Stereoselective syntheses of chiral (3S,9bS)-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones

Article abstract of DOI:10.1016/S0957-4166(02)00220-3

Chiral (3S,9bS)-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones 11a-11f, 14b,14c and 17a,b were prepared in 78-93% yields with high stereoselectivities (d.e. >99%) by the intermolecular condensations of 2-formylbenzoic acids 10 or 13 or 2-acetylbenzoic acid 15 with chiral diamines 9a-9f and 9h. Compounds 9a-9f and 9h were readily prepared in three steps from optically active N-Boc-α-amino acids 5a-5d.

Full text of DOI:10.1016/S0957-4166(02)00220-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 933–938
Stereoselective syntheses of chiral
(3S,9bS)-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones
Alan R. Katritzky,* Hai-Ying He and Akhilesh K. Verma
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA
Received 18 December 2001; accepted 19 March 2002
Abstract—Chiral (3S,9bS)-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones 11a–11f, 14b,14c and 17a,b were prepared in
78–93% yields with high stereoselectivities (d.e. >99%) by the intermolecular condensations of 2-formylbenzoic acids 10 or 13 or
2-acetylbenzoic acid 15 with chiral diamines 9a–9f and 9h. Compounds 9a–9f and 9h were readily prepared in three steps from
optically active N-Boc-a-amino acids 5a–5d. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
acids 3.1,5,6 1-Acyl derivatives of 1 were prepared by the
acylation of 1 (R1=H) with anhydrides1,6a or acid
chlorides.1 In published examples of 1, R2 and R3
groups are limited to hydrogen except for three exam-
ples (1: R1=H, R2=R3=CH3 or Ph; R1=H, R2=CH3,
R3=H).6a A less common approach to 1 involves the
reactions of 1,2-ethanediamines 2 with 2-bromobenz-
aldehyde under carbon monoxide via a palladium-cata-
lyzed cascade intramolecular acylpalladation–cycliza-
tion sequence.7 However, no stereoselective synthesis
was reported, thus the final products 1 were hitherto
obtained as racemic compounds or mixtures of
diastereoisomers.
1,2,3,9b-Tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones 1
possess antiinflammatory, analgesic, blood pressure
lowering, spasmolytic, tranquilizing, and antitussive
properties,1 and are also useful sedative and hypoten-
sive agents.2 Compounds 1 (R1=COCH2NH2, R2=
R3=H, R4=Ar) exhibit analgesic activity and are
effective in treating rheumatism.3 Furthermore, reduc-
tions of 1 with LiAlH4 led to the benzodiazocines,
which are appetite suppressants and central nervous
system stimulants.4
Following our recent stereoselective syntheses of
(3S,9bR) - 1H - imidazo[2,1 - a]isoindole - 2,5(3H,9bH)-
diones 4,8 we now report a simple and efficient synthe-
sis of functionalized chiral (3S,9bS)-1,2,3,9b-tetra-
hydro-5H-imidazo[2,1-a]isoindol-5-ones in good to
excellent yields with high stereoselectivities starting
from easily available N-Boc-a-amino acids 5.
2. Results and discussion
Reported routes to 1,2,3,9b-tetrahydro-5H-imidazo[2,1-
a]isoindol-5-ones 1 (R1=H, R2=R3=H, R4=alkyl or
aryl) involve intermolecular condensations of 1,2-
ethanediamines 2 with 2-alkanoyl-5 or 2-aroyl-benzoic
2.1. Preparation of chiral diamines 9a–9f from N-Boc-
a-amino acids 5a–5d (cf. Scheme 1)
The published method9 readily provided N-Boc-a-
amino amides 7a–7f from the corresponding optically
active N-Boc-a-amino acids 5a–5d (R2=Me, i-Pr, i-Bu,
or PhCH2) and primary amines 6 (R1=p-CH3C6H4,
PhCH2, or c-C6H11). We previously used excess HCl/
* Correponding author. Tel.: +1 352 392 0554; fax: +1 352 392 9199;
e-mail: katritzky@chem.ufl.edu
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00220-3

934
A. R. Katritzky et al. / Tetrahedron: Asymmetry 13 (2002) 933–938
single enantiomers in 78–93% yields by the reactions of
2-formylbenzoic acid 10 with 1 equiv. of the chiral
diamines 9a–9f and catalytic p-toluenesulfonic acid (0.1
equiv.) in refluxing benzene for 12 h with a Dean–Stark
apparatus to remove the water formed (Scheme 1). The
isolated yields and the d.e. values (determined by the
1H NMR spectra) of 11a–11f are summarized in Table
1
1. Structures 11a–11f are clearly supported by their H,
13C, NOESY NMR spectra and microanalyses. It is
noteworthy that the same conditions for the reaction of
10 and N1-phenyl-1,2-ethanediamine 9g gave the
desired 11g in low yield (<10%); while completing the
reaction under azeotropic reflux in toluene over 28 h
improved the yield to 74%.
Scheme 1. For designation of R1 and R2 in series a–f, see
Table 1. Reagents and conditions: (i) ClCOOBu-i, N-methyl-
morpholine; (ii) CF3COOH; (iii) aq. NaOH; (iv) LiAlH4/
THF; (v) p-TsOH, PhH, Dean–Stark.
