Gold catalysis and chiral sulfoxides: Enantioselective synthesis of dihydroisoindol-4-ols

Article abstract of DOI:10.1002/ejoc.200800656

Furfurals and enantomerically pure sulfinamides have been condensed to N-sulfinylimines. Addition of organolithium or -magnesium compounds to these imines allowed a 1,2-induction. After propargylation, the sulfinamides gave low conversion with gold catalysts. Oxidation to chiral sulfonamides, propargylation and gold-catalysed cycloisomerization to the phenol delivered non-racemic dihydroisoindol-4-ols in good yields. In situ NMR studies prove the intermediacy of the arene oxide even with the AuCl₃ catalyst. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800656

FULL PAPER
DOI: 10.1002/ejoc.200800656
Gold Catalysis and Chiral Sulfoxides: Enantioselective Synthesis of
Dihydroisoindol-4-ols
A. Stephen K. Hashmi,*[a] Sascha Schäfer,[b] Jan W. Bats,[c][‡] Wolfgang Frey,[b][‡] and
Frank Rominger[a][‡]
Keywords: Alkynes / Furans / Gold / Isoindoles / Sulfoxides / Sulfones
Furfurals and enantomerically pure sulfinamides have been
condensed to N-sulfinylimines. Addition of organolithium
or -magnesium compounds to these imines allowed a 1,2-
induction. After propargylation, the sulfinamides gave low
conversion with gold catalysts. Oxidation to chiral sulfon-
amides, propargylation and gold-catalysed cycloisomeriza-
tion to the phenol delivered non-racemic dihydroisoindol-4-
ols in good yields. In situ NMR studies prove the intermedi-
acy of the arene oxide even with the AuCl3 catalyst.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
After the successful synthesis of chiral 8-hydroxytetra-
hydroisoquinolines by catalytic hydrogenation and subse-
quent gold catalysis,[14,15] efforts are now focused on the
synthesis of chiral dihydroisoindole derivatives, which, for
example, are of significance in medical applications.[16] Re-
cently it was discovered that such compounds form a new
class of powerful 5-HT2C antagonist 3, which have shown
very promising results in the pharmaceutical treatment of
obesity (Figure 1).[17] The mazindole derivative 4, which
Introduction
Chiral sulfoxides[1] and sulfinamides[2–4] are excellent
auxiliaries for asymmetric synthesis and provide access to a
large variety of chiral amines,[5] amino acids[6,7] and hetero-
cycles.[8,9] The combination of gold-catalysed[10–12] phenol
synthesis[13] and chiral centres set by sulfoxides as asymmet-
ric auxiliaries in 1 are expected to lead to dihydroisoindol-
4-ols (2, X = NR) with a defined chiral centre at the 1-
position (Scheme 1).
Figure 1. 5-HT2C antagonist 3 and mazindol derivative 4.
Scheme 1. Gold-catalysed phenol synthesis.
[a] Organisch-Chemisches Institut, Ruprecht-Karls-Universität
Heidelberg,
Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
Fax: +49-6221-544205
E-mail: hashmi@hashmi.de
[b] Institut für Organische Chemie, Universität Stuttgart,
Pfaffenwaldring 55, 70569 Stuttgart, Germany
[c] Institut für Organische Chemie und Chemische Biologie,
Johann Wolfgang Goethe-Universität Frankfurt,
Marie-Curie-Str. 11, 60439 Frankfurt, Germany
[‡] Crystallographic investigation.
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Figure 2. Crystal structure analysis of 10.
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Scheme 2. Retrosynthesis of chiral, non-racemic dihydroisoindol-4-ols 5.
also contains the tetrahydroisoindole substructure, is a po- Table 1. Generation of the imino sulfoxides 7.
tential inhibitor of the cocaine site at the dopamine trans-
porter (Figure 2).[18]
Previous syntheses of the dihydroisoindole derivatives
were carried out by the reaction of isobenzofuranones and
urea, amides[19] or primary amines[20] and subsequent re-
duction[21] with LiAlH4. This reduction is not a suitable
method for sensitive or highly functionalized compounds.
