Asymmetric synthesis of 3-substituted dihydro-2H-isoquinolin-1-ones, dihydro- and tetrahydroisoquinolines via 1,2-addition/ring closure

Article abstract of DOI:10.1055/s-2004-834861

The asymmetric synthesis of 3-substituted dihydro-2H-isoquinolin-1-ones, dihydro- and tetrahydroisoquinolines is described. The key operation is a tandem 1,2-addition/ring closure sequence employing lithiated ortho-toluamides and aldehyde SAMP- or RAMP-hydrazones as substrates, followed by N-N bond cleavage to remove the auxiliary. Moderate to good yields and high enantiomeric excesses (ee = 85-99%) are reached.

Full text of DOI:10.1055/s-2004-834861

2980
PAPER
Asymmetric Synthesis of 3-Substituted Dihydro-2H-isoquinolin-1-ones,
Dihydro- and Tetrahydroisoquinolines via 1,2-Addition/Ring Closure
A
symmetric Synth
i
esis of
e
Substitute
d
t
Isoqui
e
nolines
a
nd
r
Isoquinolinon
E
es nders,* Volker Braig, Marine Boudou, Gerhard Raabe
Institut für Organische Chemie, Rheinisch-Westfälische Technische Hochschule, Professor-Pirlet-Straße 1, 52 074 Aachen, Germany
Fax +49(241)8092127; E-mail: Enders@rwth-aachen.de
Received 16 August 2004; revised 24 August 2004
sparteine.5b Good overall yields and high enantioselectiv-
Abstract: The asymmetric synthesis of 3-substituted dihydro-2H-
ities were obtained in a three-step process using chiral
isoquinolin-1-ones, dihydro- and tetrahydroisoquinolines is de-
scribed. The key operation is a tandem 1,2-addition/ring closure se-
quence employing lithiated ortho-toluamides and aldehyde SAMP-
sulfinimines.5c,e Later, these two concepts were combined
and 8-oxoprotoberberines were assembled upon conden-
or RAMP-hydrazones as substrates, followed by N–N bond cleav- sation of ortho-toluamides incorporating chiral auxiliaries
age to remove the auxiliary. Moderate to good yields and high enan-
with 3,4-dihydroisoquinoline in moderate yields and high
enantiomeric excesses.13 (–)-Sparteine has also been used
tiomeric excesses (ee = 85–99%) are reached.
Key words: asymmetric synthesis, nucleophilic addition, cyclisa-
tion, hydrazones, heterocycles
instead of an auxiliary giving moderate yield and low to
good enantioselectivity.14
Recently, we reported on the first asymmetric synthesis of
3-aryl-substituted 2,3-dihydro-1H-isoindol-1-ones by
1,2-addition of ortho-lithiated benzamides to aldehyde
SAMP/RAMP hydrazones.15 We now wish to disclose an
asymmetric synthesis of the title isoquinoline heterocy-
cles 4, 5 and 6 by nucleophilic 1,2-addition of lithiated
N,N-diethyl-2-methylbenzamides 1 to aldehyde SAMP-
or RAMP-hydrazones 2 and subsequent removal of the
auxiliary from the resulting 3,4-dihydro-2H-isoquinolin-
1-one derivatives 3 by N–N bond cleavage (Scheme 1).
The stereoselective synthesis of compounds containing a
tetrahydroisoquinoline skeleton is a field of growing in-
terest in synthetic organic chemistry as these compounds
display a unique structure and a broad spectrum of biolog-
ical properties.1 For instance, ecteinascidin 743 (Et 743)
belonging to the saframycin family shows strong antitu-
mor activity and is currently in phase II of clinical trials.2
Another representative example (+)-tetrahydropalmatine,
is an analgesic, sedative and hypnotic agent3 and belongs
to the protoberberine family, a large class of naturally oc-
curring alkaloids possessing antitumor, antimicrobial and
other biological activities.4d,e,5 The asymmetric synthesis
of 1-substituted tetrahydroisoquinolines has been devel-
oped to a large extent6,7 as they are part of many naturally
occurring alkaloids.1 In contrast, the stereoselective syn-
thesis of 3-substituted tetrahydroisoquinolines or tetrahy-
droisoquinolinones has less precedent in the literature.7,8
Especially, 3-aryl tetrahydroisoquinolines are of consid-
erable interest as synthetic intermediates for the elabora-
tion of related alkaloids like protoberberines, pavines or
benzo[c]phenanthridines.1,4
A first approach to synthesize N-amino-substituted 3-phe-
nyl-3,4-dihydro-2H-isoquinolin-1-one 3a employed 3.5
equivalents of lithiated N,N-diethyl-2-methylbenzamide
1a and addition to benzaldehyde-SAMP-hydrazone 2a. A
Table 1 Synthesis of (2S,3R)-3a from 1a, Optimization of Condi-
tions
Entry 1a
Metalation Additive Addition
Yield of
(equiv) Temp (°C)
Temp (°C) (2S,3R)-3a
(%)
1
2
3.5
10
–78
–78
–78
–78
–78
–40
–78
–40
–78
–78
–
–
–78 to r.t.
–78 to r.t.
37
46
21
43
31
52a
50
70
45
An important entry to the title isoquinoline heterocycles is
the general concept of nucleophilic addition/cyclization
first outlined by McLean et al., who obtained 13-hydroxy-
8-oxoprotoberberines from lithiated phthalide anions and
3,4-dihydroisoquinolines.9 In a related approach, Clark et
al. pioneered a non-stereoselective tandem addition/cy-
clization of lithiated 2-methyl-benzamides with imines to
yield 3-substituted dihydro-2H-isoquinolin-1-ones with
low to moderate yields.10 Since then, the lateral metalation
methodology11 has been applied stereoselectively in mod-
erate yields using enantiopure imines,12 or in low yields
and good enantioselectivity using racemic imines and (–)-
3
5
5
5
7
7
7
7
7
BF3·OEt2 –78 to r.t.
4
LiCl
LiI
–
–78 to r.t.
–78 to r.t.
–40
5
6
7
Yb(OTf)3 –40
8
AlMe3
AlMe3
AlMe3
–40
9
–20
10
–60 to –78 25
SYNTHESIS 2004, No. 18, pp 2980–2990
x
x.
x
x
.
