A new synthetic route to highly enantioenriched 3-substituted-2,3-dihydro-1H-isoindol-1-ones

Article abstract of DOI:10.1016/S0957-4166(03)00409-9

A concise and efficient synthesis of highly enantioenriched 3-alkyl and 3-aryl-2,3-dihydro-1H-isoindolinones is reported. The key step relies on the diastereoselective reduction of the N-acylhydrazonium salts generated by acidic treatment of hemiaminal precursors bearing the (S)-2-methoxymethylpyrrolidin-1-yl (SMP) auxiliary.

Full text of DOI:10.1016/S0957-4166(03)00409-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2253–2258
A new synthetic route to highly enantioenriched
3-substituted-2,3-dihydro-1H-isoindol-1-ones
Eric Deniau,a,* Dieter Enders,b Axel Couturea and Pierre Grandclaudona
aLaboratoire de Chimie Organique Physique, UMR 8009, Universite´ des Sciences et Technologies de Lille, Baˆtiment C3(2),
F-59655 Villeneuve d’Ascq Ce´dex, France
bInstitut fu¨r Organische Chemie, Rheinisch-Westfa¨lische Technische Hochschule, Professor-Pirlet-Straße 1,
52074 Aachen, Germany
Received 9 May 2003; accepted 15 May 2003
Abstract—A concise and efficient synthesis of highly enantioenriched 3-alkyl and 3-aryl-2,3-dihydro-1H-isoindolinones is
reported. The key step relies on the diastereoselective reduction of the N-acylhydrazonium salts generated by acidic treatment of
hemiaminal precursors bearing the (S)-2-methoxymethylpyrrolidin-1-yl (SMP) auxiliary.
© 2003 Elsevier Ltd. All rights reserved.
opening with carbon or hydride nucleophiles of tricyclic
g-lactams.9 Very recently, Royer et al. developed a new
conceptual approach10 to the synthesis of chiral 3-alkyl-
isoindolinones based upon a diastereoselective metalla-
tion, a-aminoalkylation sequence. However, these
elegant and complementary synthetic approaches suffer
from several drawbacks mainly associated with the
multistep removal of the chiral inductor.9,10 Moreover,
a few methodologies allow the connection of both
aliphatic and aromatic groups at the benzylic position
of the lactam ring.
1. Introduction
2,3-Dihydro-1H-isoindol-1-ones (isoindolinones) also
called phthalimidines represent a class of bicyclic lac-
tams which have attracted much attention from the
scientific community since they represent the core unit
of a wide range of naturally occurring and/or bio-active
substances.1
In particular, enantiopure compounds substituted at
C-3 (Fig. 1), such as thiazoloisoindolone 12 (non-
nucleosidic HIV-reverse transcriptase inhibitor), pazi-
naclone 23 (anxiolytic), 3-piperazinylethyl isoindolinone
derivative 34 (dopamine D4 receptor antagonist) as well
as the architecturally more sophisticated staurosporine
analog 45 (protein kinase C inhibitor), have been exten-
sively studied. Surprisingly, only a few efforts have
been devoted to the asymmetric synthesis of chiral
3-substituted isoindolinones even though it has been
well established that the absolute configuration of the
stereogenic center at C-3 plays a crucial role for the
biological activity.4,5 These bicyclic lactams are accessi-
ble by different chemical processes which includes (i) an
asymmetric intramolecular Heck reaction,6 (ii) the car-
bonylation of
a chiral N-pivaloyl-a-methylbenzyl-
amine,7 (iii) a tandem nucleophilic 1,2-addition/ring
closure via SAMP or RAMP hydrazones8 or (iv) the
Lewis acid mediated diastereoselective aminal ring-
Figure 1. Examples of synthetic pharmacalogically active chi-
ral 3-substituted isoidolinones.
* Corresponding author. Tel.: +33-(0)3-2043-4940; fax: +33-(0)3-
2033-6309; e-mail: eric.deniau@univ-lille1.fr
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00409-9

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E. Deniau et al. / Tetrahedron: Asymmetry 14 (2003) 2253–2258
Scheme 1. Retrosynthetic analysis of chiral 3-substituted
isoindolinones.
