Asymmetric synthesis of 3-aryl-substituted 2,3-dihydro-1H-isoindol-1-ones

Article abstract of DOI:10.1139/v01-140

The first asymmetric synthesis of 3-aryl substituted 2,3-dihydro-1H-isoindol-1-ones via a tandem nucleophilic 1,2-addition ring closure procedure from SAMP and (or) RAMP hydrazones and subsequent oxidative cleavage of the auxiliary is reported.

Full text of DOI:10.1139/v01-140

1528
Asymmetric synthesis of 3-aryl-substituted 2,3-
dihydro-1H-isoindol-1-ones
Dieter Enders, Volker Braig, and Gerhard Raabe
Abstract: The first asymmetric synthesis of 3-aryl substituted 2,3-dihydro-1H-isoindol-1-ones via a tandem nucleophilic
1,2-addition ring closure procedure from SAMP and (or) RAMP hydrazones and subsequent oxidative cleavage of the
auxiliary is reported.
Key words: isoindolinones, asymmetric synthesis, hydrazones, 1,2-addition, N—N bond cleavage.
Résumé : On a réalisé la première synthèse asymétrique de 2,3-dihydro-1H-isoindol-1-ones substituées en position 3
par un groupe aryle; la synthèse est réalisée par le biais d’une réaction de fermeture de cycle par addition nucléophile
1,2 en tandem à partir des hydrazones SAMP et (ou) RAMP, suivie d’une fermeture oxydante de l’auxiliaire.
Mots clés : isoindolinones, synthèse asymétrique, hydrazones, addition-1,2, clivage de liaisons N—N.
[Traduit par la Rédaction] Enders et al. 1535
Introduction
methods V–VII is that the isoindolinone is built with two re-
actants, one is a substituted benzene and the other reactant
contributes to the isoindolinone ring a one-atom unit. In
method V, the 3-position carbon atom is brought into the
ring (16). Method VI involves the reaction of an amine with
either 2-acyl or 2-aroyl benzoic acids or esters (17), 2-(bromo-
ethoxycarbonyl-methyl)-benzoic acid ethyl ester (18), or 2-
(2-nitro-ethylen)-benzoic acid methyl ester (19). A newer
version of method VI is based on N,O-acetals as intermedi-
ates, which can be opened, leading to enantiomerically en-
riched 3-subsituted isoindolinones (20). Method VII offers
the possibility to obtain chiral 3-substituted isoindolinones,
because the 3-position is not involved in the reaction (21).
Method VIII is based on a nucleophilic addition to a C—N
double bond to build the isoindolinone unit (22). It is also
possible to synthesize isoindolinones via rearrangements
(6a, 3b, 23) or the reduction of 3-alkylidene-isoindolinones
to 3-alkyl-isoindilinones (24, 19).
2,3-Dihydro-1H-isoindol-1-ones 1 are known under differ-
ent names in the literature such as isoindolinones or phtha-
limidines and are found as a core unit in various natural
products. Shamma and co-workers (1) isolated the compounds
neuvamine 2, chilenine 3, lennoxamine 4, magallanesine 5,
and pictonamine 6 (Fig. 1). Isoindolinone moieties can also
be found in pharmacologically active synthetic substances.
For example, compound 7 inhibits the activity of thromb-
oxane A2 analogue (U-46619)-induced vasoconstriction (2).
3-Substituted 2,3-dihydro-1H-isoindol-1-ones can also mod-
ulate the common allosteric binding site of the muscarine
M2 receptors, for example the dimer 8 (3). Finally, com-
pounds such as 9 are inhibitors of the HIV-1 reverse tran-
scriptase (4; for further examples see ref. 5).
There are many methods for the synthesis of 3-carbon-
substituted isoindolinones described in the literature. The
most common strategies are shown retrosynthetically in Fig. 2.
Method I may be achieved via substitution of a 3-chloroiso-
indolinone (6), a nucleophilic addition to either an N-acyli-
minium ion (7) or to a carbonyl group and subsequent
reduction of the N,O-acetal (8, 6b). Another possibility for
the cut I is the addition of an electrophile to a deprotonated
isoindolinone (9, 10). Ring closure reactions are involved in
methods II–IV. Method II is either possible via radical
cyclisations (11) or as palladium-catalyzed ring closure reac-
tions (12). 2-Vinyl-benzamides (13), 2-vinyl-benzonitriles
(13b), or 2-acyl-benzamides (14) can be cyclised according
to method III. The important reaction of method IV is the
formation of the lactam ring (15). The common feature of
In this paper, we report on the first asymmetric synthesis
of 3-aryl-substituted isoindolinones via nucleophilic 1,2 ad-
dition to RAMP-hydrazones according to method VIII.
Results and Discussion
As shown in Scheme 1 the RAMP or SAMP hydrazones
were prepared in good yields in a facile procedure. The
freshly distilled aldehydes were condensed with neat RAMP
or SAMP, to obtain the corresponding hydrazones 11a–c in
almost quantitative yields (Table 1).
The nucleophilic 1,2-addition to SAMP or RAMP hydra-
zones is a well-established method to obtain enantiopure
Received February 27, 2001. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on October 19, 2001.
Dedicated to Professor Victor Snieckus for his contributions to Canadian chemistry.
Dieter Enders,1 Volker Braig, and Gerhard Raabe. Institut für Organische Chemie, Rheinisch-Westfälische Technische
Hochschule, Professor-Pirlet-Strabe 1, 52074 Aachen, Germany.
1Corresponding author (fax: +49 (0)241/8092-127; e-mail: Enders@RWTH-Aachen.de).
Can. J. Chem. 79: 1528–1535 (2001)
© 2001 NRC Canada
DOI: 10.1139/cjc-79-11-1528

Enders et al.
1529
Fig. 1.
