 3.3H), 3.46-4.02 (m, 0.6H), 4.08-4.24 (m, 0.5H), 4.34-4.49 (m, 0.7H), 4.64 (td, J = 12.0,
3,0 Hz, 0.8H), 5.24-5.32 (m, 0.1H), 7.74-7.98 (m, 4H); EIMS m/z 370 (M+, 0.7), 256 (100), 243 (72.3),
215 (40.8).
Entry 4.
Cyclization of N-(1,3-Dioxoisoindolin-2-yl)-2-methylpent-4-enamide (1e). Following the typical
procedure for the cyclization reaction, compound 1e (150 mg, 0.581 mmol) was reacted with PIFA (325
mg, 0.755 mmol). After 0.5 h, workup and column chromatography (50% EtOAc-hexane) gave a mixture
1
of compounds 2e + 3e (194 mg, 90%, in a 2e : 3e = 5 : 1 ratio, as determined by H NMR). 2e + 3e: IR
1
(KBr) 1795, 1740, 1720, 1680, 1210, 1160, 880, 710 cm-1; H NMR (270 MHz, CDCl3) δ 1.32-1.45 (m,
3H), 1.57-1.76 (m, 0.6H), 2.03-3.06 (m, 2.7H), 3.86-4.18 (m, 0.3H), 4.18-4.47 (m, 1.5H), 4.52-4.63 (m,
0.8H), 5.50-5.61 (m, 0.1H), 7.74-7.98 (m, 4H); EIMS m/z 370 (M+, 1.3), 256 (100), 243 (37.7), 215
(45.3).
Entry 5.
[1-(1,3-Dioxoisoindolin-2-yl)-3,3-dimethyl-5-oxopyrrolidin-2-yl]methyl 2,2,2-Trifluoroacetate (2f).
Yield 98%, colorless crystals, mp 114-118.5 °C; IR (KBr) 2970, 1795, 1750, 1710, 1370, 1300, 1210,
1150, 880, 720, 705 cm-1; 1H NMR (270 MHz, CDCl3) δ 1.30 (s, 3H), 1.46 (s, 3H), 2.48 (q, J = 17.5 Hz,
2H), 3.88 (dd, J = 6.4, 2.6 Hz, 1H), 4.42 (dd, J = 12, 6.4 Hz, 1H), 4.66 (dd, J = 12, 2.6 Hz, 1H), 7.77-7.99
(m, 4H); EIMS m/z 384 (M+, 0.5), 270 (100), 257 (50.0), 229 (12.5), 148 (17.8), 130 (19.9).
Entry 6.
1-exo-(1,3-Dioxoisoinodolin-2-yl)-2-oxooctahydrocyclopenta[b]pyrrol-6-yl
2,2,2-Trifluoroacetate
(2g). Yield 79%, colorless crystals, mp 203-210 °C; IR (KBr) 1800, 1775, 1740, 1730, 1370, 1220, 1175,
1140, 880, 705 cm-1; 1H NMR (270 MHz, CDCl3) δ 1.75 (m, 1H), 2.00-2.54 (m, 4H), 2.90 (dd, J = 18.3,
10.4 Hz, 1H), 3.13-3.30 (m, 1H), 4.29 (d, J = 7.9 Hz, 1H), 5.28-5.40 (m, 1H), 7.76-8.08 (m, 4H); EIMS
m/z 382 (M+, 0.5), 363 (1.5), 268 (100).
Entry 7.
Cyclization of Methyl 3-endo-(1,3-Dioxoisoindolin-2-ylcarbamoyl)bicyclo[2.2.1]hept-5-ene-2-endo-
carboxylate (1h). Following the typical procedure for the cyclization reaction, compound 1 h (150 mg,

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HETEROCYCLES, Vol. 75, No. 5, 2008
0.441 mmol) was reacted with PIFA (246 mg, 0.573 mmol). After 0.5 h, workup and careful column
chromatography (85% EtOAc-hexane) gave compounds 2h (120 mg, 60%) and 2h’ (36 mg, 18%).