2. Results and discussion
Herein, we describe a new, concise and efficient syn-
thetic route that offers an easy access to chiral 3-alkyl
and 3-aryl-2,3-dihydro-1H-isoindol-1-ones 5 of high
enantiomeric purity. This new procedure, which is
depicted in the retrosynthetic Scheme 1, relies upon the
diastereoselective reduction of alkylated or arylated
hemiaminals 7, which can be obtained by reacting imide
8 equipped with a chiral auxiliary connected to the
nitogen atom with an appropriate organometallic
reagent. Crucial for the success of our strategy was,
therefore, to identify an easily incorporated stereocon-
trolling agent, which would be sufficiently robust to
survive the projected addition reaction and would be
also labile enough to be removed in the final step
without racemization. This requirement and the recent
results obtained in this area of hydrazide chemistry8,11
prompted us to incorporate the (S)-2-methoxymethyl-
pyrrolidin-1-yl (SMP)12 group in our models (Z*).
Scheme 2. Asymmetric synthesis of 3-substituted isoindoli-
nones 14a–f.
quently treated with trifluoroacetic acid and
triethylsilane14 which triggered the formation of the
3-alkyl and 3-aryl isoindolinones 13a–f released from
the hydroxy appendage. As can be seen from Table 1,
the formation of compounds 13a–f occurs with a high
level of diastereoselection. Based upon a model pro-
posed by Kibayashi et al.,15 one can reasonably assume
that high facial selectivity observed in the nucleophilic
addition onto the prochiral CꢀN group of the N-
acylhydrazonium ions 12 might be attributed to the
pyramidal stability of the adjacent trivalent nitrogen,
which thus constitutes a stereogenic center. The anti-
periplanar approach of the hydride to the azomethine
group therefore should occur preferentially from the
sterically less hindered face of the energetically favored
This new synthetic route, depicted in Scheme 2, necessi-
tated the preliminary elaboration of the chiral phthal-
hydrazide 10, which was easily prepared by
condensation between phthalic anhydride and (S)-1-
amino-2-methoxymethylpyrrolidine (SAMP)13 9. Imide
10 was then allowed to react with an array of
organometallic reagents (Table 1) and this procedure
delivered the hemiaminals 11a–f with fairly good yields
and as a mixture of diastereomers. The resulting 3-
hydroxy isoindolinone derivatives 11a–f were subse-
Table 1. Isoindolinones 11a–f, 13a–f, 14a–f prepared
Entry
RM
Compound
Yield (%)
Compound
Yield (%)a
De (%)b
Compound
Yield (%)a
Ee (%)c
1
2
3
4
5
6
MeMgCl
tert-BuMgCl
PhMgCl
2-NaphtylLi
2-MeOC6H4Li
3-MeOC6H4Li
11a
11b
11c
11d
11e
11f
88
85
84
78
74
77
13a
13b
13c
13d
13e
13f
85
62
91
92
88
91
85 (>96)d
85 (>96)d
>96
>96
>96
14a
14b
14c
14d
14e
14f
77
71
85
91
87
83
>96
>96
>96
>96
>96
>96
>96
a After purification.
b Determined by 1H NMR spectroscopy.
c In correlation to the de value of the corresponding hydrazides 13a–f assuming that the deprotecting step takes place without detectable
racemization.8
d After recrystallisation from pentane.

E. Deniau et al. / Tetrahedron: Asymmetry 14 (2003) 2253–2258
2255
conformers 12, providing the isoindolinones 13a–f. This
phenyl magnesium chloride (2.0 M in THF) were pur-
chased from Aldrich. Aryllithiums were freshly pre-
pared by halogen–metal exchange reaction from the
corresponding bromides.