The absolute configuration of the new stereogenic cen-
ter at the 9b-position in 11a–11f was determined by
NOESY experiments. 1H NMR spectra show that
H(9b) in 11a–11f appears from 4.9 ppm to 6.1 ppm as
a singlet; H(3) at 4.4–4.8 ppm as a multiplet. No
distinct NOE effect was observed between H(9b) and
H(3) in compounds 11a–11f, when either H(9b) or H(3)
was irradiated. This suggests that H(9b) and H(3) in
11a–11f are located in a trans-orientation. Further irra-
diation of 11a [at CH3(3), 1.39 ppm (d)], 11b [at i-
PrCH2-, 1.6 or 1.8 ppm (m)], 11c [at PhCH2-, 2.88 or
EtOAc (ca. 1 M) to remove the N-Boc protection
group (usually needing 12–24 h until the disappearance
of 7),8 but we now find that use of CF3COOH (8
equiv.) in dry CH2Cl2 is a more efficient method to
remove the Boc group (needing only 2–5 h) to give
a-amino amides 8a–8f (88–96%).
Crombie and Hooper reduced 2-amino-N-phenyl-
propanamide with LiAlH4 to 2-aminopropylaniline
without reporting a detailed procedure.10 Reduction of
8b (R1=p-CH3C6H4, R2=i-Bu) with 3 equiv. of
LiAlH4 in refluxing THF for 1 day gave a 1:1 mixture
of 8b and 9b. When 6 equiv. of LiAlH4 was used in
refluxing THF for 2 days, chiral diamines 9a–9f were
obtained in more than 90% yields. Intermediates 7, 8
and 9 were used as crude products without further
purification for the subsequent steps.
3.09 ppm (dd)] or 11d [at CH6 (CH3)2, 1.8 ppm (m)]
caused a strong positive NOE effect of H(9b), and vice
versa. The similar positive NOE effect was observed
between CH6 (CH3)2(3) and H(9b) for 11e,f. This evi-
dence directly demonstrates the trans-orientation of
H(9b) and H(3). Therefore, enantiopure 11a–11f were
obtained as sole trans-isomers with the formation of
three new bonds in a single step to form the tricyclic
ring system.
The reaction mechanism is similar to that previously
proposed.8 The a-amino group in 9a–9f attacks the
aldehydic carbon atom (the most electrophilic center in
10) to generate the transient intermediate a-carbinol-
amine A, which readily eliminates a molecule of water
to afford the imine intermediate with more stable
E(trans)-configuration. Conformation B of the imine
intermediate is much more stable than conformation C
due to the larger repulsion between R2 group and
-NHR1 group in C. Therefore, the lone electron pair of
the nitrogen in the predominant conformation B
attacks the imine from below the ArCꢀN- coplane,
followed by elimination of another water molecule, to
form the trans-isomers 11a–11f as the sole products.
The cis-isomers 12a–12f were not detected (cf. Fig. 1).
2.2. Syntheses and stereoselectivities of (3S,9bS)-
1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones
11a–11f
Optically active (3S,9bS)-1,2,3,9b-tetrahydro-5H-imi-
dazo[2,1-a]isoindol-5-ones 11a–11f were prepared as
Table 1. Isolated yields of 11a–11f with d.e. values
No.
R1
R2
Yield 11a (d.e.b %)
a
b
c
d
e
f
p-CH3C6H4-
p-CH3C6H4-
p-CH3C6H4-
p-CH3C6H4-
c-C6H11
CH3
i-Bu
PhCH2-
i-Pr
i-Pr
i-Pr
78 (\99)
90 (\99)
88 (\99)
93 (\99)
78 (\99)
89 (\99)
74c
Interestingly, irradiation of 11a [at CH3(3)], 11b (at
i-PrCH2), 11c (at PhCH2) or 11d–11f [at CH6 (CH3)2]
also caused a distinct positive NOE effect for one of the
methylene hydrogens at the 2-position, thus this hydro-
gen is assigned as the anti-proton Ha (for one example
11a, cf. Fig. 2). anti-Ha always appears at higher field
than syn-Hb and its coupling constant with H(3) (ca.
3.2 Hz) is smaller than that of syn-Hb with H(3) (ca. 6.9
Hz).
PhCH2-
Ph
g
H
a Isolated yield based on the chiral diamine 9a–9f.
b Determined by the 1H NMR spectrum.
c Compound 11g was obtained from N1-phenyl-1,2-ethanediamine 9g
and 10 using azeotropic distillation in toluene for 28 h.

A. R. Katritzky et al. / Tetrahedron: Asymmetry 13 (2002) 933–938
935
Figure 1.
between CH3(9b) with CH3(3) in 17a and CH
6
(CH3)2(3)
in 17b, respectively.
3. Conclusion
8
Figure 2. Nuclear Overhauser effect for 11a.
In summary, we have developed an efficient route to
enantiopure (3S,9bS)-1,2,3,9b-tetrahydro-5H-imidazo-
[2,1-a]isoindol-5-ones 11a–11f, 14b, 14c and 17a and
17b in good to excellent yields with high stereoselectivi-
ties through intermolecular condensations of 2-formyl-
benzoic acids 10 or 13 or 2-acetylbenzoic acid 15 with
chiral diamines 9a–9f and 9h, which were readily pre-
pared in three steps from N-Boc-a-amino acids 5a–5d.