OCH3
HO
H3CO
H3CO
O
O
H3CO
O
N
N
NH
O
1
2
3
R
O
O
O
O
OCH3
OCH3
O
O
OCH3
O
H3CO
H3CO
H3CO
N
N
N
H3CO
O
4
5
6
O
O
O
O
O
O
O
O
O
2 Br
H3C CH3
N
N
N
+
NH
S
2
H3C
7
8
9
HO
CH3
amines (25). For example, a recent application led to synthe-
ses of the pheromone harmonine (26) and the defence alka-
loid of the mexican bean beetle, Epilachana varivestis
(Coccinellidae) (27). In our synthesis we applied lithiated
diethylbenzamides as nucleophiles, generated by directed
ortho-metalation (DoM) (28), which underwent smooth
nucleophilic 1,2-addition to the C—N double bond of alde-
hydehydrazones 11a–c followed by in situ ring closure to af-
ford the corresponding isoindolinones 13a–e. This tandem
reaction was performed in satisfactory to good yields (Table 2)
and high diastereomeric excesses.2 To drive the reaction to
completion, we had to use 11 equiv of diethylbenzamides
12a–b and 10 equiv of sec-butyllithium. Reaction of only
4.5 equiv of both substrates gave a poor yield (17% of com-
pound (S,S)-13e). We also investigated halogen metal exchange
of 2-iodobenzoic acid esters and DoM of methylbenzamide
instead of the diethylbenzamides 12a–b, but no product was
observed. Recrystallization of the SAMP-derivative (S,S)-13e
allowed the assignment of the configuration of the new gen-
erated stereocenter by X-ray analysis (Fig. 3). It was found
to be S-configured, as expected (29).
were observed to decrease. To see if the reaction tolerated
substitution at the aromatic ring, we used the benzamide 12b
with success. To further extend the scope of this reaction
aliphatic hydrazones (R1 = tert-butyl, isopropyl) were screened
but no acceptable results could be obtained.
We next examined the N—N bond cleavage of the auxil-
iary to release the enantio-enriched amines (30). A variety of
methods were applied to the hydrazines 13a–e, but we ob-
tained either a complex mixture (BH3·THF, O3, Raney Ni–H2),
no reaction at all (Na2S2O4), or cleavage but racemisation
(Li–NH3(l), Ca–NH3(l), Zn–AcOH). The only method we
could apply with success was the oxidative cleavage with
magnesium monoperoxyphthalate hexahydrate (MMPP) de-
veloped by Lassaletta and co-workers (31). They used
MMPP to cleave N—N bonds of SAMP-derivatives. The N-
unsubstituted isoindolinones 14a–e were obtained in very
good yields and high enantiopurity. Three compounds were
purified via crystallization (14a, 14b, 14e) resulting an
enantiomeric excess higher than 99%. Compounds 14c and
14d were purified via flash chromatography, leading to an
enantiomeric excess of 97% and 99%. This indicates that we
could remove the auxiliary without racemization. Enantio-
meric excesses were determined by HPLC on a chiral sta-
tionary phase. The racemates were prepared by racemization
To obtain a good diastereomeric excess, careful control of
the reaction temperature is important: if the warm-up of the
reaction mixture was too fast the diastereomeric excesses
1
2 Determination of the diastereomeric excess of the isoindolinones 13a–e was achieved by H NMR analysis of the crude products. The sin-
glet due to the hydrogen at the 3-position of the isoindolinone ring was used (e.g., (S,S)-13e d: 5.60 ppm; (R,S)-13e d: 5.07 ppm).
© 2001 NRC Canada

1530
Can. J. Chem. Vol. 79, 2001
Fig. 2. Retrosynthetic cuts for the synthesis of isoindolinones.
under an argon atmosphere. Tetrahydrofuran (THF) was
freshly distilled from sodium lead alloy (5% Na) – benzo-
phenone ketyl.
O
O
NR1
NR1
Synthesis of the RAMP or SAMP hydrazones 11a–c
After cooling of the aldehydes 10a–c (1.2–2.4 equiv) to
0°C RAMP or SAMP (1 equiv) was added. This mixture
was stirred for 30 min at 0°C. First, diethyl ether (4.2 mL
per mmol SAMP and (or) RAMP) and then MgSO4 were
added. The reaction mixture was stirred overnight at room
temperature. The removal of MgSO4 and of the solvent af-
forded the oily crude hydrazones in virtually quantitative
yield, which were purified by Kugelrohr distillation under
reduced pressure. This reaction was typically run on a scale
of 30 mmol.
R2
O
R2
O
Method I
Method III
Method V
Method II
Method IV
Method VI
NR1
NR1
R2
O
R2
O
[(E)-Benzylidene]-[(2R)-2-methoxymethyl-pyrrolidine-1-yl]-
amine ((R)-11a)
Compound (R)-11a was prepared earlier in our group (29).
NR1
NR1
R2
O
R2
O
[(E)-Benzylidene]-[(2S)-2-methoxymethyl-pyrrolidine-1-yl]-
amine ((S)-11a)
Compound (S)-11a was prepared earlier in our group (29).
NR1
R2
NR1
[(E)-4-Methoxy-benzylidene]-[(2R)-2-methoxymethyl-
pyrrolidine-1-yl]-amine ((R)-11b)
Pale yellow solid, mp 24°C. [a]2D3 = +164.6 (c = 1.02,
CHCl3). m/z (EI): 248 (3%)(M)+, 203 (100)(M-CH3OCH2)+.
R2
Method VIII
Method VII
1
ꢀmax (film) (cm–1): 1510, 1249, 1125, 1034, 831. H NMR
(C6D6, 400 MHz) d: 1.48–1.52 (m, 1H, NCH2CHH), 1.67–1.82
(m, 3H, NCH2CHHCH2), 2.66–2.72 (m, 1H, NCHH), 3.10–3.19
(m, 4H, NCHH, OCH3), 3.34 (s, 3H, OCH3), 3.42–3.48 (m,
1H, CHHOCH3), 3.71–3.77 (m, 2H, NCHCHHOCH3), 6.83–
6.88 (m, 2H, N=CHCCH=CH), 7.15 (s, 1H, N=CH), 7.63–
7.67 (m, 2H, N=CHCCH=CH). 13C NMR (C6D6, 100 MHz)
d: 22.4, 27.3, 48.8, 54.7, 58.8, 63.4, 75.3, 114.1, 126.8,
103.9, 131.9, 159.2. Anal. calcd. for C14H20N2O2: C 67.71,
N 11.28, H 8.12; found: C 67.66, N 10.87, H 8.11.
of the enantiopure compounds with lithium diisopropylamide
(LDA) in THF at 0°C.
