Asymmetric alkylation of N-acylisoindolin-1-ones via α bromoimides: A novel route to 1-substituted isoindolines

Article abstract of DOI:10.1002/jhet.5570440312

(Chemical Equation Presented) Key intermediate in the synthesis of the title compounds 9a-c and 10a-c was the chiral α-bromoimide 1 which has been prepared by radical bromination of the corresponding N-acylisoindolin-1-one 13. 1 was alkylated with silyl enol ethers under Lewis acid catalysis using α-amidoalkylation methodology. N,N-diacyliminium ion 14 is presumably the intermediate in this reaction. Further transformations of the alkylated compounds yielded 1-substituted isoindolines as target compounds.

Full text of DOI:10.1002/jhet.5570440312

May-Jun 2007
575
Asymmetric Alkylation of N-Acylisoindolin-1-ones via ꢀ-
Bromoimides: A Novel Route to 1-Substituted Isoindolines
Andreas Müller, Kurt Polborn and Klaus T. Wanner*
Department of Pharmacy - Center of Drug Research - Ludwig-Maximilians-Universität München,
Butenandtstr. 7, Haus C, D-81377 München, Germany
e-mail: klaus.wanner@cup.uni-muenchen.de Tel: +49-89-2180 77249 Fax: +49-89-2180 77248.
Received May 12, 2006
OSiMe3
H3C
N
H3C
N
O
O
R
N
OH
OH
+
O
O
Br
Lewis Acid
R
R
R = CH3, NO2, Cl
Key intermediate in the synthesis of the title compounds 9a-c and 10a-c was the chiral ꢀ-bromoimide 1
which has been prepared by radical bromination of the corresponding N-acylisoindolin-1-one 13. 1 was
alkylated with silyl enol ethers under Lewis acid catalysis using ꢀ-amidoalkylation methodology. N,N-
diacyliminium ion 14 is presumably the intermediate in this reaction. Further transformations of the
alkylated compounds yielded 1-substituted isoindolines as target compounds.
J. Heterocyclic Chem., 44, 575 (2007).
selected isoindoline derivatives substituted with a 2-
hydroxyethyl group in the ꢀ-position of the ring nitrogen
as the 1,3-aminoalcohol moiety represents a common
motif in many pharmacologically active compounds,
[2a,3]. As stereoisomers are known to quite often display
signicantly different biological activities their preparation
in diastereomerically and enantiomerically pure form
seemed especially advisable.
For the preparation of the desired isoindoline
derivatives exhibiting a 1,3-aminoalcohol moiety we
followed the synthetic concept that can be found in
Schemes 1 and 2.
INTRODUCTION
ꢀ-Amidoalkylation is a well-established method for the
nucleophilic substitution of amino derivatives in the ꢀ-
position [1]. In recent years we have demonstrated that ꢀ-
amidoalkylation reactions can be carried out efficiently in
an asymmetric manner by using ꢀ-amidoalkylation
reagents provided with a camphoric acid derivative as a
chiral auxiliary [2]. With this approach it was possible to
prepare several ꢀ-substituted heterocycles, including
tetrahydroisoquinolines, piperidines and pyrrolidines in
high diastereoselectivity. Based on the results obtained so
far it seemed highly rewarding to apply this synthetic
concept also to the stereoselective synthesis of 1-
substituted isoindoline derivatives. As main targets we
The key step of this sequence is an asymmetric
electrophilic ꢀ-amidoalkylation reaction based on the
ꢀ-bromoimide 1. As preliminary amidoalkylation
Scheme 1
O
O
O
O
O
O
N
N
[a]
+
N
O
O
O
O
O
O
Br
O
O
R
1
R
3a-c
4a-c
OSi(CH3)3
a: R = CH3
b: R = NO2
c: R = Cl
R
2a-c
[a] Lewis acid (0.1 or 1.1 equiv.), 2a-c (1.5 equiv.), CH2Cl2

576
A. Müller, K. Polborn and K. T. Wanner
Vol 44
reactions with the corresponding N-acylisoindoline
derivative had met with no success, compound 1
representing an N-acylisoindolinone was selected for
this reaction. Interestingly, to the best of our knowledge
no amidoalkylation reactions based on imide derivatives
with N,N-diacyliminium ions as presumable inter-
mediates have been reported so far.
The synthesis of the phenacyl substituted isoindole
derivative 3a-c/4a-c should be easy to accomplish by
simply employing the silyl enol ethers 2a-c in the
amidoalkylation reactions with 1 (Scheme 1). A few
subsequent group transformations, including the reduction
of the keto function to an alcohol and of the lactam
carbonyl group to a methylene unit, should, after the
removal of the chiral auxiliary, finally lead to the desired
isoindoline derivatives (see Scheme 2).
A positive aspect of the approach described above is that
it can give access to the final compounds in stereo-
chemically pure form even if the asymmetric induction in
the amidoalkylation reaction with 1 is incomplete. In this
case the mixture of diasteromers formed during the
amidoalkylation process has simply to be purified to a
single diastereomer, a task that can be accomplished by
conventional methods. Furthermore, by controlling the
configuration of the stereocenter in the side chain both
diastereomers of the individual compounds should become
accessible, too (9a-c and 10a-c, repectively).
Synthesis of ꢀ-bromoimide 1. The preparation of ꢀ-
bromoimide 1, representing a key compound in our
synthetic project, was accomplished according to the
synthetic sequence outlined in Scheme 3. Treating
phthalimide with the acid chloride derived from the chiral
auxiliary 11 provided the N-acylphthalimide 12 in a 96 %
yield. Subsequent catalytic hydrogenation of 12 in the
presence of palladium on charcoal and trifluoro acetic
acid yielded the N-acylisoindolinone 13 in 99 % [3].
Radical bromination of 13 with N-bromosuccinimide and
AIBN in CCl4 finally led to the desired ꢀ-bromoimide 1.
Though compound 1 was found to be labile and prone to
hydrolysis we were eventually able to obtain it in pure
form by crystallization and in yields of up to 80 %.
Synthesis of amidoketones 3a-c/4a-c. With the ꢀ-
bromoimide 1 in our hand we were prepared for the
critical step of the synthetic sequence: the asymmetric ꢀ-
amidoalkylation reaction (Scheme 4). Various Lewis
acids were tested for their suitability as catalyst for the
reaction of the ꢀ-bromoimide 1 with different silyl enol
ethers 2a-c which should lead to the stereoisomeric
amidoketones 3 and 4 [4]. The reactions were carried out
in dichloromethane at 0 °C or room temperature with
catalytic (0.1 equiv.) or stochiometric (1.1 equiv.)
amounts of Lewis acid. The best diastereomeric ratios
Scheme 2
O
HN
3a-c
H3C N
N
H
O
H
OH
OH
R
R
R
7a-c
5a-c
9a-c
a: R = CH3
b: R = NO2
c: R = Cl
O
HN
N
H3C
N
H
O
H
OH
OH
R
R
R
10a-c
6a-c
8a-c

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Asymmetric Alkylation of N-Acylisoindolin-1-ones via ꢀ-Bromoimides
577
when tin(IV) chloride was used as Lewis acid (Table 1,
entries 7-9). In general, the yields of these reactions were
satisfactory considering that HgI2 and SnCl4 gave
somewhat better results (total yield of 3 and 4 ~ 50 %)
than Sn(OTf)2. Interestingly, no conversion of ꢀ-
bromoimide 1 was observed with titan(IV) chloride,
trimethylsilyl triflate or boron trifluoride etherate.
Scheme 3
O
O
O
[a][b]
N
OH
O
O
O
O
O
12
11
[c]
It was expected that the diastereoselectivity of the
amidoalkylation step could be improved by lowering the
reaction temperature. But experiments with HgI2 and
Sn(OTf)2 as Lewis acids produced no better results.
O
O
O
O
[d]
So far it remains unclear why the stereoselectivity is
highest in the addition reaction with mercury(II) iodide
as catalyst. Possibly mercury(II) iodide forms a ꢀ-
complex with the silyl enol ethers prior to their addition
reactions. The increased steric demand of the incoming
N
N
O
O
Br
O
O
13
1
[a] (COCl)2, DMFcat., CH2Cl2; [b] phthalimide, NEt3, DMAP, CH2Cl2;
[c] H2, Pd/C, TFA, EtOAc; [d] NBS, AIBN, CCl4, reflux
nucleophile alone or together with
a
putative
coordination of this complex to the amidoalkylation
reagent 1 or the reactive intermediate delineated from
the former could account for the improved stereo-
selectivity [5].
Amidoalkylation reactions with 1 proceed probably via
N,N-bisacyliminium ion 14 (Scheme 4). Though nmr
experiments to identify the intermediate remained
unsuccessful, this assumption is supported by the
stereochemical outcome of the amidoalkylation reactions.
were obtained using mercury(II) iodide as lewis acid
(80/20, Table 1, entries 1-3). When tin(II) triflate was
employed the diastereoselectivities sank slightly (75/25,
Table 1, entries 4-6). In both series the diastereomers 3a-c
exhibiting (S)-configuration at the newly created stereo
center predominated. In contrast to the results described
above the diastereoselectivity became almost insignificant
Scheme 4
O
O
O
O
[a]
N
N+
O
O
Br
O
O
1
14
O
O
O
O
N
N
+
O
O
O
O
O
O
R
R
3a-c
4a-c
a: R = CH3
OSi(CH3)3
b: R = NO2
c: R = Cl
R
2a-c
[a] Lewis acid (0.1 or 1.1 equiv.), 2a-c (1.5 equiv.), CH2Cl2

578
A. Müller, K. Polborn and K. T. Wanner
Vol 44
Table 1
Alkylation of ꢀ-bromoimide 1 [a]
Entry
Nucleophile (R)
Lewis Acid (equiv)
Products
Temp.
dr (3 : 4)
Yield (3+4) %
[b]
1
2a (-CH3)
HgI2 (0.1)
3a, 4a
rt
84 : 16
-
2
3
4
5
6
7
8
9
2b (-NO2)
2c (-Cl)
2a (-CH3)
2b (-NO2)
2c (-Cl)
2a (-CH3)
2b (-NO2)
2c (-Cl)
- " -
- " -
Sn(OTf)2 (0.1)
- " -
- " -
SnCl4 (1.1)
- " -
3b, 4b
3c, 4c
3a, 4a
3b, 4b
3c, 4c
3a, 4a
3b, 4b
3c, 4c
rt
rt
rt
rt
rt
0 °C
0 °C
0 °C
80 : 20
79 : 21
77 : 23
75 : 25
77 : 23
53 : 47
54 : 46
50 : 50
53
55
32
40
47
48
56
55
- " -
[a] CH2Cl2, 1.5 equiv. 2a-c; [b] not isolated
As a 1:1 mixture of the diastereomeric ꢀ-bromoimides 1
was used as starting material, no diastereoselection should
occurr if the reaction followed an SN2-pathway. The fact
that at least some of our experiments resulted in
significant diastereoselectivities (Table 1) points to an
butoxyaluminum hydride proved to be the most suitable
reducing agent for this purpose. When the reaction was
carried out in THF at 0 °C (Scheme 5) the (2'R,3S)-
configurated alcohols 15a-c were obtained in good to
excellent yields and with high stereoselectivities (Table 2,
Scheme 5
O
O
O
O
O
O
[a]
N
N
N
+
R*
R*
R*
3S
OH
3S
OH
3S
O
2'S
2'R
R
R
R
3a-c
15a-c
16a-c
a: R = CH3
b: R = NO2
c: R = Cl
R* =
O
O
[a] Li[Al(tBuO)3H], THF, 0°C
Table 2
Reduction of the keto group in the side chain
dr
(15 : 16)
94:6
97:3
95:5
78:22
82:18
81:19
76:24
Entry
Educt (R)
Reagent (equiv.)
Products
Solvent
Temp.
Yield (15) %
1
2
3
4
5
6
7
3a (-CH3)
3b (-NO2)
3c (-Cl)
3a (-CH3)
3b (-NO2)
3c (-Cl)
Li[Al(tBuO)3H] (5)
Li[Al(tBuO)3H] (5)
Li[Al(tBuO)3H] (5)
NaBH4 (2.5)
KBH4 (5)
KBH4 (5)
t BuNH2 · BH3 (2)
15a, 16a
15b, 16b
15c, 16c
15a, 16a
15b, 16b
15c, 16c
15a, 16a
THF
THF
THF
EtOH
MeOH
MeOH
THF
0 °C
0 °C
0 °C
0 °C
rt
90
90
76
57
23
48
96
rt
0 °C
3a (-CH3)
SN1-like mechanism with the of N,N-bisacyliminium ion
14 as the reactive intermediate.
entries 1-3). In contrast, when using NaBH4, KBH4 and
tBuNH2·BH3 as reducing agents the diastereoselectivities
(dr) became distinctly lower. In addition, the yields were
reduced slightly but the major isomers remained the same
in all cases (Table 2, entries 4-7).
Reduction of the keto group in the side chain. Next
the keto function present in the phenacyl side chain had to
be reduced to a hydroxyl group. Lithium tris-tert-

