Asymmetric synthesis of isoquinoline derivatives from amino acids

Article abstract of DOI:10.1002/ejoc.200400693

Reaction of isoquinolines 1 with N-arylsulfonylamino acid fluorides 2 provides a highly stereoselective access to new dihydroimidazo[2,1-a] isoquinolin-3-ones 5 via intermediate N-acylisoquinolinium salts 3. Addition reactions to the enamine double bond,

Full text of DOI:10.1002/ejoc.200400693

FULL PAPER
Asymmetric Synthesis of Isoquinoline Derivatives from Amino Acids
Oxana Sieck, Max Ehwald, and Jürgen Liebscher*[a]
Dedicated to Prof. Dr. habil. Karl Gewald
Keywords: Asymmetric synthesis / Heterocycles / Amino acids / Epoxidation / Imidazoisoquinolinones
Reaction of isoquinolines 1 with N-arylsulfonylamino acid
fluorides 2 provides a highly stereoselective access to new
dihydroimidazo[2,1-a]isoquinolin-3-ones 5 via intermediate
N-acylisoquinolinium salts 3. Addition reactions to the en-
amine double bond, such as hydrogenation or epoxidation
with dimethyldioxirane, leads to tetrahydroimidazo[2,1-a]iso-
quinoline-3-ones 6, 7 and oxiranes 8, respectively. Opening
of the oxirane ring of the 8 with nucleophiles allows the syn-
thesis of hydroxytetrahydroimidazo[2,1-a]isoquinolin-3-ones
10 or 12 or of the polycyclic 1,4-dioxane 13 in high stereo-
selectivity. The regioselectivity of the oxiran ring opening de-
pends on the kind of nucleophile and the conditions. Reac-
tion of dihydroisoquinoline with O-TBDMS-mandelic acid
chloride 15 leads to a tetrahydrooxazolo[2,3-a]isoquinoline
17 with opposite facial selectivity as compared with dihy-
droimidazo[2,1-a]isoquinolin-3-ones 5.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
aminopyridines as N–C–N building block and a suitable C–
C bielectrophile (Scheme 1). It has to be mentioned that a
higher homologue of condensed dihydroimidazo[2,1-a]pyri-
dines is found in the naturally occurring Evodiamine.[12]
Introduction
Recently, we investigated the stereoselective reaction of
isoquinolines with α-aminoacyl fluorides[1,2] in the presence
of AlCl3 and trimethylsilyl chloride or trimethylsilyl cyanide
affording either Reissert compounds (2-acyl-1-cyano-1,2-di-
hydroisoquinolines)[3] or novel dihydroimidazo[2,1-a]isoquin-
[4]
olin-3-ones 5
via intermediate N-acyliminium salts. Re-
markably the outcome of the reaction with trimethylsilyl
cyanide depended on the type of protective group attached
to the amino acid fluoride. While Z- and FMOC-protected
amino acid fluorides gave Reissert compounds similar to
4, the NH-acidic α-sulfonylamino acid fluorides 2 undergo
cyclisation reaction to the dihydroimidazo[2,1-a]isoquinol-
ines 5 by attack of the sulfonamido group at the position 1
of the intermediate N-α-tosylaminoacyl isoquinolium salts
3. This synthesis of imidazo[2,1-a]isoquinolines 5 corre-
sponds to a novel retrosynthetic pattern where the imid-
azo[2,1-a]pyridine core is established from a condensed
pyridine as a C-N building block and an amino acid as a
N-C-C building block (Scheme 1, pathway B). So far imid-
azo[2,1-a]pyridine systems are only known in the fully aro-
matic series,[5–7] as compounds with saturated imidazole
and pyridine ring[8,9] as systems with a C–C double bond
in the imidazole ring,[10] or with a fully aromatic pyridinium
ring.[11] Such known compounds were synthesized from 2-
Scheme 1
Here, we report the scope and limitation of this synthesis
of dihydroimidazo[2,1-a]isoquinolin-3-ones 5, the stereose-
lective transformation of the 5 into new tetrahydroimid-
azo[2,1-a]isoquinoline-3-ones and full experimental detail
of all reactions.
Results and Discussion
In order to optimize the yields of the synthesis of dihy-
droimidazo[2,1-a]isoquinolin-3-ones 5 reaction conditions
were systematically varied for the alanine-derived product
5a. Reversion of the sequence of the addition of reactants
from adding the amino acid fluoride 2 to a solution of iso-
quinoline and 0.2 equivalents of AlCl3 in dry solvent at
–10 °C followed by the addition of one equivalent of tri-
methylsilyl cyanide or trimethylsilyl chloride at –78 °C to-
ward the addition of isoquinoline to a solution of 2 and
AlCl3 followed by the addition of the TMS reagent resulted
in a considerable drop in yield from 45 % to 20 %
(Scheme 2). Lowering the ratio of TMS chloride or TMS
cyanide or omitting these reagents, again lowered the yield
[a]
Institut für Chemie, Humboldt-Universität Berlin,
Brook-Taylor-Straße 2, 12489 Berlin, Germany
Fax: (internat.) +49-30-2093-7552
E-mail: liebscher@chemie.hu-berlin.de
Supporting information for this article is available on the
WWW under http://www.eurjoc.com
Eur. J. Org. Chem. 2005, 663–672
DOI: 10.1002/ejoc.200400693
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
663

O. Sieck, M. Ehwald, J. Liebscher
FULL PAPER
of product 5a. On the other hand, increasing the quantity Table 1. Variation of type and quantities of Lewis acids in the reac-
tion of (S)-N-tosylalanine 2a with isoquinoline and TMS-Cl to im-
of TMS chloride or TMS cyanide did not increase the yield.
Working under higher dilution, in order to prevent eventual
idazo[2,1-a]isoquinolin-3-one 5a
Entry
Lewis acid
Equiv. of Lewis acid[a]
Yield of 5a
formation of oligomeric or polymeric products, such as
peptides, did not show a positive effect on the yield either.
Changing the ratio of reactants 1 and 2 had no impact on
the yield, if the yield is calculated according to the minor
component. Variation of the type and quantity of Lewis
acid revealed that other Lewis acids than AlCl3 were less
effective and that application of a Lewis acid is indispens-
able (Table 1, Entry 1). Equimolar quantities of AlCl3 pre-
vent formation of the product 5a (Table 1, Entry 4). Varia-
tion of the temperature during the addition of the amino
acid fluoride 2 from –10 °C to –78 °C and –100 °C showed
an optimal yield and stereoselectivity at –78 °C.
1
2
3
4
5
6
7
–
–
0
41
45
0
39
19
0
AlCl3
AlCl3
AlCl3
ZnCl2
ZnF2
0.1
0.2
1.0.
0.2
0.2
0.2
Et2AlCl
[a] According to the quantity of isoquinoline.
to the formation of the antipode ent-5a. The benzothiazol-
2-sulfonyl-substituted dihydroimidazo[2,1-a]isoquinolin-3-
one 5d was obtained using the corresponding alanyl chlo-
ride instead of the fluoride 2. Substituents in position 3 and
in particular in position 1 of the isoquinoline 1 – the latter
would have led to the formation of a quaternary asymmet-
ric carbon atom – hamper the formation of dihydroimida-
zoisoquinolines 5 due to steric hindrance. Thus 3-methyliso-
quinoline afforded the corresponding product 5i in lower
yield (12 %) while 1-methylisoquinoline and 6,7-dimethoxy-
1-methylisoquinoline were recovered unchanged under the
standard conditions. Interestingly, the reaction of isoquino-
line with the pentamethylbenzofurylsulfonyl-protected ala-
nyl fluoride 2 and trimethylsilyl cyanide did not result in
the formation of imidazoisoquinolines 5 but lead to the
Reissert compound 4 as a 1:1 mixtures of epimers. Obvi-
ously, the steric hindrance by the methyl groups at the
benzofurylsulfonyl group of 2 hampered the cyclization and
thus the smaller cyanide group attacks position 1 of the
corresponding intermediate N-acyliminium salt 3. In gene-
ral, yields of imidazoisoquinolines 5 were below 50 % be-
cause of the formation of considerable quantities of polar
by-products, which, however, could not be separated from
the reaction mixture and analyzed. We suppose that com-
peting formation of polyamides occurs as was reported for
other amino acid halides.[13]
Table 2. Dihydroimidazo[2,1-a]isoquinolin-3-ones 5, tetrahydrohy-
droimidazo[2,1-a]isoquinolin-3-ones 6 and 7, and oxiranes 8
R1
R2
Ar or R3
5
6
7
8
% yield[a] % yield[a] % yield[a] % yield[a]
Scheme 2
Me
Me
Me
Me
Bn
H
H
H
H
H
H
4-tolyl
5a/47
5b/46
5c/46
6a/88
6b/99
8a/98
8b/98
2-naphthyl
4-Br-phenyl
benzthiazol-2-yl 5d/24[b]
4-tolyl
H
Me
5e/45
This variation of reaction conditions resulted in an opti-
mal procedure using reactants 1 and 2 and TMS-Cl in equi-
molar quantities and 0.2 equivalents of AlCl3 at –78 °C in
dichloromethane. Applying this procedure afforded a
number of dihydroimidazo[2,1-a]isoquinolin-3-ones 5 (see
Table 2). The diastereomeric ratio was higher than 95:5 in
all cases. Application of (d)-N-tosylalanyl fluoride thus led
Bn
7a/30
7b/60
7c//89
boc
iPr
iPr
iBu
Bn
H
H
H
4-tolyl
2-naphthyl
4-tolyl
4-tolyl
5f/44
5 /46
5h/46
5i/12
Me
6c/99[c]
[a] dr Ͼ 95:5. [b] N-(Benzothiazol-2-yl)alanyl chloride was used. [c] dr = 82:12.