2
0
0
4
a With RAMP as auxiliary.
Advanced online publication: 07.10.2004
DOI: 10.1055/s-2004-834861; Art ID: Z16104SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Asymmetric Synthesis of Substituted Isoquinolines and Isoquinolinones
2981
R1
ee ≥ 95%
R1 = H
N
R2
2 = C6H5, ferrocenyl, furan-2-yl
OMe
N
R
b
4a, 4d,e
23–67%
O
O
O
R1
R1
R1
ee = 85-99%
a
NEt2
N
NH
c
R
R
1 = H
36–70%
27–93%
R2
R2
2 = C6H5, ferrocenyl, furan-2-yl
Me
5a, 5d,e
1a R1 = H
1b R1 = CH3
3a–f
d
N
de ≥ 96%
R1
N
35–85%
ee ≥ 97%
NH
OMe
R2
H
R1 = H, CH3
R2 = C6H5, p-MeOC6H4, ferrocenyl,
furan-2-yl
R2
R2 = C6H5, p-BrC6H4, p-MeOC6H4,
ferrocenyl, furan-2-yl
2a–e
6a, 6c–f
Scheme 1 Reagents and conditions: (a) LDA, THF, –40 °C then 2a–e, AlMe3, THF, –40 °C, 16–18 h; (b) Li or Ca, NH3 (l), THF, reflux, 5
min; (c) 1) acetyl chloride, MeOH; 2) Zn, AcOH, 6 N HCl, ))), 15 min then reflux, 36 h (method A) or MMPP·6H2O, MeOH, r.t., 24–96 h
(method B) or SmI2, THF, r.t., 30 min (method C); (d) 1) excess BH3·THF, THF, reflux, 4 h; 2) 1 N HCl, reflux, 1 min.
yield of 37% of 3a was obtained (Table 1, entry 1). The temperatures (entry 10) did not result in any further im-
open-chain product resulting from a single 1,2-addition provements.
reaction could not be detected, indicating that the reaction
took place in a tandem 1,2-addition ring closure process.
Consequently, 3,4-dihydro-2H-isoquinolin-1-ones 3a–e
were then synthesized under the optimized conditions em-
As shown in Table 1, the reaction conditions were opti-
ploying the aromatic aldehyde SAMP- or RAMP-hydra-
mized varying the number of equivalents of 1a, the tem-
zones 2a–e15,17 (Scheme 1, Table 2). To a further extend
perature of metalation and addition and the additive. A
the scope of the reaction was attempted by substitution at
large excess of lithiated ortho-toluamide 1a slightly im-
the aromatic ring of the N,N-diethylbenzamide 1. Indeed
N,N-diethyl-2,5-dimethylbenzamide 1b was employed
successfully with the ferrocenyl aldehyde hydrazone 2d
(entry 7 and 8). It is assumed that the lower yield could be
due to competitive deprotonation of the meta-methyl
group and addition to the SAMP-hydrazone (entries 7 and
8 vs. 4). Interestingly, the formation of 3e and 3f was
found to give better results without trimethylaluminium
proved the yield (entry 1 vs. 2). Various additives like
BF3·OEt2, LiCl, LiI and Yb(OTf)3 were examined, but
none of them was found to have a significant effect on the
reaction (entries 3 to 5, entry 7). When the metalation and
the addition were conducted at a temperature of –40 °C,
the yield could be increased to 52% (entry 6 vs. 2). Refer-
ring to the positive effects trimethylaluminum had on the
nucleophilic 1,2-addition of organolithiums to enantio-
(entry 5 vs. 6, entry 7 vs. 8).
merically pure N-sulfinyl ketimines,16 this Lewis acid was
Methods for the N–N bond cleavage of the auxiliary were
then envisaged. Its presence resulted in the best yield so
then investigated. We initially examined to use lithium in
far (70%, entry 8). Higher (entry 9) and lower reaction
Table 2 Tandem 1,2-Addition/Ring Closure of Lithiated N,N-Diethyl-2-methylbenzamides 1a,b with Aldehyde SAMP- or RAMP-Hydra-
zones 2a–e to Afford 3- and N-Substituted 3,4-Dihydro-2H-isoquinolin-1-ones 3a–f
Entry
1
R1
H
2
R2
Additive
AlMe3
AlMe3
AlMe3
AlMe3
AlMe3
–
3
Yield (%) dea (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1b
1b
(S)-2a
(S)-2b
(S)-2c
(S)-2d
(S)-2e
(R)-2e
(S)-2d
(R)-2d
Phenyl
(2S, 3R)-3a
(2S, 3R)-3b
(2S, 3R)-3c
(2S, 3R)-3d
(2S, 3R)-3e
(2R, 3S)-3e
(2S, 3R)-3f
(2R, 3S)-3f
70
65
39
63
40
45
36
46
≥96
≥96
≥96
≥96
≥96
≥96
≥96
≥96
H
p-Bromphenyl
p-Methoxyphenyl
Ferrocenyl
Furan-2-yl
Furan-2-yl
Ferrocenyl
Ferrocenyl
H
H
H
H
CH3
CH3
AlMe3
–
a Determined by 1H and 13C NMR after column chromatography.
Synthesis 2004, No. 18, 2980–2990 © Thieme Stuttgart · New York

2982
D. Enders et al.
PAPER
liquid ammonia as it had been previously employed to concentration under reduced pressure, the resulting hy-
cleave hydrazines which have been activated by prior con- drochloride salts were dissolved in acetic acid and zinc
version to amide or carbamate derivatives.18 Yet, when we powder was added. However, this method was found not
applied these conditions to hydrazine (2S,3R)-3a, only to be very effective. The yield was moderate for 5a, al-
traces of the expected 3,4-dihydro-2H-isoquinolin-1-one though displaying high enantioselectivity (Table 4, entry
(R)-5a were obtained together with 44% of 3,4-dihy- 1). Compound 5d was obtained in 91% yield with com-
droisoquinoline (R)-4a in an excellent enantiomeric ex- plete racemization (Table 4, entry 4) and a low yield was
cess (ee ≥96%) (Scheme 1, Table 3, entry 1). This product obtained for 5e together with racemization (Table 4, entry
is probably formed by reduction of the carbonyl group and 6). We then investigated a second cleavage method using
subsequent dehydration. We were interested in develop- MMPP (Scheme 1, step c, method B, Table 4) as it has al-
ing the asymmetric synthesis of this unexpected product ready been used successfully to cleave N–N bonds of hy-
because it can be readily transformed into 1,3-di- drazines derived from SAMP15,25 or related hydrazones.26
substituted tetrahydroisoquinolines. Indeed, high 1,3- This method was found to be partially effective as the
asymmetric inductions were reported by nucleophilic ad- yield of 5a was good and no racemization was observed
dition of allylic tin reagents to chiral 3-substituted 3,4-di- (Table 4, entry 2). With 3d, a complex mixture of non-
hydroisoquinolines.19 The enantioselective addition of identified by-products was obtained (Table 4, entry 5).