Thus, three new bonds are simultaneously formed in
one step to generate the novel tricyclic ring system.
2.3. Syntheses of 1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]-
isoindol-5-ones 14a,b and 17a,b
The reaction of 2-formyl-5,6-dimethoxybenzoic acid 13
with N1-phenyl-1,2-ethanediamine 9g gave 6,7-
dimethoxy-1-phenyl-1,2,3,9b-tetrahydro-5H-imi-
dazo[2,1-a]isoindol-5-one 14a in 64% yield using
azeotropic distillation in toluene for 28 h. Similarly, 14b
and 14c were obtained from the reactions of 13 with 9e
and 9f in 83 and 86% yields, respectively (Scheme 2).
Interestingly, condensation of N1-phenyl-1,2-ethanedi-
amine 9g with 2-acetylbenzoic acid 15 produced 2-(2-
anilinoethyl)-3-methylene-1-isoindolinone 16 rather
1
than a tricyclic structure. The H, 13C NMR spectra of
16 show the disappearance of the methyl group and the
existence of two hydrogens attached to a carbonꢁ
carbon double bond. The GC–MS result [GC–MS (EI):
264 (M+)] together with combustion analysis data, fur-
ther support the structure 16 (cf. Scheme 2). Further-
more, Hc is believed to appear at lower field (5.12 ppm,
doublet); while Hd resonates at higher field (4.80 ppm,
doublet), due to the positive NOE effect between Hc
and He (7.68 ppm, doublet). The formation of 16 is
probably because of competitive deprotonation at the
methyl group and the deprotonation at -NHPh moiety
in the transient N-acyliminium cation.
Nevertheless, reaction of 2-acetylbenzoic acid 15 with
chiral diamines 9h and 9f (R2"H) furnished the desired
enantiopure (3S,9bS)-1,2,3,9b-tetrahydro-5H-imidazo-
[2,1-a]isoindol-5-ones 17a,b in 88 and 89% yields,
respectively. The NOESY results also prove the trans-
configurations for 17a,b due to the positive NOE effect
Scheme 2.

936
A. R. Katritzky et al. / Tetrahedron: Asymmetry 13 (2002) 933–938
4. Experimental
4.1.3. (2S)-N1-(4-Methylphenyl)-3-phenyl-1,2-propanedi-
1
amine 9c. Yellowish oil; yield 94%; H NMR: l 1.02–
THF was distilled from sodium/benzophenone prior to
use. Melting points were determined using a Bristoline
hot-stage microscope and are uncorrected. 1H (300
MHz), 13C (75 MHz) NMR spectra, and NOESY spec-
tra were recorded on a Gemini 300 MHz NMR spec-
1.40 (br s, 2H), 2.23 (s, 3H), 2.56 (dd, J=13.3, 8.4 Hz,
1H), 2.78–2.94 (m, 2H), 3.18–3.27 (m, 2H), 3.90–4.05
(br s, 1H), 6.53 (d, J=8.2 Hz, 2H), 6.97 (d, J=8.0 Hz,
2H), 7.18–7.32 (m, 5H); 13C NMR: l 20.3, 42.7, 50.3,
52.1, 113.0, 126.3, 126.5, 128.4, 129.1, 129.6, 138.7,
146.1.
1
trometer in CDCl3 (with TMS for H and CDCl3 for
13C as the internal reference). Optical rotation values
were measured by a Perkin–Elmer 341 polarimeter
using the sodium D line. Column chromatography was
performed on silica gel (200–425 mesh). All of the
reactions were carried out under N2.
4.1.4. (2S)-N1-(4-Methylphenyl)-3-methyl-1,2-butanedi-
1
amine 9d. Yellowish oil; yield 91%; H NMR: l 0.94 (d,
J=6.4 Hz, 3H), 0.96 (d, J=6.5 Hz, 3H), 1.17 (br s,
2H), 1.60–1.70 (m, 1H), 2.23 (s, 3H), 2.69–2.84 (m, 2H),
3.20 (dd, J=11.4, 2.7 Hz, 1H), 3.99 (br s, 1H), 6.56 (d,
J=8.4 Hz, 2H), 6.98 (d, J=8.1 Hz, 2H); 13C NMR: l
17.8, 19.3, 20.3, 32.5, 48.5, 56.1, 113.1, 126.4, 129.7,
146.4.
4.1. General procedures for the preparation of chiral
diamines 9a–9f and 9h from N-Boc-a-amino acids 5a–
5d
Synthesis of N-Boc-h-amino amides 7a–7f: N-Boc-a-
amino amides 7a–7f were prepared from N-Boc-a-
amino acids 5a–d and primary amines 6a–6c in more
than 89% yields according to our recent paper.8
4.1.5. (2S)-N1-Cyclohexyl-3-methyl-1,2-butanediamine
9e. Yellowish oil; yield 90%; 1H NMR: l 0.90 (d,
J=6.3 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H), 1.05–1.40 (m,
6H), 1.56–1.92 (m, 5H), 2.23 (br s, 3H), 2.32–2.48 (m,
2H), 2.56–2.62 (m, 1H), 2.77 (dd, J=11.4, 3.3 Hz, 1H);
13C NMR: l 17.7, 19.3, 24.8, 25.0, 26.0, 32.5, 33.2, 33.4,
50.7, 56.5, 57.0.