Herein we show a new synthetic route that tolerates all
kinds of functional groups. Starting from furfurals 8 with
different substituents at the 3- or 5-position, chiral, non-
racemic imino sulfoxides 7 can be easily prepared by con-
densation using TiIV compounds as Lewis acid and water-
trapping reagent. After tethering the stereocentre by 1,2-
induction, oxidation of the sulfoxide to a sulfone and subse-
quent propargylation of the amine, substrates 6 can be
tested in the gold-catalysed phenol synthesis aiming at chi-
ral, non-racemic dihydroisoindol-4-ols 5 (Scheme 2).
Results and Discussion
Enantiomerically pure imino sulfoxides 7 were obtained
by condensation reaction of the furfurals 8 and (R)-(+)-2- magnesium bromide to 7a. The addition of phenylmagne-
methyl-2-propanesulfinamide 9a, using TiCl4 or Ti(OEt)4 sium bromide in DCM showed quite a low selectivity of
for the condensation of 5-methylfurfural (8a) and (R)-(–)- only 74:26 dr. In THF, the reaction was perfectly diastereo-
4-toluenesulfinamide (9b).[22] The desired imino sulfoxides selective. In THF, the reaction of 7a with ethylmagensium
7 were obtained in good-to-very-good yields. For the syn- bromide furnished an almost 1:1 diastereomeric mixture of
thesis of 7d all attempts to use MgSO4, TiCl4, or molecular 11b. However, in DCM the reaction was highly selective.
sieves for condensation of the corresponding starting mate- On the other hand, the low selectivity for the addition of
rials failed, only Ti(OEt)4 was successful (Table 1).
phenylmagnesium bromide to 7c was independent of the
Reaction of the (R)-configured imino sulfoxides 7 with solvent. Separation of the diastereomers by column
Grignard reagents was achieved by a modified protocol of chromatography was only possible for 11b.
Ellman and co-workers.[23] The diastereoselectivity was de-
In addition, N-sulfonylimine 10[24] could be obtained by
termined by integration of well-separated signals in specific a similar condensation of 8a and tosylamide and single
1
regions of the H NMR spectra. Although the total yields crystals could be grown (Figure 2).[25]
of the reactions were good-to-excellent and not strongly de-
All efforts to add a Grignard compound to the tolyl-
pendent on the reaction conditions, the selectivities of the substituted imino sulfoxide 7d failed, but aldol reaction
additions strongly depended on the solvent. Most reactions with N,N-dimethylacetamide furnished 11g in 88% yield.
showed the highest diastereoselectivity in DCM. In THF a Although the diastereoselectivity of the reaction was quite
high or better diastereoselectivity was observed only in the good, it was lower than in the addition of the Grignard
reactions of phenyl- and cyclopropylmagnesium bromide reagents to the tert-butyl sulfoxides 7. This expected result
with 7a. Although in both cases the diastereoselectivity derives from the lower steric demand of the p-tolyl group
doubled in comparison to the reaction in DCM, the selec- in comparison to the tert-butyl group.
tivity of the addition of cyclopropylmagnesium bromide to
Phenyllithium was also tested as the organometallic reac-
7a was relatively low. The biggest discrepancy in diastereo- tion partner. The addition of phenyllithium to ketimines is
selectivity was found in the addition of phenyl- and ethyl- known,[26] but AlMe3 is needed as a Lewis acid and the
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Enantioselective Synthesis of Dihydroisoindol-4-ols
solvent has to be toluene. The authors investigated the reac- Table 2. Effect of solvent on Grignard addition to N-sulfinylimines
7.
tion of ketimines only under these reaction conditions. Thus
we tested the addition of aldimine 7a in the absence of an
additional Lewis acid in THF and DCM. Our standard
protocol, which had already been used for the addition of
Grignard compounds to aldimines 7, could deliver 11a in
good yields and diastereoselectivities. Still, the de values are
not as good as the values obtained for the addition of phen-
ylmagnesium bromide. Compared with phenylmagnesium
bromide, which showed a higher diastereoselectivity in
THF, with phenyllithium a better stereoselectivity and a
higher yield were observed in DCM.