Methyl 6-(1,3-Dioxoisoindolin-2yl)-7-oxo-4-exo-trifluoroacetoxy-6-azatricyclo[3,2,1,13,8]nonane-2-
endo-carboxylate (2h). Oil; IR (neat) 1780, 1840, 1360, 1220, 1160, 880, 710 cm-1; 1H NMR (270 MHz,
CDCl3) δ 1.64-1.85 (m, 1H), 2.08 (d, J = 12 Hz, 1H), 2.94 (dd, J = 12, 4.5 Hz, 1H), 3.05-3.15 (m, 1H),
3.31 (dd, J = 11, 3.6 Hz, 1H), 3.50-3.60 (m, 1H), 3.80-3.92 (m, 4H), 5.58 (br s, 1H), 7.74-7.98 (m, 4H);
EI-MS m/z 452 (M+, 100), 239 (52.0). HR-EIMS for C20H15N2O7F3: 452.0831. Found: 452.0834.
Methyl 6-(1,3-Dioxoisoindolin-2yl)-7-oxo-4-endo-trifluoroacetoxy-6-azatricyclo[3,2,1,13,8]nonane-2-
1
endo-carboxylate (2h’). Oil; IR (neat) 1785, 1740, 1210, 1170, 880, 720 cm-1; H NMR (270 MHz,
CDCl3) δ 1.55-1.89 (m, 1H), 2.18 (d, J = 11 Hz, 1H), 2.83-2.98 (m, 2H), 3.17 (dd, J = 11, 3.5 Hz, 1H),
3.29-3.38 (m, 1H), 3.74 (s, 3H), 4.83 (d, J = 5.1 Hz, 1H), 5.91 (s, 1H), 7.70 (t, J = 7.4 Hz, 1H), 7.80 (t, J
= 7.4 Hz, 1H), 7.93 (d, J = 7.4 Hz, 1H), 8.11 (d, J = 7.4 Hz, 1H); EIMS m/z 452 (M+, 92.3), 267 (84.7),
239 (100), 113 (77.9). HR-EIMS for C20H15N2O7F3: 452.0831. Found: 452.0829.
Entry 8.
Cyclization of N-(1,3-Dioxoisoindolin-2-yl)-2-vinylbenzamide (1i). Following the typical procedure for
the cyclization reaction, compound 1i (150 mg, 0.514 mmol) was reacted with PIFA (343 mg, 0.668
mmol). After 0.5 h, workup and column chromatography (50% EtOAc-hexane) gave compounds 2i (125
mg, 60%) and 3i (51 mg, 34%).
2-(1,3-Dioxoisoindolin-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl 2,2,2-Trifluoroacetate (2i).
Colorless crystals, mp 156-167 °C; IR (KBr) 1795, 1740, 1730, 1230, 880, 710 cm-1; 1H NMR (270 MHz,
CDCl3) δ 4.64 (dd, J = 12, 7.8 Hz, 1H), 4.84 (dd, J = 12, 4.0 Hz, 1H), 5.23 (dd, J = 7.8, 4.0 Hz, 1H),
7.50-8.08 (m, 8H); EIMS m/z 404 (M+, 0.1), 385 (2.2), 290 (100), 277 (65.7).
2-(1-Oxoisoquinolin-2(1H)-yl)isoindoline-1,3-dione (3i). Colorless crystals, mp 221-225 °C (EtOAc);
1
IR (KBr) 1800, 1740, 1680, 1630, 1385, 880, 710 cm-1; H NMR (270 MHz, acetone-d6) δ 7.57 (d, J =
7.6 Hz, 1H), 8.33 (d, J = 7.6 Hz, 1H), 8.40 (d, J = 8.1 Hz, 1H), 8.45-8.68 (m, 2H), 8.73-8.95 (m, 4H),
13
9.09 (d, J = 8.1 Hz, 1H); C NMR (68 MHz, acetone-d6) δ 107.14, 124.68, 126.47, 127.53, 128.15,
128.39, 130.72, 133.64, 134.21, 136.08, 137.97, 159.56, 164.78; EIMS m/z 290 (M+, 90.5), 246 (100),
218 (14.9), 104 (35.1). Anal. Calcd for C17H10N2O3: C, 70.34; H, 3.47; N, 9.65. Found: C, 70.11; H, 3.42;
N, 9.50.