Removal of N-Boc protecting group: The previous con-
ditions used to remove N-Boc with HCl/EtOAc were
modified as follows: N-Boc-a-amino amide 7a–7f (3
mmol) was treated with CF3COOH (2.7 g, 24 mmol) in
dry CH2Cl2 (25 mL) at room temperature until TLC
showed the disappearance of 7 (usually needs 2–5 h).
Usual work-up gave the a-amino amides 8a–8f in more
than 88% yields.
4.1.6. (2S)-N1-Benzyl-3-methyl-1,2-butanediamine 9f.
1
Colorless oil; yield 94%; H NMR: l 0.89 (d, J=6.9
Hz, 3H), 0.90 (d, J=6.6 Hz, 3H), 1.43 (s, 3H), 1.53–
1.63 (m, 1H), 2.39 (dd, J=11.4, 9.3 Hz, 1H), 2.58–2.69
(m, 1H), 2.72 (dd, J=11.4, 3.3 Hz, 1H), 3.79 (d, J=7.5
Hz, 2H), 7.23–7.33 (m, 5H); 13C NMR: l 17.8, 19.4,
32.3, 53.6, 54.1, 56.5, 126.8, 128.0, 128.3, 140.6.
Reduction of 8a–8f with LiAlH4: A mixture of the
a-amino amide 8a–8f (3 mmol) and LiAlH4 (powder,
0.68 g, 18 mmol) in dry THF (30 mL) was heated under
reflux for 2 days. The mixture was slowly quenched
with water under ice-bath cooling. The precipitate
formed was filtered off and washed with CH2Cl2. The
combined filtrate was washed with 1 M NaOH, brine
and dried over anhyd. K2CO3. Removal of solvents
afforded chiral diamine 9a–9f, which was directly used
for the subsequent reaction. GC analyses show that the
purity of 9a–9f is more than 92%.
4.1.7. (2S)-N1-Cyclohexyl-1,2-propanediamine 9h. Yel-
1
lowish oil; yield 90%; H NMR: l 1.10 (d, J=6.3 Hz,
3H), 1.16–1.32 (m, 5H), 1.60–1.64 (m, 2H), 1.72–1.78
(m, 2H), 1.91–1.99 (m, 2H), 2.39–2.52 (m, 2H), 2.71
(dd, J=11.8, 4.1 Hz, 1H), 3.01–3.10 (m, 3H); 13C
NMR: l 21.7, 24.9, 25.0, 25.9, 32.8, 33.1, 46.6, 54.3,
56.9.
Compound 9h was similarly prepared from N-Boc-a-
amino acid 5a (R2=CH3) and cyclohexylamine.
4.2. General procedure for the preparation of 1,2,3,9b-
tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones 11a–11g
4.1.1. (2S)-N1-(4-Methylphenyl)-1,2-propanediamine 9a.
1
A mixture of a crude diamine 9a–9f (1.0 mmol), 2-
formylbenzoic acid (10, 0.15 g, 1.0 mmol) and p-
CH3C6H4SO3H·H2O (0.02 g, 0.1 mmol) was heated
under reflux in benzene (25 mL) for 12 h using a
Dean–Stark apparatus. After cooling, most of the sol-
vent was evaporated in vacuo and the residue was
diluted with EtOAc. The organic phase was washed
with 1 M NaOH, brine and dried over anhyd. Na2SO4.
After removal of solvents in vacuo, the residue was
purified by column chromatography with hexanes/
EtOAc (8:1 to 4:1) as an eluent to give the final product
11a–11f.
Yellowish oil; yield 96%; H NMR: l 1.20 (d, J=7.1
Hz, 3H), 1.20–1.80 (br s, 2H), 2.31 (s, 3H), 2.90 (dd,
J=12.1, 8.0 Hz, 1H), 3.14–3.22 (m, 2H), 3.80–4.25 (br
s, 1H), 6.62 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.1 Hz, 2H);
13C NMR: l 20.1, 21.8, 45.9, 52.3, 112.8, 126.1, 129.5,
146.0.
4.1.2. (2S)-N1-(4-Methylphenyl)-4-methyl-1,2-pentanedi-
1
amine 9b. Colorless oil; yield 93%; H NMR: l 0.91 (d,
J=6.5 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H), 1.28 (t, J=6.7
Hz, 2H), 1.20–1.40 (br s, 2H), 1.70–1.81 (m, 1H), 2.24
(s, 3H), 2.79 (dd, J=11.8, 8.7 Hz, 1H), 3.00–3.08 (m,
1H), 3.13–3.20 (m, 1H), 3.80–4.10 (br s, 1H), 6.56 (d,
J=8.1 Hz, 2H), 7.00 (d, J=8.0 Hz, 2H); 13C NMR: l
20.3, 22.1, 23.5, 24.7, 45.7, 48.4, 51.3, 113.1, 126.5,
129.7, 146.3.