1
hypothesis was corroborated by comparing H and 13C
NMR spectra of 3-phenyl isoindolinone 13c with its
previously described epimer.8 Finally, removal of the
chiral auxiliary was readily achieved by oxidative cleav-
age of the hydrazide NꢁN bond. Treatment of the
preliminarily obtained 3-alkyl and aryl isoindolinones
4.2. Typical procedure for the preparation of the imide
10
13a–f
with
magnesium
mono-peroxyphthalate
(MMPP)11a,b afforded the targeted enantioenriched 3-
substituted isoindolinones 14a–f. At this stage we were
intrigued by the specific rotation value of the (R)-3-
methyl isoindolinone 14a ([h]D=+44.0 in MeOH
instead of the reported value9c [h]D=−89.7 in the same
solvent). To clear up this point, we decided to synthe-
size the (R)-configured compound by the alternative
synthesis developed by Stevenson.7b Once again the
specific rotation value ([h]D=+40.4 in EtOH) matched
those of our synthetic compound and of the (S)-
configured epimer7b ([h]D=−38.8 in EtOH).
To a suspension of phthalic anhydride (20 g, 0.135 mol)
and hydrazine 9 (19.5 g, 0.15 mol) in toluene (300 ml)
was added p-toluenesulfonic acid (200 mg) and the
mixture was refluxed for 3 hours while removing the
reaction water via a Dean–Stark apparatus. After
warming to room temperature, the toluene was
removed under reduced pressure and the crude product
dissolved in CH2Cl2 (200 ml). The solution was then
washed sequentially with a saturated aqueous solution
of NaHCO3 (25 ml), with water (50 ml) and brine (50
ml). After drying over Na2SO4 and removal of the
solvent, the crude phthalimide was chromatographed
on SiO2 column using Et2O/hexanes as eluent (60/40)
and recrystallized from hexane to afford 10 as a pale
yellow solid.
3. Conclusion
By means of a new synthetic approach involving the
diastereoselective reduction of iminium salts bearing the
(S)-2-methoxymethylpyrrolidin-1-yl (SMP) type auxil-
iary, we have disclosed a concise and efficient asymmet-
ric synthesis of virtually enantiopure 3-alkyl and 3-aryl
isoindolinones. Owing to the efficiency and simplicity of
this new methodology, this protocol shows potential for
further development and should undoubtedly be broad-
ened to the synthesis of natural and biologically active
compounds.
4.2.1.
(2S)-2-(2-Methoxymethylpyrrolidin-1-yl)-
phthalimide 10. Mp 61–62°C; [h]2D8=+14.0 (c 1.00,
1
CHCl3); H NMR (CDCl3): 1.55–1.66 (m, 1H), 1.82–
2.10 (m, 3H), 3.11 (s, 3H, OMe), 3.24–3.30 (m, 1H),
3.32 (d, J=6.0, OCH2), 3.41 (q, J=8.1, 1H), 3.74–3.82
(m, 1H), 7.62–7.68 (m, 2H, Harom), 7.72–7.78 (m, 2H,
Harom); 13C NMR (CDCl3): C 167.3 (2CO), 130.2 (2C),
CH 133.9 (2CH), 123.0 (2CH), 61.0, CH2 75.9, 52.3,
26.8, 22.2, CH3 58.9. MS (EI) m/z (%): 260 (M+, 4), 215
(100), 130 (18). IR (KBr) w 1719, 1380, 1208, 1112, 884,
715. Anal. calcd for C14H16N2O3: C, 64.60; H, 6.20; N,
10.76. Found: C, 64.82; H, 6.36; N, 10.59.
4. Experimental
4.1. General
4.3. Typical procedure for the preparation of hemiami-
nals 11a–f
Melting points were determined on a Reichert–Thermo-
1
pan apparatus and are uncorrected. H (300 MHz) and
A solution of organometallic reagent (8.5 mmol) was
slowly added to a solution of phthalimide 10 (2.0 g, 7.7
mmol) in THF at −78°C and stirred under argon for 15
min. The mixture was then progressively warmed to
−30°C, quenched with a saturated aqueous solution of
NH4Cl (10 ml) and the aqueous layer extracted with
Et2O (3×50 ml). The combined organic layers were
washed with brine (20 ml), dried over Na2SO4 and
concentrated under vacuum to furnish the crude hemi-
aminals 11a–f which were used for the next step with-
out further purification.
13C NMR (75 MHz) spectra were recorded on a Bruker
AM 300 spectrometer and were referenced against
internal tetramethylsilane; Coupling constants (J) are
given in Hz and rounded to the nearest 0.1 Hz. IR
absorption spectra were run on a Perkin–Elmer 881.