In conclusion, we have developed the first asymmetric
synthesis of 3-aryl-substituted 2,3-dihydro-1H-isoindol-1-ones
via a tandem nucleophilic 1,2-addition ring closure proce-
dure to SAMP- and (or) RAMP-hydrazones and subsequent
oxidative removal of the auxiliary.
Experimental
[(E)-4-tert-Butyl-benzylidene]-[(2R)-2-methoxymethyl-
pyrrolidine-1-yl]-amine ((R)-11c)
All melting points (Büchi 510, system Dr. Tottoli) are un-
corrected. Proton and carbon nuclear magnetic resonance
(1H NMR and 13C NMR) were recorded on Varian Inova 400
(1H NMR: 400 MHz; 13C NMR: 100 MHz) or Varian Unity
500 (1H NMR: 500 MHz; 13C NMR: 125 MHz) spectrome-
ters. Chemical shifts are reported as d values (ppm) relative
to internal Me4Si. Coupling constants are given in Hertz
(Hz). The following abbreviations report the multiplicity and
shape of the signals: s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet), and combinations e.g., dd (doublet
of doublets). Mass spectra (MS) were obtained on Varian
MAT 212 (EI: 70 eV; CI: 100 eV, Isobutan) or Finnigan
MAT 95 (high resolution MS (HRMS): 70 eV). Intensities
are given relative to the base peak. Infrared (IR) spectra
were obtained on a PerkinElmer FT IR 1750. Elemental
analyses were performed on a Heraeus CHN-O-Rapid. Optical
rotations were measured with a PerkinElmer P 241 polari-
meter. Reactions and the progress of chromatographic sepa-
rations were monitored by TLC on silica gel (Merck
Kieselgel 60 F254). Flash chromatography was performed on
silica gel (Merck Kieselgel 60). Reactions with moisture- or
air-sensitive reagents were performed with Schlenk technique
Pale yellow solid, mp 38°C. [a]2D3 = +131.9 (c = 1.02,
CHCl3). m/z (EI): 274 (14%) (M)+, 229 (100)(M-CH3OCH2)+.
ꢀmax (film) (cm–1): 2962, 1114. 1H NMR (C6D6, 400 MHz) d:
1.24 (s, 9H, C(CH3)3), 1.45–1.55 (m, 1H, NCH2CHH), 1.65–
1.81 (m, 3H, NCH2CHHCH2), 2.65–2.74 (m, 1H, NCHH),
3.06–3.13 (m, 1H, NCHH), 3.16 (s, 3H, OCH3), 3.42–3.48
(m, 1H, CHHOCH3), 3.70–3.77 (m, 2H, NCHCHHOCH3),7.17
(s, 1H, N=CH), 7.33–7.37 (m, 2H, N=CCCH=CH), 7.71–7.74
(m, 2H, N=CCCH=CH). 13C NMR (C6D6, 100 MHz) d: 22.4,
27.2, 31.4, 34.5, 48.6, 58.8, 63.2, 75.2, 125.4, 131.6, 135.4,
149.6. Anal. calcd. for C17H26N2O: C 74.41, N 10.21, H
9.55; found: C 74.67, N 9.96, H 9.53.
1,2-Addition to aldehyde–SAMP-hydrazones 11 to
afford the isoindolinones 13a–e
sec-Butyllithium (10.0 equiv, ca. 1.3 M in cyclohexane)
was added dropwise to a solution of N,N-diethylbenzamide
12a–b (11.0 equiv) in dry THF (7.0 mL per mmol di-
ethylamide) at –78°C. After 2 h 30 min of stirring at –78°C,
a solution of the hydrazone 11a–c (1.0 equiv) in abs THF
© 2001 NRC Canada

Enders et al.
1531
Scheme 1. Asymmetric synthesis of 3-aryl-substituted isoindolinones via nucleophilic 1,2-addition to RAMP-hydrazones and subse-
quent intramolecular lactamization (13e and 14e enantiomers prepared with SAMP instead of RAMP).
O
O
NH
R2
H
R1
10a-c
31 - 69 %
R1
14a-e*
ee ≥ 97 %
RAMP,
MgSO4, 90 - 97 %
Et2O
O
MMPP,
MeOH
83 - 97 %
NEt2
R2
12a-b
H3CO
OCH3
O
sec-BuLi, 11a-c, THF, -78 °C to RT
N
N
N
N
44 - 87 %
R2
R1
H
R1
de ≥ 96 %
13a-e*
R1 = C6H5, p-(CH3)3CC6H4, p-CH3OC6H4
R2 = H, CH3O
11a-c
53.5, 54.8, 58.4, 60.2, 67.5, 77.3, 108.1, 115.0, 124.8, 125.2,
128.6, 139.1, 147.3, 163.0, 166.1.
Table 1. Synthesis of the RAMP and (or) SAMP hydrazones 11a–c.
Entry
R1
Compound
Yield (%)
(3R)-5-Methoxy-2-[(2R)-2-methoxymethyl-pyrrolidine-1-yl]-
3-(4-methoxy-phenyl)-2,3-dihydro-1H-isoindol-1-one
((R,R)-13b)
1
2
3
4
Phenyl
Phenyl
p-Methoxyphenyl
p-tert-Butylphenyl
(R)-11a
(S)-11a
(R)-11b
(R)-11c
95
95
97
90
Colorless oil. [a]2D6 = +20.4 (c = 1.17, CHCl3). m/z (EI):
382 (2%) (M)+, 337 (100)(M-CH3OCH2)+. m/z (HRMS):
382.1892 (M)+, (calcd. for C22H26N2O4: 382.1893). ꢀmax (film)
1
(cm–1): 1691, 1242. H NMR (C6D6, 400 MHz) d: 1.22–1.45
(6.0 mL per mmol hydrazone) was added slowly. The reac-
tion mixture was warmed slowly overnight to a temperature
between –40°C and –20°C, then the reaction mixture was
warmed quickly to 0°C and quenched with sat. aq NH4Cl
(5.0 mL/mmol hydrazone). After phase separation and ex-
traction of the aqueous layer with ether, the combined or-
ganic extracts were dried over MgSO4. The removal of MgSO4
and solvent in vacuo at 45°C afforded an oily residue, which
was purified by column chromatography.