Compound 11g was obtained from 10 and N1-phenyl-
1,2-ethanediamine 9g with 0.1 equiv. of p-TsOH using
azeotropic distillation in toluene for 28 h.

A. R. Katritzky et al. / Tetrahedron: Asymmetry 13 (2002) 933–938
937
4.2.1.
(3S,9bS)-1-(4-Methylphenyl)-3-methyl-1,2,3,9b-
4.2.5. (3S,9bS)-1-Cyclohexyl-3-isopropyl-1,2,3,9b-tetra-
hydro-5H-imidazo[2,1-a]isoindol-5-one 11e. Colorless
tetrahydro-5H-imidazo[2,1-a]isoindol-5-one 11a. White
needles; yield 78%; mp 108–109°C; [h]2D5=−482 (c 1.68,
CHCl3); H NMR: l 1.39 (d, J=6.6 Hz, 3H), 2.32 (s,
oil; yield 78%; [h]D25=−32.5 (c 1.66, CHCl3); H NMR:
1
1
l 0.99 (d, J=6.6 Hz, 3H), 1.08 (d, J=6.6 Hz, 3H),
1.12–1.41 (m, 5H), 1.70–2.00 (m, 5H), 2.00–2.11 (m,
1H), 2.89–2.99 (m, 2H), 3.48 (t, J=7.8 Hz, 1H), 3.78
(dt, J=15.3, 15.0 Hz, 1H), 5.17 (s, 1H, NCHN), 7.44–
7.54 (m, 3H), 7.80 (d, J=6.9 Hz, 1H); 13C NMR: l
18.6, 19.6, 24.6, 25.6, 26.2, 26.2, 32.5, 33.5, 52.9, 56.3,
59.8, 76.4, 123.4, 124.5, 129.2, 131.6, 134.2, 144.1,
173.0. Anal. calcd for C19H26N2O: C, 76.47; H, 8.78; N,
9.39. Found: C, 76.30; H, 8.83; N, 9.36%.
3H), 3.27 (dd, J=9.2, 3.2 Hz, 1H, Ha), 4.03 (dd, J=9.2,
6.9 Hz, 1H, Hb), 4.52–4.61 (m, 1H), 6.06 (s, 1H,
NCHN), 6.91 (d, J=8.4 Hz, 2H), 7.16 (d, J=8.2 Hz,
2H), 7.49 (dd, J=5.5, 3.0 Hz, 2H), 7.70 (dd, J=5.6, 3.2
Hz, 1H), 7.82 (dd, J=5.5, 3.0 Hz, 1H); 13C NMR: l
20.4, 20.8, 49.7, 61.0, 74.8, 115.4, 124.2, 124.3, 129.0,
129.6, 129.9, 132.4, 133.2, 144.6, 145.1, 172.4. Anal.
calcd for C18H18N2O: C, 77.67; H, 6.52; N, 10.06.
Found: C, 77.61; H, 6.57; N, 10.11%.
4.2.6. (3S,9bS)-1-Benzyl-3-isopropyl-1,2,3,9b-tetrahydro-
5H-imidazo[2,1-a]isoindol-5-one 11f. White needles;
yield 89%; mp 102–103°C; [h]2D5=+1.3 (c 1.58, CHCl3);
1H NMR: l 0.94 (d, J=6.9 Hz, 3H), 1.07 (d, J=6.9
Hz, 3H), 1.78–1.89 (m, 1H), 2.59 (t, J=9.2 Hz, 1H,
Ha), 3.44–3.50 (m, 2H), 3.77 (dt, J=7.8, 7.8 Hz, 1H),
4.15 (d, J=12.6 Hz, 1H), 4.93 (s, 1H, NCHN), 7.26–
7.31 (m, 5H), 7.39 (dd, J=5.1, 3.0 Hz, 1H), 7.49–7.52
(m, 2H), 7.82 (dd, J=6.6, 3.3 Hz, 1H); 13C NMR: l
18.5, 19.8, 33.6, 56.5, 59.7, 60.5, 81.4, 123.3, 124.4,
127.4, 128.4, 128.7, 129.5, 131.8, 134.2, 137.5, 143.5,
173.0. Anal. calcd for C20H22N2O: C, 78.40; H, 7.24; N,
9.14. Found: C, 78.20; H, 7.41; N, 9.07%.
4.2.2. (3S,9bS)-1-(4-Methylphenyl)-3-isobutyl-1,2,3,9b-
tetrahydro-5H-imidazo[2,1-a]isoindol-5-one 11b. Color-
less prisms; yield 90%; mp 61–62°C; [h]2D5=−449 (c 1.78,
1
CHCl3); H NMR: l 0.96 (d, J=6.6 Hz, 3H), 1.07 (d,
J=6.5 Hz, 3H), 1.33–1.39 (m, 1H), 1.56–1.63 (m, 1H),
1.80–1.85 (m, 1H), 2.31 (s, 3H), 3.27 (dd, J=9.0, 2.7
Hz, 1H, Ha), 4.00 (dd, J=9.3, 6.9 Hz, 1H, Hb), 4.47–
4.55 (m, 1H), 6.03 (s, 1H, NCHN), 6.88 (d, J=8.2 Hz,
2H), 7.15 (d, J=8.0 Hz, 2H), 7.46 (dd, J=5.4, 3.0 Hz,
2H), 7.71 (dd, J=5.4, 3.0 Hz, 1H), 7.81 (dd, J=5.4, 3.3
Hz, 1H); 13C NMR: l 20.4, 21.9, 23.1, 25.3, 43.7, 52.4,
59.7, 74.5, 114.9, 124.1, 124.1, 128.5, 129.5, 129.8,
132.3, 133.2, 144.7, 145.3, 172.4. Anal. calcd for
C21H24N2O: C, 78.71; H, 7.55; N, 8.74. Found: C,
78.67; H, 7.83; N, 8.73%.