Mass spectral analyses were performed on a Thermo–
Finnigan mass spectrometer. Optical rotations were
measured on a Perkin Elmer P 241 polarimeter. Ele-
mental analyses were determined by the CNRS micro-
analysis center. TLC was performed with plates coated
with Kiesselgel G (Merck). The silica gel used for flash
column chromatography was Merck Kieselgel of 0.040–
0.063 mm particle size. Dry glassware was obtained by
oven-drying and assembly under Ar. Ar was used as the
inert atmosphere and was passed through a drying tube
to remove moisture. The glassware was equipped with
rubber septa and reagent transfer was performed by
syringe techniques. Tetrahydrofuran (THF) was dis-
tilled from sodium benzophenone ketyl immediately
before use. Methanol was distilled from magnesium
turning. Methyl magnesium chloride (3.0 M in THF),
tert-butyl magnesium chloride (1.0 M in THF) and
4.4. Typical procedure for the preparation of 3-substi-
tuted isoindolinones 13a–f
A solution of hemiaminal 11a–f (5.9 mmol) in a mix-
ture of trifluoroacetic acid (20 ml) and CH2Cl2 (10 ml)
was cooled to −78°C and stirred under argon. The
solution was then treated with triethylsilane (1.9 ml,
11.8 mmol), progressively warmed to room temperature
and stirred until no starting material could be detected
(TLC control). The mixture was then poured into ice–
water, made alkaline by the addition of solid K2CO3

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E. Deniau et al. / Tetrahedron: Asymmetry 14 (2003) 2253–2258
and extracted with Et2O (3×50 ml). The extracts were
combined, dried over MgSO4, concentrated under vac-
uum and the residue purified by flash chromatography
on silica gel using diethyl ether/hexane as eluent (60/
40). Finally compounds 13a,b were recrystallised from
pentane.
123.1, 122.9, 65.2, 58.0, CH2 74.4, 51.6, 27.1, 22.6, CH3
61.2. MS (EI) m/z (%): 372 (M+, 4), 327 (100), 260 (54),
259 (41), 132 (56). IR (KBr) w 2861, 1688, 1462, 1358,
1113. Anal. calcd for C24H24N2O2: C, 77.39; H, 6.49; N,
7.52. Found: C, 77.52; H, 6.34; N, 7.71.
4.4.5. (2S,3S)-2-(2-Methoxymethylpyrrolidin-1-yl)-3-(2-
methoxyphenyl)-2,3-dihydro-1H-isoindol-1-one 13e. Oil;
4.4.1.
(2S,3R)-2-(2-Methoxymethylpyrrolidin-1-yl)-3-
1
methyl-2,3-dihydro-1H-isoindol-1-one 13a. Mp 96–97°C;
[h]2D5=−93.9 (c 1.14, CHCl3); H NMR (CDCl3): 1.50–
1
[h]2D8=−16.4 (c 1.30, CHCl3); H NMR (CDCl3): 1.50
1.85 (m, 3H), 1.95–2.20 (m, 1H), 2.36–2.81 (m, 2H),
2.95 (s, 3H, OMe), 3.00–3.40 (m, 2H), 3.60–3.80 (m,
1H), 3.88 (s, 3H, OMe), 6.21 (s, 1H), 6.60–7.10 (m, 3H,
(d, J=6.6, 3H, CH3), 1.70–2.05 (m, 3H), 2.07–2.22 (m,
1H), 3.13–3.24 (m, 1H), 3.29 (s, 3H, OMe), 3.31–3.37
(m, 2H), 3.48 (q, J=8.0, 1H), 4.10–4.20 (m, 1H), 4.48
(q, J=6.6, 1H, CHCH3), 7.30–7.45 (m, 2H, Harom), 7.46
(dt, J=1.4, 7.4, 1H, Harom), 7.70 (d, J=7.7, 1H, Harom);
13C NMR (CDCl3): C 167.0 (CO), 145.6, 131.7, CH
131.6, 127.9, 123.1, 122.0, 60.1, 57.3, CH2 74.2, 51.6,
26.8, 22.5, CH3 58.9. MS (EI) m/z (%): 260 (M+, 4), 215
(100), 148 (60), 114 (46). IR (KBr) w 2905, 1692, 1370,
1106, 771, 706. Anal. calcd for C15H20N2O2: C, 69.20;
H, 7.74; N, 10.76. Found: C, 69.35; H, 7.82; N, 10.59.