(m, 2H, NCH2CHHCHH), 1.67–1.76 (m, 1H, NCH2CHH),
1.97–2.07 (m, 1H, NCH2CH2CHH), 2.75 (dt, J = 7.7, 4.9,
1H, NCHH), 3.12–3.18 (m, 7H, OCH3, CHHOCH3), 3.30–3.36
(m, 4H, OCH3, CHHOCH3), 3.85 (dd, J = 8.2, 16.4, 1H,
NCHH), 4.38–4.46 (m, 1H, CHCH2OCH3), 5.59 (s, 1H,
NCHAr), 6.60 (d, J = 2.2, 1H, O=CCC=CH), 6.71–6.77
(m, 3H, O=CC=CHCH, NCHC=CHCH), 7.08–7.12 (m, 2H,
NCHC=CHCH), 7.92 (m, J = 8.5, 1H, O=CC=CH). 13C
NMR (C6D6, 100 MHz) d: 23.1, 27.4, 53.4, 54.7, 54.9, 58.4,
60.2, 66.9, 77.3, 108.1, 114.1, 115.0, 124.7, 125.3, 129.8,
130.8, 147.6, 159.8, 163.0, 165.9.
(3R)-5-Methoxy-2-[(2R)-2-methoxymethyl-pyrrolidine-1-yl]-
3-phenyl-2,3-dihydro-1H-isoindol-1-one ((R,R)-13a)
Pale yellow oil. [a]2D3 = –11.1 (c = 1.03, CHCl3). m/z (EI):
352 (2%) (M)+, 307 (100)(M-CH3OCH2)+. m/z (HRMS):
307.1444 (M–CH3OCH2)+, (calcd. for C19H19N2O2: 307.1447).
ꢀmax (film) (cm–1): 1693. 1H NMR (C6D6, 400 MHz) d:
1.19–1.42 (m, 2H, NCH2CHHCHH), 1.65–1.75 (m, 1H,
NCH2CHH), 1.95–2.05 (m, 1H, NCH2CH2CHH), 2.72 (dt,
J = 7.8, 3.5, 1H, NCHH), 3.06–3.15 (m, 7H, OCH3, OCH3,
CHHOCH3), 3.29 (dd, J = 7.7, 9.3, 1H, CHHOCH3), 3.85
(dd, J = 8.1, 16.3, 1H, NCHH), 4.37–4.44 (m, 1H,
CHCH2OCH3), 5.62 (s, 1H, NCHAr), 6.53 (d, J = 2.2, 1H,
O=CCC=CH), 6.71 (dd, J = 2.5, 8.5, 1H, O=CC=CHCH),
7.06–7.19 (m, 5H CHPhenyl), 7.91 (d, 3J = 8.5 Hz, 1H,
O=CC=CHCH). 13C NMR (C6D6, 100 MHz) d: 23.1, 27.4,
(3R)-3-(4-tert-Butyl-phenyl)-2-[(2R)-2-methoxymethyl-
pyrrolidine-1-yl]-2,3-dihydro-1H-isoindol-1-one ((R,R)-13c)
Colorless solid, mp = 123°C. [a]2D6 = +71.7 (c = 1.15,
CHCl3). m/z (EI): 378 (2%) (M)+, 333 (100)(M-CH3OCH2)+.
ꢀmax (KBr) (cm–1): 1687. 1H NMR (C6D6, 400 MHz) d:
1.15–1.36 (m, 11H, NCH2CHHCHH, C(CH3)3), 1.64–1.74
(m, 1H, NCH2CHH), 1.94–2.04 (m, 1H, NCH2CH2CHH),
2.79–2.84 (m, 1H, NCHH), 3.08 (s, 3H, OCH3), 3.11 (dd,
J = 4.5, 9.5, 1H, CHHOCH3), 3.29 (dd, J = 7.7, 9.6, 1H,
CHHOCH3), 3.90 (dd, J = 8.1, 16.1, 1H, NCHH), 4.36–4.45
(m, 1H, CHCH2OCH3), 5.66 (s, 1H, NCHAr), 6.84–6.88 (m,
1H, O=CCC=CH), 6.99–7.07 (m, 2H, O=CC=CHCH=CH),
© 2001 NRC Canada

1532
Can. J. Chem. Vol. 79, 2001
Table 2. Synthesis of compounds 13a–e.
Entry
R1
R2
Compound
Yield (%)
de (%)a
1
2
3
4
5
Phenyl
CH3O
CH3O
H
CH3O
H
(R,R)-13a
(R,R)-13b
(R,R)-13c
(R,R)-13d
(S,S)-13ec
44
55
77
76
87
O96
94, O96b
O96
p-Methoxyphenyl
p-tert-Butylphenyl
p-tert-Butylphenyl
Phenyl
O96
O96
aDetermined by NMR of the crude product.
bAfter chromatography.
cPrepared with SAMP instead of RAMP.
Fig. 3. X-ray structure of (3S)-2-[(2S)-2-methoxymethyl-
pyrrolidin-1-yl)-3-phenyl-2,3-dihydro-1H-isoindol-1-one ((S,S)-
13e).
163.0, 166.1. Anal. calcd. for C25H32N2O3: C 73.50, N 6.86,
H 7.90; found: C 73.41, N 6.69, H 7.95.
(3S)-2-[(2S)-2-Methoxymethyl-pyrrolidine-1-yl]-3-phenyl-
2,3-dihydro-1H-isoindol-1-one ((S,S)-13e)
Colorless solid, mp = 96°C. [a]2D8 = +69.6 (c = 0.65,
CHCl3). m/z (CI): 323 (100%) (MH)+. ꢀmax (KBr) (cm–1):
1685. 1H NMR (C6D6, 500 MHz) d: 1.19–1.36 (m, 2H,
NCH2CHHCHH), 1.64–1.72 (m, 1H, NCH2CHH), 1.93–2.02
(m, 1, NCH2CH2CHH), 2.70 (dt, J = 7.8, 3.7, 1H, NCHH),
3.03 (s, 3H, OCH3), 3.09 (dd, J = 4.3, 9.5, 1H, CHHOCH3),
3.25 (dd, J = 7.6, 9.5, 1H, CHHOCH3), 3.82 (dd, J = 8.2,
16.5, 1H, NCHH), 4.35–4.41 (m, 1H, CHCH2OCH3), 5.60
(s, 1H, NCHAr), 6.81–6.85 (m, 1H, O=CCC=CH), 7.02–7.18
(m, 7H, O=CC=CHCH=CH, CHPhenyl), 7.94–7.98 (m, 1H,
O=CC=CH). 13C NMR (C6D6, 125 MHz) d: 23.1, 27.4, 53.4,
58.4, 60.4, 67.7, 77.3, 123.3, 123.4, 128.2, 128.2, 128.7,
131.6,132.8, 139.0, 145.3, 166.2. Anal. calcd. for
C20H22N2O2: C 74.51, N 8.69, H 6.88; found: C 74.63, N
8.66, H 6.96.