4.2.7. 1-Phenyl-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]-
isoindol-5-one 11g. Colorless flakes; yield 74%; mp 140–
1
141°C; H NMR: l 3.48 (dt, J=11.1, 8.4 Hz, 1H), 3.64
(td, J=8.4, 2.4 Hz, 1H), 3.84 (dt, J=8.3, 8.3 Hz, 1H),
4.34 (ddd, J=11.1, 7.2, 2.4 Hz, 1H), 6.12 (s, 1H,
NCHN), 6.90 (t, J=7.5 Hz, 1H), 6.97 (d, J=8.1 Hz,
2H), 7.35 (t, J=8.1 Hz, 2H), 7.49–7.52 (m, 2H), 7.77
(dd, J=5.1, 3.3 Hz, 1H), 7.84 (dd, J=5.1, 3.3 Hz, 1H);
13C NMR: l 42.1, 52.9, 75.3, 114.4, 118.9, 124.2, 124.3,
129.4, 129.6, 132.6, 132.9, 145.4, 146.5, 172.7. Anal.
calcd for C16H14N2O: C, 76.78; H, 5.64; N, 11.19.
Found: C, 76.80; H, 5.82; N, 11.21%.
4.2.3. (3S,9bS)-1-(4-Methylphenyl)-3-benzyl-1,2,3,9b-tet-
rahydro-5H-imidazo[2,1-a]isoindol-5-one 11c. White
microcrystals; yield 88%; mp 128–129°C; [h]2D5=−376 (c
1.57, CHCl3); 1H NMR: l 2.31 (s, 3H), 2.88 (dd,
J=13.9, 8.2 Hz, 1H), 3.09 (dd, J=13.9, 6.2 Hz, 1H),
3.42 (dd, J=9.6, 3.2 Hz, 1H, Ha), 3.87 (dd, J=9.6, 6.7
Hz, 1H, Hb), 4.70–4.79 (m, 1H), 5.93 (s, 1H, NCHN),
6.83 (d, J=8.5 Hz, 2H), 7.13 (d, J=8.0 Hz, 2H),
7.21–7.30 (m, 5H), 7.47 (dd, J=5.6, 3.1 Hz, 2H), 7.67
(dd, J=5.4, 3.2 Hz, 1H), 7.81 (dd, J=5.4, 3.1 Hz, 1H);
13C NMR: l 20.4, 40.3, 54.9, 58.0, 75.2, 115.1, 124.1,
124.3, 126.7, 128.5, 128.8, 129.3, 129.5, 129.8, 132.4,
133.1, 137.2, 144.4, 145.4, 172.6. Anal. calcd for
C24H22N2O: C, 81.32; H, 6.26; N, 7.90. Found: C,
81.18; H, 6.32; N, 7.95%.
4.3. General procedure for the reaction of 2-formyl-5,6-
dimethoxybenzoic acid 13 and diamines 9e–9g
Using 2-formyl-5,6-dimethoxybenzoic acid 13 instead
of 2-formylbenzoic acid 10 to react with 9g, 9e or 9f,
the same procedure as used for the preparation of 11g
led to 14a. The same procedure as used for the prepara-
tion of 11a–11f led to 14b and 14c, respectively.
4.2.4. (3S,9bS)-1-(4-Methylphenyl)-3-isopropyl-1,2,3,9b-
tetrahydro-5H-imidazo[2,1-a]isoindol-5-one 11d. Color-
less flakes; yield 93%; mp 55–56°C; [h]2D5=−373 (c 1.66,
4.3.1. 1-Phenyl-6,7-dimethoxy-1,2,3,9b-tetrahydro-5H-
imidazo[2,1-a]isoindol-5-one 14a. Colorless flakes; yield
1
CHCl3); H NMR: l 1.01 (d, J=6.4 Hz, 3H), 1.03 (d,
1
J=6.4 Hz, 3H), 1.76–1.87 (m, 1H), 2.31 (s, 3H), 3.39
(dd, J=9.3, 3.6 Hz, 1H, Ha), 4.02 (dd, J=9.0, 7.2 Hz,
1H, Hb), 4.14 (td, J=7.5, 3.6 Hz, 1H), 5.97 (s, 1H,
NCHN), 6.91 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.1 Hz,
2H), 7.45–7.48 (m, 2H), 7.68 (dd, J=5.6, 3.3 Hz, 1H),
7.81 (dd, J=5.6, 3.3 Hz, 1H); 13C NMR: l 18.9, 19.1,
20.4, 32.5, 58.0, 59.8, 75.8, 115.5, 124.0, 124.2, 129.0,
129.4, 129.8, 132.2, 133.2, 144.6, 145.4, 172.7. Anal.
calcd for C20H22N2O: C, 78.40; H, 7.24; N, 9.14.