664
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Eur. J. Org. Chem. 2005, 663–672

Asymmetric Synthesis of Isoquinoline Derivatives from Amino Acids
FULL PAPER
The aforementioned results are in agreement with the cur from the convex side of the bowl-shaped structure (see
mechanism shown in Scheme 3. The complex of amino acid Figure 2). In practice only products of exo-attack to the
fluoride 2 and AlCl3 attacks the isoquinoline 1 at the nitro- enamine double bond were observed.
gen atom in position 2. The resulting N-acyliminium salts
3 could be in an equilibrium with the corresponding less
reactive 1,2 adduct 3A, but the silyl reagent traps the fluo-
ride ion transforming all fluoroisoquinoline 3A in the
highly reactive N-acyliminium salt 3. The latter can loose a
proton and by attack of the resulting sulfonamide anion at
position 1 of the N-acyliminium ion the final product 5 is
formed. A similar equilibrium as between 3 and 3A was
proposed in the addition of α-phthalimido acid chlorides to
(benzylidene)aniline.[14]
Figure 2. Stereochemical modes of attack at the enamine C–C
double bond of dihydroimidazo[2,1-a]isoquinolines 5
In analogy to other known N-acylenamines[15] com-
pounds 5 could be hydrogenated at atmospheric pressure in
the presence of Pd-hydroxide/C yielding the corresponding
tetrahydroimidazo[2,1-a]isoquinolines
6 (see Scheme 2).
The configuration of the new stereogenic center in position
5 of 6c could be proved by the NOE effect between the
hydrogen atoms connected to position 5 and 10b, thus re-
vealing the attack of the hydrogen from the ß-phase, i. e.
from the convex side of 5 (see Figure 2). As could be shown
with the tosyl-substituted tetrahydroisoquinoline 5e depro-
tection is possible by reaction with Na-naphthalide.[16]
Since the resulting N-unsubstituted product 7a readily de-
composed during the aqueous work-up in the presence of
NH4Cl, it was preferably N-methylated or N-boc-protected
to 7b and 7c, respectively (see Scheme 2). The structure of
the tetrahydroimidazol[2.1-a]isoquinoline 7c was proved by
X-ray crystal analysis (see Figure 3).
Scheme 3
Structure elucidation of the products 5 is based on a X-
ray crystal analysis of products 5a and 5c (see Figure 1)
[4]
and consistent spectroscopic data, and is in agreement with
the chemical behavior.
Figure 1. X-ray crystal analysis of the tetrahydroimidazo[2,1-a]iso-
quinoline 5c
Figure 3. X-ray Crystal Analysis of compound 7c
Addition reactions to the enamine double bond of the
Attempts to remove the tosyl protective group from the
dihydroimidazo[2,1-a]isoquinolines 5 can be expected to oc- 2-benzyldihydroimidazo[2,1-a]isoquinoline 5e by photore-
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O. Sieck, M. Ehwald, J. Liebscher
FULL PAPER
duction[17,18] with ascorbic acid in the presence of 1,8-di-
methoxynaphthalene resulted in the formation of a poly-
cyclic [2+2] cycloadduct 9, while the tosyl group was not
affected (Scheme 4). The configuration of 9 was tentatively
assigned on the basis of the NMR data, where the total
number of resonance signals is half the number of H-atoms
1
or C-atoms, respectively, and doublets are seen in the H
NMR spectra for the cyclobutane H-atoms.
Scheme 4
Dimethyldioxirane[19,20] has become a reliable reagent in
epoxidation of N-acylenamine moieties.[21–24] Its reaction
with dihydroimidazo[2,1-a]isoquinolines 5 was highly ster-
eoselective (dr Ͼ 95:5) affording excellent yields of the oxir-
anes 8a,b (see Scheme 2). MCPBA was successfully applied
in the epoxidation of an anthraquinone-derived acylenam-
ine.[25] This was less favorable for 5 because the stereoselec-
tivity was lower (dr about 80:20) and it was not possible to
separate the epoxidation product from resulting m-chlo-
robenzoic acid. As in the hydrogenation (vide supra) the
preferred attack of the epoxidizing reagent to the enamine
double bond of the dihydroimidazo[2,1-a]isoquinolines 5
occurred from the convex side (see Figure 2). However, the
Scheme 5
configuration of the dioxirane ring could not be proved di- incorporation of the allyl substituent. Obviously, the trimeth-
rectly but after ring opening with amines to 6-amino-5- ylsilyl triflate attacks the oxirane O-atom of 8 affording an
hydroxyimidazo[2,1-a]isoquinolines 10 (dr
Scheme 5).
Ͼ
95:5, intermediate N-acyliminium ion similar to structure 11,
which reacts with unchanged epoxide 8 under ring opening
NOE analysis showed proximity of the H-atoms at posi- and subsequent formation of the six-membered dioxane
tions 6 and 10a of 10 on the one hand, and at position 5 ring. The heptacyclic dioxane system found in compound
and the aminoalkyl substituent on the other hand. As ex- 13 has not been reported in the literature before.
pected, the attack of the amine at the oxirane ring of 8
In our research about scope and outcome of reactions of
occurred by inversion of configuration. Remarkably, the re- isoquinolines with chiral acyl halides and nucleophiles we
gioselectvity of the cleavage of the oxirane ring of 8 was also included reaction of 3,4-dihydroisoquinoline 14 with
inverted when methanol was used as nucleophile. Acidic (S)-O-TBDMS mandelic acid chloride 15 and TMS cyanide
conditions had to be applied in order to implement the re- (Scheme 6). As in the cases of sulfonylamino acid fluorides
action, which led to the formation of 6-hydroxy-5-(meth- 2 the TMS-CN was not incorporated into the product, but
oxy)tetrahydroimidazo[2,1-a]isoquinolines 12 (Scheme 5). cyclisation of the corresponding intermediate N-acylisoqui-
Presumably, protonation of the ring O-atom by the acid nolinium salt 16 occurred. Obviously the TBDMS group
caused formation of intermediate N-acyliminium ions 11, was split off as TBDMS-Cl in the course of the intramol-
which react with the nucleophile at position 5 rather than ecular attack of the α-O-atom of the acyl substituent at po-
6. The trans-coupling constants of the H-atoms at positions sition 1 of the isoquinolinium salt 16 leading to the ox-
5 and 6 of the 6-hydroxy-5-(methoxy)tetrahydroimid- azolo[2,3-a]isoquinoline 17. Similar formation of oxazoline
azo[2,1-a]isoquinoline 12 is in agreement with the assigned rings was observed before in reactions of dihydro-ß-carbol-
configuration. The ring-opened products 12 were formed in ines with 15 [26] or α-hydroxylactones,[27] however in modest
high yield but repeated column chromatography led only to stereoselectivity. We also used (R)-O-TBDMS mandelic
34 % yield of analytically pure material. Attempts to open acid chloride ent-15 in the reaction with TMSCN in the
the oxirane ring in 8b by allylation with allyltrimethylsilane presence of AlCl3 and obtained the other antipode ent-17
in the presence of trimethylsilyl triflate as used by Burgess from which a X-ray crystal analysis was obtained (Fig-
et al.[23] resulted in the formation of a dimer 13 without the ure 4).
666
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Asymmetric Synthesis of Isoquinoline Derivatives from Amino Acids
FULL PAPER
Experimental Section
General Remarks: All reactions were carried out under argon in
oven-dried glassware. Solvents were dried and deoxygenated by
standard procedures. If not otherwise mentioned, starting materials
were commercial. (Benzthiazolylsulfonyl)alanyl chloride was ob-
tained from the known (benzthiazolylsulfonyl)alanine.[28]
TLC analysis was performed on Merck silica gel 60F254 plates and
visualized by exposure to UV light and charring with phosphomo-
lybdic acid in EtOH (5 %, v/v) or 0.3 % ninhydrine in EtOH. Col-
umn chromatography was conducted with Merck silica gel 60 (400–
1
639 mesh). H NMR and 13C NMR spectra were recorded at 300
and 75.5 MHz, respectively with a Bruker AC-300 in CDCl3 with
TMS as internal standard. Mass spectra were measured at 70 eV.
Optical rotations were determined with a Perkin–Elmer polarime-
ter 241 (d = 2 mm). Enantiomeric purity was proved by analytical
HPLC with a Chiracel-OD column (Daicel Chemical Industries
LTD).
Scheme 6
2-{[(2,2,4,6,7-Pentamethyl-2,3-dihydro-5-benzofuryl)sulfonylamino]-
1-ethylcarbonyl}-1,2-dihydroisoquinoline-1-carbonitrile (4): A solu-
tion of isoquinoline (0.299 g, 232 mmol) in dry CH2Cl2 (50 mL)
was added dropwise to a mixture of the racemic α-amino acid fluo-
ride (0.885 g, 2.59 mmol), CH2Cl2 (20 mL) and anhydrous AlCl3
at –40 °C over a period of 30 min. After stirring for 2 h the tem-
perature was lowered from –40 °C to –78 °C and a solution of
TMS-CN (0.206 g, 0.26 mL, 2.07 mmol) in dry CH2Cl2 (10 mL)
was slowly added within 1 h. After stirring at –78 °C for 4 h the
mixture was poured into ice/water (100 mL). It was extracted with
CH2Cl2 (3 × 20 mL). The combined organic layers were washed
with satd. aq. NH4Cl and 5 % aq. NaHCO3 and dried with MgSO4.