organometallic compounds to 3,4-dihydroisoquinoline in The yield of 5e was very low, although the reaction took
the presence of oxazoline ligands is also known.20 Addi- place without any racemization (Table 4, entry 7). We
tion of phthalide anions9 or ortho-toluamide anions13,14 to then opted for SmI2 (Scheme 1, step c, method C, Table 4)
these chiral 3-substituted dihydroisoquinolines could be as it has been reported to be efficient for hydrazines acti-
envisaged too, to give 6-substituted 8-oxoprotober- vated through a benzoyl function.27 Compound 3a was the
berines.
only substrate subjected to these conditions, however, the
result was very promising as the product was obtained in
excellent yield and enantiomeric excess (Table 4, entry 3).
We then decided to use calcium as the reducing agent
since it is considered to be less reactive than the alkali
metals.21 Yet, when calcium was employed, a predomi-
nant formation of 4a (67%) was observed (Table 3, entry
2). Interestingly, replacement of lithium by calcium for
the auxiliary cleavage of 3d resulted in lower yields
(Table 3, entry 3 vs. 4) in addition to the formation of con-
siderable amounts of 5d (44%, ee = 95%). In the same
manner, 4e (32%) was obtained using the calcium cleav-
age conditions (Table 3, entry 5).
Table 4 Various N–N Cleavage Methods from 3-Subtituted 3,4-Di-
hydro-2H-isoquinolin-1-ones 5a, 5d and 5e
Entry
5
R2
Method Yield (%) eea (%)
1
2
3
4
5
6
7
(R)-5a
(R)-5a
(R)-5a
(R)-5d
(R)-5d
(S)-5ee
(R)-5e
Phenyl
Ab
Bc
Cd
Ab
Bc
Ab
Bc
43
71
93
91
0
≥96
≥99
≥98
0
Phenyl
Phenyl
In order to obtain 3-substituted 3,4-dihydro-2H-isoquino-
lin-1-ones 5, another cleavage method using zinc in acetic
acid was investigated (Scheme 1, step c, method A,
Table 4) that had already been reported for N–N bond
cleavage22 and in particular for hydrazines derived from
SAMP23 or related hydrazones.24 Using standard condi-
tions only minor conversion of 3a into the desired product
5a could be observed, which led us to conclude that prior
to any cleavage the N–N bond should be weakened first.
Hence, the hydrazines 3a, 3c and 3e were first reacted
with a methanolic solution of hydrochloric acid. After
Ferrocenyl
Ferrocenyl
Furan-2-yl
Furan-2-yl
–
27
14
85
99
a Determined by HPLC on a chiral stationary phase.
b Zinc in acetic acid.
c MMPP·6H2O.
d SmI2.
e (2R,3S)-3e was used as starting material.
Table 3 N–N Cleavage with Lithium or Calcium in Liquid Ammonia to Form the 3-Substituted 3,4-Dihydroisoquinolines 4a, 4d and 4f
Entry
3
R2
Metal
Li
4
Yield (%)
eea (%)
≥96
≥96
≥96
95
1
2
3
4
5
(2S,3R)-3a
(2R,3S)-3a
(2S,3R)-3d
(2R,3S)-3d
(2R,3S)-3e
Phenyl
(R)-4a
(S)-4a
(R)-4d
(S)-4d
(S)-4e
44
67
40
23b
32
Phenyl
Ca
Ferrocenyl
Ferrocenyl
Furan-2-yl
Li
Ca
Ca
n.d.
a Determined by 1H NMR with (R)-(–)-anthr-9-yl-2,2,2-trifluoroethanol.
b 44% of (S)-5d (ee = 95%) was also formed.
Synthesis 2004, No. 18, 2980–2990 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of Substituted Isoquinolines and Isoquinolinones
2983
Recrystallization of (R)-5a allowed us to perform an X- tions and the various N–N bond cleavage conditions to re-
ray structure analysis (Figure 1).28 The assignment of the move the chiral auxiliary.
absolute configuration of the new stereocenter was not
possible, however, Davis et al. reported the asymmetric
All chemicals were purchased from commercial sources and used
without further treatment unless otherwise indicated. Solvents were
synthesis of (S)-5a ([a]D20 = –203.4 (c = 1.03, CHCl3).5e
dried using standard procedures, and reactions requiring anhydrous
conditions were performed under argon. All melting points were
measured on a Büchi 510 (Dr. Tottoli system) melting point appa-
ratus and are uncorrected. Optical rotations were measured on a Per-
kin-Elmer P241 polarimeter. NMR spectra were recorded on a
Varian VXR 300, Varian Gemini 300, Varian Inova 400 or Varian
Unity 500 spectrometer using Me4Si as an internal standard. IR
spectra were recorded on a Perkin-Elmer FT/IR 1760 spectropho-
tometer. MS spectra were recorded on a Finnigan SSQ7000 mass
spectrometer. HRMS spectra were recorded on a Finnigan MAT95
mass spectrometer. Elementary analyses were obtained with a Her-
aeus CHN-O-Rapid analyzer. Preparative column chromatography:
Figure 1 X-ray crystal structure of (R)-5a.28
Silica gel 60, particle size 0.040–0.063 mm, Merck. Analytical
By comparison with the optical rotation of (R)-5a TLC: Pre-coated F254 silica gel 60 plates, Merck, Darmstadt.