Harom), 7.15–7.45 (m, 4H, Harom), 7.77 (dd, J=2.0, 7.6,
1H, Harom); 13C NMR (CDCl3): C 167.0 (CO), 157.6,
144.7, 130.9, 125.9, CH 131.1, 128.6, 127.1, 122.4,
122.2, 120.1, 110.8, 60.3, 57.7, CH2 74.4, 51.1, 26.8,
22.1, CH3 56.1, 55.3. MS (EI) m/z (%): 352 (M+, 6), 307
(100), 240 (58), 239 (31), 132 (28). IR (CHCl3) w 2865,
1684, 1490, 1465, 1106. Anal. calcd for C21H24N2O3: C,
71.57; H, 6.86; N, 7.95. Found: C, 71.73; H, 6.51; N,
7.70.
4.4.2.
(2S,3R)-3-tert-Butyl-2-(2-methoxymethylpyrro-
4.4.6. (2S,3R)-2-(2-Methoxymethylpyrrolidin-1-yl)-3-(3-
methoxyphenyl)-2,3-dihydro-1H-isoindol-1-one 13f. Mp
82–83°C; [h]2D6=−75.2 (c 1.05, CHCl3); 1H NMR
(CDCl3): 1.52–1.90 (m, 3H), 2.00–2.18 (m, 1H), 2.41–
2.55 (m, 1H), 2.57–2.70 (m, 1H), 2.92 (s, 3H, OMe),
3.07–3.32 (m, 2H), 3.62–3.78 (m, 4H), 5.40 (s, 1H), 6.64
(s, 1H, Harom), 6.74 (d, J=7.6, 1H, Harom), 6.82 (dd,
J=2.4, 8.3, 1H, Harom), 7.02–7.10 (m, 1H, Harom), 7.20
(t, J=7.9, 1H, Harom), 7.32–7.47 (m, 2H, Harom), 7.79
(dd, J=1.7, 7.6, 1H, Harom); 13C NMR (CDCl3): C
167.3 (CO), 159.6, 144.5, 139.6, 131.2, CH 131.9, 129.4,
128.1, 123.2, 122.9, 120.9, 114.1, 113.6, 65.0, 61.3, CH2
74.8, 51.7, 27.4, 22.8, CH3 58.4, 55.0. MS (EI) m/z (%):
352 (M+, 4), 307 (100), 240 (62), 239 (34), 132 (25). IR
(KBr) w 2923, 1682, 1462, 1370, 1274, 1109, 1034. Anal.
calcd for C21H24N2O3: C, 71.57; H, 6.86; N, 7.95.
Found: C, 71.80; H, 7.02; N, 7.72.
lidin-1-yl)-2,3-dihydro-1H-isoindol-1-one 13b. Mp 88–
1
89°C; [h]2D6=+40.0 (c 0.93, CHCl3); H NMR (CDCl3):
1.07 (s, 9H), 1.58–1.92 (m, 3H), 2.05–2.40 (m, 1H),
2.81–3.43 (m, 7H), 3.68–3.92 (m, 1H), 4.25 (s, 1H),
7.35–7.45 (m, 3H, Harom), 7.72–7.76 (m, 1H, Harom); 13C
NMR (CDCl3): C 169.7 (CO), 143.1, 132.8, 31.0, CH
130.5, 127.6, 124.6, 122.8, 69.6, 61.2, CH2 74.0, 52.6,
27.9, 23.1, CH3 58.5, 27.2. MS (EI) m/z (%): 302 (M+,
6), 257 (100), 190 (55), 188 (45), 149 (57), 134 (40), 114
(31), 83 (32). IR (KBr) w 2918, 1683, 1470, 1386, 1107.
Anal. calcd for C18H26N2O2: C, 71.49; H, 8.67; N, 9.26.
Found: C, 71.28; H, 8.83; N, 8.97.
4.4.3.