The solvent was removed under vacuum and the residue was puri-
fied by column chromatography (CH2Cl2/CH3OH, 100:1.5) afford-
ing 0.427 g (0.89 mmol, 43 %) of the product 4 as colorless oil. dr
1
= 50:50. Rf = 0.57 (CH2Cl2/CH3OH, 100:2). H NMR (CDCl3): δ
= 1.32 (s, 6 H, 2 CH3), 1.47 (d, J = 6.2 Hz, 3 H, CH-CH3), 2.19
(s, 3 H, CH3), 2.52 (s, 3 H, CH3), 2.55 (s, 3 H, CH3), 2.97 (s, 2 H,
CH2), 3.38 (m, 1 H, CH-CH3), 5.50 (1 H, NH), 6.15 (d, J = 7.6 Hz,
1 H, CHCH-N), 6.75 (d, J = 7.6 Hz, 1 H, CHCH-N), 6.87 (s, 1 H,
CH-CN), 7.21–7.54 (m, 4 H, CHar.) ppm. 13C NMR (CDCl3): δ =
12.5 (CH-CH3), 17.4 (CH3), 19.3 (CH3), 26.7 (CH3), 28.4 (CH3),
30.1 (CH3), 43.1 (CH2), 45.9 (CH-CN), 53.1 (CH-CH3), 87.0 (Cq-
O), 104.6 (CH-CH-N), 116.9 (CN), 118.2 (Car.), 120.9 (Car.), 121.6
(CHar.), 122.4 (Car.), 123.3 (CHar.), 123.7 (CHar.), 125.9 (Car.), 126.7
(CH-CH-N), 127.2 (Car.), 128.1 (CHar.) 134.3 (Car.), 139.7 (Car.),
163.1 (Car.-O), 169.9 (CO) ppm. HRMS (+EI): C26H29N3O4S:
calcd. 479.1878; found 479.1878.
Figure 4. X-ray crystal analysis of ent-17
Remarkably, the stereochemical outcome in the forma-
tion 17 is opposite to the reaction of isoquinolines 1 with
amino acid fluorides 2. This phenomenon is probably
caused by the different conformation of the six-membered
N-containing ring in the N-acyliminium intermediates 3 as
compared with 16. We observed similar changes in stereo-
selectivity in intermolecular 1,2-additions to isoquinolines
versus 3,4-dihydroisoquinolines. These results will be pub-
lished in more detail in due course.
General Procedure for the Synthesis of 1-Arylsulfonyl-Substituted
(2S,10bR)-1,10b-Dihydroimidazo[2,1-a]isoquinolin-3(2H)-ones
5:
Isoquinoline (1.76 mL, 2.000 g, 15.48 mmol) was added to a sus-
pension of dry AlCl3 (0.351 g, 2.60 mmol) in dry CH2Cl2 (60 mL)
under argon in a Schlenk flask. After cooling to –78 °C, a solution
of the amino acid fluoride 2 (13.00 mmol) in dry CH2Cl2 (5–10 mL)
was added dropwise whilst stirring over a period of 45 min. The
mixture was stirred at –78 °C for additional 45 min and at –10 °C
for 2 h. After cooling to –78 °C TMS-Cl (1.64 mL, 1.410 g,
13.00 mmol) was added dropwise whilst stirring within a period of
1 h. The mixture was warmed up whilst stirring overnight. The
mixture was quenched by pouring into ice water (230 mL). After
extraction with CH2Cl2 (3 × 120 mL) the combined organic layers
were dried with MgSO4 and concentrated under vacuum. The resi-
due was purified by flash column chromatography providing the
pure product as colorless solid. NMR spectra of the crude products
showed only one diastereomer, i.e. dr Ͼ 95:5.
Conclusions
Reaction of isoquinolines with N-arylsulfonylamino acid
fluorides provides a straightforward and highly stereoselec-
tive access to dihydroimidazo[2,1-a]isoquinolines 5. Ad-
dition reactions to the enamine moiety of these products 5
allow to synthesize a variety of new interesting tetrahy-
droisoquinoline derivatives, which all are formed in high
regio- and stereoselectivity.
Eur. J. Org. Chem. 2005, 663–672
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O. Sieck, M. Ehwald, J. Liebscher
FULL PAPER
(2S,10bR)-2-Methyl-1-(p-tolylsulfonyl)-1,10b-dihydroimidazo[2,1-a]-
isoquinolin-3(2H)-one (5a): Yield: 47 %. M.p. 142–143 °C, Rf (hex-
anes/AcOEt, 6:4) = 0.36. [α]2D0 = +159.5 (c = 1, CH2Cl2). 1H NMR
157 °C, Rf (CH2Cl2) = 0.46. [α]2D0 = + 73.6 (c = 1; CH2Cl2). ee Ն
99 % (HPLC: Chiralcell ODH, hexane/isopropyl alcohol, 95:5,
0.5 mL/cm, λ = 254 nm). 1H NMR (CDCl3): δ = 1.52 (d, J =
7.0 Hz, 3 H, CH-CH3), 4.65 (q, J = 7.0 Hz, 1 H, CH-CH3), 6.22
(d, J = 7.4 Hz, 1 H Car.-CH=CH), 6.35 [s, 1 H, N-CH(-Car.)N],
(CDCl3): δ = 1.40 (d, J = 7.2 Hz, 3 H, CH-CH3), 2.39 (s, 3 H, Car.
-
CH3), 4.09 (q, J = 7.0 Hz, 1 H, CH-CH3), 5.91 [s, 1 H, N-CH-
(Car.)N], 6.19 (d, J = 7.5 Hz, 1 H, Car.-CH=CH), 6.60 (d, J = 7.3 Hz, 6.71 (d, J = 7.4 Hz, 1 H, CH=CH-N), 7.09–8.13 (m, 8 H, CHar.
)
1 H, CH=CH-N), 7.09–7.79 (m, 8 H, CHar.) ppm. 13C NMR ppm. 13C NMR (CDCl3): δ = 20.5 (CH-CH3), 58.3 (CH-CH3), 72.6
(CDCl3): δ = 20.5 (CH-CH3), 21.7 (Car.-CH3), 57.5 (CH-CH3), 72.1
(CHar.), 116.5 (N-CH=CH), 120.9 (N-CH=CH), 124.8 (CHar.),
(N-CH(-Car.)N), 116.4 (CH=CH-N), 121.0 (Car.-CH=CH), 122.1
(CHar.), 124.4 (CHar.), 15.4 (CHar.), 125.6 (CHar.), 127.9 (CHar.),
125.2(CHar.), 128.1 (2 CHar.), 128.9 (CHar.), 129.0 (CHar.), 130.2 128.2 (CHar.), 129.0 (2 CHar.), 130.2 (Car.), 130.3 (Car.), 136.2 (Car.),
(Car.), 130.5 (2 CHar.), 130.9 (Car.), 132.3 (Car.), 145.3 (Car.), 168.8 152.4 (Car.), 162.1 (Car.), 168.2 (C=O) ppm. C19H15N3O3S2
(CO) ppm. C19H18N2O3S (354.42): calcd. C 64.39, H 5.12, N 7.90,
S 9.05; found C 64.44, H 5.01, N 7.88, S 9.02. The (2R,10bS)-
enantiomer was obtained accordingly starting from (2R)-alanyl
fluoride as colorless solid. M.p. 143–145 °C, [α]2D0 = –159.6 (c = 1;
CH2Cl2).
(397.47): calcd. C 57.42, H 3.80, N 10.57, S 16.13; found C 57.29,
H 3.98, N 10.22, S 16.12. Racemic 5d was analogously obtained
starting from racemic alanine.
(2S,10bR)-2-Benzyl-1(p-tolylsulfonyl)-1,10b-dihydroimidazo[2,1-a]-
isoquinolin-3(2H)-one (5e): Yield: 45 %. M.p. 187–189 °C, Rf
(CH2Cl2/CH3OH, 100:1) = 0.38. [α]2D0 = +224.7 (c = 1, CH2Cl2).
1H NMR (CDCl3): δ = 2.38 (s, 3 H, Car.-CH3), 3.08–3.23 (m, 2 H,
(2S,10bR)-2-Methyl-1-(2-naphthylsulfonyl)-1,10b-dihydroimidazo-
[2,1-a]isoquinolin-3(2H)-one (5b): Yield: 46 %. M.p. 101–103 °C, Rf
(hexane/ethyl acetate, 7:3) = 0.34. [α]2D0 = +134.9 (c = 1, CH2Cl2).
CH-CH -Ph), 4.34 (m, 1 H, CH-CH2), 5.81 [s, 1 H, N-CH(-Car.
)
2
1H NMR (CDCl3): δ = 1.47 (d, J = 7.0 Hz, 3 H, CH-CH3), 4.21 N], 5.99 (d, J = 7.4 Hz, 1 H, Car.-CH=CH), 6.53 (d, J = 7.4 Hz, 1
(q, J = 7.0 Hz, 1 H, CH-CH3), 6.02 [s, 1 H, N-CH(-Car.)N], 6.17 H, CH=CH-N), 6.71–7.69 (m, 13 H, CHar.) ppm. 13C NMR
(d, J = 7.4 Hz, 1 H, CH=CH-N), 6.55 (d, J = 7.4 Hz, 1 H,
CH=CH-N), 7.07–7.96 (m, 10 H, CHar.), 8.39 (s, 1 H, Car.