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Asymmetric Alkylation of N-Acylisoindolin-1-ones via ꢀ-Bromoimides
579
Removal of the chiral auxiliary. While imides
generally can be easily transformed into the corre-
sponding amides by alkaline hydrolysis, treatment of the
imidoalcohol 15a with dilute sodium or potassium
hydroxide solution (in MeOH or EtOH) did not lead to
the corresponding isoindolinone 5a. Instead a mixture of
compounds 17a and 18a arising from a rearrangement
reaction was obtained. Spectroscopic data made the
diastereomeric nature of the two compounds, 17a and
18a, immediately evident, but not their stereochemistry.
The latter could be assigned based on the results of a
deutaration experiment. When the rearrangement
reaction was performed with 0.9 M of NaOCD3 in
DOCD3 no incorporation of deuterium was observed for
17a whereas in case of 18a exactly one proton, the
proton at C-3 of the isoindolinone ring was exchanged
by deuterium (Scheme 6). The configuration of
compound 17a therefore can not have changed and must
be the same as the configuration of the starting
compound 15a. Compound 18a which is a diastereomer
of 17a can differ from the latter only with respect to the
configuration at C-3 of the isoindoline system.
Consequently, the compound must exhibit the
stereochemical configuration depicted in Scheme 6.
Likewise, the chiral auxiliary could not be removed
when a protocol for the cleavage of imides with lithium
hydroperoxide according to Evans et al. was applied [6].
Again we observed predominat formation of amidoester
17a while only small amounts of the desired isoindol-
inone 5a were obtained.
Finally, we discovered that the removal of the chiral
auxiliary could be best effected by a reductive procedure
employing LiBH4 as reducing agent. This led to the
isoindolinones 5a-c in moderate to good yields (66 –
90 %) without any rearranged or epimerized products
being observed (Scheme 7).
Inversion of configuration at the asymmetric center
in the side chain. To gain access to the isomers 6a-c with
(2'S,3S)-configuration, the stereocenter in 2'-position of
the side chain of the isoindoline moiety had to be
inverted. This was accomplished by subjecting the
amidoalcohols 5a-c to a Mitsunobu reaction which is
known to proceed with inversion of the affected carbon
[7]. This way, the benzoates 19a-c were obtained from
5a-c by treatment with DIAD and PPh3. Upon reductive
cleavage of the newly created ester function this finally
afforded the desired (2'S,3S)-amidoalcohols 6a-c in
satisfactory yields (Scheme 8).
Scheme 6
CH3
CH3
O
O
O
O
O
O
[a]
N
O
O
+
O
O
O
NH
O
O
NH
O
OH
CH3
15a
18a
17a
[a] NaOH, MeOH
Transformation of the isoindolinone into an iso-
Scheme 7
indoline moiety. The reduction of amides to the
corresponding amines is commonly effected by using
either borane, borane·THF or borane·dimethylsulfide
(BMS). Since BMS is the most stable of those reagents,
we regarded it as the most suitable for our purposes
even though the removal of dimethyl sulfide can be
difficult in some cases [8].
O
O
O
[a]
HN
N
O
O
OH
OH
R
R
15a-c
5a-c
a: R = CH3
b: R = NO2
c: R = Cl
[a] LiBH4, THF

580
A. Müller, K. Polborn and K. T. Wanner
Vol 44
When the isoindolinones 5a-c and 6a-c were treated
with BMS in refluxing tetrahydrofurane the starting
oxazinanes 7a-c and 8a-c. This was easily accomplished
by treating the crude reaction product resulting from the
Scheme 8
O
O
O
[b]
[a]
HN
HN
HN
OH
OH
O
O
R
R
R
6a-c
19a-c
5a-c
a: R = CH3
b: R = NO2
c: R = Cl
[a] DIAD, PPh3, benzoic acid, THF; [b] Li[AlH2(OMe)2], THF, 0 °C or LiBH4, THF
Scheme 9
O
[b]
[a]
N
H
HN
HN
O
H
OH
OH
R
R
R
5a-c
7a-c
20a-c
O
[a]
[b]
N
H
HN
HN
O
H
OH
OH
R
R
R
6a-c
21a-c
8a-c
a: R = CH3
b: R = NO2
c: R = Cl
[a] BMS, THF, reflux; [b] HCHO, THF
material was completely consumed within several hours.
Unfortunately, we did not succeed in isolating compounds
20a-c and 21a-c, neither in reasonable yields nor in pure
form even though there was clear evidence that the
desired aminoalcohols 20a-c and 21a-c, respectively, had
formed. To ease the isolation we therefore decided to
transform 20a-c and 21a-c directly to the corresponding
reduction of 5a-c and 6a-c with BMS for 16 hours with
formaldehyde (15 equiv.). The desired oxazinanes 7a-c
and 8a-c could then be isolated in moderate yields
(Scheme 9).
Formation of the N-Methylisoindolines 9a-c and
10a-c. The last step of our synthetic sequence involved
the reduction of the oxazinanes 7a-c and 8a-c to give the

May-Jun 2007
Asymmetric Alkylation of N-Acylisoindolin-1-ones via ꢀ-Bromoimides
581
N-methylisoindolines 9a-c and 10a-c, respectively.
This step was efficiently accomplished by treating the
oxazinanes 7a-c and 8a-c with sodium cyanoborohydride
in methanol at pH 4-5 providing the target compounds 9a-
c and 10a-c in good yields (Scheme 10).
(R)-Configuration at C-3 could be confirmed for 4b and
4c, too, by comparison of both nmr- and chromato-
graphical data obtained for these compounds.
Consequently, compounds 3a-c as diastereomers of 4a-c
must have (S)-configuration at C-3 of the isoindoline ring.
Scheme 10
[a]
[a]
N
H3C N
H3C
N
N
H
H
O
O
OH
OH
H
H
R
R
R
R
7a-c
8a-c
9a-c
10a-c
a: R = CH3
b: R = NO2
c: R = Cl
[a] Na[BH3CN], MeOH, HOAc
Stereochemistry. In order to determine the
configuration of the stereocenter generated in the
course of the amidoalkylation reaction of the
bromoimide 1 and the silylenolether 2a, an X-ray
analysis of minor isomer 4a, which had given suitable
crystals, was perfomed. By taking the stereochemistry
To determine the configuration of the stereocenter in
the side chain (C-2') it was necessary to prepare the
oxazinanone 22, as nmr spectra of the oxazinanes 7a-c did
not allow conclusive analysis, even though the nmr data
for 7a-c were very similar to each other indicating that all
compounds possessed the same relative configuration.
Scheme 11
O2
O1
C18 C19
C10
O
O
C17
N1
C1
C13
C9
C2
C3
C5
N
C11
C12
C4
C8
C7
O
O
O3
C20
O4
C27
C6
C21
OO5
C22
C26
C23
C25
C24
H3C
C28
4a
of the chiral auxiliary into account the results of the X-
ray analysis revealed (R)-configuration at C-3 of the
isoindolinone ring (Scheme 11).
Compound 22 was prepared by BMS reduction of
isoindolinone 5a followed by treatment with
carbonyldiimidazole (Scheme 12).

582
A. Müller, K. Polborn and K. T. Wanner
Vol 44
Scheme 12
O
H
8
O
H
9
8a
HN
[a][b]
O
9a
7
6
N
1
N
H
4b
2
O
4a
OH
5
H
O
3
4
H
H
CH3
CH3
CH3
22
5a
[a] BMS, THF, reflux; [b] CDI, THF
commercially available. Silyl enol ethers were prepared as
described in literature [2a,4]. Solvents were dried prior to use.
THF was freshly distilled from sodium metal/benzophenone
ketyl, CH2Cl2 from CaH2 and CH3OH from Mg prior to use.
Melting points were determined on a Büchi melting point
apparatus no. 510 (Dr. Tottoli) and are uncorrected. Infrared
spectra were recorded with a Perkin Elmer FT-IR spectrometer
Paragon 1600. Solids were measured as KBr pellets, liquids as
films between NaCl plates. Nmr spectra were obtained with
JEOL JNMR-GX 400 (400MHz), JNM-ECP 400 (400 MHz) or
JNM-ECP 500 (500 MHz) spectrometers, respectively.
Tetramethylsilane was used as internal standard. The nmr
spectra were recalculated with NUTS, 2D version 2002. Mass
spectra were recorded on a Hewlett Packard 5989 A mass
spectrometer with 59980 B particle beam LC/MS interface.
Hrms spectra were obtained with a JEOL JMS 700 and a JEOL
JMS GC-Mate II mass spectrometer. CHN-analyses were
determined an HERAEUS Rapid or an ELEMENTAR Vario EL
elemental analysator. Tlc: Merck 60 F-254. Column
chromatrography (CC) was performed as flash chromatography
with silica gel 60 (Merck, 0.040- 0.063 mm) Analytical hplc: L-
6200, L-7100 or L7100 pump, L-4000 or L-7400 UV/Vis
detector, D-7000 HPLC-System-Manager (Merck-Hitachi)
LiChroCart® with LiChroSpher® 100 RP-18 cartridge (5 μm,
250x4 mm with precolumn 4x4 mm), (Merck). Preparative hplc:
L-6000 pump, L-4000 UV/Vis detector, D-2000 Chromato
Integrator (Merck Hitachi), column #1: Hibar RT LiChrosorb®
Si 60 (7 μm, 250x25 mm) (Merck); column #2: Hibar RT
Lichrosorb® RP-18 (7μm, 250x25 mm) (Merck).
NOE-DIF nmr experiments as well as the analysis of the
coupling constants in the H nmr spectrum of 22 indicated
cis-configuration of the methin protons at C-3 and C-4a
(Scheme 12). As we already had conclusively assigned the
absolute configuration of C-4a (= C-3 in compound 4a), we
could ascribe (3R,4aS)-configuration to 22.
1
Since the preparation of oxazinanes 7a-c was very
similar to that of oxazinanone 22 and none of the
stereogenic centres was affected during all other reaction
steps, the configuration of 22 must also apply to the
oxazinanes 7a-c, the isoindolinones 5a-c, the imido-
alkohols 15a-c and the target isoindolines 9a-c.
Consequently, the diastereomeres of these compounds,
the oxazinanes 8a-c, the isoindolinones 6a-c, the
imidoalcohols 16a-c as well as the final compounds 10a-c
must possess (S,S)-configuration [(3S,4aS) for 8a-c,
(2'S,3S) for 6a-c and 16a-c and (1S,2'S) for 10a-c], as they
differ from the aforementioned compounds only with
respect to the configuration of the stereocenter located
outside the isoindoline moiety.
Finally, in each case the (R,S)-configured compounds
5a-c, 15a-c, 9a-c and 7a-c showed nmr data which
significantly differed from that of the corresponding (S,S)-
isomers 6a-c, 16a-c, 10a-c and 8a-c. It was therefore
possible to verify the stereochemical purity of these
compounds simply by analyzing their nmr spectra.
General Procedures.
Conclusion. The ꢀ-bromoimide 1 was successfully
employed in asymmetric ꢀ-amidoalkylation reactions with
silyl enol ethers 2a-c providing the phenacyl substituted
isoindolinone derivatives 3a-c as major diastereomers. N,N-
bisacyliminium ion 14 is thought to be the intermediate in
these reactions. The addition products 3a-c proved to be
valuable starting materials for the construction of the N-
methylisoindoline derivatives 9a-c and 10a-c.
General Procedure for the Alkylation of 1 with SnCl4 and
Silyl Enol Ethers 2a-c - GP1. A 0.2 M solution of 1 in CH2Cl2
was cooled to 0 °C. After dropwise addition of 1.1 equivalents
of SnCl4 the solution was stirred for 1 hour. Then 1.5
equivalents of the appropriate silyl enol ether 2a-c were added.
After 16 hours the reaction was terminated by addition of
saturated NH4Cl-solution and warmed to room temperature. The
aqueous layer was extracted with CH2Cl2 (4x) and the combined
organic layers were dried over MgSO4 and concentrated in
vacuo. Diastereoselectivity was determined by hplc from the
crude product.
EXPERIMENTAL
General Procedure for the Alkylation of 1 with Sn(OTf)2
and Silyl Enol Ethers 2a-c - GP2. A 0.05 M solution of 1 in
CH2Cl2 was treated with 1.5 equivalents of the appropriate silyl
All reactions were carried out in vacuum dried glassware
under nitrogen atmosphere. All reagents were used as