(2S,3R)-2-(2-Methoxymethylpyrrolidin-1-yl)-(3-
phenyl-2,3-dihydro-1H-isoindol-1-one 13c. Mp 170–
171°C; [h]2D8=−49.5 (c 1.05, CHCl3); 1H NMR (CDCl3):
1.54–1.92 (m, 3H), 2.04–2.18 (m, 1H), 2.40 (dd, J=4.0,
9.3, 1H), 2.54 (dd, J=7.4, 9.3, 1H), 3.10 (s, 3H, OMe),
3.16 (dt, J=2.7, 7.4, 1H), 3.27 (q, J=8.0, 1H), 3.68–
3.80 (m, 1H), 5.43 (s, 1H), 7.05–7.18 (m, 3H, Harom),
7.27–7.34 (m, 3H, Harom), 7.39–7.49 (m, 2H, Harom),
7.83 (dd, J=1.9, 7.6, 1H, Harom); 13C NMR (CDCl3): C
167.3 (CO), 144.7, 138.2, 131.5, CH 132.0, 128.8, 128.5
(2CH), 128.4 (2CH), 128.2, 123.3, 123.1, 65.3, 61.3,
CH2 74.7, 52.2, 27.4, 23.0, CH3 58.5. MS (EI) m/z (%):
322 (M+, 4), 277 (100), 210 (36), 165 (22), 114 (31). IR
(KBr) w 2873, 1686, 1368, 1208, 1115. Anal. calcd for
C20H22N2O2: C, 74.51; H, 6.88; N, 8.69. Found: C,
74.35; H, 6.86; N, 8.71.
4.5. Typical procedure for the preparation of isoindoli-
nones 14a–f
MMPP (1.9 g, 3.75 mmol) was added to a solution of
hydrazide 13a–f (1.5 mmol) in methanol (20 ml). Stir-
ring at room temperature continued until no starting
material remained (TLC monitoring). The reaction
mixture was then diluted with Et2O (100 ml) and
treated with a saturated aqueous NaHCO3 solution (65
ml). The aqueous layer was extracted with CH2Cl2
(2×50 ml) after phase separation. The combined
organic extracts were dried over Na2SO4 and the sol-
vents removed under vacuum to furnish the crude
isoindolinones 14a–f which were finally recrystallized
from hexane–toluene for 14a,b and from EtOH for
14c–f.
4.4.4.
(2S,3R)-2-(2-Methoxymethylpyrrolidin-1-yl)-3-
(naphthalen-2-yl)-2,3-dihydro-1H-isoindol-1-one 13d. Mp
108–109°C; [h]D26=−126.0 (c 1.23, CHCl3); 1H NMR
(CDCl3): 1.58–1.88 (m, 3H), 2.05–2.18 (m, 1H), 2.43–
2.56 (m, 2H), 2.70 (s, 3H, OMe), 3.19–3.31 (m, 2H),
3.75–3.83 (m, 1H), 5.65 (s, 1H), 7.02 (dd, J=1.7, 8.5,
1H, Harom), 7.09–7.12 (m, 1H, Harom), 7.46–7.52 (m, 4H,
4.5.1. (3R)-3-Methyl-2,3-dihydro-1H-isoindol-1-one 14a.
Mp 118–119°C, lit.9c 129–133°C; [h]2D5=+44.0 (c 0.56,
MeOH), lit.9c [h]D25=−89.7 (c 1.7, MeOH); 1H NMR
(CDCl3): 1.52 (d, J=6.8, 3H), 4.72 (q, J=6.8, 1H),
7.38–7.50 (m, 2H, Harom), 7.51–7.62 (m, 1H, Harom),
7.87 (d, J=7.3, 1H, Harom), 8.93 (brs, 1H, NH); 13C
H
arom), 7.74–7.91 (m, 5H, Harom); 13C NMR (CDCl3): C
167.2 (CO), 144.4, 135.2, 133.0, 132.1, 131.2, CH 131.7,
128.5, 128.2, 128.0, 127.5, 127.3, 126.1 (2CH), 124.9,

E. Deniau et al. / Tetrahedron: Asymmetry 14 (2003) 2253–2258
2257
NMR (CDCl3): C 171.5 (CO), 149.1, 131.8, CH 131.7,
127.9, 123.5, 122.2, 52.8, CH3 20.2. MS (EI) m/z (%):
147 (M+, 78), 132 (100), 104 (24), 77 (22). IR (KBr) w
3198, 1706, 1419, 1357, 1311, 1202, 1140. Anal. calcd
for C9H9NO: C, 73.45; H, 6.16; N, 9.52. Found: C,
73.57; H, 6.10; N, 9.45.