Single crystals for the crystal structure analysis of 11b
and 11c were obtained.[25] By knowing the absolute config-
uration at the sulfur atom (which could also be confirmed
by anomalous diffraction), the configuration of the newly
formed stereogenic centre could be determined (Figure 3).
Figure 3. Solid-state structures of 11b and 11c showing the stereo-
genic centres at the carbon atoms (C1 for 11b and C9 for 11c)
to be (S)-configured and at the sulfur atoms to be (R)-configured
(anomalous diffraction).
Crystal structures of all the stereochemically pure prod-
ucts 11 or of products derived from them were obtained.
The absolute configurations of the stereogenic centres at the
carbon atoms are indicated for the products 11 in Table 2.
In the cases of 11d, 11f and 11g the diastereomeric mixtures
were used for further transformations (after the oxidation
to the sulfonamides as enantiomeric mixtures).
The elementary cells of both 11b and 11c contain only
two molecules that are connected by a hydrogen bridge. In
both structures the molecules form chains that are perfectly
aligned. The (S) configuration of the newly generated ste-
reogenic centres in the products suggests the transition state
shown in Figure 4 for the addition of the organometallic
compound to the chiral imino sulfoxide. Less polar solvents
should favour the proposed transition state.[26]
For further transformations diastereomerically pure
compounds 11a–c and 11e were used, whereas for 11d, 11f
and 11g the diastereomeric mixtures could not be separated
and the mixtures were used for further reactions.
Initial efforts to propargylate the sulfinamide 11e failed.
The tested bases, Cs2CO3, K2CO3, Hünig’s base and NEt3,
furnished only decomposition products. Even under Mitsu-
nobu conditions, decomposition of the starting material
was observed.[27,28] So the direct propargylation of 11e was
carried out with NaH and propargyl bromide in DMF.[29]
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ure 5). Although the oxidation was not carried out with ste-
reochemically pure material, only the (S)-configured enanti-
omer crystallized. Unfortunately not enough enantiomer-
ically pure material could be obtained to measure the [α]D20
value.
Figure 4. Proposed transition state for the addition of the Grignard
reagent to 7.
Under these conditions the desired product 12e was ob-
tained in 85% yield. The same protocol delivered 12a from
11a in 82% yield (Table 3).
Table 3. N-Propargylation of sulfinamide 11a and 11e.
Figure 5. Solid-state structure of 14g showing the stereogenic centre
(C6) to be (S)-configured (anomalous diffraction).
Another route to some of the substrates 14 in racemic
form involved the addition of the organometallic reagents
to 10 (Table 5).
Entry
11
11a
11e
R
R1
R2
R3
% Yield of 12
1
2
phenyl
phenyl 3-CF3-phenyl
Me
H
H
tert-butyl
tert-butyl
12a (82)
12e (85)
Compounds 14a–d and 14f were obtained by oxidation
of the sulfoxide to the corresponding sulfone with 1.1–
2 equiv. of mCPBA in 36 (14d) to 63% (14f) yields. These
low yields are caused by unselective reactions with numer-
ous side-products. Different reaction conditions were
tested, but most unfortunately gave no better results
(Table 4).
Table 5. N-Sulfonylimines 10 as precursors for 14.
After oxidation using the same conditions as used for
11a–d and 11f, 11e was accessible in 57% yield. For the p-
tolyl-substituted 11g, the same synthetic route for 8 to 11
was chosen. As observed for compounds 8, the oxidation
did not work well, but the subsequent propargylation af-
forded the desired product in a quantitative yield without
purification. For compound 14g, single crystals suitable for
Entry
R-Met
% Yield of 14
1
2
10 phenyllithium
10 cyclopropylmagnesium bromide
14h (48)
14i (94)
In an effort to crystallize 14e, oxidation product 13 was
X-ray structure analysis were obtained.[25] For this com- obtained (Figure 6). The CF3 groups are disordered. Again,
pound, the absolute configuration of the new stereogenic the absolute configuration at the carbon atom showed an
centre was also obtained by anomalous diffraction (Fig- (S) configuration.[25] Thus, the absolute configuration of the
Table 4. Oxidation of the sulfoxide to the sulfone.