May-Jun 2007
Asymmetric Alkylation of N-Acylisoindolin-1-ones via ꢀ-Bromoimides
583
enol ethers 2a-c and stirred for 15 minutes at room temperature.
Then 0.1 equivalents of Sn(OTf)2 were added and the mixture
was stirred for 5 hours. After addition of saturated NH4Cl-
solution, the aqueous layer was extracted with CH2Cl2. The
combined organic layers were dried over MgSO4 and
concentrated in vacuo.
General Procedure for the Alkylation of 1 with HgI2 and
Silyl Enol Ethers 2a-c - GP3. Like GP2 using HgI2 instead of
Sn(OTf)2.
General Procedure for the Preparation of Imidoalcohols
15a-c and 16a-c by Li[Al(tBuO)3H] Reduction of Imido-
ketones 3a-c - GP4. A 0.05 M solution of the appropriate
imidoketone 3a-c in THF was cooled to 0 °C and treated with 5
equivalents of Li[Al(tBuO)3H]. After stirring for 16 hours,
KH2PO4-solution (10%) was added to terminate the reaction.
The mixture then was allowed to warm to room temperature.
The aqueous layer was extracted with Et2O (4x). The combined
organic layers were washed with brine (2x), dried over MgSO4
and concentrated in vacuo.
General Procedure for the Conversion of the Oxazinanes
7a-c and 8a-c into the N-methylaminoalcohols 9a-c and 10a-c
- GP9. A 0.025 M solution of the appropriate oxazinane 7a-c,
8a-c in CH3OH was treated with 5 equivalents of Na[BH3CN].
By dropwise addition of glacial acetic acid the solution was
adjusted to pH 4-5. After stirring for 2.5 hours the solvent was
removed in vacuo and the residue was dissolved in 1 N HCl.
This solution was washed with Et2O (3x) and the organic layers
were discarded. The aqueous layer was alkalized with KOH,
saturated with NaCl and extracted with Et2O (5x). The combined
organic layers were dried over MgSO4. To obtain the
hydrochlorides of the desired N-methylaminoalkohols the
solution and was concentrated treated with HCl (1 M in Et2O)
and the resulting precipitate was isolated by centrifugation. To
obtain the free bases of the N-methylaminoalcohols the dried
organic layers were concentrated in vacuo.
2-[(1S,5R)-5,8,8-Trimethyl-2-oxo-3-oxabicyclo[3.2.1]-
octane-1-carbonyl]isoindol-1,3-dione (12). 209 mg (0.99
mmol) 11 [2e] were dissolved in 2 ml of CH2Cl2. The solution
was cooled in an ice bath and mixed with 89 μl (1.04 mmol) of
oxalyl chloride and 4 μl (0.05 mmol) of DMF. After 10 minutes
the ice bath was removed and the mixture was stirred at room
temperature until gas formation had ceased. The solvent was
removed in vacuo and the residue was dissolved in 1.2 ml of
CH2Cl2. This solution was cooled in an ice bath and transferred
to an ice cold mixture of 231 mg (1.57 mmol) of phthalimide, 6
mg (0.05 mmol) of DMAP, 280 μl (2.01 mmol) of NEt3 and 0.5
ml of CH2Cl2. The resulting mixture was stirred for 16 hours at
room temperature. Then it was washed with 5 ml of 2 N NaOH
(2x), 5 ml of 2 N HCl (2x) and 5 ml of H2O and dried over
MgSO4. After the solvent had been removed in vacuo, 326 mg
(96%) of 12 were obtained as a yellowish solid, mp 188 °C; tlc:
Rf = 0.16 (n-heptane/EtOAc = 60/40); [ꢀ]D20 = +96.0 (c = 1.10 in
CH2Cl2); ir: 2973, 1800, 1740, 1469, 1285, 1213, 1052, 1021,
721 cm-1; 1H nmr (CDCl3, rt): ꢁ = 0.93 (s, 3H, CH3), 1.05 (s, 3H,
CH3), 1.35 (s, 3H, CH3), 1.85-1.98 (m, 2H, CH2CH2), 2.38 (ddd,
J = 14.5/11.5/5.5 Hz, 1H, CH2CH2), 2.75 (ddd, J = 14.5/9.5/5.5
Hz, 1H, CH2CH2), 4.00 (d, J = 11 Hz, 1H, OCH2), 4.20 (dd, J =
11/2 Hz, 1H, OCH2), 7.80-7.84 (m, 2H, Harom.), 7.91-7.95 (m,
General Procedure for the Removal of the Chiral
Auxiliary by Reductive Cleavage of Imidoalcohols 15a-c with
LiBH4
- GP5. A 0.044 M solution of the appropriate
imidoalcohol 15a-c was added to a 0.21 M solution of 5
equivalents of LiBH4 at 0 °C. The mixture was allowed to warm
to room temperature and stirred for 24 hours. After addition of
2 N HCl and after the evolution of gas had ceased, the mixture
was saturated with NaCl and extracted with Et2O (5x). The
combined extracts were washed with brine, dried over MgSO4
and concentrated in vacuo.
General Procedure for the Mitsunobu Esterification of the
Amidoalcohols 5a-c - GP6. 2.05 equivalents of PPh3 were
dissolved in THF and cooled to 0 °C (ice bath) before 2.0
equivalents of DIAD were added. The mixture was stirred for 15
minutes, then 2.1 equivalents of benzoic acid were added. After
30 minutes a 0.15 M solution of the appropriate educt (5a-c) in
THF was added dropwise. Then the ice bath was removed and
the mixture was stirred for 30 minutes. The solvent was removed
in vacuo and the crude product was purified by CC.
General Procedure for the Cleavage of the Benzoates
19b-c - GP7. A 0.1 M solution of the benzoate 19b-c in THF
was cooled to 0 °C and added to an ice cold 0.23 M solution of 5
equivalents of LiBH4 in THF. The mixture was allowed to warm
to room temperature and stirred for 16-24 hours. Excessive
LiBH4 was destroyed by addition of 2 N HCl (ice bath). The ice
bath was removed. When gas formation had stopped, Et2O was
added and the organic layer was separated. The aqueous layer
was saturated with NaCl and extracted with Et2O (5x). The
combined organic layers were dried with MgSO4 and
concentrated in vacuo.
General Procedure for the Preparation of the Oxazinanes
7a-c and 8a-c - GP8. A 0.025 M solution of the appropriate
amidoalcohol 5a-c, 6a-c was cooled with an ice bath and
treated with 5 equivalents of borane dimethylsulfide (BMS,
2 M in THF) The mixture was allowed to warm to room
temperature before it was refluxed for 6 hours. After addition
of CH3OH (ice bath) the solvent was removed in vacuo. To
remove decomposition products of BMS the residue was
repeatedly dissolved in 5 ml CH3OH and the solvent was
removed in vacuo. Next, the residue was dissolved in THF
(~0.05 M) and 15 equivalents of HCHO (35% in H2O) were
added. The resulting mixture was stirred for 16 hours and then
concentrated in vacuo.
+
2H, Harom.);ms (CI, CH5 ): 342 (34) [M+H]+, 227 (40), 212 (6),
195 (100), 85 (12). Anal. Calcd. for C19H19NO5 (341.37): C,
66.85; H, 5.61; N, 4.10. Found: C, 66.57; H, 5.79; N 4.29.
2-[(1S,5R)-5,8,8-Trimethyl-2-oxo-3-oxabicyclo[3.2.1]-
octane-1-carbonyl]-2,3-dihydroisoindol-1-one (13). 7.016 g
(20.55 mmol) of 12 were dissolved in 700 ml of EtOAc. 1.404 g
of Pd/C (10% palladium) and 35 ml of trifluoroacetic acid were
added. The mixture was stirred for 4 days under hydrogen at
normal pressure and room temparature. The catalyst was filtered
off and the filtrate was concentrated in vacuo to give 6.647 g
(99%) of 13 as white solid, mp 218-221 °C; tlc: Rf = 0.27 (n-
heptane/EtOAc = 60/40); ir: = 3428, 2961, 1725, 1685, 1325,
1295, 1274, 1120, 1020, 854, 736 cm-1; [ꢀ]D20 = +53.5 (c = 1.03
1
in CH2Cl2); H nmr (C5D5NO2, 140 °C): ꢁ = 1.03 (s, 3H, CH3),
1.25 (s, 3H, CH3), 1.50 (s, 3H, CH3), 1.96-2.10 (m, 2H,
CH2CH2), 2.63-2.72 (m, 1H, CH2CH2), 3.12-3.21 (m, 1H,
CH2CH2), 4.12 (d, J = 11 Hz, 1H, OCH2), 4.37 (d, J = 11 Hz,
1H, OCH2), 4.86 (d, J = 17.5 Hz, 1H, NCH2), 5.05 (d, J = 17.5
Hz, 1H, NCH2), 7.50-7.56 (m, 2H, Harom.), 7.67 (t, J = 8 Hz, 1H,
+
Harom.), 7.89 (d, J = 8 Hz, 1H, Harom.); ms (CI, CH5 ): 328 (100)
[M+H]+, 227 (10), 195 (45), 167 (8). Anal. Calcd. for
C19H21NO4 (327.38): C, 69.71; H, 6.47; N, 4.28. Found: C,
69.52; H, 6.78; N, 4.25.

584
A. Müller, K. Polborn and K. T. Wanner
Vol 44
3-Bromo-2-[(1S,5R)-5,8,8-trimethyl-2-oxo-3-oxabicyclo-
3a: The compound was obtained as white solid, mp 103 °C.;
tlc: R = 0.21 (isohexane/EtOAc/CH Cl = 70:20:10); [ꢁ]D20
[3.2.1]octane-1-carbonyl]-2,3-dihydroisoindol-1-one (1). 50
mg (0.28 mmol) of NBS and a catalytic amount AIBN were
added to a suspension of 80 mg of 13 in 2.4 ml of CCl4. The
mixture was refluxed for 5.5 hours and then cooled to room
temperature. Floating succinimide was filtered off. The filtrate
was washed with aqueous NaHSO3 solution (20%, 3x5 ml) and
water (2x5 ml). The organic layer was concentrated, mixed with
1 ml of pentane and stored at 4 °C over night. The precipitate was
isolated by filtration and washed with pentane (5x2 ml). This
yielded 81 mg (80 %) of 1 as white to yellow solid, mp 206 °C;
tlc: diastereomer 1: Rf = 0.64, diastereomer 2: Rf = 0.44
(CH2Cl2/EtOAc = 96/4); ir: 2975, 1754, 1723, 1686, 1607, 1467,
1455, 1410, 1393, 1372, 1312, 1288, 1274, 1245, 1213, 1193,
1167, 1151, 1128, 1097 cm-1 1H nmr (CD2Cl2): ꢀ = 0.92 (s, 0.5 x
3 H,CH3), 0.93 (s, 0.5 x 3H, CH3), 0.97 (s, 0.5 x 3H, CH3), 1.14
(s, 0.5 x 3H, CH3), 1.26 (s, 0.5 x 3H, CH3), 1.30 (s, 0.5 x 3H,
CH3), 1.81-1.99 (m, 2H, CH2-CH2), 2.06-2.27 (m, 1H, CH2CH2),
2.91-3.05 (m, 0.5 x 1H, CH2CH2), 3.20-3.35 (m, 0.5 x 1H,
CH2CH2), 3.95 (d, J = 10.5 Hz, 0.5 x 1H, OCH2), 4.04 (d, J =
10.5 Hz, 0.5 x 1H, OCH2), 4.14 (d, J = 10.5Hz, 0.5 x 1H, OCH2),
4.36 (d, J = 10.5Hz, 0.5 x 1H, OCH2), 7.29 (s, 0.5 x 1H, NCH),
7.35 (s, 0.5 x 1H, NCH), 7.60 (t, J = 7.5 Hz, 1H, Harom.), 7.67 (d, J
= 7.5 Hz, 1H, Harom.), 7.77 (m, 1H, Harom.), 7.84 (d, J = 7.5 Hz, 1
H, Harom.); (diastereomeric ratio = 50:50); 13C nmr (CDCl3, rt): ꢀ =
15.20 (0.5 x 1 C, CH3), 15.28 (0.5 x 1 C, CH3), 18.63 (0.5 x 1 C,
CH3), 18.95 (0.5 x 1 C, CH3), 19.83 (0.5 x 1 C, CH3), 20.35 (0.5
x 1 C, CH3), 27.83 (0.5 x 1 C, CH2), 31.79 (0.5 x 1 C, CH2),
33.05 (0.5 x 1 C, CH2), 34.19 (0.5 x 1 C, CH2), 44.10 (0.5 x 1 C,
Cq), 44.23 (0.5 x 1 C, Cq), 46.81 (0.5 x 1 C, Cq), 46.88 (0.5 x 1 C,
Cq), 57.38 (0.5 x 1 C, CH), 57.64 (0.5 x 1 C, CH), 66.49 (0.5 x 1
C, Cq), 66.84 (0.5 x 1 C, Cq), 78.34 (0.5 x 1 C, OCH2), 79.89 (0.5
x 1 C, OCH2), 124.37 (0.5 x 1 C, Carom.), 124.52 (0.5 x 1 C,
Carom.), 125.40 (0.5 x 1 C, Carom.), 125.66 (0.5 x 1 C, Carom.),
128.90 (0.5 x 1 C, Cq), 129.20 (0.5 x 1 C, Cq), 130.60 (0.5 x 1 C,
Carom.), 130.62 (0.5 x 1 C, Carom.), 134.89 (0.5 x 1 C, Carom.),
135.16 (0.5 x 1 C, Carom.), 143.23 (0.5 x 1 C, Cq), 143.56 (0.5 x 1
C, Cq), 163.45 (0.5 x 1 C, C=O), 164.06 (0.5 x 1 C, C=O), 166.44
(0.5 x 1 C, C=O), 166.74 (0.5 x 1 C, C=O), 170.89 (0.5 x 1 C,
C=O), 171.08 (0.5 x 1 C, C=O); (diastereomeric ratio = 50:50);
=
f
2
2
+200.8 (c = 0.500 in CH2Cl2); ir: 2923, 1740, 1680, 1606, 1325,
1
1295, 1250, 1213, 1123, 753, 703 cm-1; H nmr (C6D5NO2, 130
°C): ꢀ = 0.93 (s, 3H, CH3), 1.08 (s, 3H, CH3), 1.47 (s, 3H, CH3),
1.83-1.99 (m, 2H, CH2CH2), 2.35 (s, 3H, C6H4CH3), 2.58-2.72 (m,
1H, CH2CH2), 2.79-2.92 (m, 1H, CH2CH2), 3.45 (dd, J = 17/8 Hz,
1H, CH2), 4.00 (d, J = 10.5 Hz, 1H, OCH2), 4.14 (d, J = 17 Hz, 1H,
CH2), 4.37 (d, J = 10.5 Hz, 1H, OCH2), 5.84-5.93 (m, 1H, NCH),
7.20 (d, J = 7.5 Hz, 2H, C6H4CH3), 7.39-7.48 (m, 1H, Hisoindol.),
7.52-7.60 (m, 2H, Hisoindol.), 7.77-7.88 (m, 1H, Hisoindol. and 2H,
+
C6H4CH3); ms (CI, CH5 ): 460 [M+H]+ (36), 325 (8), 293 (18), 279
(14), 233 (100), 212 (13), 195 (13). Anal. Calcd. for C28H29NO5
(459.55): C, 73.18; H, 6.36; N, 3.05. Found: C, 72.93; H, 6.75; N,
2.76.
4a: The compound was obtained as white solid, mp 223 °C;
=
tlc: R = 0.26 (isohexane/EtOAc/CH Cl = 70:20:10); [ꢁ]D20
f
2
2
-104.6 (c = 0.545 in CH2Cl2); ir: 2956, 1731, 1684, 1605, 1323,
1
1297, 1270, 1228, 1123 cm-1; H nmr (C6D5NO2, 130 °C): ꢀ =
0.91 (s, 3H, CH3), 1.16 (s, 3H, CH3), 1.42 (s, 3H, CH3), 1.85-
2.02 (m, 2H, CH2CH2), 2.35 (s, 3H, C6H4CH3), 2.42-2.59 (m,
1H, CH2CH2), 3.29-3.34 (m, 1H, CH2CH2), 3.48 (dd, J = 17/7
Hz, 1H, CH2), 3.91 (d, J = 17 Hz, 1H, CH2), 4.06 (d, J = 10.5
Hz, 1H, OCH2), 4.23 (d, J = 10.5 Hz, 1H, OCH2), 5.98 (d, J = 7
Hz, 1H, NCH), 7.20 (d, J = 7.5 Hz, 2H, C6H4CH3), 7.38-7.48 (m,
1H, Hisoindol.), 7.52-7.60 (m, 2H, Hisoindol.), 7.78-7.89 (m, 1H,
+
Hisoindol. and 2H, C6H4CH3); ms (CI, CH5 ): 460 [M+H]+ (100),
264 (12), 227 (16), 212 (10), 195 (36), 167 (10), 134 (30), 132
(25). Anal. Calcd. for C28H29NO5 (459.55): C, 73.18; H, 6.36; N,
3.05. Found: C, 73.08; H, 6.31; N, 3.02.
(3S)-3-[2-(4-Nitrophenyl)-2-oxoethyl]-2-[(1S,5R)-5,8,8-tri-
methyl-2-oxo-3-oxabicyclo[3.2.1]octane-1-carbonyl]-2,3-
dihydroisoindol-1-one (3b) and (3R)-3-[2-(4-Nitrophenyl)-2-
oxoethyl]-2-[(1S,5R)-5,8,8-trimethyl-2-oxo-3-oxabicyclo-
[3.2.1]octane-1-carbonyl]-2,3-dihydroisoindol-1-one (4b).
Method A: 4282 mg (10.54 mmol) of 1 were reacted with 2b
according to GP1. hplc (CH3CN/H2O = 65/35, 1 ml/min): 3b: tR
= 8.0 minutes, 54%; 4b: tR = 9.1 minutes, 46%. Repeated CC
(isohexane/EtOAc/CH2Cl2 = 65/25/10) yielded 1534 mg (30%)
3b and 1360 mg (26%) 4b.
Method B: 116 mg (0.29 mmol) of 1 were reacted with 2b
according to GP2. hplc (CH3CN/H2O = 65/35, 1 ml/min): 3b: tR
= 8.1 minutes, 75%; 4b: tR = 9.1 minutes, 25%. Purification by
CC (isohexane/EtOAc/CH2Cl2 = 65/25/10) and prep. hplc
(column #1, isohexane/EtOAc/CH2Cl2 = 70/20/10) yielded 38
mg (27%) 3b and 18 mg (13%) 4b.
+
ms (CI, CH5 ): 406 [M+H]+ (1), 326 (100), 227 (14), 216 (7), 195
(23); hrms (FAB+): Calcd. (C19H21BrNO4, [M+H]+): 406.0654,
found: 406.0661; Anal. Calcd. for C19H20BrNO4 (406.28): C,
56.17; H, 4.96; N, 3.45. Found: C, 55.47; H, 5.05; N, 3.42.
(3S)-3-[2-(4-Methylphenyl)-2-oxoethyl]-2-[(1S,5R)-5,8,8-
trimethyl-2-oxo-3-oxabicyclo[3.2.1]octane-1-carbonyl]-2,3-
dihydroisoindol-1-one (3a) and (3R)-3-[2-(4-Methylphenyl)-
2-oxoethyl]-2-[(1S,5R)-5,8,8-trimethyl-2-oxo-3-oxabicyclo-
[3.2.1]octane-1-carbonyl]-2,3-dihydroisoindol-1-one (4a)
Method A: The synthesis was performed according to GP1
employing 1421 mg (3.5 mmol) of 1 and 1.5 equivalents of 2a. hplc
(CH3CN/H2O = 60/40; 1 ml/min): 3a: tR = 14.7 minutes, 53%; 4a: tR
= 17.3 minutes, 47%. Repeated CC (isohexane/ EtOAc/CH2Cl2 =
70/20/10) gave the crude diastereomers. Prep. hplc (column #2,
CH3OH /H2O = 75/25) then yielded 412 mg (26%) 3a and
crystallization (n-heptane/EtOAc = 80/20) gave 357 mg (22%) 4a.
Method B: 116 mg (0.29 mmol) of 1 were reacted with 2a
according to GP2. The diastereomeric ratio was determined in
the 1H nmr spectrum of the crude product: 3a:4a = 77:23.
Purification by CC (isohexane/EtOAc/CH2Cl2 = 70/20/10) and
prep. hplc (column #1, isohexane/EtOAc/CH2Cl2 = 70:20:10)
yielded 34 mg (26%) 3a and 8 mg (6%) 4a.
Method C: 117 mg (0.29 mmol) of 1 were reacted with 2b
according to GP3. hplc (CH3CN/H2O = 65/35, 1 ml/min): 3b: tR
= 8.1 minutes, 80%; 4b: tR = 9.1 minutes, 20%. Purification by
CC (isohexane/EtOAc/CH2Cl2 = 65/25/10) and prep. hplc
(column #1, isohexane/EtOAc/CH2Cl2 = 70/20/10) yielded 57
mg (40%) 3b and 19 mg (13%) 4b.
3b: The compound was obtained as white solid, mp 203 °C;
=
tlc: R = 0.16 (isohexane/EtOAc/CH Cl = 65/25/10); [ꢁ]D20
f
2
2
+173.0 (c = 0.52 in CH2Cl2); ir: 2969, 1741, 1691, 1526, 1346,
1321, 1295, 1250, 1213, 1124 cm-1; 1H nmr (C6D5NO2, 130 °C):
ꢀ = 0.91 (s, 3H, CH3), 1.07 (s, 3H, CH3), 1.42 (s, 3H, CH3),
1.82-1.98 (m, 2H, CH2CH2), 2.63-2.84 (m, 2H, CH2CH2), 3.56
(dd, J = 17/7 Hz, 1H, CH2), 3.98 (d, J = 11 Hz, 1H, OCH2), 4.15
(dd, J = 17/2 Hz, 1H, CH2), 4.33 (d, J = 11 Hz, 1H, OCH2), 5.82-
5.88 (m, 1H, NCH), 7.42-7.49 (m, 1H, Hisoindol.), 7.54-7.62 (m,
2H, Hisoindol.), 7.83 (d, J = 7.5 Hz, 1H, Hisoindol.), 8.06-8.11 (m, 2H,