C15H13NO2: C, 75.30; H, 5.48; N, 5.85. Found: C,
75.21; H, 5.83; N, 5.98.
Acknowledgements
4.5.2. (3R)-3-tert-Butyl-2,3-dihydro-1H-isoindol-1-one
This work was supported by the Deutsche Forschungs-
gemeinschaft (Leibniz-Preis) and the Fonds der
Chemischen Industrie. We thank Degussa AG, BASF
AG, the former Hoechst AG, and Bayer AG for the
donation of chemicals.
1
14b. Mp 178–179°C; [h]2D5=+25.0 (c 0.76, MeOH); H
NMR (CDCl3): 1.04 (s, 9H), 4.35 (s, 1H), 7.45–7.54 (m,
3H, Harom), 7.87 (d, J=7.1, 1H, Harom), 8.58 (brs, 1H,
NH); 13C NMR (CDCl3): C 171.7 (CO), 145.8, 133.1,
35.2, CH 131.1, 127.9, 124.1, 123.6, 66.5, CH3 26.4. MS
(EI) m/z (%): 189 (M+, 2), 133 (100), 132 (24), 77 (19).
IR (KBr) w 3217, 2961, 1702, 1473, 1362, 1211, 1141.
Anal. calcd for C12H15NO: C, 76.16; H, 7.99; N, 7.40.
Found: C, 76.22; H, 8.12; N, 7.69.
References
1. (a) Valencia, E.; Weiss, I.; Firdous, S.; Freyer, A. J.;
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4. Belliotti, T. R.; Brink, W. A.; Kesten, S. R.; Rubin, J. R.;
Wustrow, D. J.; Zoski, K. T.; Whetzel, S. Z.; Corbin, A.
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4.5.3. (3R)-3-Phenyl-2,3-dihydro-1H-isoindol-1-one 14c.
Mp 242–243°C; [h]D25=−193.3 (c 0.73, DMSO); 1H
NMR (DMSO-d6): 5.73 (s, 1H), 7.24–7.39 (m, 6H,
H
arom), 7.43–7.55 (m, 2H, Harom), 7.71 (d, J=7.6, 1H,
Harom), 9.08 (brs, 1H, NH); 13C NMR (DMSO-d6): C
169.9 (CO), 148.3, 139.8, 131.6, CH 132.0, 129.0 (2CH),
128.3, 128.1, 126.8 (2CH), 123.7, 123.1, 59.7. MS (EI)
m/z (%): 209 (M+, 6), 207 (100). IR (KBr) w 3187, 1693,
1643. Anal. calcd for C14H11NO: C, 80.36; H, 5.30; N,
6.69. Found: C, 80.18; H, 5.36; N, 6.80.
4.5.4. (3R)-3-(Naphthalen-2-yl)-2,3-dihydro-1H-isoindol-
1-one 14d. Mp 224–225°C; [h]2D5=−201.0 (c 0.71,
1
DMSO); H NMR (DMSO-d6): 5.90 (s, 1H), 7.22–7.34
(m, 2H, Harom), 7.42–7.54 (m, 4H, Harom), 7.72–7.81 (m,
1H, Harom), 7.82–7.98 (m, 4H, Harom), 9.23 (s, 1H, NH);
13C NMR (DMSO-d6): C 170.0 (CO), 148.3, 137.3,
133.1, 132.9, 131.7, CH 132.1, 128.8, 128.4, 127.9,
127.8, 126.7, 126.4, 125.9, 124.5, 123.8, 123.2, 59.9. MS
(EI) m/z (%): 259 (M+, 4), 257 (100). IR (KBr) w 3205,
1689, 1650, 1206. Anal. calcd for C18H13NO: C, 83.38;
H, 5.05; N, 5.40. Found: C, 83.25; H, 5.12; N, 5.57.