Entry
11
R
R1
R2
R3
R4
Product
% Yield
1
2
3
4
5
6
7
8
11a
11b
11c
11d
11e
12e
11f
11g
phenyl
ethyl
propargyl
cyclopropyl
phenyl
phenyl
phenyl
CH2C(O)NMe2
Me
Me
Me
Me
H
H
H
H
H
H
Me
H
tert-butyl
tert-butyl
tert-butyl
tert-butyl
tert-butyl
tert-butyl
tert-butyl
p-tolyl
H
H
H
H
14a
14b
14c
14d
14e
6e
41
58
51
36
70
57
63
52
m-CF3-phenyl
m-CF3-phenyl
H
Me
H
propargyl
H
H
14f
14g
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Enantioselective Synthesis of Dihydroisoindol-4-ols
starting material for the reaction sequence of this substrate single crystals of 15 were obtained, suitable for X-ray dif-
could also be determined. The crystals were unstable, losing fraction. Anomalous diffraction showed that the crystal
an included diethyl ether.
contains a diastereomeric mixture of 15 with an (R) config-
uration at the sulfur atom and both an (R) and (S) configu-
ration at the carbon atom (Figure 7).[25]
Figure 7. Solid-state structure of 15 showing the stereogenic centre
(C8).
The gold-catalysed reactions of 6a–g were carried out on
the NMR scale by using either AuCl3 in deuteriated aceto-
nitrile or the Gagosz catalyst,[30] [Ph3PAu]NTf2, in deuter-
1
Figure 6. Crystal structure of 13 with an (S) configuration at C1
(absolute configuration by anomalous diffraction).
iated DCM and were monitored by in situ H NMR spec-
troscopy. Gold(III) catalysis with 5 mol-% AuCl3 as catalyst
furnished for the compounds 6a–g the expected dihydroiso-
indol-4-ols in good-to-excellent isolated yields. Compound
6a was converted into 5a within 3 min and the desired prod-
uct was isolated in quantitative yield. Also 5c was obtained
in 99% yield after 3 min of reaction. The reaction times of
6d and 6g at 10 and 6 min, respectively, were also quite
short and the isolated yields of 96 and 90% very good. Af-
ter 19 h 6e was converted into 5e in 53% isolated yield. The
conversion of 6b was finished after 3 min and 85% of the
corresponding dihydroisoindol-4-ol could be isolated. The
longest reaction time was observed for 6f which needed
6 days for full conversion. Compound 5f was isolated in
51% yield (Table 7). Single crystals of 5a, 5b, 5f and rac-
5g were obtained.[25] The absolute configurations of these
compounds could be obtained by anomalous diffraction.
Products 5a and 5b showed only the (S) configuration at
the carbon atoms (C8 for 5a and C1 for 5b). As compound
5b derives from 11b and both show the same configuration,
this shows that no significant racemization occurred during
the synthetic route (Figure 8). With this result in hand, the
configuration of the starting material for the synthesis of
5a (11a) could also be determined. The crystal structures of
5g and 5f showed the stereogenic centres at C1 to be (R)-
and (S)-configured, respectively. As compounds 11g and
11f were used as diastereomeric mixtures in further trans-
formations leading to the catalysis products 5g and 5f, these
The last step in the reaction sequence for providing the
starting material for the gold catalysis involved propar-
gylation of the nitrogen moiety. Propargylation of com-
pounds 14 under mild conditions with 3 equiv. Cs2CO3 and
3 equiv. propargyl bromide afforded the desired products 6
in good-to-excellent yields. Only traces of byproducts were
detected. For some of the products (14g and 14i) no purifi-
cation was necessary (Table 6).