([a]D23 = +195.3 (c = 1.05, CHCl3), the stereogenic center
N,N-Diethyl-2-methylbenzamide (1a)
To a solution of diethylamine (22.71 g, 311 mmol) and Et3N (31.42
g, 311 mmol) in Et2O (500 mL) cooled to 0 °C was slowly added 2-
methylbenzoyl chloride (48.0 g, 311 mmol). Upon completion of
the addition the precipitate was filtered off, washed with Et2O (100
mL) and discarded. The combined organic layers were concentrated
could be assigned as R. This configuration also correlated
with the relative topicity previously observed in our group
in the asymmetric synthesis of 2,3-dihydro-1H-isoindol-
1-ones employing a related methodology.15a Moreover, a
crystal structure of (2S,3R)-3d was obtained which al-
lowed us to determine the absolute configuration with cer- under vacuum and the crude product was recrystallized from hex-
anes to give 1a (57.58 g, 97%) as a colorless crystalline solid.
Mp 48 °C (lit.31 49–50 °C).
tainty, but the quality of the crystals did not allow a further
refinement of the crystallographic data.15b
MS (EI): m/z (%) = 191 (M+, 26), 190 (31), 176 (23), 120 (9), 119 (
[M+ – N(CH2CH3)2, 100], 118 (16), 91 (33), 65 (9).
The other analytical data correspond with those of the literature.31,32
Access to 3-substituted 1,2,3,4-tetrahydroisoquinolines
6a and 6c–f was easily accomplished using an excess of
the borane-tetrahydrofuran complex. This method is
known to reduce carbonyl groups of amides29 and hydra-
zines to amines by reductive N–N bond cleavage.30 Each
N,N-Diethyl-2,5-dimethylbenzamide (1b)
of hydrazines 3a and 3c–f was successfully cleaved in To a solution of 2,5-dimethylbenzoic acid (50.0 g, 330 mmol) and
DMF (0.7 mL, 9 mmol) in CH2Cl2 (650 mL) was added a solution
moderate to good yields without racemization. The results
of oxalyl chloride (44.20 g, 350 mmol) in CH2Cl2 (500 mL). The re-
obtained are summarized in Table 5.
action mixture was stirred for 1 h at r.t. (gas evolution allows to
monitor the reaction). Upon removal of the solvent, the residue was
Table 5 N–N Cleavage of 3a and 3c–f with BH3·THF to form
1,2,3,4-Tetrahydroisoquinolines 6a and 6c–f
purified by distillation to give 2,5-dimethylbenzoyl chloride (35.60
g, 75%); bp 84–86 °C/3 mbar (lit.33 89–90 °C/2 Torr).
6
R1
H
R2
Yield (%) eea (%)
To a solution of diethylamine (15.36 g, 210 mmol) and Et3N (21.25
g, 210 mmol) in Et2O (400 mL) cooled to 0 °C was slowly added
2,5-dimethylbenzoyl chloride (35.30 g, 209 mmol). At the end of
addition the precipitate was filtered off, washed with Et2O (100 mL)
and discarded. The combined organic layers were concentrated un-
der vacuum and the crude product was distilled under reduced pres-
sure to give 1b (40.20 g, 94%) as a colorless liquid.
(S)-6a
(R)-6c
(R)-6d
(S)-6e
(R)-6f
Phenyl
85b
76
≥97
≥97
≥97
≥99
≥97
H
p-Methoxyphenyl
Ferrocenyl
Furan-2-yl
Ferrocenyl
H
35
H
47c
67
Bp 117–120 °C/3 mbar (lit.34 108–115 °C/1 Torr).
The analytical data correspond with those of the literature.34
CH3
a Determined by HPLC on a chiral stationary phase.
b (2R,3S)-3a was used as starting material.
e (2R,3S)-3e was used as starting material.
SAMP- or RAMP-Hydrazones 2a–e; General Procedure (GP 1)
RAMP or SAMP (1 equiv) was added to the aldehyde (1.2–2.4
equiv) at 0 °C. This mixture was stirred for 30 min at 0 °C followed
by dilution with Et2O (4.2 mL/mmol SAMP or RAMP). MgSO4 was
then added and the mixture was stirred overnight at r.t. After filtra-
tion and concentration in vacuum, the oily crude hydrazones were
purified by distillation under reduced pressure.
In summary, the asymmetric synthesis of the title com-
pounds has been achieved by a tandem 1,2-addition/ring
closure protocol in moderate to good yields and high
enantiomeric excesses (ee = 85–99%) employing lithiated
N,N-diethyl-2-methylbenzamides and aldehyde SAMP-
or RAMP-hydrazones as easily available substrates. The
advantages of this entry are the high asymmetric induc-
(2S)-2-(Methoxymethyl)-N-[(1E)-phenylmethylene]pyrrolidin-
1-amine [(S)-2a]
Compound (S)-2a was prepared earlier in our group.17c
Synthesis 2004, No. 18, 2980–2990 © Thieme Stuttgart · New York

2984
D. Enders et al.
PAPER
(2R)-2-(Methoxymethyl)-N-[(1E)-phenylmethylene]pyrrolidin-
1-amine [(R)-2a]
2.90–2.97 (m, 1 H, NCH2), 3.11 (s, 3 H, OCH3), 3.39 (dd, 1 H,
J = 7.0, 9.1 Hz, CH2OCH3), 3.61 (dd, 1 H, J = 3.6, 9.1 Hz,
CH2OCH3), 3.65–3.71 (m, 1 H, NCH), 6.20 (dd, 1 H, J = 1.8, 3.3
Hz, OCH=CH), 6.46 (d, 1 H, J = 3.3 Hz, OC=CH), 7.04 (s, 1 H,
N=CH), 7.16 (dd, 1 H, J = 0.8, 1.8 Hz, OCH).
13C NMR (100 MHz, C6D6): d = 22.3, 27.2, 48.3, 58.8, 63.1, 74.9,
104.9, 111.5, 122.1, 141.1, 153.9.
Compound (R)-2a was prepared earlier in our group.17c
(2S)-N-[(1E)-(4-Bromophenyl)methylene]-2-(methoxymeth-
yl)pyrrolidin-1-amine [(S)-2b]
According to the general procedure GP 1, 4-bromo-benzaldehyde
(10.0 g, 54 mmol) and SAMP (4.03 mL, 30 mmol) were reacted
over night. After Kugelrohr distillation under high vacuum, (S)-4b
(8.36 g, 94%) was obtained as a colorless solid.