CH=Car.) ppm. 13C NMR (CDCl3): δ = 20.6 (CH-CH3), 57.6 (CH-
CH3), 72.1 [N-CH(-Car.)N], 116.5 (CH=CH-N), 121.0 (Car.
(CDCl3): δ = 21.7 (Car.-CH3), 38.7 (CH-CH2-Ph), 62.8(CH-CH2-
Ph), 72.4 [N-CH(-Car.)N], 116.2 (CH=CH-N), 120.2 (Car.
CH=CH), 124.7 (CHar.), 125.3 (CHar.), 126.8 (CHar.), 128.0 (2 CH),
-
-
-
128.2 (2 CH), 128.3 (CHar.), 128.4 (CHar.), 129.4 (Car.), 129.8 (Car.),
CH=CH), 122.6 (CHar.), 124.8 (CHar.), 125.3 (CHar.), 127.9 (CHar.), 129.9 (2 CH), 130.5 (2 CH), 132.1 (Car.), 134.4 (Car.), 145.3 (Car.),
128.0 (CHar.), 128.9 (CHar.), 129.0 (Car.), 129.5 (CHar.), 129.6 167.4 (CO) ppm. C25H22N2O3S (430.52): calcd. C 69.75, H 5.15, N
(CHar.), 130.1 (CHar.), 130.2 (CHar.), 130.2 (CHar.), 130.8 (Car.), 6.51, S 7.45; found C 69.82, H 5.18, N 6.47, S 7.58.
132.2 (2 Car.), 135.4 (Car.), 168.6 (CO) ppm. C22H18N2O3S (390.45):
(2S,10bR)-2-Isopropyl-1-(p-tolylsulfonyl)-1,10b-dihydroimidazo[2,1-a]-
calcd. C 67.68, H 4.65, N 7.17, S 8.21; found C 66.90, H 4.67, N
isoquinolin-3(2H)-one (5f): Yield: 44 %. M.p. 147 °C, Rf (hexane/
7.00, S 8.28.
ethyl acetate, 7:3) = 0.28. [α]2D0 = +164.1 (c = 1, CH2Cl2). 1H NMR
(2S,10bR)-1-(4-Bromophenylsulfonyl)-2-methyl-1,10b-dihydroimidazo- (CDCl3): δ = 0.82–0.87 [m, 6 H, CH(CH3)2], 2.11–2.17 [m, 1 H,
[2,1-a]isoquinolin-3(2H)-one (5c): Yield: 46 %. M.p. 144–146 °C, Rf
CH-CH(CH3)2], 2.38 (s, 1 H, Car.-CH3), 3.98 [d, J = 4.0 Hz, 1 H,
CH-CH(CH3)2], 5.94 [s, 1 H, N-CH(-Car.)N], 6.11 (d, J = 7.4 Hz,
(CH2Cl2) = 0.42. [α]2D0 = +168.7 (c = 1, CH2Cl2). 1H NMR
(CDCl3): δ = 1.44 (d, J = 7.0 Hz, 3 H, CH-CH3), 4.07 (q, J = 1 H, Car.CH=CH), 6.60 (d, J = 7.4 Hz, 1 H, CH=CH-N), 7.05–
7.0 Hz, 1 H, CH-CH3), 5.88 [s, 1 H, N-CH(-Car.)N], 6.20 (d, J = 7.78 (m, 8 H, CHar.) ppm. 13C NMR (CDCl3): δ = 18.0, 18.3
7.5 Hz, 1 H, Car.-CH=CH), 6.61 (d, J = 7.5 Hz, 1 H, CH=CH-N), [CH(CH3)2], 21.7 (Car.-CH3), 32.8 [CH-CH(CH3)2], 66.7 [CH-
7.08–7.73 (m, 8 H, CHar.) ppm. 13C NMR (CDCl3): δ = 20.5 (CH-
CH(CH3)2], 72.6 [N-CH(-Car.)N], 115.7 (Car.CH=CH), 120.7
CH3), 57.6 (CH-CH3), 72.1 (CHar.), 116.6 (N-CH=CH), 120.9 (N- (CH=CH-N), 124.9 (CHar.), 125.4 (CHar.), 128.2 (2 CHar.), 128.7
CH=CH), 124.6 (CHar.), 125.4 (CHar.), 129.0 (2 CHar.), 129.4 (CHar.), 128.8 (CHar.), 130.2 (Car.), 130.4 (2 CHar.), 130.5 (Car.),
(CHar.), 129.6 (CHar.), 130.2 (Car.), 130.5 (Car.), 131.0 (Car.), 133.1 132.2 (Car.), 145.3 (Car.), 167.4 (CO) ppm. C21H22N2O3S (382.48):
(2 CHar.), 134.3 (Car.), 168.4 (CO) ppm. C18H15BrN2O3S (419.29):
calcd. C 51.56, H 3.61, N 6.68, S 7.65, Br 19.06; found C 50.98, H
3.55, N 6.69, S 7.80, Br 19.90.
calcd. C 65.95, H 5.80, N 7.32, S 8.38; found C 65.99, H 5.71, N
7.25, S 8.60.
(2S,10bR)-2-Isopropyl-1-(2-naphthylsulfonyl)-1,10b-dihydroimidazo-
[2,1-a]isoquinolin-3(2H)-one (5g): Yield: 46 %. M.p. 82 °C, Rf
X-ray Crystal Analysis of 5c:[29] Empirical formula:
C18H15BrN2O3S, formula mass: 419.29, temperature: 180(2) K, (CH2Cl2/CH3OH, 100:1) = 0.41. [α]2D0 = +141.2 (c = 1, CH2Cl2).
wavelength: 0.71073 Å, crystal system: orthorhombic, space group:
P 21 21 21, unit cell dimensions: a = 10.0035(12), b = 13.167(2), c
= 26.577(8) Å, Volume: 3500.6(13) Å3, Z = 8, density (calcd.): 1.591
Mg/m3, absorption coefficient: 2.488 mm–1, F o = 1696, crystal size:
0.96 × 0.80 × 0.645 mm, Theta range for data collection: 1.53 to
25.25 °, limiting indices: –12 Յ h Յ 12, –15 Յ k Յ 15, –0 Յ l Յ
31; reflections collected/unique 8662/6254 [R(int) = 0.0598], com-
pleteness to theta = 25.25 (100 %), absorption correction: empirical
(Ψ-scan), max. and min. transmission: 0.9960 and 0.9674, refine-
ment method: Full-matrix least-squares on F2, data/restraints/
1H NMR (CDCl3): δ = 0.86 [d, J = 7.0 Hz, 3 H , CH-(CH3)2], 0.90
[d, J = 7.0 Hz, 3 H, CH-(CH3)2], 2.16–2.22 [m, 1 H, CH-CH(CH3)
2], 4.13 [d, J = 4.1 Hz, 1 H, CH-CH(CH3)2], 6.06 [s, 1 H, N-CH-
(-Car.)N], 6.10 [d, J = 7.4 Hz, 1 H, Car.-CH=CH], 6.55 (d, J =
7.4 Hz, 1 H, CH=CH-N), 7.06–7.97 (m, 10 H, CHar.), 8.38 (s, 1 H,
Car. = CH-Car.) ppm. 13C NMR (CDCl3): δ = 18.0 [CH-(CH3)2],
18.4 [CH-(CH3)2], 32.9 [CH-CH-(CH3)2], 66.7 [CH-CH-(CH3)2],
72.7 [N-CH(-Car.)N], 115.6 (CH=CH-N), 120.8 (Car.-CH=CH),
122.6 (CHar.), 125.0 (CHar.), 125.5 (CHar.), 128.0 (2 CHar.), 128.9
(CHar.), 129.5 (CHar.), 129.6 (CHar.), 130.2 (Car.), 130.2 (CHar.),
parameters: 6254/0/541, goodness-of-fit on F2: 1.089, final Rint [I 130.3 (CHar.), 130.5 (Car.), 132.2 (2 Car.), 135.4 (Car.), 167.3 (CO)
Ͼ 2σ(I)]: R1 = 0.0488, wR2 = 0.1107, Rint (all data): R1 = 0.0702, ppm. C24H22N2O3S (418.51) calcd. C 68.88, H 5.30, N 6.69, S 7.66;
wR2 = 0.1278, absolute structure parameter: –0.007(11), largest
found C 68.51, H 5.35, N 6.57, S 7.68.
diff. peak and hole: 0.545 and –0.475 e·Å3
(2S,10bR)-2-Isobutyl-1-(p-tolylsulfonylamino)-1,10b-dihydroimidazo-
(2S,10bR)-1-(1,3-Benzothiazol-2-ylsulfonyl)-2-methyl-1,10b-dihy- [2,1-a]isoquinolin-3(2H)-one (5h): Yield: 40 %. M.p. 152 °C, Rf
droimidazo[2,1-a]isoquinolin-3(2H)-one (5d): Yield: 24 %. M.p.
(CH2Cl2/CH3OH, 100:1) = 0.38. [α]2D0 = +203.5 (c = 1, CH2Cl2),
668
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 663–672

Asymmetric Synthesis of Isoquinoline Derivatives from Amino Acids
FULL PAPER
1H NMR (CDCl3): δ = 0.74 [d, J = 6.6 Hz, 3 H, CH(CH3)2], 0.89
(Car.), 134.1 (Car.), 134.2 (Car.), 145.1 (Car.), 168.8 (CO) ppm.
[d, J = 6.6 Hz, 3 H, CH(CH3)2], 1.42–1.65 [m, 2 H, CH-CH2- HRMS (EI): C25H24N2O3S: calcd. 432.1508; found 432.1502.