O
O
N
N
Crystal data and refinement details for (S,S)-13e: C20H22N2O2;
fw = 322.41; orthorhombic; space group P212121 (no. 19);
a = 6.1386(8), b = 12.392(1), c = 22.328(6) Å; V = 1698.5(5)
Å3; Z = 4; ꢁc = 1.261 g cm–3; = 6.51 cm–1, no absorption
correction; T = 150 K; CuKa (1.54179 Å). An irregularly
shaped crystal (-0.3 × 0.3 × 0.3 mm3) was mounted on top
of a capillary in a stream of cooled nitrogen. 3472 unique
reflections were collected in the range: h: ±7, k: ±15, and
l: ±27 (rav = 0.01(5)) on an Enraf–Nonius CAD4 diffracto-
meter in the ꢂ /2Q mode. The structure has been solved by
direct methods (GENSIN/GENTAN) as implemented in
the Xtal3.4 suite of crystallographic routines (32).
3130 observed reflections (I > 2ꢃ(I)) in the final full-
matrix least-squares refinement of 217 variables ter-
minating at r = 0.061 (rw = 0.066, w = ꢃ–2), a residual
electron density of –0.33/+0.40 e Å–3, a max shift/error of
0.13 × 10–3, and a goodness-of-fit of 1.744. The atomic
scattering factors are those from ref. 33. No extinction cor-
rection. Hydrogen atoms were calculated in idealized po-
sitions and their Us were fixed at 1.5 times U of the
relevant heavy atom prior to final refinement. No refine-
ment of hydrogen positions. The chirality of the new gener-
ated stereocenter was fixed using the known configuration of
the auxiliary (Fig. 3).
7.12–7.17 (m, 2H, NCHC=CHCH=CC(CH3)3), 7.20–7.24 (m,
2H, NCHC=CHCH=CC(CH3)3), 7.97–8.01 (m, 1H, O=CC=CH).
13C NMR (C6D6, 100 MHz) d: 23.1, 27.4, 31.3, 34.4, 53.4,
58.4, 60.4, 67.4, 77.2, 123.2, 123.3, 125.5, 128.0, 128.3,
131.4,132.6, 135.8, 145.5, 150.8, 166.1. Anal. calcd. for
C24H30N2O2: C 76.16, N 7.40, H 7.99; found: C 76.10, N
7.34, H 7.71.
(3R)-3-(4-tert-Butyl-phenyl)-5-methoxy-2-[(2R)-2-
methoxymethyl-pyrrolidine-1-yl]-2,3-dihydro-1H-isoindol-1-
one ((R,R)-13d)
Colorless solid, mp 138°C. [a]2D8 = –6.6 (c = 1.09, CHCl3).
m/z (EI): 408 (2%) (M)+, 363 (100)(M-CH3OCH2)+. ꢀmax
1
(KBr) (cm–1): 1684, 1608, 1286. H NMR (C6D6, 400 MHz)
d: 1.15–1.37 (m, 11H, NCH2CHHCHH, C(CH3)3), 1.66–1.76
(m, 1H, NCH2CHH), 1.97–2.06 (m, 1H, NCH2CH2CHH),
2.80–2.86 (m, 1H, NCHH), 3.03 (s, 3H, OCH3), 3.12 (s, 3H,
OCH3), 3.15 (dd, J = 4.5, 9.5, 1H, CHHOCH3), 3.33 (dd,
J = 7.7, 9.4, 1H, CHHOCH3), 3.92 (dd, J = 8.2, 16.2, 1H,
NCHH), 4.39–4.46 (m, 1H, CHCH2OCH3), 5.67 (s, 1H, NCHAr),
6.55 (d, J = 2.5, 1H, O=CCC=CH), 6.71 (dd, J = 2.2, 8.2,
1H, O=CC=CHCH), 7.19–7.27 (m, 4H, (CH3)3CCCH=CH),
7.92 (d, J = 8.2, 1H, O=CC=CH). 13C NMR (C6D6, 100 MHz)
d: 23.1, 27.4, 31.3, 34.5, 53.5, 54.7, 58.4, 60.4, 67.3, 77.3,
108.0, 115.1, 124.8, 125.1, 125.6, 128.3, 136.2, 147.6, 150.8,
The refined non-hydrogen atomic coordinates for (S,S)-13e
are listed in Table 4 while the hydrogen coordinates, temper-
ature factors (anisotropic for carbon atoms), scale factor, and
© 2001 NRC Canada

Enders et al.
1533
Table 3. Synthesis of compounds 14a–e.