May-Jun 2007
Asymmetric Alkylation of N-Acylisoindolin-1-ones via ꢀ-Bromoimides
585
+
C4H6NO2), 8.17-8.22 (m, 2H, C4H6NO2); ms (CI, CH5 ): 491
[M+H]+ (5), 461 (10), 212 (48), 195 (9), 132 (100). Anal. Calcd.
for C27H26N2O7 (490.52): C, 66.11; H, 5.34; N, 5.71. Found: C,
66.03; H, 5.60; N, 5.48.
= 11 Hz, 1H, OCH2), 4.21 (d, J = 11 Hz, 1H, OCH2), 5.94 (dd, J =
7.5/3 Hz, 1H, NCH), 7.34-7.38 (m, 2H, C6H4Cl), 7.43 (t, J = 7.5 Hz,
1H, Hisoindol.), 7.53-7.60 (m, 2H, Hisoindol.), 7.81 (d, J = 7.5 Hz, 1H,
Hisoindol.), 7.87-7.91 (m, 2H, C6H4Cl); ms (CI, CH5+): 480 [M+H]+
(95), 284 (10), 227 (55), 212 (21), 195 (100), 167 (23), 132 (48).
Anal. Calcd. for C27H26ClNO5 (479.96): C, 67.57; H, 5.46; N 2.92.
Found: C, 67.21; H, 5.28; N, 2.83.
(3S)-3-[(2R)-2-Hydroxy-2-(4-methylphenyl)ethyl)-2-[(1S,5R)-
5,8,8-trimethyl-2-oxo-3-oxabicyclo[3.2.1]octane-1-carbonyl]-
2,3-dihydroisoindol-1-one (15a) and (3S)-3-[(2S)-2-Hydroxy-
2-(4-methylphenyl)ethyl)-2-[(1S,5R)-5,8,8-trimethyl-2-oxo-3-
oxabicyclo[3.2.1]octane-1-carbonyl]-2,3-dihydroisoindol-1-
one (16a). 638 mg (1.39 mmol) of 3a were reacted with
Li[Al(tBuO)3H] according to GP4. hplc (CH3CN/H2O = 55/45, 1
ml/min): 15a: tR = 15.1 minutes, 94%; 16a: tR = 16.7 minutes;
6%. Purification by CC (isohexane/EtOAc = 70/30) yielded 576
mg (90%) of 15a and 54 mg (8%) of 16a.
4b: The compound was obtained as white solid, mp 230 °C;
=
tlc: R = 0.23 (isohexane/EtOAc/CH Cl = 65/25/10); [ꢀ]D20
f
2
2
-93.0 (c = 1.02 in CH2Cl2); ir: 2970, 1734, 1690, 1526, 1346,
1321, 1296, 1271, 1213 cm-1; H nmr (C6D5NO2, 130 °C): ꢁ =
1
0.88 (s, 3H, CH3), 1.12 (s, 3H, CH3), 1.37 (s, 3H, CH3), 1.82-
1.99 (m, 2H, CH2CH2), 2.42-2.56 (m, 1H, CH2CH2), 3.21-3.44
(m, 1H, CH2CH2), 3.60 (dd, J = 17/7.5 Hz, 1H, CH2), 3.95 (dd, J
= 7.5/3.5 Hz, 1H, CH2), 4.03 (d, J = 11 Hz, 1H, OCH2), 4.21 (d,
J = 11 Hz, 1H, OCH2), 5.90-5.96 (m, 1H, NCH), 7.40-7.49 (m,
1H, Hisoindol.), 7.54-7.64 (m, 2H, Hisoindol.), 7.81 (d, J = 7.5 Hz, 1H,
Hisoindol.), 8.06-8.13 (m, 2H, C6H4NO2), 8.17-8.23 (m, 2H,
C6H4NO2); ms (CI, CH5 ): 491 [M+H]+ (5), 461 (4), 212 (13),
+
195 (10), 132 (100). Anal. Calcd. for C27H26N2O7 (490.52): C,
66.11; H, 5.34; N, 5.71. Found: C, 65.88; H, 5.33; N, 5.65.
(3S)-3-[2-(4-Chlorophenyl)-2-oxoethyl]-2-[(1S,5R)-5,8,8-
trimethyl-2-oxo-3-oxabicyclo[3.2.1]octane-1-carbonyl]-2,3-
dihydroisoindol-1-one (3c) and (3R)-3-[2-(4-Chlorophenyl)-
2-oxoethyl]-2-[(1S,5R)-5,8,8-trimethyl-2-oxo-3-oxabicyclo-
[3.2.1] octane-1-carbonyl]-2,3-dihydroisoindol-1-one (4c).
Method A: 1148 mg (28.26 mmol) of 1 were reacted with 2c
according to GP1. hplc (CH3CN/H2O, 1 ml/min): 3c: tR = 12.8
minutes, 50%; 4c: tR = 14.5 minutes, 50%. Repeated CC
(isohexane/EtOAc/CH2Cl2 = 75/15/10) yielded 3733 mg (28%)
of 3c and 3725 mg (27%) of 4c.
Method B: 116 mg (0.29 mmol) of 1 were reacted with 2c
according to GP2. hplc (CH3CN/H2O, 1 ml/min): 3c: tR = 12.7
minutes, 77%; 4c: tR = 14.5 minutes, 23%. Purification by CC
(isohexane/EtOAc/CH2Cl2 = 70/20/10) and prep. hplc (column
#1, isohexane/EtOAc/CH2Cl2 = 70/20/10) yielded 52 mg (37%)
of 3c and 14 mg (10%) of 4c.
15a: The compound was obtained as white solid, mp 175 °C;
tlc: R = 0.13 (isohexane/EtOAc = 70/30); [ꢀ]2D0 = +104.9 (c =
f
0.710 in CH2Cl2); ir: 3546, 2956, 1734, 1677, 1468, 1295,
1
1248,1213, 1123 cm-1; H nmr (C2Cl4D2, 130 °C): ꢁ = 0.89 (s,
3H, CH3), 1.00 (s, 3H, CH3), 1.27 (s, 3H, CH3), 1.79-1.90 (m,
2H, CH2), 2.25 (ddd, J = 14.5/7.5/3.5 Hz, 1H, CH2), 2.30 (s, 3H,
C6H4CH3), 2.58-2.69 (m, 3H, CH2), 3.88 (d, J = 11 Hz, 1H,
OCH2), 4.24 (d, J = 11 Hz, 1H, OCH2), 4.93 (dd, J = 10/3.5 Hz,
1H, OCH), 5.51 (dd, J = 7.5/3.0 Hz, 1H, NCH), 7.09 (d, J = 8
Hz, 2H, C6H4CH3), 7.17 (d, J = 8 Hz, 2H, C6H4CH3), 7.41-7.48
(m, 2H, Hisoindol.), 7.60 (td, J = 7.5/1 Hz, 1H, Hisoindol.), 7.81 (d, J =
+
7.5 Hz, 1H, Hisoindol.); ms (CI, CH5 ): 462 [M+H]+ (13), 444 (4),
344 (6), 266 (53), 250 (33), 227 (11), 213 (23), 197 (100), 169
(23). Anal. Calcd. for C28H31NO5 (461.56): C, 72.86; H, 6.77; N,
3.03. Found: C, 72.96; H, 7.06; N, 2.88.
16a: The compound was obtained as white solid, mp 210 °C;
tlc: Rf = 0.17 (isohexane/EtOAc = 70/30); ir: 3561, 2968, 1749,
1
Method C: 117 mg (0.29 mmol) of 1 were reacted with 2c
according to GP3. hplc (CH3CN/H2O, 1 ml/min): 3c: tR = 12.8
minutes, 79%; 4c: tR = 14.5 minutes, 21%. Purification by CC
(isohexane/EtOAc/CH2Cl2 = 70/20/10) and prep. hplc (column
#1, isohexane/EtOAc/CH2Cl2 = 70/20/10) yielded 64 mg (46%)
of 3c and 13 mg (9%) of 4c.
1234, 1659, 1467, 1357, 1297, 1257, 1211, 1124 cm-1; H nmr
(C2Cl4D2, 130 °C): ꢁ = 0.91 (s, 3H, CH3), 1.06 (s, 3H, CH3), 1.32
(s, 3H, CH3), 1.77-1.89 (m, 2H, CH2), 2.20-2.31 (m, 1H, CH2),
2.28 (s, 3H, C6H4CH3), 2.46-2.76 (m, 3H, CH2), 3.89 (d, J = 11
Hz, 1H, OCH2), 4.26 (d, J = 11 Hz, 1H, OCH2), 4.72 (dd, J =
9/3.5 Hz, 1H, OCH), 5.50 (t, J = 4.5 Hz, 1H, NCH), 7.06 (d, J =
8 Hz, 2H, C6H4CH3), 7.13 (d, J = 8 Hz,2 H, C6H4CH3), 7.33 (d, J
= 7.5 Hz, 1H, Hisoindol.), 7.40 (t, J = 7.5 Hz, 1H, Hisoindol.), 7.55 (td,
J = 7.5/1 Hz, 1H, Hisoindol.), 7.78 (d, J = 7.5 Hz, 1H, Hisoindol.); ms
3c: The compound was obtained as white solid, mp 114 °C;
=
tlc: R = 0.24 (isohexane/EtOAc/CH Cl = 75/15/10); [ꢀ]D2 0
f
2
2
+196.5 (c = 0.592 in CH2Cl2);ir: 2966, 1739, 1683, 1589, 1325,
1295, 1250, 1213, 1123 cm-1; H nmr (C6D5NO2, 130 °C): ꢁ =
+
(CI, CH5 ): 462 [M+H]+ (37), 444 (20), 344 (16), 327 (3), 266
1
(13), 251 (18), 233 (12), 212 (32), 199 (20), 132 (100).
(3S)-3-[(2R)-2-Hydroxy-2-(4-nitrophenyl)ethyl]-2-[(1S,5R)-
5,8,8-trimethyl-2-oxo-3-oxabicyclo[3.2.1]octane-1-carbonyl]-
2,3-dihydroisoindol-1-one (15b) and (3S)-3-[(2S)-2-Hydroxy-
2-(4-nitrophenyl)ethyl]-2-[(1S,5R)-5,8,8-trimethyl-2-oxo-3-
oxabicyclo[3.2.1]octane-1-carbonyl]-2,3-dihydroisoindol-
1-one (16b). 1524 mg (3.11 mmol) of 3b were reacted with
Li[Al(tBuO3)H] according to GP4. hplc (CH3CN/H2O = 50/50,
1.5 ml/min) 15b: tR = 19.5 minutes, 97%; 16b: tR = 20.3 minutes;
3%. Purification by CC (isohexane/EtOAc = 60:40) yielded
1384 mg (90%) of 15b.
0.91 (s, 3H, CH3), 1.06 (s, 3H, CH3), 1.43 (s, 3H, CH3), 1.81-
1.99 (m, 2H, CH2CH2), 2.62-2.72 (m, 1H, CH2CH2), 2.82 (ddd, J
= 14.5/11.5/6.5 Hz, 1H, CH2CH2), 3.46 (dd, J = 17/7.5 Hz, 1H,
CH2), 3.98 (d, J = 11 Hz, 1H, OCH2), 4.11 (ddd, J = 17/3/1.5 Hz,
1H, CH2), 4.33 (d, J = 11 Hz, 1H, OCH2), 5.86 (br d, J = 7.5 Hz,
1H, NCH), 7.33-7.37 (m, 2H, C6H4Cl), 7.44 (t, J = 7.5 Hz, 1H,
Hisoindol.), 7.53-7.60 (m, 2H, Hisoindol.), 7.81 (d, J = 7.5 Hz, 1H,
+
Hisoindol.), 7.85-7.89 (m, 2H, C6H4Cl); ms (CI, CH5 ): 480 [M+H]+
(100), 284 (11), 227 (46), 212 (20), 195 (94), 167 (22), 132 (72).
Anal. Calcd. for C27H26ClNO5 (479.96): C, 67.57; H, 5.46; N,
2.92. Found: C, 67.37; H, 5.83; N, 2.78.
15b: The compound was obtained as white solid, mp 210 °C;
4c: The compound was obtained as white solid, mp 245 °C; tlc:
tlc: R = 0.1 (isohexane/EtOAc = 60/40); [ꢀ]2D0 = +93.2 (c = 0.325
R = 0.29 (isohexane/EtOAc/CH Cl = 75:15:10); [ꢀ]2D0 = -86.5 (c =
f
f
2
2
in CH3OH); ir: 3523, 3370, 2923, 1738, 1719, 1701, 1686, 1597,
1521, 1468, 1413, 1344, 1295, 1270 cm-1; 1H nmr (C2Cl4D2, 130
°C): ꢁ = 0.97 (s, 3H, CH3), 1.13 (s, 3H, CH3), 1.34 (s, 3H, CH3),
1.85-2.00 (m, 2H, CH2), 2.28 (d, J = 4 Hz, 1H, OH), 2.45-2.65
(m, 3H, CH2), 2.83-2.97 (m, 1H, CH2), 3.99 (d, J = 11 Hz, 1H,
0.200 in CHCl3).ir: 2955, 1729, 1685, 1588, 1320, 1293, 1269,
1216, 1123 cm-1. 1H nmr (C6D5NO2, 130 °C): ꢁ = 0.89 (s, 3H, CH3),
1.13 (s, 3H, CH3), 1.38 (s, 3H, CH3), 1.80-1.99 (m, 2H, CH2CH2),
2.40-2.56 (m, 1H, CH2CH2), 3.25-3.42 (m, 1H, CH2CH2), 3.49 (dd,
J = 17/7.5 Hz, 1H, CH2), 3.88 (dd, J = 17/3 Hz, 1H, CH2), 4.03 (d, J