Table 3: Products 4a, 4c-i, and 5c-d obtained by removal of trifluoroacetyl group under acidic conditions.
Entry 1.
2-(4-Hydroxy-7-oxo-6-azabicyclo[3.2.1]octan-6-yl)isoindoline-1,3-dione (4a): Typical Procedure for
Table 4. Compound 2a (206 mg, 0.539 mmol) in AcOH-THF-H2O (3 : 1 : 1, 10 mL) was heated at 70 ºC

HETEROCYCLES, Vol. 75, No. 5, 2008
1145
for 30 min. After the reaction was complete, the reaction mixture was diluted with water and extracted
with EtOAc (2 x 30 mL). The combined organic solvent was washed with brine (2 x 25 mL), dried over
Na2SO4, and concentrated. The residue was washed with 50% Et2O-hexane to give the product 4a (125
1
mg, 81%, endo : exo = 2 : 1, as determined by H NMR). 4a: colorless crystals, mp 247-250 ºC
1
(EtOAc-hexane); IR (KBr) 3370, 1800, 1740, 1700, 1680, 1375, 880, 705 cm-1; H NMR (270 MHz,
CDCl3) δ 1.40-2.00 (m, 3.5H), 2.11-2.33 (m, 2H), 2.43-2.65 (m, 1.5H, CH2), 3.73-3.85 (m, 1H),
3.92-4.03 (m, 0.64H), 4.30-4.39 (m, 0.36H), 5.07 (d, J = 4.3 Hz, 0.65H), 5.32 (d, J = 4.3 Hz, 0.35H),
13
7.89-8.01 (m, 4H); C NMR (68 MHz, DMSO-d6) δ 19.41, 21.59, 23.63, 26.21, 30.16, 33.36, 61.54,
61.63, 63.15, 66.09, 123.55, 123.57, 129.21, 129.27, 135.04, 135.09, 164.34, 164.59, 172.28, 173.40;
EIMS m/z 286 (M+, 94.5), 148 (100), 130 (51.8). Anal. Calcd for C15H14N2O4: C, 62.93; H, 4.93; N, 9.78.
Found: C, 62.86; H, 4.90; N, 9.77.
Entry 2.
2-[2-(Hydroxymethyl)-5-oxopyrrolidin-1-yl]isoindoline-1,3-dione
(4c)
and
2-(5-Hydroxy-2-
oxopiperidin-1-yl)isoindoline-1,3-dione (5c). Following the typical procedure, a mixture of compounds
2c + 3c (201 mg, 0.526 mmol) was hydrolyzed in AcOH-THF-H2O (3 : 1 : 1, 10 mL). After 10 min,
workup and column chromatography (30 % acetone-toluene) gave 4c + 5c (104 mg, 76%, in a 3 : 1 ratio,
1
as determined by H NMR). After careful chromatography, only small amounts of the pure components
4c and 5c could be isolated.
4c: colorless crystals, mp 179-182 ºC (EtOAc-hexane); IR (KBr) 3420, 1800, 1740, 1695, 1375, 880, 715
cm-1; 1H NMR (270 MHz, CDCl3) δ 2.26-2.48 (m, 2H), 2.50-2.79 (m, 2H), 3.38 (dd, J = 11, 3.2 Hz, 1H),
13
3.55 (td, J = 13, 1.6 Hz, 1H), 3.77 (d, J = 13 Hz, 1H), 3.90-4.03 (m, 1H), 7.97-8.01 (m, 4H); C NMR
(68 MHz, CDCl3) δ 19.32, 27.94, 60.47, 61.27, 124.18, 124.25, 129.62, 129.77, 134.90, 135.11, 164.10,
167.17, 173.20; EIMS m/z 260 (M+, 0.8), 242 (10.9), 229 (100), 201 (93.3). Anal. Calcd for C13H12N2O4:
C, 60.00; H, 4.65; N, 10.76. Found: C, 59.85; H, 4.63; N, 10.73.