Found: C, 78.01; H, 7.54; N, 9.06%.
64%; mp 142–143°C; H NMR: l 3.39 (dt, J=9.3, 9.3
Hz, 1H), 3.58 (t, J=8.4 Hz, 1H), 3.82 (dt, J=8.7, 8.7
Hz, 1H), 3.85 (s, 3H), 4.08 (s, 3H), 4.26–4.36 (m, 1H),
5.99 (s, 1H, NCHN), 6.86 (t, J=7.2 Hz, 1H), 6.92 (d,
J=8.1 Hz, 2H), 7.00 (d, J=8.4 Hz, 1H), 7.33 (t, J=7.2
Hz, 2H), 7.39 (d, J=8.4 Hz, 1H); 13C NMR: l 42.1,
52.5, 56.5, 62.3, 74.2, 114.4, 116.6, 118.7, 119.1, 124.6,
129.3, 138.5, 146.5, 147.3, 153.4, 170.9. Anal. calcd for
C18H18N2O3: C, 69.66; H, 5.85; N, 9.03. Found: C,
69.75; H, 6.07; N, 8.97%.

938
A. R. Katritzky et al. / Tetrahedron: Asymmetry 13 (2002) 933–938
4.3.2. (3S,9bS)-1-Cyclohexyl-3-isopropyl-6,7-dimethoxy-
1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-one 14b.
Colorless oil; yield 83%; [h]2D5=−47.5 (c 1.66, CHCl3);
1H NMR: l 0.97 (d, J=6.9 Hz, 3H), 1.07 (d, J=6.6
Hz, 3H), 1.26–1.42 (m, 4H), 1.68–1.81 (m, 5H), 1.91–
1.95 (m, 1H), 2.04–2.08 (m, 1H), 2.83–2.96 (m, 2H),
3.45 (t, J=8.3 Hz, 1H), 3.75 (dt, J=7.7, 7.7 Hz, 1H),
3.89 (s, 3H), 4.07 (s, 3H), 5.05 (s, 1H, NCHN), 7.06,
7.09 (AB, J=8.1 Hz, 2H); 13C NMR: l 18.8, 19.8, 24.4,
25.7, 26.2, 26.3, 32.7, 33.6, 52.8, 56.1, 56.6, 60.1, 62.4,
75.3, 116.1, 118.5, 126.1, 137.3, 147.6, 153.6, 171.5.
Anal. calcd for C21H30N2O3: C, 70.36; H, 8.44; N, 7.81.
Found: C, 70.18; H, 8.56; N, 7.79%.
1H), 1.83–1.92 (m, 1H), 2.66–2.78 (m, 1H), 3.08 (dd,
J=10.5, 7.7 Hz, 1H), 3.61 (dd, J=10.5, 7.8 Hz, 1H),
3.88–4.04 (m, 1H), 7.42–7.58 (m, 3H), 7.76 (d, J=7.2
Hz, 1H); 13C NMR: l 21.7, 23.3, 25.7, 25.8, 26.3, 31.8,
32.4, 50.0, 55.2, 56.2, 86.1, 122.4, 124.3, 128.9, 132.0,
133.2, 148.0, 172.4. Anal. calcd for C18H24N2O: C,
76.02; H, 8.51; N, 9.85. Found: C, 75.92; H, 8.73; N,
9.59%.
4.4.3. (3S,9bS)-1-Benzyl-3-isopropyl-9b-methyl-1,2,3,9b-
tetrahydro-5H-imidazo[2,1-a]isoindol-5-one 17b. White
needles; yield 89%; mp 157–158°C; [h]2D5=+25.3 (c 1.51,
1
CHCl3); H NMR: l 0.90 (d, J=6.6 Hz, 3H), 1.13 (d,
4.3.3.
(3S,9bS)-1-Benzyl-3-isopropyl-6,7-dimethoxy-
J=6.9 Hz, 3H), 1.66 (s, 3H), 1.74–1.81 (m, 1H), 2.83
(dd, J=9.9, 8.1 Hz, 1H), 3.41 (d, J=9.9 Hz, 1H), 3.44,
3.87 (AB, J=12.9 Hz, 2H), 3.64 (dt, J=7.8, 7.8 Hz,
1H), 7.16–7.26 (m, 5H), 7.36–7.39 (m, 1H), 7.48–7.50
(m, 2H), 7.80 (dd, J=6.1, 3.4 Hz, 1H); 13C NMR: l
18.4, 19.0, 20.9, 35.0, 54.0, 58.9, 60.2, 85.4, 121.7, 124.4,
127.2, 128.3, 128.4, 129.2, 132.1, 132.6, 138.4, 148.1,
173.5. Anal. calcd for C21H24N2O: C, 78.71; H, 7.55; N,
8.74. Found: C, 78.52; H, 7.66; N, 8.75%.
1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-one 14c.