586
A. Müller, K. Polborn and K. T. Wanner
Vol 44
OCH2), 4.26 (d, J = 11 Hz, 1H, OCH2), 5.10-5.18 (m, 1H, OCH),
5.51-5.57 (m, 1H, NCH), 7.47-7.57 (m, 2H, Hisoindol. and 2H,
C6H4NO2), 7.69 (t, J = 7.5 Hz, 1H, Hisoindol.), 7.89 (d, J = 7.5 Hz,
(CH2Cl2/1,4-dioxane = 80/20) yielded 267 mg (66%) of 5a as a
white solid, mp 52 °C; tlc: Rf = 0.18 (CH2Cl2/1,4-dioxane =
80/20); ir: 3387, 2922, 1686, 1467, 1079, 820, 747 cm-1; 1H nmr
(CD2Cl2): ꢀ = 1.83 (dt, J = 14.5/10.5 Hz, 1H, CH2), 2.30-2.32
(m, 1H, CH2), 2.34 (s, 3H, CH3), 2.69 (s, 1H, OH), 4.76 (dd, J =
10.5/2 Hz, 1H, CH), 5.06 (dd, J = 10.5/3 Hz, 1H, CH), 7.11 (s,
1H, NH), 7.19 (d, J = 8 Hz, 2H, C6H4CH3), 7.30 (d, J = 8 Hz,
2H, C6H4CH3), 7.44-7.48 (m, 2H, Hisoindol.), 7.56 (dt, J = 7.5/1
+
1H, Hisoindol.), 8.16 (d, J = 8.5 Hz, 2H, C6H4NO2); ms (CI, CH5 ):
493 [M+H]+ (1), 475 (0), 447 (1), 283 (50), 253 (14), 212 (29),
197 (8), 150 (100), 134 (28), 132 (40). Anal. Calcd. for
C27H28N2O7 (492.53): C, 65.84; H, 5.73; N, 5.69. Found: C,
65.80; H, 5.67; N, 5.67.
+
16b: tlc: Rf = 0.04 (CH2Cl2/EtOAc = 95/5); ir: 3441, 2968,
2818, 1739, 1671, 1599, 1520, 1468, 1455, 1408, 1346, 1325,
Hz, 1H, Hisoindol.), 7.77 (d, J = 8 Hz, 1H, Hisoindol.); ms (CI, CH5 ):
268 [M+H]+ (40), 250 (12), 225 (39), 211 (15), 197 (25), 132
(41), 105 (100); hrms (EI+): Calcd. (C17H17NO2): 267.1259,
found: 267.1224. Anal. Calcd. for C17H17NO2 (267.33): C, 76.38;
H, 6.41; N, 5.24. Found: C, 73.99; H, 6.83; N, 5.24.
1
1293, 1250 cm-1; H nmr (C2Cl4D2. 130 °C): ꢀ = 0.91 (s, 3H,
CH3), 1.10 (s, 3H, CH3), 1.31 (s, 3H, CH3), 1.78-1.91 (m, 2H,
CH2), 2.15-2.24 (m, 1H, CH2), 2.46-2.58 (m, 1H, CH2), 2.63
(ddd, J = 15/9/4 Hz, 1H, CH2), 2.71-2.83 (m, 1H, CH2), 3.19 (br
s, 1H, OH), 3.93 (d, J = 11 Hz, 1H, OCH2), 4.23 (d, J = 11 Hz,
1H, OCH2), 4.79-4.85 (m, 1H, OCH), 5.52 (t, J = 4.5 Hz, 1H,
NCH), 7.35 (d, J = 7.5 Hz, 1H, Hisoindol.), 7.39 (d, J = 8.5 Hz, 2H,
C6H4NO2), 7.44 (t, J = 7.5 Hz, 1H, Hisoindol.), 7.59 (td, J = 7.5/1.0
Hz, 1H, Hisoindol.), 7.80 (d, J = 7.5 Hz, 1H, Hisoindol.), 8.06 (d, J =
(3S)-3-[(2R)-2-Hydroxy-2-(4-nitrophenyl)ethyl]-2,3-dihydro-
1H-isoindol-1-one (5b). 896 mg (1.82 mmol) of 15b were
reacted with LiBH4 according to GP5. Purification by CC
(CH2Cl2/THF = 80/20) yielded 488 mg (90%) of 5b as a white
solid; tlc: Rf = 0.23 (CH2Cl2/THF = 80/20); ir: 3424, 3321, 2924,
2853, 1674, 1597, 1511, 1472, 1376, 1342, 1262, 1201 cm-1; 1H
nmr (C2D6OS): ꢀ = 1.87 (dt, J = 13.5/8 Hz, 1H, CH2), 2.11 (ddd,
J = 13.5/6/5.5 Hz, 1H, CH2), 4.46 (dd, J = 8/5 Hz, 1H, CH), 5.02
(dd, J = 7.5/6 Hz, 1H, CH), 5.84 (d, J = 4.5 Hz, 1H, OH), 7.48
(td, J = 7/1 Hz, 1H, Hisoindol.), 7.59 (td, J = 7/1 Hz, 1H, Hisoindol.),
7.63 (d, J = 7 Hz, 1H, Hisoindol.), 7.66 (d, J = 7 Hz, 1H, Hisoindol.),
7.70-7.74 (m, 2H, C6H4NO2), 8.21-8.25 (m, 2H, C6H4NO2), 8.65
+
8.5 Hz, 2H, C6H4NO2); ms (CI, CH5 ): 493 [M+H]+ (10), 475
(2), 445 (0), 283 (19), 251 (12), 227 (6), 213 (11), 195 (8), 150
(34), 132 (36).
(3S)-3-[(2R)-2-Hydroxy-2-(4-chlorophenyl)ethyl]-2-[(1S,5R)-
5,8,8-trimethyl-2-oxo-3-oxabicyclo[3.2.1]octane-1-carbonyl]-
2,3-dihydroisoindol-1-one (15c) and (3S)-3-[(2S)-2-Hydroxy-
2-(4-chlorophenyl)ethyl]-2-[(1S,5R)-5,8,8-trimethyl-2-oxo-3-
oxabicyclo[3.2.1]octane-1-carbonyl]-2,3-dihydroisoindol-1-
one (16c). 1602 mg (3.34 mmol) of 3c were reacted with
Li[Al(tBuO)3H] according to GP4. hplc (CH3CN/H2O = 45/55,
1.5 ml/min): 15c: tR = 35.7 minutes, 95%; 16c: tR = 39.2
minutes; 5%. Purification by CC (isohexane/EtOAc = 65/35)
yielded 1215 mg (76%) of 15c.
+
(1, 1H, NH); ms (CI, CH5 ): 299 [M+H]+ (100), 283 (11), 267
(10), 251 (52), 219 (34), 200 (79), 183 (19), 146 (33); hrms
(EI+): Calcd. (C16H14N2O4): 298.0954, found: 298.0972.
(3S)-3-[(2R)-2-Hydroxy-2-(4-chlorphenyl)ethyl]-2,3-dihydro-
1H-isoindol-1-one (5c). 795 mg (1.65 mmol) of 15c were
reacted according to GP5. Purification by CC (CH2Cl2/THF =
80/20) yielded 371 mg (78%) as 5c white solid; tlc: Rf = 0.23
(CH2Cl2/THF = 80/20); ir: 3427, 3316, 2909, 2853, 1675, 1488,
15c: The compound was obtained as white solid, mp 212 °C;
tlc: R = 0.1 (isohexane/EtOAc = 65/35); [ꢁ]2D0 = +5.8 (c = 0.775
1
1470, 1410, 1383, 1334, 1294, 1260 cm-1; H nmr (C2D6OS, rt):
f
in CH2Cl2); ir: 3536, 2918, 1736, 1722, 1680, 1614, 1469, 1368,
ꢀ = 1.82 (dt, J = 13.5/8 Hz, 1H, CH2), 2.02-2.09 (m, 1H, CH2),
4.39 (dd, J = 8/5 Hz, 1H, CH), 4.89 (ddd, J = 7/7/4 Hz, 1H, CH),
5.60 (d, J = 4 Hz, 1H, OH), 7.41 (d, J = 8.5 Hz, 2H, C6H4Cl),
7.45-7.40 (m, 1H, Hisoindol.), 7.47 (d, J = 8.5 Hz, 2H, C6H4Cl),
7.56-7.62 (m, 2H, Hisoindol.), 7.65 (d, J = 7.5 Hz, 1H, Hisoindol.),
1
1294, 1266 cm-1; H nmr (C2Cl4D2, 130 °C): ꢀ = 0.96 (s, 3H,
CH3), 1.08 (s, 3H, CH3), 1.33 (s, 3H, CH3), 1.85-1.97 (m, 2H,
CH2), 2.12 (br s , 1H, OH), 2.40 (ddd, J = 14.5/7/3.5 Hz, 1H,
CH2), 2.55-2.79 (m, 3H, CH2), 3.96 (d, J = 11 Hz, 1H, OCH2),
4.28 (d, J = 11 Hz, 1H, OCH2), 5.01 (dd, J = 11/3 Hz, 1H,
OCH), 5.55 (dd, J = 7.5/2.5 Hz, 1 H, NCH), 7.28 (d, J = 8.5 Hz,
2H, C6H4Cl), 7.32 (d, J = 8.5 Hz, 2H, C6H4Cl), 7.48-7.56 (m,
2H, Hisoindol.), 7.67 (t, J = 7.5 Hz, 1H, Hisoindol.), 7.87 (d, J = 7.5
8.63 (s, 1H, NH); ms (CI, CH5 ): 288 [M+H]+ (71), 200 (16),
+
160 (8), 146 (10), 132 (100); hrms (EI+): Calcd. (C16H14ClNO2):
287.0713, found: 287.0750.
{(1S)-2-[(1S)-3-Oxo-2,3-dihydro-1H-isoindol-1-yl]-1-(4-
methylphenyl)ethyl} benzoate (19a). 374 mg (1.40 mmol) of
5a were reacted with benzoic acid according to GP6. CC (n-
heptane/acetone = 65:35) yielded 249 mg (48%) of 19a as white
solid; mp 56 -59 °C; tlc: Rf = 0.30 (n-heptane/acetone = 60:40);
[ꢁ]2D0 = +7.4 (c = 0.175 in CH3OH); ir: 3265, 2980, 1698, 1468,
+
Hz, 1H, Hisoindol.); ms (CI, CH5 ): 482 [M+H]+ (6), 461 (7), 272
(47), 270 (66), 197 (58), 146 (25), 139 (84), 134 (100). Anal.
Calcd. for C27H28NO5Cl (481.98): C, 67.29; H, 5.86; N, 2.91.
Found: C, 67.15; H, 5.76; N, 2.88.
16c: tlc: Rf = 0.06 (CH2Cl2/EtOAc = 95/5); ir: 3444, 2920,
2850, 1738, 1469, 1296, 1249 cm-1; 1H nmr (C2Cl4D2, 130 °C): ꢀ =
0.91 (s, 3H, CH3), 1.07 (s, 3H, CH3), 1.32 (s, 3H, CH3), 1.77-1.91
(m, 2H, CH2), 2.16-2.30 (m, 1H, CH2), 2.52-2.67 (m, 3H, CH2),
2.81 (br s, 1H, OH), 3.90 (d, J = 11 Hz, 1H, OCH2), 4.25 (d, J = 11
Hz, 1H, OCH2), 4.72 (dd, J = 9.0/3.5 Hz, 1H, OCH), 5.50 (t, J =
4.5 Hz, 1H, NCH), 7.17 (d, J = 8.5 Hz, 2H, C6H4Cl), 7.23 (d, J =
8.5 Hz, 2H, C6H4Cl), 7.31 (d, J= 7.5 Hz, 1H, Hisoindol.), 7.42 (t, J =
7.5 Hz, 1H, Hisoindol.), 7.57 (td, J = 7.5/1 Hz, 1H, Hisoindol.), 7.78 (d, J
1
1388, 1316, 1270, 1178, 1110 cm-1; H nmr (CDCl3): ꢀ = 1.93
(ddd, J = 14.5/11/4 Hz, 1H, CH2), 2.36 (s, 3H, C6H4CH3), 2.71
(ddd, J = 14.5/10/3 Hz, 1H, CH2), 4.61 (br d, J = 11 Hz, 1H,
NCH), 6.31 (dd, J = 10/4 Hz, 1H, OCH), 6.72 (br s, 1H, NH),
7.21 (d, J = 8 Hz, 2H, C6H4CH3), 7.36 (d, J = 8 Hz, 2H,
C6H4CH3), 7.41 (dd, J = 7.5/1 Hz, 1H, Harom.), 7.43-7.50 (m, 3H,
Harom.), 7.53 (td, J = 7.5/1 Hz, 1H, Harom.), 7.60 (tt, J = 7.5/1.5 Hz,
1H, Harom.), 7.84 (d, J = 7.5 Hz, 1H, Harom.), 8.10-8.14 (m, 2H,
+
= 7.5 Hz, 1H, Hisoindol.); ms (CI, CH5 ): 482 [M+H]+ (6), 406 (5),
Harom.)
13C nmr (CDCl3, rt): ꢀ = 21.16 (CH3), 42.92 (CH2), 53.36
369 (10), 355 (12), 329 (22), 301 (11), 271 (11), 225 (68), 211
(21), 197 (33), 133 (18), 132 (12), 105 (100).
(3S)-3-[(2R)-2-Hydroxy-2-(4-methylphenyl)ethyl]-2,3-
dihydro-1H-isoindol-1-one (5a). 689 mg (1.49 mmol) of 15a
were reacted with LiBH4 according to GP5. Purification by CC
(NCH), 74.09 (OCH), 122.18 (Carom.), 124.03 (Carom.), 126.15 (2
C, Carom.), 128.36 (Carom.), 128.54 (2 C, Carom.), 129.58 (2 C,
Carom.), 129.61 (Cq), 129.84 (2 C, Carom.), 131.61 (Cq), 131.88
(Carom.), 133.48 (Carom.), 136.42 (Cq), 138.45 (Cq), 147.00 (Cq),
+
166.34 (C=O), 170.33 (C=O). ms (CI, CH5 ): 372 [M+H]+ (4),