Entry
R1
R2
Compound
Yield (%)
ee (%)a
1
2
3
4
5
Phenyl
CH3O
CH3O
H
CH3O
H
(R)-14a
(R)-14b
(R)-14c
(R)-14d
(S)-14ec
74
85
97
85
83
O99
O99
97b
99b
O99
p-Methoxyphenyl
p-tert-Butylphenyl
p-tert-Butylphenyl
Phenyl
aDetermined by HPLC on chiral phase.
bPurified by column chromatography.
cPrepared with SAMP instead of RAMP.
secondary estimation coefficient for (S,S)-13e are available
Table 4. Fractional atomic coordinates for non-hydrogen atoms,
with estimated standard deviations in parentheses, for (3S)-2-
[(2S)-2-methoxymethyl-pyrrolidin-1-yl)-3-phenyl-2,3-dihydro-1H-
isoindol-1-one ((S,S)-13e) and the isotropic equivalent displace-
ment parameters.
on request.3
N—N bond cleavage for the synthesis of title
compounds 14a–e
MMPP·6 H2O (2.0 to 2.5 equiv) was added to a solution
of hydrazine 13a–e (1.0 equiv) in methanol (13.0 mL per mmol
hydrazine). Stirring at room temperature (24–96 h) was con-
tinued until no hydrazine remained (TLC monitoring). If the
reaction stops before all hydrazine has reacted, it is possible
to add a further amount of MMPP·6 H2O (0.5 equiv). After
dilution of the reaction mixture with ether (60.0 mL per mmol
hydrazine), a sat. aq NaHCO3 solution (43.0 mL per mmol
hydrazine) was added. The aqueous layer was extracted with
chloroform after phase separation. The combined organic ex-
tracts were dried (MgSO4) and the solvent was removed in
vacuo. The residue was either purified by flash chromatogra-
phy or crystallization from ethyl acetate.
Atom
x
y
z
Ueq (Å2)
N1
N2
O1
O2
C1
C2
C3
C4
C5
C6
C7
C8
0.9131(5)
0.8949(5)
1.2427(5)
0.6337(4)
1.0743(7)
1.0645(7)
0.9234(9)
0.8745(7)
0.7408(7)
0.8195(6)
0.7257(7)
0.8349(8)
1.0373(8)
1.1332(7)
1.0223(6)
1.0796(6)
0.6479(7)
0.4219(8)
0.7126(6)
0.5187(7)
0.4961(8)
0.6681(9)
0.8625(8)
0.8850(7)
0.4598(2)
0.4844(2)
0.3690(2)
0.2484(2)
0.5517(3)
0.5341(4)
0.4338(4)
0.3892(3)
0.4930(3)
0.4436(3)
0.4432(3)
0.3933(3)
0.3453(3)
0.3463(3)
0.3952(3)
0.4043(3)
0.3438(3)
0.2016(3)
0.6140(3)
0.6629(3)
0.7724(4)
0.8370(3)
0.7891(3)
0.6791(3)
0.6268(1)
0.6877(1)
0.6257(1)
0.7545(1)
0.7110(2)
0.7781(2)
0.7883(2)
0.7264(2)
0.5854(2)
0.5276(2)
0.4706(2)
0.4242(2)
0.4337(2)
0.4904(2)
0.5369(2)
0.5997(2)
0.7207(2)
0.7506(2)
0.5829(2)
0.5983(2)
0.5961(2)
0.5786(2)
0.5625(2)
0.5647(2)
0.0264(9)
0.0268(9)
0.0371(8)
0.0369(9)
0.036(1)
0.046(2)
0.053(2)
0.029(1)
0.027(1)
0.027(1)
0.034(1)
0.039(1)
0.039(1)
0.034(1)
0.027(1)
0.027(1)
0.032(1)
0.049(1)
0.025(1)
0.038(1)
0.052(2)
0.049(2)
0.044(1)
0.036(1)
(3R)-5-Methoxy-3-phenyl-2,3-dihydro-1H-isoindol-1-one
((R)-14a)
C9
C10
C11
C12
C13
C14
C15
C16
C17
C18
C19
C20
Colorless solid, mp = 219°C. [a]2D6 = –52.2 (c = 0.81,
CHCl3). m/z (EI): 239 (100%)(M)+, 208 (43)(M-CH3O)+,
1
162 (34)(M-Ph)+. ꢀmax (KBr) (cm–1): 1690, 1664, 1610. H
NMR (d6-DMSO, 400 MHz) d: 3.69 (s, 3H, OCH3), 5.60 (s,
1H, NHCH), 6.73 (d, J = 1.5, 1H, O=CCCCH), 6.98 (dd, J =
8.5, 1.9, 1H, O=CCCH=CH), 7.21–7.35 (m, 5H, CHPhenyl),
7.59 (d, J = 8.5, 1H, O=CCCH=CH), 8.81 (s, 1H, NH). 13C
NMR (d6-DMSO, 100 MHz) d: 56.4, 60.1, 108.7, 115.5,
124.4, 125.0, 127.2, 128.6, 129.4, 140.3, 151.1, 163.1, 170.3.
Anal. calcd. for C15H13NO2: C 75.30, N 5.85, H 5.48; found:
C 74.96, N 5.84, H 5.76.
(3R)-5-Methoxy-3-(4-methoxy-phenyl)-2,3-dihydro-1H-
isoindol-1-one ((R)-14b)
100 MHz) d: 55.6, 55.9, 60.4, 108.1, 114.6, 115.3, 124.7,
125.3, 128.3, 130.7, 150.9, 159.9, 163.5, 171.0.
Colorless solid, mp = 168°C. [a]2D7 = +3.6 (c = 0.73,
CHCl3). m/z (EI): 269 (100%)(M)+, 238 (38)(M-CH3O)+. m/z
(HRMS): 269.10513 (M)+, (calcd. for C16H15NO3: 269.10519).
(3R)-3-(4-tert-Butyl-phenyl)-2,3-dihydro-1H-isoindol-1-one
((R)-14c)
1
ꢀmax (KBr) (cm–1): 1706, 1620, 1278, 1241. H NMR(CDCl3,
Colorless solid, mp = 226°C. [a]2D7 = –117.4 (c = 1.00,
CHCl3). m/z (EI): 265 (100%)(M)+, 250 (67)(M-CH3)+, 208
400 MHz) d: 3.78 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 5.51
(s, 1H, NHCH), 6.66 (d, J = 2.2, 1H, O=CCCCH), 6.83 (s,
1H, NH), 6.85–6.89 (m, 2H, NHCHCCH=CH) 6.97 (dd, J = 8.2,
2.2, 1H, O=CCCH=CH), 7.15–7.19 (m, 2H, NHCHCCH=CH),
7.77 (d, J = 8.5, 1H, O=CCCH=CH). 13C NMR (CDCl3,
1
(34)(M-C(CH3)3)+. ꢀmax (KBr) (cm–1): 1698, 1657. H NMR
(CDCl3, 400 MHz) d: 1.29 (s, 9H, C(CH3)3), 5.61 (s, 1H,
NHCH), 7.18–7.22 (m, 2H, NHCHCCH=CH), 7.23–7.27 (m,
1H, O=CC=CCH), 7.30 (s, 1H, NH), 7.34–7.38 (m, 2H,
3 Supplementary material may be purchased from the Depository of Unpublished Data, Document Delivery, CISTI, National Research Coun-
cil Canada, Ottawa, ON K1A 0S2, Canada (http://www.nrc.ca/cisti/irm/unpub_e.shtml for information on ordering electronically). Crystal-
lographic data for the structure reported in this paper have been deposited with the Cambridge Crystallographic Data Centre (CCDC 158
453). Copies of the data can be obtained, free of charge, on application to the Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, U.K.