5c: colorless crystals, mp 245-247 ºC (EtOAc-hexane); IR (KBr) 3400, 1800, 1740, 1690, 1220, 1120,
1
1085, 885, 715 cm-1; H NMR (270 MHz, CDCl3) δ 2.09-2.27 (m, 2H), 2.50 (br s, 1H), 2.62 (dt, J = 18,
5.3 Hz, 1H), 2.80-2.98 (m, 1H), 3.66 (ddd, J = 11, 3.7, 1.1 Hz, 1H), 3.99 (dd, J = 11, 3.7 Hz, 1H), 4.40 (br
13
s, 1H), 7.76-7.99 (m, 4H); C NMR (68 MHz, DMSO-d6) δ 27.51, 28.02, 57.62, 62.44, 123.55, 123.57,
129.26, 129.34, 135.06, 135.10, 164.10, 164.29, 167.34; EIMS m/z 260 (M+, 6.1), 242 (16.8), 229 (32.5),
201 (22.2), 175 (100). Anal. Calcd for C13H12N2O4: C, 60.00; H, 4.65; N, 10.76. Found: C, 59.81; H,
4.48; N, 10.54.
Entry 3.
2-(5-Hydroxy-2-oxopiperidin-1-yl)isoindoline-1,3-dione
(4d)
and
2-(5-Hydroxy-4-methyl-2-
oxopiperidin-1-yl)isoindoline-1,3-dione (5d). Following the typical procedure, a mixture of compounds

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HETEROCYCLES, Vol. 75, No. 5, 2008
2d + 3d (200 mg, 0.540 mmol) was hydrolyzed in AcOH-THF-H2O (3 : 1 : 1, 10 mL). After 10 min,
workup and column chromatography (30 % acetone-toluene) gave 4d + 5d (124 mg, 84%, in a 5 : 1 ratio,
as determined by 1H NMR). After careful chromatography, small amounts of the pure components 4d and
5d could be isolated.
cis-4d: colorless crystals: mp 164-165 ºC (EtOAc-hexane); IR (KBr) 3520, 3460, 2970, 1795, 1750, 1730,
1705, 1360, 1225, 1075, 880, 710 cm-1; 1H NMR (500 MHz, CDCl3) δ 1.34 (d, J = 6.8 Hz, 3H), 2.52 (d, J
= 2.1 Hz, 1H), 2.54 (s, 1H), 2.88-2.99 (m, 1H), 3.63 (dd, J = 10, 4.2 Hz, 1H) 3.68-3.83 (m, 3H), 7.81-7.86
13
(m, 2H), 7.91-7.96 (m, 2H); C NMR (126 MHz, CDCl3) δ 14.92, 29.43, 36.30, 59.32, 64.08, 124.16,
124.24, 129.57, 129.85, 134.88, 125.12, 164.45, 167.15, 172.83; EIMS m/z 274 (M+, 0.2), 256 (5.3), 243
(100). Anal. Calcd for C14H14N2O4: C, 61.31; H, 5.14; N, 10.21. Found: C, 61.44; H, 4.94; N, 10.18.