Table 6. N-Propargylation of the sulfonamide 14.
Entry
R
R1
R2
R3
% Yield of 6
1
2
3
4
14a phenyl
14b ethyl
14c propargyl
14d cyclopropyl
14f phenyl
Me
Me
Me
Me
H
H
H
H
H
tert-butyl
tert-butyl
tert-butyl
tert-butyl
6a (60)
6b (84)
6c (82)
6d (80)
6f (92)
7
Me tert-butyl
8
9
10
14g CH2C(O)NMe2
14h phenyl
Me
Me
Me
H
H
H
p-tolyl
p-tolyl
p-tolyl
6g (quant.)
6h (92)
6i (84)
14i
cyclopropyl
In an initial test reaction, the diastereomeric mixture of products gave the expected racemic mixtures.
12a was treated with 5 mol-% AuCl3 in deuteriated acetoni- Gold(I) catalysis with 5 mol-% [Ph3PAu]NTf2 catalyst
trile to afford the corresponding diastereomeric mixture of furnished for 6a–c, 6e and 6f the expected dihydroisoindol-
dihydroisoindol-4-ol 15 in 13% yield after 24 h. The rela- 4-ols in medium-to-excellent yields in different periods of
tively low yield is due to the fact that many side-products time (Table 7). All the catalytic reactions with [Ph3PAu]-
were observed during the reaction. One problem is the free NTf2 as catalyst were finished in 3–5 min except for 6a
electron pair at sulfur, which can coordinate the gold cata- which needed 20 h for complete conversion. Compounds 5a
lyst. Gold(I) catalysis with [Ph3PAu]NTf2 delivered a mix- and 5c were isolated in 65 and 76% yields, values that are
ture of three inseparable products. After recrystallization significantly lower than those obtained in the gold(III) ca-
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Table 7. Gold-catalysed conversion of 12a, 6a–i.
talysis, whereas 5b was isolated in quantitative yield, which
With 5 mol-% AuCl3 complete conversion was observed
was higher than in the reaction with gold(III) chloride. The after only 3 min, with 2 mol-% catalyst the reaction time
same isolated yield (57%) was observed for 5e in gold(I) increased to 5 min and with 1 mol-% to 10 min (Table 8,
and gold(III) catalysis, but the reaction was faster with only entries 1–3). Within the error limits this means that half the
5 min required for complete conversion in the gold(I) catal- amount of catalyst needs about twice the time. With only
ysis (Table 3).
0.1 mol-% AuCl3 loading, the reaction time increased dra-
In order to find the lower limit of catalyst loading, com- matically to about 6 days, a clear deviation from linearity
pound 6h was subjected to decreasing amounts of AuCl3 (Table 8, entry 4). Still, even with the long reaction time, the
1
and the reaction was monitored by H NMR spectroscopy. catalyst remained active until full conversion was achieved.
In analogy to the previous conversions, the reactions were The formation of a side-product was observed during the
conducted at room temperature in deuteriated acetonitrile.
experiment with 0.1 mol-% AuCl3. For several hours this
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Enantioselective Synthesis of Dihydroisoindol-4-ols
Table 8. Gold-catalysed reaction of 6h.
Entry
AuCl3
t
% Yield of phenol 5h[a] % Conversion[a]
[mol-%]
1
2
3
4
5
2
1
3 min
5 min
10 min
6 d
96
95
97
97
quant.
quant.
quant.
quant.
0.1
1
[a] Determined by H NMR spectroscopy.
Figure 8. Solid-state structures of 5a, 5b, 5g and 5f showing the
stereogenic centre (C8 for 5a, C1 for 5b, 5g and 5f) to be (S)-config-
ured for 5a and 5b and racemic for 5f and 5g, respectively (anoma-
lous diffraction).
intermediate, probably the arene oxide 16, increased in the
reaction mixture (reaching a steady-state concentration af-
ter about 90 min; see Figure 10).[31] The in situ H NMR
1
Figure 10. Concentration of the intermediate 16 and the product
5h during the first 800 min.
spectroscopic data supports this assignment (Figure 9).