MS (EI): m/z (%) = 208 (M+, 23), 164 (10), 163 (M+ – CH3OCH2,
100), 94 (11), 70 (12), 45 (6).
Bp 130 °C/0.1–0.01 mbar; mp 38 °C; [a]D25 = –144.8 (c = 1.01,
CHCl3).
Anal. Calcd for C11H16N2O2: C, 63.44; N, 13.45; H, 7.74. Found: C,
63.29; N, 13.46; H, 7.73.
IR (KBr): 3427, 3082, 3054, 2979, 2920, 2875, 2825, 2808, 1914,
1580, 1549, 1483, 1459, 1397, 1376, 1342, 1304, 1279, 1246, 1193,
1126, 1094, 1068, 1005, 969, 878, 822, 708, 513 cm–1.
1H NMR (400 MHz, C6D6): d = 1.41–1.53 (m, 1 H, NCH2CH2),
1.63–1.78 (m, 3 H, NCH2CH2CH2), 2.58–2.64 (m, 1 H, NCH2),
2.94–3.01 (m, 1 H, NCH2), 3.14 (s, 3 H, OCH3), 3.37 (dd, 1 H,
J = 7.0, 9.1 Hz, CH2OCH3), 3.60 (dd, 1 H, J = 3.6, 9.1 Hz,
CH2OCH3), 3.64–3.71 (m, 1 H, NCHCH2OCH3), 6.83 (s, 1 H,
N=CH), 7.34 (s, 4 H, CHarom).
(2R)-N-[(1E)-1-(Furan-2-yl)methylene]-2-(methoxymeth-
yl)pyrrolidin-1-amine [(R)-2e]
According to the general procedure GP 1, furan-2-carbaldehyde
(3.5 mL, 36.7 mmol) and RAMP (2.7 mL, 20.0 mmol) were reacted
over night. After Kugelrohr distillation under high vacuum, (R)-2e
(3.3 g, 79%) was obtained as a yellow oil.
Bp 120 °C/0.1–0.01 mbar; [a]D24 = +125.0 (c = 1.01, CHCl3).
All other analytical data correspond to those of the enantiomer (S)-
2e.
13C NMR (100 MHz, C6D6): d = 22.4, 27.2, 48.3, 58.9, 63.2, 75.0,
120.4, 127.0, 129.5, 131.8, 137.2.
1,2-Addition/Ring Closure to Afford 3,4-Dihydro-2H-isoquino-
lin-1-ones 3a–f; General Procedure (GP 2)
MS (CI, isobutane): m/z (%) = 300 (15), 299 [M(81Br)H+, 96], 298
(22), 297 [M(78Br)H+, 100], 296 (7), 220 (7), 219 (45), 218 (5).
n-BuLi (6.57 mL, 10.5 mmol, 1.6 M in hexane) was added to a so-
lution of diisopropylamine (1.48 mL, 10.5 mmol) in absolute THF
(50 mL) at 0 °C. The solution was stirred 15 min at 0 °C and cooled
to –45 °C before a solution of N,N-diethylbenzamide 1a or 1b (10.5
mmol) in absolute THF (10 mL) was added. A solution of hydra-
zone 2a–e (1.5 mmol) in absolute THF (6 mL) with or without
AlMe3 (0.83 mL, 1.65 mmol, 2 M in heptane) was added and the re-
action mixture was stirred overnight at –40 °C. The reaction was
quenched with a 10% solution of potassium and sodium tartrate (5
mL) and sat. aq NH4Cl (10 mL). After phase separation, the aqueous
layer was extracted with Et2O (3 × 30 mL). The combined organic
phases were dried over MgSO4, filtered and concentrated under re-
duced pressure. The crude mixture was purified by column chroma-
tography.
Anal. Calcd for C13H17BrN2O: C, 52.54; N, 9.43; H, 5.77. Found: C,
52.54; N, 9.31; H, 5.76.
(2S)-2-(Methoxymethyl)-N-[(1E)-(4-methoxyphenyl)methyl-
ene]pyrrolidin-1-amine [(S)-2c]
According to the general procedure GP 1, 4-methoxy-benzaldehyde
(7.5 mL, 62 mmol) and SAMP (3.5 mL, 26 mmol) were reacted over
night. After Kugelrohr distillation under high vacuum, (S)-2c (5.93
g, 91%) was obtained as a yellow solid.
Bp 115 °C/0.1–0.01 mbar; mp 24 °C (lit.15 24 °C); [a]D23 = –150.2
(c = 1.08, CHCl3).
All other analytical data correspond to those of the enantiomer (R)-
2c.15
(3R)-2-[(2S)-2-(Methoxymethyl)pyrrolidin-1-yl]-3-phenyl-3,4-
dihydroisoquinolin-1(2H)-one [(2S,3R)-3a]
According to the general procedure GP 2, (S)-2a and 1a were react-
ed over night. After purification by column chromatography (Et2O–
hexanes, 55:45), (2S,3R)-3a (355 mg, 70%) was obtained as a pale
yellow oil which crystallized on standing as a colorless solid.
(2R)-2-(Methoxymethyl)-N-[(1E)-(4-methoxyphenyl)methyl-
ene]pyrrolidin-1-amine [(R)-2c]
Compound (R)-2c was prepared earlier in our group.15
(2S)-N-[(1E)-1-(Ferrocenyl)methylene]-2-(methoxymethyl)pyr-
rolidin-1-amine [(S)-2d]
Mp 81 °C; Rf = 0.68 (Et2O–hexanes, 2:1); [a]D24 = –29.7 (c = 1.02,
CHCl3).
Compound (S)-2d was prepared earlier in our group.17a
IR (capillary): 2971, 2934, 2873, 1652, 1634, 1603, 1494, 1458,
1427, 1406, 1382, 1293, 1099, 769, 735, 701 cm–1.