trans-4d: colorless crystals: mp 163-164.5 ºC (EtOAc-hexane); IR (KBr) 3480, 1795, 1720, 1470, 1240,
1
1070, 880, 710 cm-1; H NMR (500 MHz, CDCl3) δ 1.29 (d, J = 6.8 Hz, 3H), 2.24 (dd, J = 17, 6.2 Hz,
1H), 2.76 (dq J = 8.9, 6.3 Hz, 1H), 2.83 (dd, J = 16.7, 8.3 Hz, 1H), 3.34 (dd, J = 11.5, 3.6 Hz, 1H), 3.48
(dt, J = 6.3, 2.1 Hz, 1H), 3.62 (ddd, J = 13, 12, 2.1 Hz, 1H), 3.74 (ddd, J = 14 3.6, 2.1 Hz, 1H), 7.79-7.87
13
(m, 2H), 7.89-7.97 (m, 2H); C NMR (126 MHz, CDCl3) δ 19.26, 27.04, 36.44, 59.55, 68.05, 124.16,
124.24, 129.63, 129.72, 134.89, 135.09, 163.94, 167.17, 172.87; EIMS m/z 274 (M+, 0.1), 256 (5.1), 243
(100), 215 (31.9). Anal. Calcd for C14H14N2O4: C, 61.31; H, 5.14; N, 10.21. Found: C, 61.42; H, 5.01; N,
10.19.
cis- and trans-5d: colorless crystals, mp 229-232 ºC (EtOAc-hexane); IR (KBr) 3350, 1795, 1745, 1660,
1
1220, 1090, 880, 710 cm-1; H NMR (500 MHz, CDCl3) δ 1.07 (d, J = 6.3 Hz, 3H), 1.97-2.07 (m,
13
2H), .2.22-2.96 (m, 2H), 3.49 (q, J = 5.5 Hz, 1H), 3.90-4.03 (m, 2H), 7.76-7.93 (m, 4H); C NMR (126
MHz, DMSO-d6) δ 16.72, 33.44, 35.23, 55.54, 67.41, 123.52, 129.25, 129.31, 135.02, 164.10, 164.23,
167.10; EIMS m/z 274 (M+, 4.3), 256 (11.8), 175 (100), 148 (16.8). Anal. Calcd for C14H14N2O4: C,
61.31; H, 5.14; N, 10.21. Found: C, 61.33; H, 4.95; N, 10.21.
Entry 4.
2-(5-(Hydroxymethyl)-3-methyl-2-oxopyrrolidin-1-yl)isoindoline-1,3-dione (4e) and 2-(5-Hydroxy-
3-methyl-2-oxopiperidin-1-yl)isoindoline-1,3-dione (5e). Following the typical procedure, a mixture of
compounds 2e + 3e (194 mg, 0.524 mmol) was hydrolyzed in AcOH-THF-H2O (3 : 1 : 1, 10 mL). After
10 min, workup and column chromatography (30 % acetone-toluene) gave 4e + 5e (122 mg, 85%, in a
1
6 : 1 ratio, as determined by H NMR). After careful chromatography, small amounts of the pure
components 4e and 5e could be isolated.
cis- and trans-4e: colorless crystals: mp 141-148 ºC (EtOAc-hexane); IR (KBr) 3450, 1795, 1740, 1705,
1225, 885, 710 cm-1; 1H NMR (270 MHz, CDCl3) δ 1.34 (d, J = 7.1 Hz, 0.5H), 1.35 (d, J = 7.1 Hz, 2.5H),
2.00-2.15 (m, 1H), 2.36-2.59 (m, 1H), 2.69-2.90 (m, 1H), 3.30 (dd, J = 12, 2.6 Hz, 0.7H), 3.38 (dd, J = 12,

HETEROCYCLES, Vol. 75, No. 5, 2008
1147
13
3.2 Hz, 0.3H), 3.50-3.61 (m, 1H), 3.73-3.80 (m, 1H), 3.90 (t, J = 6.4 Hz, 1H), 7.80-7.96 (m, 4H); C
NMR (68 MHz, CDCl3) δ 16.12, 17.05, 27.18, 29.03, 33.82, 34.22, 59.12, 59.25, 59,88, 61.72, 124.16,
124.22, 129.66, 129.72, 134.89, 135.07, 163.96, 167.24, 175.96; EIMS m/z 274 (M+, 1.1), 256 (10.1), 243
(100), 215 (56.1). Anal. Calcd for C14H14N2O4: C, 61.31; H, 5.14; N, 10.21. Found: C, 61.38; H, 5.07; N,
10.13.