CH(CH3)2], 1.98–2.05 [m, 1 H, CH2-CH(CH3)2], 2.38 (s, 3 H, Car.
CH3), 4.09 (t, J = 6.2 Hz, 1 H, CH-CH2), 5.95 [s, 1 H, N-CH(-Car.
N], 6.14 (d, J = 7.4 Hz, 1 H, Car.-CH=CH), 6.57 (d, J = 7.4 Hz, 1
H, CH=CH-N), 7.06–7.73 (m, 8 H, CHar.) ppm. 13C NMR
(CDCl3): δ = 21.7 (Car.-CH3), 22.4 [2 CH3, CH(CH3)2], 23.9 [CH-
CH2-CH(CH3)2], 43.4 [CH-CH2-CH(CH3)2], 60.1 [CH-CH2-
-
)
(2S,5S,10bR)-2-Benzyl-5-methyl-1-(p-tolylsulfonyl)-1,5,6,10b-tetra-
hydroimidazo[2,1-a]isoquinolin-3(2H)-one (6c): Yield: 99 %. M.p.
133 °C, Rf = 0.42 (CH2Cl2). Major Isomer: H NMR (CDCl3): δ =
1
0.95 (d, J = 6.5 Hz, 3 H, CH-CH3), 2.40 (s, 3 H, Car.-CH3), 2.41–
1
2
2.48 [dd, J = 4.7, J = 15.4 Hz, 1 H, trans-CH(H)-CH(-CH3)N],
2
2.66–2.71 [dd, = 5.0, J = 15.2 Hz, 1 H, cis-CH(H)-CH(-CH3)N],
CH(CH3)2], 72.4 [N-CH(-Car.)N], 116.1 (CH=CH-N), 121.2 (Car.
-
3.11 (d, J = 4.2 Hz, 2 H, CH-CH -Ph), 3.71–3.77 [m, 1 H, CH2-
2
CH=CH), 124.0 (CHar.), 125.4 (CHar.), 128.0 (2 CHar.), 128.8
(CHar.), 128.9 (CHar.), 130.2 (Car.), 130.5 (2 CHar.), 130.7 (Car.),
132.5 (Car.), 145.2 (Car.), 169.1 (CO) ppm. HRMS (+EI):
C22H24N2O3S: calcd. 396.1508; found 396.1494.
CH(-CH3)N], 4.21 (t, J = 4.2 Hz, 1 H, CH-CH2-Ph), 5.61 [s, 1 H,
N-CH(-Car.)N], 6.73–7.71 (m, 13 H, CHar.) ppm. 13C NMR
(CDCl3): δ = 17.4 (CH-CH3), 21.6 (Car.-CH3), 35.2 [Car.-CH2-CH(-
CH3)N], 37.9 (CH-CH2-Ph), 48.3 [Car.-CH2-CH(-CH3)N], 63.6
(NH-CH-CH2-Ph), 72.3 [N-CH(-Car.)N], 125.4 (CHar.), 126.6 (2
CHar.), 127.5 (2 CHar.), 127.7 (CHar.), 127.8 (CHar.), 128.3 (2 CHar.),
130.3 (2 CHar.), 130.7 (2 CHar.), 132.2 (Car.), 133.3 (Car.), 134.7
(Car.), 135.0 (Car.), 145.1 (Car.), 167.8 (CO) ppm. NOE: Irradiation
at 3.71–3.77 [m, 1 H, CH2-CH(-CH3)N] resulted in a NOE-signal
at 0.95 [d, 3 H, CH2-CH(-CH3)N], 2.66–2.71 [dd, 1J = 5.0, 2J =
(2S,10bR)-2-Benzyl-5-methyl-1-(p-tolylsulfonyl)-1,10b-dihydroimid-
azo[2,1-a]isoquinolin-3(2H)-one (5i): Yield: 12 %. M.p. 194 °C, Rf
(CH2Cl2) = 0.40. [α]2D0 = +263.1 (c = 1, CH2Cl2). 1H NMR
(CDCl3): δ = 2.15 [s, 3 H, CH=C(-N)CH3], 2.39 (s, 3 H, Car.-CH3),
3.07–3.11 (m, 2 H, CH-CH 2-Ph), 4.29–4.35 (m, 1 H, CH-CH2-Ph),
5.84 [s, 1 H, Car.-CH=C(-N)CH3], 5.85 [s, 1 H, N-CH(-Car.)N],
6.79–7.67 (m, 13 H, CHar.) ppm. 13C NMR (CDCl3): δ = 18.6
[CH=C(-N)CH3], 21.7 (Car.-CH3), 38.6 (CH-CH2-Ph), 62.9 (CH-
CH2-Ph), 73.5 [N-CH(-Car.)N], 115.3 [CH=C(-N)CH3], 123.9
(CHar.), 124.5 (CHar.), 126.9 (CHar.), 127.7 (CHar.), 128.0 (2 CHar.),
128.1 (2 CHar.), 129.9 (2 CHar.), 130.3 (CHar.), 130.4 (2 CHar.), 130.4
(Car.), 132.6 (Car.), 133.5 (Car.), 135.1 (Car.), 145.1 (Car.), 168.7 (CO)
ppm. C26H24N2O3S (444.55): calcd. C 70.25, H 5.44, N 6.30, S
7.21; found C 70.11, H 5.95, N 6.05, S 6.90.
15.2 Hz, 1 H, Car.-CH(H)-CH(-CH3)N], 5.61 [s, 1 H, N-CH(-Car.
)
N], irradiation at 5.61 [s, 1 H, N-CH(-Car.)N] gave a NOE signal
at 2.66–2.71 [dd, 1J = 5.0, 2J = 15.2 Hz, 1 H, cis-CH(H)-CH(-CH3)
N], 3.71–3.77 [m, 1 H, CH2-CH(-CH3)N], 7.38–7.71 (m, 3 H,
CHar.
)
ppm. Minor Isomer (2S,5R,10bR-Epimer): 1H NMR
1
(CDCl3): δ = 0.96 [d, J = 6.5 Hz, 3 H, CH-CH3], 2.11–2.18 [dd, J
= 4.7, J = 15.4 Hz, 1 H, trans-CH(H)-CH(-CH3)N], 2.39 (s, 3 H,
2
1
2
Car.-CH3), 2.47–2.53 [dd, J = 5.0, J = 15.2 Hz, 1 H, cis-CH(H)-
CH(-CH3)N], 2.96 (d, J = 4.2 Hz, 2 H, CH-CH 2-Ph), 4.02–4.07
[m, 1 H, CH2-CH(-CH3)N], 4.28 (t, J = 4.2 Hz, 1 H, CH-CH2-Ph),
5.79 [s, 1 H, N-CH(-Car.)N], 6.73–7.71 (m, 13 H, CHar.) ppm. 13C
1,5,6,10b-Tetrahydroimidazo[2,1-a]isoquinolin-3(2H)-ones 6. Gene-
ral Procedure: 10 % Pd-hydroxide/C (50 mg) were added to a solu-
tion of dihydroimidazo[2,1-a]isoquinolin-3-one 5. The mixture was
hydrogenated under atmospheric pressure whilst stirring for 3 h.
The resulting mixture was filtered through Celite and the filtrate
was evaporated under vacuum.
NMR (CDCl3): δ = 17.5 (CH-CH3), 21.6 (Car.-CH3), 33.4 [Car.
-
CH2-CH(-CH3)N], 38.1 (CH-CH2-Ph), 44.3 [Car.-CH2-CH(-CH3)
N], 63.9 (NH-CH-CH2-Ph), 69.7 [N-CH(-Car.)N], 125.4 (CHar.),
126.7 (2 CHar.), 127.7 (CHar.), 127.8 (CHar.), 127.9 (2 CHar.), 128.0
(2 CHar.), 130.2 (2 CHar.), 130.7 (2 CHar.), 132.1 (Car.), 133.5 (Car.),
135.1 (Car.), 135.6 (Car.), 145.1 (Car.), 168.7 (CO) ppm.
C26H26N3O2S (446.56): calcd. C 69.93, H 5.87, N 6.27, S 7.18;
found C 69.90, H 5.91, N 6.08, S 6.86.
(2S,10bR)-2-Methyl-1-(p-tolylsulfonyl)-1,5,6,10b-tetrahydroimidazo-
[2,1-a]isoquinolin-3(2H)-one (6a): Yield: 88 %. M.p. 171 °C, Rf (hex-
ane/EtOAc, 1:1) = 0.16. [α]2D0 = +25.9 (c = 1, CH2Cl2). H NMR
1
(CDCl3): δ = 1.19 (d, J = 7.1 Hz, 3 H, CH-CH3), 2.38 (s, 3 H, Car.