The intermediate concentration increased for the first
90 min, stayed constant for about 700 min and then slowly
decreased to an undetectable amount at the end of the reac-
If one takes a close look at the first 40 min (Figure 12),
tion (Figures 10 and 11). The concentration of the phenol it becomes clear that a significant concentration of 16 has
5h increased continuously (Figure 12).
to build up before 5h starts to form; the induction period
1
Figure 9. H NMR spectra recorded during the conversion of 6h showing signals of the intermediate 16 and the phenol 5h.
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cation. Unless indicated otherwise, all reactions were carried out
using Schlenk techniques under nitrogen. NMR spectra were re-
corded with Bruker ARX500, ARX300 and ARX250 spectrome-
ters. 13C NMR assignment was achieved by analysis of DEPT 90
and DEPT 135 spectra. Mass spectra were recorded with a Finni-
gan MAT 90, Varian 711 or Bruker daltonics microtof spectrome-
ter. IR spectra were recorded with a Bruker Vector 22 spectrometer.
Elemental analyses were performed with a Carlo–Erba Strumenta-
zione Elemental Analyser Modell 1106. Optical rotations were
measured with a Perkin–Elmer 241 instrument.
Figure 11. Concentration of the intermediate 16 during the first
31 h.
General Procedure 1 (GP 1) Ϫ Synthesis of Imino Sulfoxides from
Substituted Furfural Derivatives and (R)-(+)-2-Methyl-2-propanesul-
finamide: In a Schlenk flask furfural, (R)-(+)-2-methyl-2-propane-
sulfinamide and Et3N (5 equiv.) were dissolved in DCM under ni-
trogen and cooled to 0 °C. Afterwards TiCl4 (0.5 equiv.) was added
dropwise and the reaction mixture was stirred for 20 min at 0 °C
and 2 h at r.t. The reaction was quenched by adding saturated
aqueous NaHCO3. The mixture was extracted with DCM and the
combined organic phases were dried with MgSO4, filtered and con-
centrated under reduced pressure. The crude product was purified
by column chromatography on silica gel (PE/EA) or recrystalli-
zation.
General Procedure 2 (GP 2) Ϫ Addition of Grignard Compounds or
Phenyllithium to Imino Sulfoxides or Imino Sulfones:[23] In a Schlenk
flask the imino sulfoxide was dissolved in DCM or THF under
nitrogen and cooled to –50 °C. Afterwards the Grignard compound
(2 equiv.) was added dropwise and the reaction mixture was stirred
for 6 h at –50 °C, allowed to warm up to r.t. and then stirred over-
night. The reaction was quenched by adding saturated aqueous
NH4Cl. The mixture was extracted with DCM or Et2O and the
combined organic phases were dried with Na2SO4, filtered and con-
centrated under reduced pressure. The crude product was purified
by column chromatography on silica gel (PE/EA) or recrystalli-
zation.
Figure 12. Concentration of the intermediate 16 and the product
5h during the first 40 min.
for the formation of 5h is about 20 min. These observations
fit with the initial findings of arene oxides as transient spe-
cies in the phenol synthesis.[32] The difference is the use of
gold–pyridine complexes in the former case and the use of
AuCl3 as the catalyst here.
General Procedure 3 (GP 3) Ϫ Propargylation of Amino Sulfox-
ides:[29] In a Schlenk flask the amino sulfoxide was dissolved in
DMF under nitrogen. After 15 min of stirring, NaH was added
followed by propargyl bromide (80% solution in toluene). The reac-
tion mixture was stirred overnight at r.t. The reaction was quenched
by adding saturated aqueous NH4Cl. The mixture was extracted
with Et2O and the combined organic phases were dried with
Na2SO4, filtered and concentrated under reduced pressure. The
crude product was purified by column chromatography on silica
gel (PE/EA).