cis- and trans- 5e: colorless crystals: mp 229-232 ºC (EtOAc-hexane); IR (KBr) 3440, 1790, 1740, 1680,
1
1650, 1210, 880, 710 cm-1; H NMR (270 MHz, CDCl3) δ 1.21-1.41 (m, 3H), 1.75-2.10 (m, 1.3H),
2.16-2.30 (m, 0.7H), 2.35-2.47 (m, 0.4H), 2.57-2.93 (m, 1.1H), 2.96-3.13 (m, 0.6H), 3.60-3.72 (m, 1.0H),
3.95 (ddd, J = 12, 4.7, 1.0 Hz, 0.4H), 4.05 (dd, J = 12, 4.7 Hz, 0.6H), 4.39 (br s, 0.9H), 7.73-7.98 (m, 4H,
ArH); 13C NMR (68 MHz, CDCl3) δ 16.69, 16.78, 31.79, 34.15, 36.10, 38.58, 57.97, 58.85, 63.43, 64.69,
123.87, 123.93, 123.96, 129.79, 129.85, 129.88, 129.99, 134.64, 134.74, 164.60, 164.81, 165.12, 171.20,
171.45; EIMS m/z 274 (M+, 5.8), 256 (8.6), 175 (100), 130 (26.1). Anal. Calcd for C14H14N2O4: C, 61.31;
H, 5.14; N, 10.21. Found: C, 61.36; H, 4.90; N, 10.05.
Entry 5.
2-[2-(Hydroxymethyl)-3,3-dimethyl-5-oxopyrrolidin-1-yl]isoindoline-1,3-dione (4f). Yield 76%,
colorless crystals, mp 143-144 ºC (EtOAc-hexane); IR (KBr) 3510, 2980, 1795, 1740, 1390, 1300, 1210,
1
1080, 880, 710 cm-1; H NMR (270 MHz, CDCl3) δ 1.34 (s, 3H), 1.41 (s, 3H), 2.19 (d, J = 17 Hz, 1H),
2.71 (d, J = 17 Hz, 1H), 3.30-3.39 (m, 1H), 3.53 (dd, J = 11, 5.7 Hz, 1H), 3.65-3.88 (m, 2H, 7.78-8.00 (m,
4H, ArH); 13C NMR (68 MHz, CDCl3) δ 23.41, 30.63, 35.33, 43.28, 59.73, 70.51, 124.11, 124.21, 129.61,
129.87, 134.85, 135.09, 164.41, 167.13, 172.33; EIMS m/z 288 (M+, 0.2), 257 (100), 229 (16.1), 148
(22.2), 130 (23.1). Anal. Calcd for C15H16N2O4: C, 62.49; H, 5.59; N, 9.72. Found: C, 62.47; H, 5.55; N,
9.74.
Entry 6.
2-(6-exo-Hydroxy-2-oxohexahydrocyclopenta[b]pyrrol-1(2H)-yl)isoindoline-1,3-dione (4g). Yield
87%, colorless crystals, mp 231-233 ºC (EtOAc-hexane); IR (KBr) 3370, 1785, 1730, 1695, 1360, 880,
1
710 cm-1; H NMR (270 MHz, DMSO-d6) δ 1.42 (m, 2H), 1.84-2.20 (m, 2H), 2.26 (dd, J = 18, 3.5 Hz,
1H), 2.78 (dd, J = 11, 18 Hz, 1H), 2.92-3.13 (m, 1H), 3.98 (d, J = 7.9 Hz, 1H), 4.07 (d, J = 3.1 Hz, 1H),
4.81 (d, J = 3.5 Hz, 1H), 7.92-8.14 (m, 4H, ArH); 13C NMR (68 MHz, DMSO-d6) δ 30.90, 31.60, 32.15,
34.15, 70.66, 73.70, 123.88, 124.00, 129.16, 129.33, 135.49, 135.55, 164.54, 164.80, 172.29; EIMS m/z
286 (M+, 2.2), 268 (100), 162 (12.4), 148 (43.7), 104 (46.3), 76 (38.6). Anal. Calcd for C15H14N2O4: C,
62.93; H, 4.93; N, 9.79. Founds: C, 62.87; H, 4.81; N, 9.68.