-
(2S,10bS)-2-Benzyl-1,5,6,10b-tetrahydroimidazo[2,1-a]-
isoquinolin-3(2H)-one (7a): In a Schlenk flask a solution of Na-
naphthalide (10.00 mmol) was prepared by addition of sublimed
naphthalene (1.280 g, 10.00 mmol) to a mixture of Na (0.230 g,
10.00 mmol) in dry THF (25 mL). The mixture was kept in an ul-
trasound bath for 2 min and was then stirred for 2–3 h resulting in
a homogeneous dark green solution of Na-naphthalide. This can
be used as a stock solution in several reduction experiments but it
must be used within 1 day. Portions of the stock solutions were
added dropwise to a solution of the N-tosylated precursor 6b
(0.105 g, 0.24 mmol) in dry THF (20 mL) until decolorization ce-
ased. After stirring at –100 °C for 30 min. satd. aq. NH4Cl (20 mL)
was added in portions at –100 °C. The mixture was warmed to
room temp. and was extracted with AcOEt (5 × 15 mL). The com-
bined organic layers were dried with MgSO4 and the solvent was
evaporated under vacuum. 7a (0.020 g, 30 %) was obtained as col-
orless oil after column chromatography with AcOEt. Rf (EtOAc)
= 0.31. [α]2D0 = +4.2 (c = 1, CH2Cl2). 13C NMR (CDCl3): δ = 28.3
(Car.-CH2-CH2-N), 37.0 (CH-CH2-Ph), 37.2 (Car.-CH2-CH2-N),
61.9 (CH-CH2-Ph), 70.0 [NH-CH(-Car.)N], 125.1 (CHar.), 126.7
(CHar.), 127.0 (CHar.), 128.0 (CHar.), 128.5 (2 CHar.), 129.0 (CHar.),
129.3 (2 CHar.), 133.7 (Car.), 135.3 (Car.), 137.4 (Car.), 172.9 (CO)
ppm. HRMS (+EI): C18H18N2O: calcd. 278.1419; found 278.1412.
CH3), 2.67–2.72 (m, 1 H, Car.-CH -CH2), 2.90–2.96 (m, 1 H, Car.
CH 2-CH2, CH2-CH 2-N), 3.12–3.21 (m, 1 H, CH2-CH 2-N), 3.80–
-
2
3.86 (m, 1 H, CH2-CH -N), 4.05 (q, J = 7.0 Hz, 1 H, CH-CH3),
2
5.93 [s, 1 H, N-CH-
(Car.)N], 7.03–7.86 (m, 8 H, CHar.) ppm. 13C NMR (CDCl3): δ =
19.6 (CH-CH3), 21.6 (Car.-CH3), 26.6 (Car.-CH2-CH2), 38.5 (CH2-
CH2-N), 57.5 (CH-CH3), 71.5 [N-CH(-Car.)N], 126.2 (CHar.), 127.2
(CHar.), 127.7 (2 CHar.), 128.3 (CHar.), 128.6 (CHar.), 130.3 (2
CHar.), 133.4 (Car.), 133.5 (Car.), 135.7 (Car.), 144.9 (Car.), 171.3
(CO) ppm. HRMS (+EI): C19H20N2O3S: calcd. 356.1195; found
356.1184.
(2S,10bR)-2-Benzyl-1-(p-tolylsulfonyl)-1,5,6,10b-tetrahydroimidazo-
[2,1-a]isoquinolin-3(2H)-one (6b): Yield: 99 % M.p. 206–207 °C, Rf
(CH2Cl2/CH3OH, 100:1) = 0.40. [α]2D0 = +13.4 (c = 1, CH2Cl2). ee
Ն 99 %, HPLC: Chiralcell OD, hexane/isopropyl alcohol, 95:5,
1
0.5 mL/min, λ = 254 nm). H NMR (CDCl3): δ = 2.28–2.30 (m, 2
H, Car.-CH -CH2-N), 2.39 (s, 3 H, Car.-CH3), 2.84–3.07 (m, 3 H,
2
Car.-CH -CH2-N, CH-CH -Ph), 3.88–3.94 (m, 1 H, Car.-CH2-CH
2
2
2-N), 4.30 (t, J = 4.1 Hz, 1 H, CH-CH2-Ph), 5.86 [s, 1 H, N-CH(-
Car.)N], 6.65–7.72 (m, 13 H, CHar.) ppm. 13C NMR (CDCl3): δ =
21.6 (Car.-CH3), 27.1 (Car.-CH2-CH2-N), 38.0 (CH-CH2-Ph), 38.5
(Car.-CH2-CH2-N), 63.5 (CH-CH2-Ph), 72.1 [N-CH(-Car.)N], 126.6
(CHar.), 126.8 (CHar.), 127.3 (CHar.), 127.4 (2 CHar.), 127.8 (CHar.), (2S,10bS)-2-Benzyl-1-methyl-1,5,6,10b-tetrahydroimidazo[2,1-a]-
128.0 (2 CHar.), 128.6 (CHar.), 130.3 (4 CHar.), 132.8 (Car.), 133.2 isoquinolin-3(2H)-one (7b): According to the procedure used for the
Eur. J. Org. Chem. 2005, 663–672
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
669

O. Sieck, M. Ehwald, J. Liebscher
FULL PAPER
synthesis of 7a (vide supra) 6b (0.240 g, 0.56 mmol) was detosyl-
ated. Before quenching the mixture with satd. aq. NH4Cl, methyl
iodide (0.08 mL, 0.018 g, 123 mmol) was added and stirring at
(4S,5aR)-4-Methyl-5-(p-tolylsulfonyl)-4,5,5a,9b-tetrahydroimidazo-
[2,1-a]oxirano[2,3-c]isoquinolin-3(1aH)-one (8a): Yield: 99 %. Col-
orless solid. M.p. 140–143 °C, Rf (hexane/EtOAc, 6:4) = 0.64.
–100 °C was continued for another 30 min. After extraction the [α]D20 = +72.4 (c = 1, CH2Cl2). H NMR (CDCl3): δ = 1.33 (d, J =
1
combined organic layers were washed with aq. 2 m NaS2O3 solution
(50 mL) and dried with MgSO4. Yield: 0.104 g (60 %) of light yel-
7.2 Hz, 3 H, CH-CH3), 2.48 (s, 3 H, Car.-CH3), 4.01 [d, J = 2.3 Hz,
1 H, Car.-CH(O)CH-N], 4.21 (q, J = 7.2 Hz, 1 H, CH-CH3), 5.39
low oil after column chromatography (CH2Cl2/MeOH, 100:1). Rf [d, J = 2.3 Hz, 1 H, Car.-CH(O)CH-N], 6.05 [s, 1 H, N-CH(-Car.
)
(CH2Cl2/CH3OH, 100:1) = 0.27. [α]2D0 = +16.2 (c = 1, CH2Cl2). 13 N], 7.26–7.91 (m, 8 H, CHar.) ppm. 13C NMR (CDCl3): δ = 20.0
C
NMR (CDCl3): δ = 28.0 (Car.-CH2-CH2-N), 38.1 (CH-CH2-Ph), (CH-CH3), 21.7 (Car.-CH3), 52.4 [CH(O)CH-N], 58.9 (CH-CH3),
38.6 (Car.-CH2-CH2-N), 42.9 (N-CH3), 69.9 (CH-CH2-Ph), 77.2 [N- 60.4 [CH(O)CH-N], 69.8 [N-CH(-Car.)N], 125.8 (CHar.), 127.8
CH(-Car.)N], 124.6 (CHar.), 126.1 (CHar.), 126.7 (CHar.), 127.6 (CHar.), 128.9 (2 CHar.), 129.3 (CHar.), 129.8 (CHar.), 130.4 (Car.),
(CHar.), 128.0 (2 CHar.), 128.3 (CHar.), 129.8 (2 CHar.), 134.5 (Car.), 130.5 (2 Car.), 132.7 (Car.), 133.4 (Car.), 145.3 (Car.),171.6 (CO) ppm.
137.3 (Car.), 138.3 (Car.), 171.4 (CO) ppm. HRMS (EI):
C19H20N2O: calcd. 292.1576; found 292.1546.
C19H18N2O4S (370.42): calcd. C 61.61, H 4.90, N 7.56, S 8.65;
found C 60.04, H 5.21, N 7.24, S 8.15.
tert-Butyl (2S,10bR)-2-Benzyl-3-oxo-2,3,6,10b-tetrahydroimidazo
[2,1-a]isoquinolin-1(5H)-carboxylate (7c): According to the pro-
cedure used for the synthesis of 7a (vide supra) 6b (0.400 g,
0.92 mmol) was detosylated. After the addition of Na-naphthalide
was completed and the resulting solution was stirred at –100 °C
for 1 h, di-tert-butyl dicarbonate (0.59 mL, 0.605 g, 2.77 mmol) was
added. The mixture was slowly warmed to room temperature. Aq.
satd. NH4Cl solution (50 mL) was added and the mixture was ex-
tracted with AcOEt (4 × 20 mL). After drying of the combined
organic layers with MgSO4, evaporation of solvent and column
chromatography (hexane/AcOEt, 7:3 Ǟ AcOEt) 0.288 g (83 %) of
the product 7c was obtained as colorless solidifying oil, which
could be recrystallized from EtOH. M.p. 215 °C, Rf (hexane/
EtOAc, 7:3) = 0.45. [α]2D0 = +6.7 (c = 1, CH2Cl2). 1H NMR
(CDCl3): δ = 1.42 [s, 9 H, C(CH3)3], 2.39–2.51 (m, 2 H, Car.-CH2-
CH2-N), 2.83 [br. m, 1 H, Car.-CH(H)-CH2-N], 2.96–3.12 (m, 2 H,
(4S,5aR)-4-Benzyl-5-(p-tolylsulfonyl)-4,5,5a,9b-tetrahydroimidazo-
[2,1-a]oxirano[2,3-c]isoquinolin-3(1aH)-one (8b): Yield: 98 %. Col-
orless solid. M.p. 149–151 °C, Rf (hexane/EtOAc, 6:4) = 0.60. [α]
20
1
= +88.1 (c = 1, CH2Cl2). H NMR (CDCl3): δ = 2.39 (s, 3 H,
D
Car.-CH3), 3.03–3.11 (m, 2 H, CH-CH2-Ph), 3.78 [d, J = 3.0 Hz, 1
H, Car.-CH(O)CH-N], 4.36–4.39 (m, 1 H, CH-CH2-Ph), 5.30 [d, J
= 3.0 Hz, 1 H, CH(O)CH-N], 5.83 [s, 1 H, N-CH(-Car.)N], 6.73–
7.71 (m, 13 H, CHar.) ppm. 13C NMR (CDCl3): δ = 21.7 (Car.