Colorless needles; yield 86%; mp 79–80°C; [h]2D5=+4.3
(c 1.66, CHCl3); H NMR: l 0.92 (d, J=6.6 Hz, 3H),
1
1.06 (d, J=6.6 Hz, 3H), 1.72–1.83 (m, 1H), 2.52 (t,
J=9.3 Hz, 1H), 3.41–3.45 (m, 1H), 3.43, 4.12 (AB,
J=12.9 Hz, 2H), 3.74 (dt, J=7.8, 7.8 Hz, 1H), 3.89 (s,
3H), 4.10 (s, 3H), 4.79 (s, 1H, NCHN), 7.03, 7.07 (AB,
J=8.1 Hz, 2H), 7.22–7.32 (m, 5H); 13C NMR: l 18.6,
19.9, 33.6, 56.3, 56.6, 59.9, 60.3, 62.4, 80.4, 116.1, 118.3,
125.9, 127.4, 128.4, 128.7, 136.6, 137.5, 147.4, 153.4,
171.4. Anal. calcd for C22H26N2O3: C, 72.11; H, 7.15;
N, 7.64. Found: C, 72.38; H, 7.08; N, 7.61%.
References
4.4. General procedure for the reaction of 2-acetylben-
zoic acid 15 with diamines
1. Geigy, J. R. Neth. Appl. 6,613,264, 1967; Chem. Abstr.
1967, 67, 82204q.
2. (a) Graf, W. Swiss 481,123, 1969; Chem. Abstr. 1970, 72,
100709t; (b) Graf, W. Swiss 481,124, 1969; Chem. Abstr.
1970, 72, 100710m.
Using 2-acetylbenzoic acid 15 instead of 2-formylben-
zoic acid 10 to react with 9g, 9h or 9f, the same
procedure as used for the preparation of 11a–f led to
16, 17a and 17b, respectively.
3. Graf, W. Swiss 482,697, 1970; Chem. Abstr. 1970, 73,
25474c.
4. (a) Sulkowski, T. S. US 3,663,532, 1972; Chem. Abstr.
1972, 77, 88559n; (b) Sulkowski, T. S. US 3,994,920,
1976; Chem. Abstr. 1977, 86, 106681p.
4.4.1. 2-(2-Anilinoethyl)-3-methylene-1-isoindolinone 16.
1
Yellowish oil; yield 94%; H NMR: l 3.37 (t, J=5.8
5. Geigy, J. R. Belg. 659,530, 1965; Chem. Abstr. 1966, 64,
6664.
Hz, 2H), 3.96 (t, J=6.0 Hz, 2H), 4.06 (br s, 1H, NH),
4.79 (d, J=2.4 Hz, 1H, Hd), 5.12 (d, J=2.7 Hz, 1H,
Hc), 6.54 (d, J=7.8 Hz, 2H), 6.60 (t, J=7.3 Hz, 1H),
7.08 (t, J=7.8 Hz, 2H), 7.41 (t, J=7.4 Hz, 1H), 7.49 (t,
J=6.9 Hz, 1H), 7.58 (d, J=7.5 Hz, 1H), 7.74 (d, J=7.2
Hz, 1H); 13C NMR: l 38.9, 42.6, 88.8, 112.5, 117.4,
119.9, 123.1, 128.9, 129.3, 129.5, 132.0, 136.3, 141.8,
147.6, 167.9; GC–MS (EI): 264 (M+), 159, 119, 106
(base), 77, 51. Anal. calcd for C17H16N2O: C, 77.25; H,
6.10; N, 10.60. Found: C, 77.08; H, 5.85; N, 10.68%.
6. (a) Sulkowski, T. S.; Wille, M. A.; Mascitti, A.; Diebold,
J. L. J. Org. Chem. 1967, 32, 2180–2184; (b) Metlesics,
W.; Anton, T.; Sternbach, L. H. J. Org. Chem. 1967, 32,
2185–2187; (c) Houlihan, W. J. US 3,379,733, 1968;
Chem. Abstr. 1968, 69, 51995k; (d) Aeberli, P.; Houlihan,
W. J. J. Org. Chem. 1969, 34, 1720–1726.
7. Cho, C. S.; Jiang, L. H.; Shim, S. C. Synth. Commun.
1998, 28, 849–857.
8. Katritzky, A. R.; Xu, Y.-J.; He, H.-Y.; Steel, P. J. J.
Chem. Soc., Perkin Trans. 1 2001, 1767–1770.
9. Douat, C.; Heitz, A.; Martinez, J.; Fehrentz, J.-A. Tetra-
hedron Lett. 2000, 41, 37–40.
10. Crombie, L.; Hooper, K. C. J. Chem. Soc. 1955, 3010–
3016.
4.4.2. (3S,9bS)-1-Cyclohexyl-3,9b-dimethyl-1,2,3,9b-tet-
rahydro-5H-imidazo[2,1-a]isoindol-5-one 17a. Colorless
1
oil; yield 88%; [h]D25=+2.6 (c 1.50, CHCl3); H NMR: l
0.92–1.70 (m, 4H), 1.80–1.31 (m, 2H), 1.42 (d, J=6.3
Hz, 3H), 1.53–1.56 (m, 2H), 1.61 (s, 3H), 1.72–1.82 (m,