Entry 7.
Methyl 6-(1,3-Dioxoisoindolin-2yl)-7-oxo-4-exo-hydroxy-6-azatricyclo[3,2,1,13,8]nonane-2-endo-
carboxylate (4h). Yield 68%, colorless crystals, mp 194-196 ºC (EtOAc): IR (KBr) 3510, 1790, 1730,

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1
1695, 880, 705 cm-1; H NMR (270 MHz, CDCl3) δ 1.57 (d, J = 11 Hz, 1H), 2.16 (d, J = 11 Hz, 1H),
2.26-2.40 (m, 1H), 2.73-2.92 (m, 2H), 3.17 (dd, J = 11, 3.9 Hz, 1H), 3.40-3.53 (m, 1H), 3.69 (d, J = 5.1
13
Hz, 1H), 3.75 (s, 3H), 4.59 (br s, 1H), 7.72-7.95 (m, 4H); C NMR (68 MHz, CDCl3) δ 32.42, 41.30,
47.52, 48.27, 52.11, 68.80, 72.54, 123.80, 123.93, 129.77, 129.79, 134.57, 134.63, 163.73, 164.29, 170.27,
172.55; EIMS m/z 356 (M+, 9.8), 328 (80.4), 229 (100), 210 (56.1), 122 (72.3). Anal. Calcd for
C18H16N2O6: C, 60.67; H, 4.53; N, 7.86. Found: C, 60.54; H, 4.36; N, 7.64.
Entry 8.
2-(4-Hydroxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)isoindoline-1,3-dione (4i). Yield 83%, colorless
1
crystals, mp 215-218 ºC (EtOAc-hexane); IR (KBr) 3515, 1795, 1745, 1730 cm-1; H NMR (270 MHz,
CDCl3) δ 3.34 (t, J = 7.0 Hz, 1H), 4.05-4.23 (m, 2H), 4.90 (s, 1H), 7.56 (t, J = 6.8 Hz, 2H), 7.71 (t, J =
13
7.8 Hz, 1H), 7.80-8.07 (m, 5H); C NMR (68 MHz, CDCl3) δ 60.45, 63.66, 122.39, 124.25, 124.35,
124.49, 128.75, 129.17, 129.83, 129.87, 133.12, 134.99, 135.18, 142.00; 164.49, 166.12, 167.16; EIMS
m/z (M+, 0.3), 278 (100). Anal. Calcd for C17H12N2O4: C, 66.23; H, 3.92; N, 9.09. Found: C, 66.07; H,
3.85; N, 8.94.
Table 4: Products 6a, 6c, and 6d obtained by removal of phthaloyl group.
Entry 1.
6-Amino-4-hydroxy-6-azabicyclo[3.2.1]octan-7-one (6a): Typical Procedure for Table 4. A solution
of compound 2a (200 mg, 0.523 mmol) and hydrazine monohydrate (105 mg, 2.615 mmol) in EtOH (5
mL) was heated at 100 ºC for 0.5 h. After the reaction was complete, the solvent was concentrated in
vacuo. Insoluble phthaloyl hydrazide was removed by filtration and washed with toluene. The filtrate was
concentrated in vacuo and the residue was purified by short column chromatography using 20%
MeOH-EtOAc to give the product 6a (72 mg, 88%). 6a: colorless crystals, mp 174-177 ºC (EtOAc); IR
1
(KBr) 3300, 1650, 1420, 1235, 1085, 1040, 965 cm-1; H NMR (270 MHz, DMSO-d6) δ 1.16-1.29 (m,
0.5H), 1.34-1.82 (m, 4.5H), 1.92-2.11 (m, 1H), 2.23 (br s, 0.6H), 2.29 (br s, 0.4H), 3.38-3.52 (m, 1H),
3.89-4.03 (m, 1H), 4.53 (s, 1.3H), 4.75 (s, 0.7H), 4.89 (d, J = 4.1 Hz, 0.7H), 5.06 (dd, J = 4.1 Hz, 0.3H);
13C NMR (68 MHz, DMSO) δ 18.96, 22.10, 23.95, 26.55, 27.55, 33.45, 37.95, 38.58, 61.88, 61.92, 62.07,
66.22, 172.48, 174.33; EIMS m/z 156 (M+, 100), 140 (84.8), 122 (25.4), 84 (87.8). Anal. Calcd for
C7H12N2O2: C, 53.83; H, 7.74; N, 17.94. Found: C, 53.71; H, 7.51; N, 17.72.