5. (a) Wood, J. L.; Petsch, D. T.; Stoltz, B. M.; Hawkins, E.
M.; Elbaum, D.; Stover, D. R. Synthesis 1999, 1529–
1533; (b) Bishop, A. C.; Ubersax, J. A.; Petsch, D. T.;
Matheos, D. P.; Gray, N. S.; Blethrow, J.; Shimizu, E.;
Tsien, J. Z.; Schultz, P. G.; Rose, M. D.; Wood, J. L.;
Morgan, D. O.; Shokat, K. M. Nature (London) 2000,
407, 395–401.
6. Grigg, R.; Dorrity, M. J. R.; Malone, J. F.; Mongkolaus-
savaratana, T.; Norbert, W. D. J. A.; Sridharan, V.
Tetrahedron Lett. 1990, 31, 3075–3076.
7. (a) Oppolzer, W.; Wills, M.; Kelly, M. J.; Signer, M.;
Blagg, J. Tetrahedron Lett. 1990, 31, 5015–5018; (b)
McAlonan, H.; Murphy, J. P.; Nieuwenhuyzen, M.;
Reynolds, K.; Sarma, P. K. S.; Stevenson, P. J.; Thomp-
son, N. J. Chem. Soc., Perkin Trans. 1 2002, 69–79.
8. Enders, D.; Braig, V.; Raabe, G. Can. J. Chem. 2001, 79,
1528–1535.
9. (a) Allin, S. M.; Northfield, M. I.; Slawin, A. M. Z.
Tetrahedron Lett. 1999, 40, 141–142; (b) Allin, S. M.;
Northfield, M. I. P.; Slawin, A. M. Z. Tetrahedron Lett.
1999, 40, 143–146; (c) Allin, S. M.; Northfield, C. J.;
Page, M. I.; Slawin, A. M. Z. J. Chem. Soc., Perkin
Trans. 1 2000, 1715–1721.
4.5.5. (3S)-3-(2-Methoxyphenyl)-2,3-dihydro-1H-isoin-
dol-1-one 14e. Mp 170–171°C; [h]2D5=−294.5 (c 0.84,
DMSO); 1H NMR (DMSO-d6): 3.89 (s, 3H, OMe), 6.04
(s, 1H), 6.76–7.18 (m, 3H, Harom), 7.21–7.60 (m, 4H,
Harom), 7.70 (d, J=7.7, 1H, Harom), 8.92 (brs, 1H, NH);
13C NMR (DMSO-d6): C 170.1 (CO), 157.0, 148.4,
132.0, 127.5, CH 131.8, 129.2, 128.2, 126.1, 123.5,
123.1, 120.8, 111.6, 55.9, CH3 54.2. MS (EI) m/z (%):
239 (M+, 6), 237 (100). IR (KBr) w 3174, 1692, 1659,
1249. Anal. calcd for C15H13NO2: C, 75.30; H, 5.48; N,
5.85. Found: C, 75.45; H, 5.52; N, 5.90.
4.5.6. (3R)-3-(3-Methoxyphenyl)-2,3-dihydro-1H-isoin-
dol-1-one 14f. Mp 183–184°C; [h]2D5=−216.4 (c 1.03,
DMSO); 1H NMR (DMSO-d6): 3.72 (s, 3H, OMe), 5.70
(s, 1H), 6.80–6.92 (m, 3H, Harom), 7.20–7.34 (m, 2H,
Harom), 7.41–7.56 (m, 2H, Harom), 7.71 (d, J=7.7, 1H,
Harom), 9.09 (brs, 1H, NH); 13C NMR (DMSO-d6): C
169.7 (CO), 159.5, 148.0, 141.2, 131.3, CH 131.8, 129.9,
128.1, 123.5, 122.9, 118.4, 113.1, 112.3, 59.4, CH3 55.1.
MS (EI) m/z (%): 239 (M+, 5), 237 (100). IR (KBr) w
3215, 1697, 1658, 1285, 1048. Anal. calcd for

2258
E. Deniau et al. / Tetrahedron: Asymmetry 14 (2003) 2253–2258
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hedron 2002, 58, 5103–5108.
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Tetrahedron 2002, 58, 2253–2329.
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