May-Jun 2007
Asymmetric Alkylation of N-Acylisoindolin-1-ones via ꢀ-Bromoimides
587
250 (20), 132 (100), 105 (4); hrms (FAB+): Calcd. (C24H22NO3,
[M+H]+): 372.1600, found: 372.1605.
nmr (CDCl3, rt): ꢁ = 1.86 (ddd, J = 14.5/10.5/4 Hz, 1H, CH2),
2.35 (s, 3H, CH3), 2.43 (ddd, J = 14.5/7.5/3 Hz, 1H, CH2), 4.79
(br dd, J = 10.5/2.5 Hz, 1H, CH), 5.05 (dd, J = 7.5/4 Hz; 1H,
CH), 7.09 (br s, 1H, NH), 7.19 (d, J = 8 Hz, 2H, C6H4CH3), 7.30
(d, J = 8 Hz, 2H, C6H4CH3), 7.35 (d, J = 7.5 Hz, 1H, Hisoindol.),
7.44 (t, J = 7.5 Hz, 1H, Hisoindol.), 7.53 (td, J = 7.5/1 Hz, 1H,
{(1S)-2-[(1S)-3-Oxo-2,3-dihydro-1H-isoindol-1-yl]-1-(4-nitro-
phenyl)ethyl} benzoate (19b). 301 mg (1.01 mmol) of 5b were
reacted with benzoic acid according to GP6. CC (n-
heptane/EtOAc = 50:50) yielded 317 mg (78%) of 19b as white
solid, mp 84 - 88 °C;tlc: Rf = 0.23 (n-heptane/EtOAc = 50:50);
[ꢀ]2D0 = +60.6 (c = 0.165 in CH3OH); ir: 3209, 3076, 2922, 2855,
+
Hisoindol.), 7.83 (d, J = 7.5 Hz, 1H, Hisoindol.); ms (CI, CH5 ): 268
[M+H]+ (85), 250 (8), 160 (10), 146 (10), 132 (100), 119 (6).
(3S)-3-[(2S)-2-Hydroxy-2-(4-nitrophenyl)ethyl]-2,3-dihydro-
1H-isoindol-1-one (6b). 275 mg (0.68 mmol) of 19b were
reacted with LiBH4 according to GP7. CC (isohexane/acetone =
55:45) yielded 183 mg (90%) of 6b as white solid. As despite
several attempts 6b could not be obtained in pure form it was
directly used for the subsequent reaction; tlc: Rf = 0.3
(isohexane/acetone = 60:40); ir: 3219, 2966, 2853, 1665, 1517,
1
1697, 1601, 1522, 1469, 1451, 1420, 1348, 1316 cm-1. H nmr
(CDCl3): ꢁ = 1.97 (ddd, J = 14/11/3 Hz, 1H, CH2), 2.68 (ddd, J =
14/11/3 Hz, 1H, CH2), 4.67 (br d, J = 11 Hz, 1H, NCH), 6.41
(dd, J = 11/3 Hz, 1H, OCH), 6.99 (br s, 1H, NH), 7.38 (d, J = 7.5
Hz, 1H, Harom.), 7.45-7.56 (m, 4H, Harom.), 7.61-7.67 (m, 3H,
Harom.), 7.86 (d, J = 7.5 Hz, 1H, Harom.), 8.12-8.16 (m, 2H,
C6H4NO2), 8.23-8.27 (m, 2H, C6H4NO2); 13C nmr (CDCl3): ꢁ =
42.91 (CH2), 53.11 (NCH), 72.76 (OCH), 122.13 (Carom.), 124.13
(2 C, Carom.), 124.21 (Carom.), 126.88 (2 C, Carom.), 128.63 (Carom.),
128.74 (2 C, Carom.), 128.91 (Cq), 129.88 (2 C, Carom.), 131.61
(Cq), 132.08 (Carom.), 133.96 (Carom.), 146.49 (Cq), 146.77 (Cq),
1
1472, 1420, 1347 cm-1; H nmr (C2D6OS): ꢁ = 1.55 (ddd, J =
13.5/10/3 Hz, 1H, CH2), 2.23 (ddd, J = 13.5/10.5/3 Hz, 1H,
CH2), 4.84 (dd, J = 10/3 Hz, 1H, CH), 5.05 (br d, J = 10.5 Hz,
1H, CH), 5.87 (d, J = 4.5 Hz, 1H, OH), 7.43-7.49 (m, 1H,
Hisoindol.), 7.54-7.58 (m, 2H, Hisoindol.), 7.61-7.67 (m, 1H, Hisoindol.
and 2H, C6H4NO2), 8.19 (d, J = 8.5 Hz, 2H, C6H4NO2), 8.97 (s,
+
147.76 (Cq), 166.05 (C=O), 170.60 (C=O); ms (CI, CH5 ): 403
(28), 283 (71), 281 (15), 267 (3), 251 (13), 231 (15), 150 (90),
132 (100), 123 (65); hrms (FAB+): Calcd. (C23H19N2O5,
[M+H]+): 403.1294, found: 403.1244.
1H, NH); ms (CI, CH5 ): 299 [M+H]+ (100), 269 (5), 251 (13),
+
200 (11), 146 (20), 132 (24); hrms (EI+): Calcd.
(C16H14N2O4):298.0954, found: 298.0938.
{(1S)-2-[(1S)-3-Oxo-2,3-dihydro-1H-isoindol-1-yl]-1-(4-chloro-
phenyl)ethyl} benzoate (19c). 346 mg (1.2 mmol) of 5c were
reacted with benzoic acid according to GP6. CC (n-heptane/
acetone = 65:35) yielded 316 mg (67%) of 19c as white solid,
(3S)-3-[(2S)-2-Hydroxy-2-(4-chlorphenyl)ethyl]-2,3-dihydro-
1H-isoindol-1-one (6c). 247 mg (0.63 mmol) of 19c were
reacted with LiBH4 according to GP7. CC (isohexane/acetone =
60:40) yielded 151 mg (83%) of 6c white solid. As despite
several attempts 6c could not be obtained in pure form it was
directly used for the subsequent reaction; tlc: Rf = 0.28
(isohexane/acetone = 60:40); ir: 3227, 2942, 2913, 1666, 1490,
mp 76 - 79 °C; tlc: R = 0.33 (n-heptane/acetone = 65:35); [ꢀ]D20
f
= +27.2 (c = 0.25 in CH3OH); ir: 3204, 3068, 2921, 2854, 1695,
1616, 1599, 1491, 1469, 1450, 1419, 1353, 1315, 1268, 1200
1
cm-1; H nmr (CDCl3): ꢁ = 1.92 (ddd, J = 14.5/11/3.5 Hz, 1H,
1
1473, 1367, 1323, 1200, 1093 cm-1; H nmr (C2D6OS, rt): ꢁ =
CH2), 2.67 (ddd, 14.5/10.5/3 Hz, 1H, CH2), 4.62 (br d, J = 10
Hz, 1H, NCH), 6.31 (dd, J = 10.5/3.5 Hz, 1H, OCH), 6.88 (br s,
1H, NH), 7.35-7.42 (m, 5H, Harom.), 7.44-7.52 (m, 3H, Harom.),
7.54 (td, J = 7.5/1 Hz, 1H, Harom.), 7.62 (tt, J = 7.5/1.5 Hz, 1H,
Harom.), 7.85 (d, J = 7.5 Hz, 1H, Harom.), 8.10-8.14 (m, 2H, Harom.);
13C nmr (CDCl3): ꢁ = 42.96 (CH2), 53.19 (NCH), 73.26 (OCH),
122.15 (Carom.), 124.12 (Carom.), 127.52 (2 C, Carom.), 128.48
(Carom.), 128.64 (2 C, Carom.), 129.09 (2 C, Carom.), 129.29 (Cq),
129.85 (2 C, Carom.), 131.61 (Cq), 131.96 (Carom.), 133.69 (Carom.),
134.35 (Cq), 138.06 (Cq), 146.78 (Cq), 166.24 (C=O), 170.43
1.48 (ddd, J = 13.5/10/3 Hz, 1H, CH2), 2.22 (ddd, J =
13.5/10.5/3 Hz, 1H, CH2), 4.81 (dd, J = 10/3 Hz, 1H, CH), 4.88-
4.93 (m, 1H, CH), 5.61 (d, J = 4 Hz, 1H, OH), 7.37 (s, 4 H,
C6H4Cl), 7.44-7.48 (m, 1H, Hisoindol.), 7.55-7.58 (m, 2H, Hisoindol.),
+
7.65 (d, J = 8 Hz, 1H, Hisoindol.), 8.92 (s, 1H, NH); ms (CI, CH5 ):
288 [M+H]+ (88), 270 (3), 200 (21), 160 (5), 146 (12), 132
(100), 105 (2).
(3R,4aS)-3-(4-Methylphenyl)-3,4,4a,9-tetrahydrooxazino-
[4,3-a]isoindole (7a). 113 mg (0.42 mmol) of 5a were reacted
with BMS according to GP8. Purification by CC (n-
pentane/EtOAc = 70/30) yielded 65 mg (58%) of 7a as white
solid, mp 135 °C; tlc: R = 0.15 (n-pentane/Et O = 70/30); [ꢀ]D20
+
(C=O); ms (CI, CH5 ): 392 [M+H]+ (3), 270 (8), 146 (2), 133
(17), 132 (100); hrms (FAB+): Calcd. (C23H19NO3Cl, [M+H]+):
392.1065, found: 392.1058. Anal. Calcd. for C22H18NO3Cl
(391.86): C, 70.50; H, 4.63; N, 3.57. Found: C, 70.15; H, 4.98;
N, 3.37.
f
2
= -53.5 (c = 0.155 in CH3OH); ir: 451, 2925, 2854, 1461, 1369,
1145, 861, 773, 700 cm-1; 1H nmr (CDCl3): ꢁ = 1.61 (dt, J =
13.5/9.5 Hz, 1H, CH2), 1.86 (ddd, J = 13.5/4/2 Hz, 1H, CH2),
2.32 (s, 3H, CH3), 4.17 (d, J = 12.5 Hz, 1H, NCH2), 4.49-4.55
(m, 1H, NCH and 1H, OCH), 4.58 (d, J = 12.5 Hz, 1H, NCH2),
4.86 (d, J = 12.5 Hz, 1H, NCH2O), 4.94 (d, J = 12.5 Hz, 1H,
NCH2O), 7.13 (d, J = 8.5 Hz, 2H, Harom.), 7.18-7.25 (m, 5H,
(3S)-3-[(2S)-2-Hydroxy-2-(4-methylphenyl)ethyl]-2,3-
dihydro-1H-isoindol-1-one (6a). 68 mg (0.18 mmol) of 19a
were dissolved in 1.8 ml of THF and cooled to 0 °C. A solution
of 0.9 mmol of Li[AlH2(OCH3)2] in THF was added dropwise.
The mixture was stirred for 2 hours at 0 °C. Excessive
Li[AlH2(OCH3)2] was destroyed by addition of KH2PO4-solution
(10%). The mixture was allowed to warm to room temperature.
After gas formation had stopped, Et2O was added and the
organic layer was separated. The aqueous layer was saturated
with NaCl and extracted with Et2O (5x). The combined organic
layers were dried with MgSO4 and concentrated in vacuo. CC
(isohexane/acetone = 60:40) yielded 32 mg (67%) of 6a as white
solid. As despite several attempts 6a could not be obtained in
pure form it was directly used for the subsequent reaction; tlc: Rf
= 0.32 (isohexane/acetone = 60:40); ir: 3221, 2950, 2917, 1666,
Harom.), 7.28-7.32 (m, 1 H, Harom.); ms (CI, CH5 ): 266 [M+H]+
+
(13), 254 (3), 225 (50), 211 (11), 197 (17), 105 (100). Anal.
Calcd. for C18H19NO (265.36): C, 81.48; H, 7.22; N, 5.28.
Found: C, 81.20; H, 7.35; N, 5.13.
(3R,4aS)-3-(4-Nitrophenyl)-3,4,4a,9-tetrahydrooxazino-
[4,3-a]isoindole (7b). 213 mg (0.72 mmol) of 5b were reacted
with BMS according to GP8. Purification by CC (n-heptane/Et2O
= 50/50) yielded 65mg (30%) of 7b as white solid, mp 143-147
°C; tlc: R = 0.12 (n-heptane/Et O = 50/50); [ꢀ]2D0 = +85.6 (c =
f
2
0.160 in CH3OH); ir: 3029, 2966, 2942, 2912, 2871, 2859, 2801,
1
1616, 1595, 1512, 1469, 1432, 1418,1370, 1327, 1253 cm-1; H
1
1603, 1514, 1475, 1464, 1431, 1383, 1345, 1314 cm-1; H nmr