-
CH3), 38.4 (CH-CH2-Ph), 52.1 (CH(O)CH-N), 60.1 (CH-CH2-Ph),
64.6 (CH(O)CH-N), 69.9 [N-CH(-Car.)N], 126.4 (CHar.), 126.9
(CHar.), 127.7 (CHar.), 127.8 (2 CHar.), 128.0 (2 CHar.), 128.1
(CHar.), 128.9 (Car.), 129.3 (CHar.), 130.0 (2 CHar.), 130.5 (2 CHar.),
132.2 (Car.), 132.4 (Car.), 134.6 (Car.), 145.4 (Car.), 169.6 (CO) ppm.
HRMS (EI): C25H22N2O4S: calcd. 446.1300; found 446.1297.
[2+2] Cycloadduct 9 of Dihydroimidazo[2,1-a]isoquinolin-3(2H)-one
5e: A solution of the dihydroimidazoisoquinolinone 5e (0.092 g,
0.25 mmol), 1,5-dimethoxynaphthalene (0.024 g, 0.13 mmol), and
ascorbic acid (0.229 mg, 1.30 mmol) in 96 % EtOH (120 mL) was
irradiated by a 150-W Hg lamp at room temp for 4 h. The resulting
solution was concentrated under vacuum and the residue was dis-
solved in CH2Cl2 (20 mL). The solution was washed with water,
dried with MgSO4 and the solvent was removed under vacuum.
The residue was purified by column chromatography (hexane/
EtOAc, 7:3) affording 0.061 g (66 %) of unreacted starting material
and 0.027 g (29 %) of the product 9 as colorless solid. M.p. Ͼ
240 °C under decomposition. Rf = 0.18. 1H NMR (CDCl3): δ =
1.18 (d, J = 7 Hz, 6 H, 1 Hz, 2 CH-CH3), 2.33 (s, 6 H, 2 Car.-CH3),
3.52 (d, J = 8.1 Hz, 2 H, 2 CH [cyclobutane]), 4.04–4.11 (m, 2 H,
2 CH-CH3), 4.48 (d, J = 8.1 Hz, 2 H, 2 CH [cyclobutane]), 6.93 [s,
2 H, 2 N-CH(-Car.)N], 7.19–7.87 (m, 16 H, CHar.) ppm. 13C NMR
(CDCl3): δ = 19.4 (2 CH-CH3), 21.6 (2 Car.-CH3), 44.0 (2 CH[cyclo-
butane]), 49.3 (2 CH[cyclobutane]), 57.4 (2 CH-CH3), 69.6 [2 N-
CH(-Car.)N], 126.7 (2 CHar.), 127.3 (4 CHar.), 128.1 (4 CHar.), 129.6
(2 CHar.), 130.6 (4 CHar.), 132.9 (2 Car.), 134.3 (2 Car.), 134.6 (2
Car.), 145.4 (2 Car.), 169.7 (2 C=O) ppm. HRMS (+EI):
C38H36N4O6S2: calcd. 708.2076; found 708.2081.
CH-CH -Ph), 4.08 [br. m, 1 H, Car.-CH(H)-CH2-N], 4.51 (br. m,
2
CH-CH2-Ph), 6.12 [br. s, 1 H, N-CH(-Car.)N], 6.75–7.38 (m, 9 H,
CHar.) ppm. 13C NMR (CDCl3): δ = 27.4 (Car.-CH2-CH2-N), 28.3
[C(CH3)3], 37.5 (CH-CH2-Ph), 37.8 (Car.CH2-CH2-N), 62.2 (CH-
CH2-Ph), 70.2 [N-CH(-Car.)N], 81.5 [O-C(CH3)3], 126.4 (CHar.),
126.6 (CHar.), 127.5 (CHar.), 128.5 (CHar.), 130.0 (4 CHar.), 133.2
(Car.), 135.4 (Car.), 136.0 (Car.), 155.6 (N-COOtBu), 169.6 (CO)
ppm. C23H26N2O3 (378.46): calcd. C 72.99, H 6.92, N 7.40; found
C 72.51, H 6.89, N 7.24.
[29]
X-ray Crystal Analysis of 7c:
Empirical formula: C23H26N2O3,
formula mass: 378.46, temperature: 180(2) K, wavelength:
0.71073 Å, crystal system: orthorhombic, space group: Pbca, unit
cell dimensions: a = 11.971(2), b = 10.3825(14), c = 32.237(5) Å,
volume 4006.9(12) Å3, Z = 8, density (calcd.): 1.255 Mg/m3, ab-
sorption coefficient: 0.083 mm–1, F = 1616, crystal size: 0.40 ×
o
0.24 × 0.05 mm, Theta range for data collection: 2.67 to 25.25 °,
limiting indices: –14 Յ h Յ 14, –11 Յ k Յ 11, –38 Յ l Յ 38;
reflections collected/unique 23584/3531 [R(int) = 0.0573], com-
pleteness to theta = 25.25 (97.2 %), absorption correction: empiri-
cal (Ψ-scan), max. and min. transmission: 0.9960 and 0.9674, re-
finement method: full-matrix least-squares on F2, data/restraints/
parameters: 3531/0/332, goodness-of-fit on F2: 0.975, final Rint [I
Ͼ 2σ(I)]: R1 = 0.0388, wR2 = 0.0885, Rint (all data): R1 = 0.0526,
wR2 = 0.0945, extinction coefficient: 0.0063(9), largest diff. peak
and hole: 0.300 and –0.223 e·Å3.
(1R,2S,5R,6S)-5-Hydroxy-2-methyl-6-propylamino-1-(p-tolylsulf-
onyl)-1,5,6,10b-tetrahydro-2H-imidazo[2,1-a]isoquinolin-3-one (10a):
A solution of the oxirane 8a 0.300 g (0.80 mmol) and the corre-
sponding amine (0.80 mmol) in CH2Cl2 (20 mL) was refluxed for
10 h (TLC). The solution was evaporated and the residue was
recrystallized from hexane/AcOEt affording 0.305 g (88 %) of the
light-yellow product. M.p. 127–130 °C, Rf (hexane/EtOAc, 6:4) =
Tetrahydroimidazo[2,1-a]oxirano[2,3-c]isoquinolin-3(1aH)-ones 8: A
freshly prepared 0.1 m solution of dimethyldioxirane in acetone
(125 mL) was added to a solution of the dihydroimidazo[2,1-a]iso-
quinoline 5 (0.28 mmol) in acetone (30 mL) at 0 °C whilst stirring.
The solution was allowed to warm up to r. t. slowly and was stirred
overnight. The solution was dried with MgSO4 and the solvent was
distilled off. No sign of formation of diastereomers was observed
in the NMR spectra of the crude products.
0.42. [α]2D0 = –26.4 (c = 1, CH2Cl2). H NMR (CDCl3): δ = 0.92–
1
0.96 (m, 3 H, CH2-CH3), 1.33 (d, J = 7.1 Hz, 3 H, CH-CH3), 1.52–
1.58 (m, 2 H, CH -CH3), 2.21 (br., OH), 2.44 (s, 3 H, Car.-CH3),
2
2.70–2.74 (m, 2 H, NH-CH -CH2), 3.74 [d, J = 6.4 Hz, 1 H, Car.
-
2
CH(NH)CH-N], 4.09–4.13 (m, 1 H, CH-CH3), 5.13 [d, J = 6.4 Hz,
670
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 663–672

Asymmetric Synthesis of Isoquinoline Derivatives from Amino Acids
FULL PAPER
1 H, Car.-CH-CH -(OH)-N], 6.10 [s, 1 H, N-CH-(Car.)N], 7.38–7.81 CH-(Car.)N], 88.0 [Car.-CH-CH(OCH3)-N], 125.3 (CHar.), 127.8
(m, 8 H, CHar.) ppm. 13C NMR (CDCl3): δ = 11.7 (CH2-CH3), (CHar.), 128.0 (CHar.), 129.0 (CHar.), 129.1 (CHar.), 130.3 (Car.),
19.6 (CH-CH3), 21.6 (Car.-CH3), 23.5 (NH-CH2-CH2), 42.7 (NH- 132.8 (2 Car.), 134.2 (Car.), 136.1 (Car.), 145.1 (Car.), 171.7 (CO)
CH2-CH2), 50.0 [Car.-CH(NH)CH-N], 57.6 (CH-CH3), 60.3 [Car.
-
ppm. HRMS (EI): C20H22N2O5S: calcd. 402.1249; found 402.1247.
CH-CH-(OH)-N], 69.5 [N-CH-(Car.)N], 124.5 (CHar.), 126.1
(CHar.), 127.2 (CHar.), 127.8 (CHar.), 128.8 (CHar.), 130.4 (Car.),
133.2 (Car.), 134.7 (Car.), 136.1 (Car.), 145.0 (Car.), 171.5 (CO) ppm.
HRMS (EI): C22H27N3O4S: calcd. 429.1722; found 429.1729.