Conclusions
A combination of enantiomerically pure sulfoxides as
chiral auxiliaries for the addition of Grignard reagents to
form diastereomeric pure sulfoxamines and subsequent
gold-catalysed cyclization offers a short and easy access to
chiral, non-racemic 2,3-dihydro-1H-isoindol-4-ol systems.
No significant racemization was observed during the reac-
tion sequence. The absolute configurations of the newly
formed stereogenic centres were unambiguously assigned by
anomalous diffraction. Alkyl, phenyl, amide and alkynyl
groups are tolerated at the position γ to the alkyne moiety
during the cyclization process. A range of different furan
precursors were successfully applied in the synthesis of the
new dihydroisoindol-4-ol derivatives. Newly designed gold
catalysts will provide dihydroisoindol-4-ol derivatives faster
and in better yield.
General Procedure 4 (GP 4) Ϫ Oxidation of Propargylated or Non-
propargylated Amino Sulfoxides to Propargylated or Non-propar-
gylated Amino Sulfones: In a Schlenk flask the amino sulfoxide was
dissolved in DCM under nitrogen and cooled to 0 °C. Afterwards
mCPBA dissolved in DCM was added dropwise and the reaction
mixture was stirred for 20 min at 0 °C, allowed to warm up to r.t.
and stirred overnight. The reaction was quenched by adding satu-
rated aqueous NaHCO3. The mixture was extracted with DCM
and the combined organic phases were dried with Na2SO4, filtered
and concentrated under reduced pressure. The crude product was
purified by column chromatography on silica gel (PE/EA).
Experimental Section
General Procedure 5 (GP 5) Ϫ Propargylation of Amino Sulfones:[29]
General Methods: Chemicals were purchased from commercial sup- The amino sulfone was dissolved in acetone and Cs2CO3 (3 equiv.)
pliers (Aldrich, Fluka, Lancaster, Strem and Merck) and were used
without further purification. THF and Et2O were distilled from
Na/benzophenone prior to use. Et3N was distilled from LiAlH4.
DCM was dried with Al2O3. Dry DMF was placed under a protect-
ing atmosphere with a crown cap and used without further purifi-
and propargyl bromide (3 equiv., 80% solution in toluene) were
added. The mixture was stirred at r.t. overnight. Afterwards the
solvent was removed under reduced pressure. The resulting solid
was partitioned between water and DCM and the aqueous phase
extracted with DCM. The combined organic phases were dried
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Enantioselective Synthesis of Dihydroisoindol-4-ols
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with Na2SO4, filtered and concentrated under reduced pressure.
The crude product was purified by column chromatography on sil-
ica gel (PE/EA).
General Procedure 6 (GP 6) Ϫ Gold Catalysis on the NMR Scale
Using Gold(III) Chloride as Catalyst: In a NMR tube the starting
material (1 equiv.) was dissolved in deuteriated acetonitrile and the
catalyst precursor was added. The reaction was followed by 1H
NMR spectroscopy. After completion, the solvent was removed un-
der reduced pressure and the crude product was purified by column
chromatography on silica gel (PE/EA) or recrystallization.
General Procedure 7 (GP 7) Ϫ Gold Catalysis on the NMR Scale
Using [Ph3PAu]NTf2 (or [Mes3PAu]NTf2 and [nBu(Ad)2Au]NTf2,
respectively) as Catalyst: In a NMR tube 1 equiv. of the starting
material was dissolved in deuteriated DCM and the catalyst precur-
sor was added. The reaction was followed by 1H NMR spec-
troscopy. After completion, the solvent was removed under reduced
pressure and the product was purified by column chromatography
on silica gel (PE/EA) or recrystallization.
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Supporting Information (see also the footnote on the first page of
this article): Full characterisation of all unknown compounds.
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Received: July 2, 2008
Published Online: September 2, 2008
Eur. J. Org. Chem. 2008, 4891–4899
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4899