588
A. Müller, K. Polborn and K. T. Wanner
Vol 44
(CDCl3): ꢀ = 1.50 (dt, J = 13.5/11.5 Hz, 1H, CH2), 1.92 (ddd, J =
13.5/4/2 Hz, 1H, CH2), 4.20 (d, J = 12.5 Hz, 1H, NCH2), 4.52-4.58
(m, 1H, NCH2 and 1H, NCH), 4.67 (dd, J = 11.5/2 Hz, 1H, OCH),
4.87 (d, J = 11.5 Hz, 1H, NCH2O), 4.97 (d, J = 11.5 Hz, 1H,
NCH2O), 7.19-7.26 (m, 3H, Harom.), 7.28-7.31 (m, 1H, Harom.),
7.49-7.52 (m, 2H, C6H4NO2), 8.16-8.20 (m, 2H, C6H4NO2); ms
(3S,4aS)-3-(4-Chlorphenyl)-3,4,4a,9-tetrahydrooxazino-
[4,3-a]isoindole (8c). 155 mg (0.54 mmol) of 6c were reacted
with BMS according to GP8. CC (n-heptane/EtOAc = 60:40)
yielded 76 mg (50%) of 8c as yellowish solid, mp 87 °C; tlc: Rf
= 0.13 (n-heptane/EtOAc = 60:40); [ꢁ]2D0 = +106.9 (c = 0.275 in
CH3OH); ir: 3053, 2926, 2892, 1654, 1491, 1478, 1458, 1399,
+
1
(CI, CH5 ): 297 [M+H]+ (100), 281 (3), 267 (2), 146 (10), 132 (4),
1345, 1334, 1304, 1246, 1229, 1211 cm-1; H nmr (CDCl3): ꢀ =
131 (4). Anal. Calcd. for C17H16N2O3 (296.33): C, 68.91; H, 5.44;
N, 9.39. Found: C, 69.05; H, 5.39; N, 9.39.
2.13 (ddd, J = 14.5/5.5/4 Hz, 1H, CH2), 2.38 (ddd, J = 14.5/8/6
Hz, 1H, CH2), 4.27 (d, J = 13.5 Hz, 1H, NCH2), 4.42 (d, J = 10.5
Hz, 1H, NCH2O), 4.49 (dd, J = 13.5/2 Hz, 1H, NCH2), 4.71 (dd,
J ~8/4 Hz, 1H, CH), 4.73 (br td, J ~5/2 Hz, 1H, CH), 4.84 (d, J =
10.5 Hz, 1H, NCH2O), 7.22-7.37 (m, 8H, Harom.); 13C nmr
(CDCl3): ꢀ = 33.08 (CH2), 54.75 (NCH2), 59.69 (CH), 71.19
(CH), 76.51 (NCH2O), 122.13 (Cisoindol.), 123.16 (Cisoindol.), 127.22
(Cisoindol.), 127.46 (Cisoindol.), 127.82 (2 C, C6H4Cl), 128.64 (2 C,
C6H4Cl), 133.10 (Cq), 140.08 (Cq), 140.17 (Cq), 143.15 (Cq); ms
(3R,4aS)-3-(4-Chlorophenyl)-3,4,4a,9-tetrahydrooxazino-
[4,3-a]isoindole (7c). 200 mg (0.70 mmol) of 5c were reacted
with BMS according to GP8. Purification by CC (n-heptane/
Et2O = 50/50) yielded 105 mg (53%) of 7c as white solid, mp
154 °C; tlc: R = 0.13 (n-heptane/Et O = 50/50); [ꢁ]2D0 = +61.3 (c
f
2
= 0.315 in CH3OH); ir: 3028, 2936, 1654, 1597, 1491, 1476,
1
1461, 1427, 1410, 1382, 1352, 1296, 1252, 1208 cm-1; H nmr
(CI, CH5 ): 286 [M+H]+ (100), 268 (1), 250 (3), 174 (12), 155
+
(CDCl3): ꢀ = 1.54 (dt, J = 13.5/11.5 Hz, 1H, CH2), 1.86 (ddd, J =
13.5/4/2 Hz, 1H, CH2), 4.18 (d, J = 12.5 Hz, 1H, NCH2), 4.50-
4.58 (m, 1H, NCH, 1 H, OCH and 1H, NCH2), 4.85 (d, J = 11.5
Hz, 1H, NCH2O), 4.94 (d, J = 11.5 Hz, 1H. NCH2O), 7.17-7.25
(8), 146 (15), 132 (49), 118 (10); hrms (EI+): Calcd.
(C17H16NOCl): 285.0920, Found: 285.0914.
(1R)-2-[(1S)-2-Methyl-2,3-dihydro-1H-isoindol-1-yl]-1-(4-
methylphenyl)ethanol hydrochloride (9a). 74 mg (0.28 mmol)
of 7a were reacted with Na[CNBH3] according to GP9. After
centrifugation 28 mg (46%) of 9a were obtained as white solid,
mp 187 °C (decomposition); [ꢁ]2D0 = +48.2 (c = 0.145 in
CH3OH); ir: 3330, 2923, 2587, 2539, 1513, 1466, 1410, 1203,
+
(m, 3H, Harom.), 7.27-7.32 (m, 5H, Harom); ms (CI, CH5 ): 286
[M+H]+ (100), 200 (15), 174 (18), 146 (19), 132 (33), 118 (10).
Anal. Calcd. for C17H16ClNO (285.78): C, 71.45; H, 5.64; N,
4.90. Found: C, 71.40; H, 5.57; N; 4.81.
(3S,4aS)-3-(4-Methylphenyl)-3,4,4a,9-tetrahydrooxazino-
[4,3-a]isoindole (8a). 135 mg (0.51 mmol) of 6a were reacted
with BMS according to GP8. CC (n-heptane/Et2O = 55/45)
yielded 68 mg (50%) of 8a as yellow oil; tlc: Rf = 0.15 (n-
1
1087 cm-1. H nmr (CD3OD): ꢀ = 2.14-2.23 (m, 2H, CH2), 2.31
(s, 3H, CH3), 3.07 (s, 3H, NCH3), 4.47 (d, J = 15 Hz, 1H,
NCH2), 4.97-5.08 (m, 1H, OCH; 1H, NCH and 1H, NCH2), 7.16
(d, J = 8 Hz, 2H, C6H4CH3), 7.31 (d, J = 8 Hz, 2H, C6H4CH3),
7.41-7.48 (m, 4H, Hisoindol.); 13C nmr (CDCl3): ꢀ = 21.09 (CH3),
42.03 (CH2), 43.87 (NCH3), 60.33 (NCH2), 73.68 (CH), 75.56
(CH), 123.07 (Cisoindol.) , 123.20 (Cisoindol.), 125.93 (2 C,
C6H4CH3), 129.32 (2 C, C6H4CH3), 129.67 (2 C, Cisoindol.), 131.80
heptane/Et O = 55/45); [ꢁ]2D0 = +61.5 (c = 0.2 in CH3OH); ir:
2
3031, 2922, 2865, 1704, 1663, 1515, 1459, 1351, 1299, 1252,
1
1101, 1052 cm-1; H nmr (CDCl3): ꢀ = 2.13 (ddd, J = 14/6/4.5
Hz, 1H, CH2), 2.35 (s, 3H, CH3), 2.42 (ddd, J = 14/7.5/5.5 Hz,
1H, CH2), 4.24 (d, J = 13 Hz, 1H, NCH2), 4.39 (d, J = 10.5 Hz,
1H, NCH2O), 4.49 (dd, J = 13/2 Hz, 1H, NCH2), 4.70-4.75 (m,
2H, OCH and NCH), 4.84 (d, J = 10.5 Hz, 1H, NCH2O), 7.18 (d,
J = 8 Hz, 2H, Harom.), 7.22-7.37 (m, 6H, Harom.); 13C nmr (CDCl3):
ꢀ = 21.10 (CH3), 32.59 (CH2), 54.49 (NCH2), 59.60 (CH), 71.74
(CH), 76.30 (NCH2O), 122.10 (Cisoindol.), 123.18 (Cisoindol.), 126.48
(2 C, C6H4CH3), 127.15 (Cisoindol.), 127.33 (C-isoindol.), 129.20 (2 C,
C6H4CH3), 137.04 (Cq), 138.21 (Cq), 140.24 (Cq), 143.52 (Cq);
+
(Cq), 137.15 (Cq), 137.57 (Cq), 140.08 (Cq); ms (CI, CH5 ): 268
[M-Cl]+ (60), 146 (3), 132 (100); hrms (FAB+): Calcd.
(C18H22NO): 268.1701, found: 268.1746. Anal. Calcd. for
C18H22ClNO (303.83): C, 71.16; H, 7.30; N, 4.61. Found: C,
70.53; H, 7.08; N, 4.50.
(1R)-2-[(1S)-2-Methyl-2,3-dihydro-1H-isoindol-1-yl]-1-(4-
nitrophenyl)ethanol hydrochloride (9b). 37 mg (0.13 mmol)
of 7b were reacted with Na[CNBH3] according to GP9. After
centrifugation 29 mg (70%) of 9b were obtained as yellowish
solid, mp 95 °C (decomposition); [ꢁ]2D0 = +45.80 (c = 0.120 in
CH3OH); ir: 3284, 2942, 2670, 2593, 2528, 1600, 1518, 1463,
+
ms (CI, CH5 ): 266 [M+H]+ (100), 239 (2), 211 (5), 197 (7), 174
(13), 162 (7), 146 (31), 132 (70), 118 (31), 105 (21); hrms (EI+):
Calcd. (C18H19NO): 265.1467, found: 265.1461.
(3S,4aS)-3-(4-Nitrophenyl)-3,4,4a,9-tetrahydrooxazino-
[4,3-a]isoindole (8b). 174 mg (0.58 mmol) of 6b were reacted
with BMS according to GP8. CC (n-heptane/ EtOAc = 60:40)
yielded 77 mg (45%) of 8b yellowish solid, mp 122 °C; tlc: Rf =
0.12 (n-heptane/EtOAc = 60:40); [ꢁ]2D0 = +112.1 (c = 0.290 in
CH3OH); ir: 2924, 2859, 2788, 1605, 1519, 1462, 1346, 1159,
1
1420, 1348 cm-1; H nmr (C2D6OS, 130 °C): ꢀ = 2.26-2.37 (m,
1H, CH2), 2.41-2.54 (m, 1H, CH2), 2.98 (s, 3H, NCH3), 4.45 (d,
J = 14.5 Hz, 1H, NCH2), 4.77-4.89 (m, 1H, NCH2), 4.90-4.97
(m, 1H, CH), 5.08-5.17 (m, 1H, CH), 7.38-7.43 (m, 3H,
Hisoindol..), 7.50-7.56 (m, 1H, Hisoindol.), 7.73 (d, J = 6.5 Hz, 2H,
C6H4NO2), 8.19 (d, J = 7.5 Hz, 2H, C6H4NO2); 13C nmr (CDCl3):
ꢀ = 41.55 (CH2), 44.18 (NCH3), 60.40 (NCH2), 72.93 (CH),
75.55 (CH), 123.07 (Cisoindol.), 123.38 (Cisoindol.), 123.85 (2 C,
C6H4NO2), 126.96 (2 C, C6H4NO2), 129.82 (Cisoindol.), 130.00
1
1107, 1054 cm-1; H nmr (CDCl3): ꢀ = 2.17 (dt, J = 14.5/4.5 Hz,
1H, CH2), 2.41 (ddd, J = 14.5/9/6 Hz, 1H, CH2), 4.32 (d, J = 13.5
Hz, 1H, NCH2), 4.48 (d, J = 10.5 Hz, 1H, NCH2O), 4.51 (dd, J =
13.5/2 Hz, 1H, NCH2), 4.75-4.79 (m, 2H, NCH and OCH), 4.89
(d, J = 10.5 Hz, 1H, NCH2O), 7.24-7.27 (m, 1H, Harom.), 7.28-7.32
(m, 3H, Harom.), 7.51-7.55 (m, 2H, C6H4NO2), 8.20-8.24 (m, 2H,
C6H4NO2); 13C nmr (CDCl3): ꢀ = 33.77 (CH2), 55.11 (NCH2),
59.96 (CH), 71.06 (CH), 76.93 (NCH2O), 122.27 (Cisoindol.), 123.21
(Cisoindol.), 123.78 (2 C, C6H4NO2), 127.03 (2 C, C6H4NO2), 127.44
(Cisoindol.), 127.73 (Cisoindol.), 140.10 (Cq), 142.61 (Cq), 147.22 (Cq),
(Cisoindol.), 131.65 (Cq), 136.52 (Cq), 147.47 (Cq), 150.43 (Cq); 13
C
nmr (free base, CDCl3): ꢀ = 40.65 (CH2), 44.14 (NCH3), 59.42
(NCH2), 72.93 (CH), 73.52 (CH), 122.70 (Cisoindol.), 122.99
(Cisoindol.), 123.33 (2 C, C6H4NO2), 126.27 (2 C, C6H4NO2),
127.27 (Cisoindol.), 127.55 (Cisoindol.), 138.35 (Cq), 141.57 (Cq),
+
146.76 (Cq), 152.85 (Cq); ms (CI, CH5 ): 299 [M-Cl]+ (41), 283
+
149.51 (Cq); ms (CI, CH5 ): 297 [M+H]+ (100), 281 (5), 267 (1),
(3), 269 (1), 251 (8), 150 (13), 146 (9), 136 (7), 132 (100), 120
(38); hrms (FAB+): Calcd. (C17H19N2O3): 299.1396, found:
298.1389.
146 (14), 132 (11), 131 (7). hrms (EI+): Calcd. (C17H16N2O3):
296.1161, found: 296.1158.