1,4-Dioxane 13: TMS-OTf (44 µL, 0.24 mmol) was added to a solu-
tion of the oxirane 8b in dry CH2Cl2 (25 mL). After 30 min stirring
allyl-TMS (28 mg, 0.24 mmol) was added at –78 °C. Stirring was
continued for 1 h. The mixture was warmed to room temp. and
was washed with satd. aq. Na2CO3. The organic layer was sepa-
rated and the aqueous phase was extracted with CH2Cl2 (3 ×
20 mL). The combined organic layers were dried with MgSO4 and
the solvent was distilled off under vacuum. After column chroma-
tography with hexane/EtOAc (6:4) the product was obtained as col-
orless solid (0.068 g, 58 %). M.p. 95–96 °C, Rf (hexane/EtOAc, 6:4)
= 0.72. HRMS (FAB): C50H44N4O8S2: calcd. 915.2497 [M + Na+];
found 915.2492.
(1R,2S,5R,6S)-5-Hydroxy-2-methyl-6-pyrrolidinyl-1-(p-tolylsulf-
onyl)-1,5,6,10b-tetrahydro-2H-imidazo[2,1-a]isoquinolin-3-one (10b):
In analogy to 10a, pyrrolidine (0.60 mL, 0.050 g, 0.67 mmol) was
reacted with the epoxide 8a (0.250 g, 0.67 mmol) in CH2Cl2
(20 mL) for 3 h. 10b was obtained as a yellow solid product
(0.272 g, 91 %) after recrystallisation from hexane/EtOAc. M.p.
1
137–139 °C, Rf (EtOAc) = 0.64. [α]2D0 = –19.1 (c = 1, CH2Cl2). H
NMR (CDCl3): δ = 1.27 (d, J = 6.8 Hz, 3 H, CH-CH3), 1.82–1.88
(m, 4 H, N-CH2-CH 2), 2.14 (br., OH), 2.43 (s, 3 H, Car.-CH3),
(2S,10bR)-2-Phenyl-6,10b-dihydro-5H-[1,3]oxazolo[2,3-a]-
isoquinolin-3(2H)-one (17): In analogy to the synthesis of the Reis-
sert product 4 (S)-O-TBDMS mandelic acid chloride 15 (0.346 g,
1.21 mmol) was reacted with AlCl3 (0.032 g, 0.24 mmol), 3,4-dihy-
droisoquinoline (0.159 g, 1.21 mmol) and TMS-CN (0.18 mL,
0.144 g, 1.21 mmol) affording 0.132g (41 %) of the product 17 as
colorless crystals. M.p. 124–126 °C, [α]2D0 = –23.4 (c = 0.5, CH2Cl2),
3.03–3.07 (m, 4 H, NH-CH -CH2), 3.75 [d, J = 2.6 Hz, 1 H, Car.
-
2
CH(NH)CH-(OH)], 4.09–4.13 (m, 1 H, CH-CH3), 5.65 [d, J =
3.0 Hz, 1 H, Car.-CH-CH-(OH)-N], 6.15 [s, 1 H, N-CH-(Car.)N],
6.52 (s, 1 H, OH), 7.34–7.93 (m, 8 H, CHar.) ppm. 13C NMR
(CDCl3): δ = 19.9 (CH-CH3), 21.6 (Car.-CH3), 23.6 und 24.7 (NH-
CH2-CH2), 45.5 und 50.1 (NH-CH2-CH2), 58.3 [N-CH-(Car.)N],
63.6 (CH-CH3), 69.2 [Car.-CH(N)CH-N], 74.4 [Car.-CH-CH(OH)-
N], 125.8 (CHar.), 127.9 (CHar.), 128.0 (2 CHar.), 128.2 (CHar.),
129.5 (CHar.), 130.3 (Car.), 133.5 (2 Car.), 134.7 (Car.), 144.8 (Car.),
170.3 (CO) ppm. HRMS (EI): C23H27N3O4S: calcd. 441.1722;
found 441.1726.
1
Rf (hexane/EtOAc, 6:4) = 0.42. H NMR (CDCl3): δ = 2.73 (m, 1
H, CH2), 3.03 (m, 1 H, CH2), 3.26 (m, 1 H, CH2), 4.16 (m, 1 H,
CH2), 5.23 (s, 1 H, CH), 6.30 (s, 1 H, CH), 7.12–7.46 (m, 9 H,
CHar.) ppm. 13C NMR (CDCl3): δ = 27.6 (CH2), 37.4 (CH2), 79.9
(CH), 86.1 (CH), 125.6 (CHar.), 126.2 (2 CHar.), 127.1 (CHar.), 128.6
(CHar.), 128.7 (2 CHar.), 128.8 (CHar.), 128.9 (CHar.), 133.8 (Car.),
134.5 (Car.), 136.3 (Car.), 169.5 (CO) ppm. C17H15NO2 (265.31):
calcd. C 76.96, H 5.70, N 5.28; found C 76.05, H 5.99, N 5.31. The
(2R,10bS)-enantiomer ent-17 was obtained accordingly from (R)-
O-TBDMS mandelic acid chloride.
(1R,2S,5R,6S)-5-Hydroxy-2-methyl-6-phenylamino-1-(p-tolylsulf-
onyl)-1,5,6,10b-tetrahydro-2H-imidazo[2,1-a]isoquinolin-3-one (10c):
In analogy to 10a, aniline (0.050 g, 0.54 mmol) was reacted with
8a (0.200 g, (0.54 mmol) in CH2Cl2 (20 mL). After 8 h reflux and
evaporation of the solvent 0.211 g (80 %) of the product were ob-
tained as yellow oil. Rf (EtOAc) = 0.38. [α]2D0 = –39.8 (c = 1,
CH2Cl2). 1H NMR (CDCl3): δ = 1.35 (d, J = 6.8 Hz, 3 H, CH-
CH3), 2.37 (s, 3 H, Car.-CH3), 3.69 (br., 2 H, NH, OH), 4.15 (q, J
= 6.8 Hz, 1 H, CH-CH3), 4.41 [d, J = 6.4 Hz, 1 H, Car.-CH(N)
CH(OH)], 5.17 [d, J = 6.8 Hz, 1 H, Car.-CH-CH-(OH)-N], 6.19 [s,
1 H, N-CH-(Car.)N], 6.62–7.83 (m, 13 H, CHar.) ppm. 13C NMR
[29]
X-ray Crystal Analysis of ent-17:
Empirical formula:
C17H15NO2, formula mass: 265.30, temperature: 180(2) K, wave-
length: 0.71073 Å, crystal system: monoclinic, space group: P21,
unit cell dimensions: a = 9.724(2), α = 90 °, b = 6.4224(12), ß =
93.75(4) °, c = 10.883(4), γ = 90 °. volume: 678.2(3) Å3, Z = 2.
density (calcd.): 1.299 Mg/m3, absorption coefficient: 0.085 mm–1,
F(000) = 280, crystal size: 0.80 × 0.69 × 0.16 mm, Theta range for
data collection: 2.72 to 25.83 °, limiting indices:–11 Յ h Յ 11, –7
Յ k Յ 7, –13 Յ l Յ 13; reflections collected/unique 4673/2542
[R(int) = 0.0202], completeness to theta = 25.83 (97.8 %), absorp-
tion correction: empirical (Ψ-scan), max. and min. transmission:
0.9865 and 0.9348, refinement method: full-matrix least-squares on
F2, data/restraints/parameters: 2542/1/241, goodness-of-fit on F2:
(CDCl3): δ = 19.6 (CH-CH3), 21.6 (Car.-CH3), 56.7 [N-CH-(Car.
)
N], 57.4 (CH-CH3), 69.3 [Car.-CH(N)CH-N], 76.1 [Car.-CH-
CH(OH)-N], 113.5 (CHar.), 115.2 (CHar.), 118.6 (CHar.), 124.2
(CHar.), 126.8 (CHar.), 127.8 (CHar.), 129.2 (2 CHar.), 129.3 (CHar.),
130.4 (CHar.), 133.0 (Car.), 133.6 (2 Car.), 136.2 (Car.), 145.1 (Car.),
146.3 (CHar.), 147.0 (CHar.), 171.4 (CO) ppm. HRMS (EI):
C25H25N3O4S: calcd. 463.1565; found 463.1570.
1.049, final R
[I Ͼ 2σ(I)]: R1 = 0.0250, wR2 = 0.0631, Rint (all
inr
(1R,2S,5S,6R)-6-Hydroxy-5-methoxy-2-methyl-1-(p-tolylsulfonyl)-
1,5,6,10b-tetrahydro-2H-imidazo-[2,1-a]isoquinolin-3-one (12): Con-
centrated sulfuric acid (3 drops) was added to a solution of the
epoxide 8a (0.200 g, 0.51 mmol) in MeOH (15 mL). After 5 h
(TLC) the solvent was evaporated and the residue was dissolved in
CH2Cl2 (about 20 mL). The solution was washed with water and
dried with MgSO4. The product (0.072 g, 34 %) was isolated as
colorless oil by evaporation first with a rotary evaporator followed
by high-vacuum conditions. Rf = 0.60 (hexane/EtOAc, 6:4) = 0.60.
data): R1 = 0.0276 wR2 = 0.0643, absolute structure parameter:
0.2(8), largest diff. peak and hole: 0.125 and –0.125 e·Å3.
Acknowledgments
We gratefully acknowledge financial support by the Fonds der
Chemischen Industrie and by Elbion AG Radebeul.
[α]2D0 = –23.3 (c = 1, CH2Cl2). H NMR (CDCl3): δ = 1.29 (d, J =
1
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Eur. J. Org. Chem. 2005, 663–672
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
671

O. Sieck, M. Ehwald, J. Liebscher
FULL PAPER
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672
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 663–672