Entry 2.
1-Amino-5-(hydroxymethyl)pyrrolidin-2-one (6c). Yield 73%, oil, IR (neat) 3300, 1670, 1420, 1290
cm-1; 1H NMR (270 MHz, CDCl3) δ 1.68-1.83 (m, 1H), 2.01-2.18 (m, 1H), 2.29-2.52 (m, 2H), 3.33 (br s,
13
1H), 3.60-3.84 (m, 2H), 3.85-3.97 (m, 1H), 4.12 (br s, 2H); C NMR (68 MHz, CDCl3) δ 18.71, 28.70,
61.40, 62.31, 174.32; EI-MS m/z 130 (M+, 13.0), 99 (100), 84 (1.8), 57 (46.3); HR-EIMS for C5H10N2O3.

HETEROCYCLES, Vol. 75, No. 5, 2008
1149
130.0742. Found: 130.0748.
Entry 3.
1-Amino-5-(hydroxymethyl)-4,4-dimethylpyrrolidin-2-one (6f). Yield 88%, yellow crystals, mp
1
125-127 ºC (EtOAc-hexane); IR (KBr) 3300, 1680, 1080, 990 cm-1; H NMR (270 MHz, CDCl3) δ 1.06
(s, 3H), 1.19 (s, 3H), 2.21 (dd, J = 27, 17 Hz, 2H), 3.36 (dd, J = 6.5, 2.4 Hz, 1H), 3.42-3.56 (m, 1H),
13
3.72-3.94 (m, 2H), 4.16 (s, 2H); C NMR (68 MHz, CDCl3) δ 23.01, 29.44, 33.70, 44.69, 60.50, 70.98,
174.00; EIMS m/z 158 (M+, 9.4), 127 (100), 111 (0.8), 85 (69.3). Anal. Calcd for C7H14N2O2: C, 53.15; H,
8.92; N, 17.71. Found: C, 53.26; H, 8.90; N, 17.53.
REFERENCES AND NOTES
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2.
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Y. Kikugawa and M. Kawase, Chem. Lett., 1990, 581.
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P. G. Gassman, F. Hoyda, and J. Dygos, J. Am. Chem. Soc., 1968, 90, 2716; P. G. Gassman and J.
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(a) A. Correa, I. Tellitu, E. Domínguez, and R. SanMartín, J. Org. Chem., 2006, 71, 8316. (b) S.
Serena, I. Tellitu, E. Domínguez, I. Moreno, and R. SanMartín, Tetrahedron, 2004, 60, 6533. (c) S.
Serena, I. Tellitu, E. Domínguez, I. Moreno, and R. SanMartín, Tetrahedron Lett., 2003, 44, 3483.
J. E. Baldwin, J. Chem. Soc., Chem. Commun., 1976, 734.
7.
8.
An aziridinium ion intermediate is assumed in a similar PIFA promoted olefin amidohydroxylation:
see ref. 6a-c.
9.
J. W. Bastable, J. D. Hobson, and W. D. Riddell, J. Chem. Soc., Perkin Trans. 1, 1972, 2205.
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1065.