(Fax: +44-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
© 2001 NRC Canada

1534
Can. J. Chem. Vol. 79, 2001
9. (a) A. Couture, E. Deniau, D. Ionescu, and P. Grandclaudon.
Tetrahedron Lett. 39, 2319 (1998); (b) E. Deniau and D. End-
ers. Tetrahedron. In press (2001).
10. V.A. Kovtunenko, T.T. Dobrenko, A.K. Tiltin, and F.S. Babichev.
Chem. Heterocycl. Compd. (N.Y.), 21, 830, (1985); Khim.
Geterotsikl. Soedin. 996, (1985).
NHCHCCH=CH), 7.42–7.51 (m, 2H, O=CCCH=CHCH),
7.85–7.88 (m, 1H, O=CCCH). 13C NMR (CDCl3, 100 MHz)
d: 31.6, 34.9, 60.9, 123.6, 123.9, 126.2, 126.7, 128.4, 131.1,
132.4, 135.5, 148.3, 151.7, 171.4. Anal. calcd. for C18H19NO:
C 81.48, N 5.28, H 7.22; found: C 81.18, N 5.14, H 7.31.
11. (a) H. Ishibashi, H. Kawanami, H. Iriyama, and M. Ikeda. Tetrahe-
dron Lett. 36, 6733 (1995); (b) W. Zhang and G. Pugh. Tetrahe-
dron Lett. 40, 7591 (1999); (c) H. Ishibashi, H. Kawanami, and M.
Ikeda. J. Chem. Soc. Perkin Trans. 1, 817 (1997); (d) M. Black,
J.I.G. Cadogan, and H. McNab. J. Chem. Soc. Perkin Trans. 1, 155
(1994); (e) D.P. Curran and H. Liu. J. Chem. Soc. Perkin Trans. 1,
1377 (1994); (f) V. Snieckus, J.-C. Cuevas, C.P. Sloan, H. Liu, and
D.P. Curran. J. Am. Chem. Soc. 112, 896 (1990).
(3R)-3-(4-tert-Butyl-phenyl)-5-methoxy-2,3-dihydro-1H-
isoindol-1-one ((R)-14d)
Colorless solid, mp = 211°C. [a]2D6 = –4.2 (c = 0.78,
CHCl3). ꢀmax (KBr) (cm–1): 1690, 1652, 1621. m/z (EI): 295
(100%)(M)+, 294 (43)(M-CH3)+, 264 (42)(M-OCH3)+, 238
1
(49)(M-C(CH3)3)+. H NMR (d6-DMSO, 400 MHz) d: 1.26
(s, 9H, C(CH3)3), 3.75 (s, 3H, OCH3), 5.61 (s, 1H, NHCH),
6.78 (d, J = 1.9, 1H, O=CCCCH), 7.03 (dd, J = 8.5, 2.2, 1H,
O=CCCH=CH), 7.18–7.23 (m, 2H, NHCHCCH=CH), 7.37–
7.41 (m, 2H, NHCHCCH=CH), 7.63 (d, J = 8.3, 1H,
O=CCCH=CH), 8.79 (s, 1H, NH). 13C NMR (d6-DMSO,
100 MHz) d: 30.9, 34.1, 55.4, 58.9, 107.9, 114.4, 123.6,
124.1, 125.2, 126.0, 136.3, 150.0, 150.2, 162.1, 169.2. Anal.
calcd. for C19H21NO2: C 77.26, N 4.74 H, 7.17; found: C
77.13, N 4.62, H 6.96.
12. B. Burns, R. Grigg, V. Santhakumar, V. Sridharan, P. Stevenson,
and T. Worakun. Tetrahedron, 48, 7297 (1992).
13. (a) R.S. Mali and S. Yeola. Synthesis, 755 (1986); (b) T.R.
Belliotti, W.A. Brink, S.R. Kesten, J.R. Rubin, D.J. Wustrow,
K.T. Zoski, S.Z. Whetzel, A.E. Corbin, T.A. Pugsley, T.G.
Heffner, and L.D. Wise. Bioorg. Med. Chem. Lett. 8, 1499
(1998); (c) E. Napolitano, R. Fiaschi, and A. Marsili. Tetrahe-
dron Lett. 24, 1319 (1983).
14. (a) S. Gabriel and R. Stelzner. Chem. Ber. 29, 2743 (1896);
(b) S. Gabriel and G. Giebe. Chem. Ber. 29, 2518 (1896);
(c) F.A. Mason and W.H. Perkin, Jr. J. Chem. Soc. 105, 2013
(1914).
15. G. Cauquis and A. Deronzier. J. Chem. Soc. Chem. Commun.
807 (1978).
(3S)-3-(Phenyl)-5-methoxy-2,3-dihydro-1H-isoindol-1-one
((S)-14e)
The analytical and spectroscopic data were in agreement
with recent literature (20c).
16. N. Barr, J.P. Bartley, P.W. Clark, P. Dunstan, and S.F. Dyke. J.
Organomet. Chem. 302, 117 (1986).
Acknowledgments
18. (a) M. Othman and B. Decroix. Synth. Commun. 26, 2803
(1996); (b) M. Othman, P. Pigeon, and B. Decroix. Tetrahe-
dron, 54, 8737 (1998); (c) M. Othman, P. Pigeon, and B.
Decroix. J. Heterocycl. Chem. 36, 735 (1999).
19. J.-M. Ferland, C.A. Demerson, and L.G. Humber. Can. J.
Chem. 63, 361 (1985).