(2R)-N-[(1E)-1-(Ferrocenyl)methylene]-2-(methoxymeth-
yl)pyrrolidin-1-amine [(R)-2d]
Compound (R)-2d was prepared earlier in our group.17b
1H NMR (500 MHz, C6D6): d = 1.25–1.33 (m, 1 H, NCH2CH2CH2),
1.35–1.46 (m, 1 H, NCH2CH2CH2), 1.81–1.89 (m, 1 H,
NCH2CH2CH2), 2.02–2.10 (m, 1 H, NCH2CH2CH2), 2.67 (dd, 1 H,
J = 2.7, 15.6 Hz, O=CNCHCH2), 2.84 (td, 1 H, J = 7.8, 4.2 Hz,
NCH2), 3.16 (s, 3 H, OCH3), 3.19 (dd, 1 H, J = 4.6, 9.4 Hz,
CH2OCH3), 3.35 (dd, 1 H, J = 7.5, 9.4 Hz, CH2OCH3), 3.51 (dd, 1
H, J = 7.0, 15.6 Hz, O=CNCHCH2), 3.96 (dd, 1 H, J = 7.8, 15.9 Hz,
NCH2), 4.36–4.41 (m, 1 H, CHCH2OCH3), 5.07 (dd, 1 H, J = 2.7,
7.0 Hz, O=CNCH), 6.60 (d, 1 H, J = 7.3 Hz, O=CCCCH), 6.93–
7.00 (m, 4 H, CHarom), 7.02–7.07 (m, 1 H, CHarom), 7.09–7.13 (m, 2
H, CHarom), 8.49 (dd, 1 H, J = 1.2, 7.6 Hz, O=CCCH).
(2S)-N-[(1E)-1-(Furan-2-yl)methylene]-2-(methoxymethyl)pyr-
rolidin-1-amine [(S)-2e]
According to the general procedure GP 1, furan-2-carbaldehyde (9
mL, 110 mmol) and SAMP (8 mL, 60 mmol) were reacted over
night. After distillation under high vacuum, (S)-2e (10.0 g, 80%)
was obtained as a yellow oil.
Bp 90 °C/0.1–0.01 mbar; [a]D25 = –132.4 (c = 1.01, CHCl3).
IR (capillary): 3114, 2974, 2926, 2878, 2827, 1602, 1580, 1566,
1545, 1490, 1480, 1459, 1392, 1342, 1323, 1306, 1285, 1270, 1228,
1196, 1162, 1121, 1075, 1012, 973, 932, 884, 732 cm–1.
1H NMR (400 MHz, C6D6): d = 1.38–1.49 (m, 1 H, NCH2CH2),
1.59–1.73 (m, 3 H, NCH2CH2CH2), 2.54–2.61 (m, 1 H, NCH2),
13C NMR (125 MHz, C6D6): d = 23.5, 27.6, 36.9, 52.2, 58.6, 60.5,
66.4, 77.9, 127.0, 127.1, 127.4, 127.5, 128.1, 128.5, 131.5, 131.7,
135.7, 142.5, 162.9.
Synthesis 2004, No. 18, 2980–2990 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of Substituted Isoquinolines and Isoquinolinones
2985
MS (EI): m/z (%) = 336 (M+, 1), 304 (6), 292 (21), 291(M+
–
Anal. Calcd for C22H26N2O3: C, 72.11; N, 7.64; H, 7.15. Found: C,
CH3OCH2, 100), 224 (7), 222 (8), 207 (23), 179 (7), 178 (12), 114
(55), 113 (10), 83 (5), 68 (6), 57 (5).
71.99; N, 7.52; H, 7.64.
(3R)-3-Ferrocenyl-2-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]-
3,4-dihydroisoquinolin-1(2H)-one [(2S,3R)-3d]
According to the general procedure GP 2, (S)-2d and 1a were react-
ed over night. After purification by column chromatography (Et2O–
hexanes, 9:11) and recrystallization from petroleum ether (2S,3R)-
3d (418 mg, 63%) was obtained as orange-red crystals.
Anal. Calcd for C21H24N2O2: C, 74.97; N, 8.33; H, 7.19. Found: C,
74.91; N, 8.31; H, 7.33.
(3R)-3-(4-Bromophenyl)-2-[(2S)-2-(methoxymethyl)pyrrolidin-
1-yl]-3,4-dihydroisoquinolin-1(2H)-one [(2S,3R)-3b]
According to the general procedure GP 2, (S)-2b and 1a were react-
ed over night. After purification by column chromatography (Et2O–
hexanes, 1:1), (2S,3R)-3b (403 mg, 65%) was obtained as a color-
less solid.
Mp 150 °C; Rf = 0.37 (Et2O–hexanes, 1:1); [a]D24 = +197.4
(c = 1.01, CHCl3).
IR (KBr): 3087, 2966, 2918, 2873, 1649, 1602, 1458, 1389, 1310,
1249, 1154, 1132, 1096, 842, 813, 743, 706 cm–1.
Mp = 79 °C; Rf = 0.39 (Et2O–hexanes, 3:2); [a]D23 = –17.3
(c = 1.02, CHCl3).
1H NMR (400 MHz, C6D6): d = 1.34–1.44 (m, 1 H, NCH2CH2CH2),
1.53–1.64 (m, 1 H, NCH2CH2CH2), 1.92–2.11 (m, 2 H,
NCH2CH2CH2), 3.09–3.28 (m, 3 H, O=CNCHCH2, NCH2,
CH2OCH3), 3.17 (s, 3 H, OCH3), 3.42 (dd, 1 H, J = 6.9, 9.3 Hz,
CH2OCH3), 3.53–3.55 (m, 1 H, NCHC5H4), 3.59 (dd, 1 H,
J = 6.9, 15.5 Hz, O=CNCHCH2), 3.66–3.68 (m, 1 H, NCHC5H4),
IR (KBr): 2969, 2932, 2873, 2824, 1655, 1488, 1459, 1388, 1326,
1241, 1118, 1010, 742 cm–1.
1H NMR (300 MHz, C6D6): d = 1.19–1.32 (m, 1 H, NCH2CH2CH2),
1.33–1.49 (m, 1 H, NCH2CH2CH2), 1.79–1.92 (m, 1 H,
NCH2CH2CH2), 1.96–2.10 (m, 1 H, NCH2CH2CH2), 2.56 (dd, 1 H,
J = 3.0, 15.8 Hz, O=CNCHCH2), 2.76 (td, 1 H, J = 7.6, 4.3 Hz,
NCH2), 3.15 (s, 3 H, OCH3), 3.12–3.19 (m, 1 H, CH2OCH3), 3.29
(dd, 1 H, J = 7.6, 9.2 Hz, CH2OCH3), 3.44 (dd, 1 H, J = 6.8, 15.8
Hz, O=CNCHCH2), 3.86 (dd, 1 H, J = 7.9, 15.9 Hz, NCH2), 4.25–
4.36 (m, 1 H, CHCH2OCH3), 4.96 (dd, 1 H, J = 6.8, 2.9 Hz,
O=CNCH), 6.65 (d, 1 H, J = 7.0 Hz, O=CCCCH), 6.77–6.83 (m, 2
H, CHarom), 6.99–7.11 (m, 4 H, CHarom), 8.42 (dd, 1 H, J = 1.5, 7.6
Hz, O=CCCH).