May-Jun 2007
Asymmetric Alkylation of N-Acylisoindolin-1-ones via ꢀ-Bromoimides
589
(1R)-2-[(1S)-2-Methyl-2,3-dihydro-1H-isoindol-1-yl]-1-(4-
chlorophenyl)ethanol hydrochloride (9c). 65 mg (0.23 mmol)
of 7c were reacted with Na[CNBH3] according to GP9. After
centrifugation 40 mg (54%) of 9c were obtained as white solid,
mp 162-167 °C (decomposition); [ꢀ]2D0 = -41.6 (c = 0.185 in
CH3OH); ir: 3304, 2925, 2604, 2580, 2538, 1490, 1466, 1408,
1364, 1202, 1089 cm-1; 1H nmr (CD3OD): ꢁ = 2.12-2.23 (m, 2H,
CH2), 3.09 (s, 3H, NCH3), 4.46 (d, J = 15 Hz, 1H, NCH2), 5.00-
5.13 (m, 1H, OCH, 1H, NCH and 1H, NCH2), 7.34 (d, J = 8.5
Hz, 2H, Harom.), 7.40-7.48 (m, 6H, Harom.); 13C nmr (CDCl3): ꢁ =
41.77 (CH2), 43.91 (NCH3), 60.25 (NCH2), 72.72 (CH), 75.28
(CH), 123.16 (Cisoindol.), 123.31 (Cisoindol.), 127.47 (2 C, C6H4Cl),
128.69 (2 C, C6H4Cl), 129.65 (Cisoindol.), 129.75 (Cisoindol.), 131.69
1H, CH), 7.17 (d, J = 7 Hz, 1H, Harom.), 7.25-7.35 (m, 7H, Harom.);
13C nmr (CDCl3): ꢁ = 37.62 (CH2), 40.43 (NCH3), 60.14
(NCH2), 70.17 (CH), 70.65 (CH), 121.97 (Cisoindol.), 122.63
(Cisoindol.), 127.00 (2 C, C6H4Cl), 127.32 (Cisoindol.), 127.63
(Cisoindol.), 128.33 (2 C, C6H4Cl), 132.46 (Cq), 139.56 (Cq), 140.47
(Cq), 143.56 (Cq); ms (EI, 70 eV): 288 [M+H]+ (49), 270 (1),
176 (2), 160 (1), 146 (2), 132 (100), 117 (2). hrms (EI+): Calcd.
(C17H18NOCl): 287.1077, found: 287.1078.
(3R,4aS)-3-(4-Methylphenyl)-3,4,4a,9-tetrahydrooxazino-
[4,3-a]isoindol-1-one (22). 50 mg (0.19 mmol) of 5a were
dissolved in 7 ml THF. The solution was cooled in an ice bath
and treated with 0.5 ml BMS (2 M in THF). The mixture was
allowed to warm to room temperature before it was refluxed for
6 hours. Then 1 ml of CH3OH was added (ice bath). When the
gas formation had ceased, the solvent was removed in vacuo. To
remove decomposition products of BMS the residue was
repeatedly dissolved in 5 ml of CH3OH and the solvent was
removed in vacuo. Next, the residue was dissolved in 3.6 ml of
THF and 5 equivalents of carbonyldiimidazole (CDI) were
added. The resulting mixture was stirred for 16 hours. After
addition of 2 ml of phosphate buffer (pH7) the mixture was
extracted with Et2O (4x3 ml). The combined extracts were dried
over MgSO4 and then concentrated in vacuo. Purification by CC
(Et2O) yielded 27 mg (51%) of 22 white solid, mp 158-168 °C;
tlc: Rf = 0.4 (Et2O); [ꢀ]20 = +13.14 (c = 0.175 in CH3OH); ir:
2922, 1700, 1465, 1412D, 1339, 1306, 1284, 1108, 1080, 1050
cm-1; 1H nmr (CDCl3,): ꢁ = 1.93 (dt, J = 13.5/11.5 Hz, 1H, CH2),
2.36 (s, 3H, CH3), 2.72 (ddd, J = 13.5/3.5/2.5 Hz, 1H, CH2), 4.70
(dd, J = 15/1.5 Hz, 1H, NCH2), 5.10 (br d, J = 11.5 Hz, 1H,
NCH), 5.16 (dd, J = 15/2 Hz, 1H, NCH2), 5.48 (dd, J = 11.5/2.5
Hz, 1H, OCH), 7.17-7.22 (m, 3H, Harom.), 7.28-7.36 (m, 5H,
Harom.); 13C nmr (CDCl3): ꢁ = 21.19 (CH3), 35.60 (CH2), 52.98
(NCH2), 60.63 (CH), 79.15 (CH), 121.64 (Cisoindol.), 122.92
(Cisoindol.), 125.89 (2 C, C6H4CH3), 127.79 (Cisoindol.), 128.44
(Cisoindol.), 129.31 (2 C, C6H4CH3), 135.96 (Cq), 136.73 (Cq),
+
(Cq), 133.46 (Cq), 136.85 (Cq), 141.80 (Cq); ms (CI, CH5 ): 288
[M+H]+ (40), 176 (2), 146 (3), 132 (100), 117 (2). hrms (EI+):
Calcd. (C17H19NOCl, free base): 288.1155, found: 288.1115.
(1S)-2-[(1S)-2-Methyl-2,3-dihydro-1H-isoindol-1-yl]-1-(4-
methylphenyl)ethanol (10a). 60 mg (0.23 mmol) of 8a were
reacted with Na[CNBH3] according to GP9. This yielded 36 mg
(52%) of 10a as white solid, mp 128-131 °C; [ꢀ]2D0 = +43.85 (c =
0.135 in CH3OH); ir: 3108, 3021, 2971, 2941, 2911, 1657, 1513,
1477, 1464, 1354, 1301, 1354, 1285, 1256 cm-1; 1H nmr
(CDCl3): ꢁ = 2.15 (dt, J = 15/2 Hz, 1H, CH2), 2.24 (ddd, J =
15/10.5/4 Hz, 1H, CH2), 2.33 (s, 3H, CH3), 2.65 (s, 3H, NCH3),
3.69 (dd, J = 13/3 Hz, 1H, NCH2), 4.10 (br s, 1H, NCH), 4.33
(dd, J = 13/1.5 Hz, 1H, NCH2), 4.70 (dd, J = 10.5/2 Hz, 1H,
OCH), 7.14 (d, J = 7.5 Hz, 2H, C6H4CH3), 7.17 (d, J = 7.5 Hz,
2H, C6H4CH3), 7.23-7.34 (m, 4H, Harom.); 13C nmr (CDCl3): ꢁ =
21.38 (CH3), 37.94 (CH2), 40.74 (NCH3), 60.49 (NCH2), 70.54
(CH), 71.36 (CH), 122.35 (Cisoindol.), 122.83 (Cisoindol.), 125.85 (2
C, C6H4CH3), 127.50 (Cisoindol.), 127.77 (Cisoindol.), 129.18 (2 C,
C6H4CH3), 136.74 (Cq), 139.97 (Cq), 141.11 (Cq), 142.40 (Cq);
ms (CI, CH5 ): 268 [M+H]+ (50), 176 (4), 146 (9), 132 (100),
+
121 (6), 105 (1); hrms (EI+): Calcd. (C18H21NO): 267.1623,
found 267.1624.
+
138.42 (Cq), 139.26 (Cq), 152.66 (C=O); ms (CI, CH5 ): 280
(1S)-2-[(1S)-2-Methyl-2,3-dihydro-1H-isoindol-1-yl]-1-(4-
nitrophenyl)ethanol (10b). 55 mg (0.19 mmol) of 8b were
reacted with Na[CNBH3] according to GP9. This yielded 36 mg
(63%) of 10b as white solid, mp 163 °C; [ꢀ]2D0 = +91.6 (c = 0.215
in CH3OH); ir: 3443, 2923, 2859, 2796, 1600, 1516, 1461, 1346,
[M+H]+ (6), 162 (100), 118 (16); hrms (FAB+): Calcd.
(C18H18NO2, [M+H]+): 280.1338, found: 280.1329.
X-ray Diffraction of 4a.
1
1304, 1260 cm-1; H nmr (CDCl3): ꢁ = 2.15-2.22 (m, 2H, CH2),
Data collection: MACH3 Diffractometer, crystal mounted in
a glass capillary, cell constants from 25 centered reflections.
MoKꢀ-radiation, ꢂ = 0.71073 Å, graphite monochromator, ꢃ-
scan, maximum measuring time 60 s, intensity of three standard
reflections checked every 7200 s. Structure solution by
SHELXS-86 [9] and refinement by SHELXL-97 [10], non-
hydrogen atoms refined anisotropically, hydrogens with Ui = 1.2
Ueq of the adjacent non-hydrogen atom. Full matrix refinement
against F2. Weight SHELXL-97. Maximum and minimum of the
final Fourier synthesis 0.128 and –0.145 eÅ-3. The drawing was
made by ZORTEP [11]. The complete data are available from
Cambridge Crystallographic Data Center (deposit@ccdc.
cam.ac.uk). The deposition number is CCDC-277321.
2.68 (s, 3H, NCH3), 3.74 (dd, J = 13.5/2.5 Hz, 1H, NCH2), 4.17
(br s, 1H, OCH), 4.43 (d, J = 13.5 Hz, 1H, NCH2), 4.83 (t, J =
6.5 Hz, 1H, NCH), 7.21 (d, J = 7 Hz, 1H, Harom.), 7.27-7.37 (m,
3H, Harom.), 7.54 (d, J = 8.5 Hz, 2H, C6H4NO2), 8.19 (d, J = 8.5
Hz, 2H, C6H4NO2); 13C nmr (CDCl3): ꢁ = 37.47 (CH2), 40.38
(NCH3), 60.12 (NCH2), 70.17 (CH), 70.68 (CH), 121.88
(Cisoindol.), 122.76 (Cisoindol.), 123.58 (2 C, C6H4NO2), 126.32 (2 C,
C6H4NO2), 127.46 (Cisoindol.), 127.83 (Cisoindol.), 139.59 (Cq),
+
140.13 (Cq), 146.95 (Cq), 152.62 (Cq); ms (CI, CH5 ): 299
[M+H]+ (29), 288 (4), 280 (3), 268 (6), 251 (7), 150 (10), 146
(8), 132 (100), 120 (32); hrms (EI+): Calcd. (C17H18N2O3):
298.1317, found: 298.1317.
(1S)-2-[(1S)-2-Methyl-2,3-dihydro-1H-isoindol-1-yl]-1-(4-
chlorophenyl)ethanol (10c). 78 mg (0.27 mmol) of 8c were
reacted with Na[CNBH3] according to GP9. This yielded 45 mg
(57%) of 10c as white solid, mp 123 °C; [ꢀ]2D0 = +55.3 (c = 0.17
in CH3OH); ir: 3108, 3026, 2924, 2944, 2912, 1487, 1462, 1402,
1351, 1294, 1261 cm-1; 1H nmr (CDCl3): ꢁ = 2.13 (dt, J = 15/2.5
Hz, 1H, CH2), 2.20 (ddd, J = 15/10/3.5 Hz, 1H, CH2), 2.66 (s,
3H, NCH3), 3.71 (dd, J = 13/1.5 Hz, 1H, NCH2), 4.13 (br s, 1H,
CH), 4.41 (d, J = 13 Hz, 1H, NCH2), 4.70 (dd, J = 10/2.5 Hz,
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