We thank Bayer AG, BASF AG, and Degussa AG for the
donation of chemicals, the DFG (SFB 380) for financial sup-
port, and Mr. Thomas Klumpen who carried out parts of the
work during an undergraduate research program.
20. (a) S.M. Allin, C.J. Northfield, M.I. Page, and A.M.Z. Slawin.
Tetrahedron Lett. 40, 141 (1999); (b) S.M. Allin, C.J. North-
field, M.I. Page, and A.M.Z. Slawin. Tetrahedron Lett. 40, 143
(1999); (c) S.M. Allin, C.J. Northfield, M.I. Page, and A.M.Z.
Slawin. J. Chem. Soc. Perkin Trans. 1, 1715 (2000).
21. (a) W. Oppolzer, M. Wills, M.J. Kelly, M. Signer, and J. Blagg.
Tetrahedron Lett. 31, 5015 (1990); (b) A. Böhm, K. Polborn, K.
Sünkel, and W. Beck. Z. Naturforsch. B 53, 448 (1998).
22. J. Campbell, R.F. Dedinas, and S.A. Trumbower-Walsh. J. Org.
Chem. 61, 6205 (1996).
References
1. (a) V. Fajardo, V. Elango, B.K. Cassels, and M. Shamma. Tet-
rahedron Lett. 23, 39 (1982); (b) E. Valencia, J. Freyer, and M.
Shamma. Tetrahedron Lett. 25, 599 (1984); (c) E. Valencia, I.
Weiss, S. Firdous, A.J. Freyer, and M. Shamma. Tetrahedron,
40, 3957 (1984); (d) E. Valencia, V. Fajardo, A.J. Freyer, and
M. Shamma. Tetrahedron Lett. 26, 993 (1985).
2. Y. Kato, M. Takemoto, and K. Achiwa. Chem. Pharm. Bull.
41, 2003 (1993).
23. J.L. Moniot, D.M. Hindenlang, and M. Shamma. J. Org. Chem.
44, 4343 (1979).
3. (a) U. Holzgrabe, W. Bender, H.M Botero Cid, M. Staudt, R.
Pick, C. Pfletschinger, E. Balatková, C. Tränkle, and K. Mohr.
Pharm. Helv. Acta, 74, 149 (2000); (b) H.M Botero Cid, C.
Tränkle, K. Baumann, R. Pick, E. Mies-Klomfass, E. Kostenis,
K. Mohr, and U. Holzgrabe. J. Med. Chem. 43, 2155 (2000).
4. (a) A. Mertens, H. Zilch, B. König, W. Schäfer, T. Poll, W.
Kampe, H. Seidel, U. Leser, and H. Leinert. J. Med. Chem. 36,
2526 (1993); (b) P.P. Mager. Drug Des. Discovery, 14, 241
(1996).
5. N.G. Kundu and M.W. Khan. Tetrahedron, 56, 4777 (2000).
6. (a) R.P. Kreher, H. Hennige, M. Konrad, J. Uhrig, and A.
Clemens. Z. Naturforsch. B 46, 809 (1991); (b) M. Othman, P.
Pigeon, and B. Decroix. Tetrahedron, 53, 2495 (1997).
7. (a) S.M. Allin, C.J. Northfield, M.I. Page, and A.M.Z. Slawin.
Tetrahedron Lett. 39, 4905 (1998); (b) P. Pigeon and B. Decroix.
Tetrahedron Lett. 38, 1041 (1997); (c) R. Alonso, L. Castedo, and
D. Domínguez. Tetrahedron Lett. 26, 2925 (1985).
24. (a) P. Pigeon, and B. Decroix. Tetrahedron Lett. 37, 7707
(1996); (b) N.G. Kundu, M.W. Kahn, and R. Mukhopadhyay.
Tetrahedron, 55, 12 361 (1999); (c) A. Couture, E. Deniau, P.
Grandclaudon, and C. Hoarau. Tetrahedron, 56, 1491 (2000);
(d) J. Honzl. Coll. Czech. Chem. Commun. 21, 725 (1956);
(e) S. Sugasawa and Y. Kanaoka. Pharm. Bull. 3, 266 (1955);
(f) J.H. Helberger, and D.B. Hevér. Ann. Chem. 536, 173
(1938); (g) S. Natelson and S.P. Gottfried. J. Am. Chem. Soc.
63, 487 (1941); (h) P.L. Barili, R. Fiaschi, E. Napolitano, L.
Pistelli, V. Scartoni, and A. Marsili. J. Chem. Soc. Perkin
Trans. 1, 1654 (1981); (i) H.P. Soetens and U.K. Pandit. Recl.
J. Royal Neth. Chem. Soc. 99, 271 (1980); (j) R.P. Linstead
and G.A. Rowe. J. Chem. Soc. 1070 (1940).
25. D. Enders, H. Schubert, and C. Nübling. Angew. Chem. 98,
1118 (1986); Angew. Chem. Int. Ed. Engl. 25, 1109 (1986).
26. D. Enders and D. Bartzen. Liebigs Ann. Chem. 569 (1991).
8. E. Deniau and D. Enders. Tetrahedron Lett. 41, 2347 (2000).
© 2001 NRC Canada

Enders et al.
1535
27. D. Enders and C. Thiebes. Synthesis, 510 (2000).
28. V. Snieckus. Chem. Rev. 90, 879 (1990).
29. D. Enders, C. Nübling, and H. Schubert. Liebigs Ann. 1089
(1997).
30. D. Enders, R. Lochtman, M. Meiers, S. Müller, and R. Lazny.
Synlett, 1182 (1998).
31. R. Fernández, A. Ferrete, J.M. Lassaletta, J.M. Llera, and A.
Monge. Angew. Chem. 112, 3015 (2000); Angew. Chem. Int.
Ed. 39, 2893 (2000).
32. S.R. Hall, G.S.D. King, and J.M. Stewart (Editors). Xtal3.4
User’s Manual. Universities of Western Australia, Leuven, and
Maryland. Lamb, Perth. 1995.
33. D.T. Cromer, and J.T. Weber. In International tables for X-ray
crystallography. Edited by J.A. Ibers and W.C. Hamicton. Vol.
IV. Kluwer Academic Publishers, Dordrecht. 1989. Tables 2.2B
and 2.3.1.
© 2001 NRC Canada