3.78–3.86 (m,
2
H, NCH2, NCHC5H4), 3.97 [s,
5 H,
NCH(C5H4)Fe(C5H5)], 4.26–4.35 (m,
2
H, CHCH2OCH3,
NCHC5H4), 4.77 (dd, 1 H, J = 6.9, 1.9 Hz, O=CNCH), 6.96 (d, 1 H,
J = 7.4 Hz, O=CCCCH), 7.02–7.07 (m, 1 H, CHarom), 7.12–7.17 (m,
1 H, CHarom), 8.43 (dd, 1 H, J = 1.4, 7.7 Hz, O=CCCH).
13C NMR (100 MHz, C6D6): d = 23.7, 27.9, 34.9, 52.6, 58.5, 60.8,
62.1, 66.3, 67.4, 68.4, 68.8, 70.2, 77.6, 89.8, 126.7, 126.8, 128.3,
131.1, 131.5, 137.4, 161.6.
13C NMR (75 MHz, C6D6): d = 23.5, 27.5, 36.6, 52.3, 58.5, 60.5,
65.7, 77.7, 121.3, 127.2, 127.5, 128.1, 128.8, 131.2, 131.6, 131.9,
135.4, 141.5, 162.7.
MS (EI): m/z (%) = 416 [M(81Br)+, 0.2], 414 [M(79Br)+, 0.2], 372
(14), 371 [M(81Br)+ –CH3OCH2, 64], 370 (14), 369 [M(79Br)+ –
CH3OCH2, 66], 302 (8), 287 (10), 285 (10), 239 (5), 237 (5), 206
(13), 178 (19), 119 (6), 118 (5), 115 (7), 114 (C6H12NO+ – H, 100),
113 (9), 91 (5), 90 (7), 89 (6), 83 (5), 70 (7), 68 (13), 45 (6).
MS (EI): m/z (%) = 445 (5), 444 (M+, 20), 399 (M+ – CH3OCH2,
16), 333 (6), 332 (20), 331 (M+ – C6H12NO + H, 100), 330 (19), 329
(55), 328 (8), 266 (10), 265 (17), 264 (23), 263 (7), 248 (5), 237 (6),
221 (7), 213 (6), 199 (9), 186 (9), 177 (5), 166 (7), 165 (20), 120 (9),
83 (16), 82 (6), 70 (6), 68 (5), 59 (7), 58 (19), 55 (5).
Anal. Calcd for C25H28FeN2O2: C, 67.57; N, 6.30; H, 6.35. Found:
C, 67.66; N, 6.21; H, 6.44.
(3S)-3-Furan-2-yl-2-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]-
3,4-dihydroisoquinolin-1(2H)-one [(2R,3S)-3e]
According to the general procedure GP 2, (R)-2e and 1a were react-
ed over night. After purification by column chromatography (Et2O–
hexanes, 9:11) and recrystallization from hexanes (2R,3S)-3e (220
mg, 45%) was obtained as brown needles.
Anal. Calcd for C21H23BrN2O2: C, 60.73; N, 6.74; H, 5.58. Found:
C, 60.68; N, 6.73; H, 5.73.
(3R)-2-[(2S)-2-(Methoxymethyl)pyrrolidin-1-yl]-3-(4-methoxy-
phenyl)-3,4-dihydroisoquinolin-1(2H)-one [(2S,3R)-3c]
According to the general procedure GP 2, (S)-2c and 1a were react-
ed over night. After purification by column chromatography (Et2O–
hexanes, 1:1), (2S,3R)-3c (213 mg, 39%) was obtained as a color-
less oil.
Mp 61 °C; Rf = 0.41 (Et2O–hexanes, 9:11); [a]D27 = +96.0
(c = 0.81, CHCl3).
IR (capillary): 2968, 2874, 1656, 1605, 1460, 1402, 1380, 1325,
1246, 1137, 1102, 1012, 742 cm–1.
Rf = 0.42 (Et2O–hexanes, 3:2); [a]D23 = –36.4 (c = 1.08, CHCl3).
IR (CHCl3): 3068, 2951, 2875, 2835, 1651, 1611, 1583, 1512, 1461,
1427, 1402, 1334, 1305, 1251, 1179, 1158, 1102, 1036, 985, 967,
829, 814, 747 cm–1.
1H NMR (300 MHz, C6D6): d = 1.25–1.53 (m, 2 H, NCH2CH2CH2,
NCH2CH2CH2), 1.80–1.94 (m, 1 H, NCH2CH2CH2), 2.01–2.15 (m,
1H NMR (400 MHz, C6D6): d = 1.25–1.35 (m, 1 H, NCH2CH2CH2),
1.47–1.58 (m, 1 H, NCH2CH2CH2), 1.89–2.00 (m, 1 H,
NCH2CH2CH2), 2.01–2.10 (m, 1 H, NCH2CH2CH2), 2.84 (dd, 1 H,
J = 2.6, 15.8 Hz, O=CNCHCH2), 3.09 (s, 3 H, OCH3), 3.07–3.17
(m, 2 H, NCH2, CH2OCH3), 3.28 (dd, 1 H, J = 7.7, 9.3 Hz,
CH2OCH3), 3.40 (dd, 1 H, J = 6.4, 15.7 Hz, O=CNCHCH2), 3.96
(dd, 1 H, J = 8.0, 15.7 Hz, NCH2), 4.25–4.34 (m, 1 H,
CHCH2OCH3), 5.12 (dd, 1 H, J = 6.4, 2.6 Hz, O=CNCH), 5.86–
5.91 (m, 2 H, OC=CHCH), 6.68–6.72 (m, 1 H, O=CCCCH), 6.91
(dd, 1 H, J = 1.9, 0.8 Hz, OCH=CH), 6.98–7.05 (m, 2 H, CHarom),
8.41–8.43 (m, 1 H, O=CCCH).
1
H, NCH2CH2CH2), 2.67 (dd, 1 H, J = 2.8, 15.7 Hz,
O=CNCHCH2), 2.89 (td, 1 H, J = 6.8, 5.2 Hz, NCH2), 3.17 (s, 3 H,
OCH3), 3.21 (s, 3 H, OCH3), 3.15–3.24 (m, 1 H, CH2OCH3), 3.38
(dd, 1 H, J = 7.3, 9.2 Hz, CH2OCH3), 3.52 (dd, 1 H, J = 6.9, 15.7
Hz, O=CNCHCH2), 3.97 (dd, 1 H, J = 7.8, 15.8 Hz, NCH2), 4.33–
4.45 (m, 1 H, CHCH2OCH3), 5.04 (dd, 1 H, J = 6.9, 2.8 Hz,
O=CNCH), 6.53–6.59 (m, 2 H, CHarom), 6.67 (d, 1 H, J = 7.4 Hz,
O=CCCCH), 6.99–7.12 (m, 4 H, CHarom), 8.51 (dd, 1 H, J = 1.5, 7.6
Hz, O=CCCH).
13C NMR (100 MHz, C6D6): d = 23.7, 27.7, 34.0, 52.3, 58.5, 60.7,
77.8, 106.9, 110.2, 126.9, 127.2, 128.1, 131.0, 131.5, 136.1, 141.6,
155.1, 162.4.
13C NMR (75 MHz, C6D6): d = 23.5, 27.6, 37.0, 52.2, 54.6, 58.6,
60.5, 65.9, 77.8, 113.9, 127.1, 127.6, 128.0, 128.1, 131.6, 131.8,
134.3, 136.0, 159.3, 162.9.
MS (EI): m/z (%) = 326 (M+, 0.6), 294 (17), 282 (19), 281 (M+ –
CH3OCH2, 100), 195 (5), 169 (12), 141 (13), 115 (6), 114 (19), 45
(5).
MS (CI, isobutane): m/z (%) = 368 (24), 367 (MH+, 100).
Synthesis 2004, No. 18, 2980–2990 © Thieme Stuttgart · New York

2986
D. Enders et al.
PAPER
Anal. Calcd for C19H22N2O3: C, 69.92; N, 8.58; H, 6.79. Found: C,
69.84; N, 8.65; H, 6.89.
bath was removed and the reaction mixture was stirred for 5 min at
reflux. The solution was cooled again to –78 °C. The reaction was
quenched by slowly adding solid NH4Cl (1 g/mmol hydrazine). Af-
ter evaporation of the ammonia, the residue was diluted in H2O and
extracted 3 times with CH2Cl2. The combined organic layers were
dried over MgSO4, filtered and concentrated in vacuum.
(3S)-3-Ferrocenyl-2-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]-
7-methyl-3,4-dihydroisoquinolin-1(2H)-one [(2R,3S)-3f]
According to the general procedure GP 2, (R)-2d and 1b were react-
ed over night. After purification by column chromatography (Et2O–
hexanes, 9:11) and recrystallization (CH2Cl2–hexanes mixture)
(2R,3S)-3f (317 mg, 46%) was obtained as orange-red crystals.
(3S)-3-Phenyl-3,4-dihydroisoquinoline [(S)-4a]
Compound (2R,3S)-3a (328 mg, 0.97 mmol) was reacted according
to the general procedure GP 3 using calcium in liquid ammonia. Af-
ter purification by column chromatography (Et2O–hexanes, 6:4),
(S)-4a (134 mg, 67%) was obtained as colorless crystals.
ee ≥96% (1H NMR, (R)-(–)-anthr-9-yl-2,2,2-trifluoroethanol as
shift-reagent).
Mp 165 °C; Rf = 0.42 (Et2O–hexanes, 1:1); [a]D22 = –219.3
(c = 1.00, CHCl3).
IR (KBr): 3432, 2957, 2873, 1648, 1612, 1426, 1387, 1313, 1254,
1128, 1097, 818 cm–1.
1H NMR (400 MHz, C6D6): d = 1.36–1.47 (m, 1 H, NCH2CH2CH2),
1.54–1.65 (m, 1 H, NCH2CH2CH2), 1.93–2.12 [m, 5 H,
NCH2CH2CH2, O=CCCH=C(CH3)], 3.18 (s, 3 H, OCH3), 3.11–
3.28 (m, 3 H, O=CNCHCH2, NCH2, CH2OCH3), 3.43 (dd, 1 H,
J = 6.9, 9.3 Hz, CH2OCH3), 3.57–3.64 (m, 2 H, NCHC5H4,
O=CNCHCH2), 3.68–3.71 (m, 1 H, NCHC5H4), 3.80–3.88 (m, 2 H,
NCH2, NCHC5H4), 3.99 [s, 5 H, NCH(C5H4)Fe(C5H5)], 4.27–4.37
(m, 2 H, CHCH2OCH3, NCHC5H4), 4.78 (dd, 1 H, J = 6.9, 1.9 Hz,
O=CNCH), 6.93 (d, 1 H, J = 7.7 Hz, CHarom), 7.07 (dd, 1 H,
J = 7.7, 14 Hz, CHarom), 8.18 (d, 1 H, J = 1.7 Hz, CHarom).
Mp 58 °C (lit.35 80.5–81.5 °C, rac-6a); Rf = 0.31 (Et2O–
hexanes, 1:1); [a]D23 = –129.8 (c = 1.00, CHCl3).
1H NMR (300 MHz, C6D6): d = 2.50–2.69 (m, 2 H, NCHCH2), 4.54
(ddd, 1 H, J = 3.0, 6.6, 13.1 Hz, NCHCH2), 6.72–6.77 (m, 1 H,
CHarom), 6.84–6.89 (m, 1 H, CHarom), 6.93–7.05 (m, 2 H, CHarom),
7.09–7.17 (m, 1 H, CHarom), 7.21–7.28 (m, 2 H, CHarom), 7.45–7.51
(m, 2 H, CHarom), 8.38 (d, 1 H, J = 3.0 Hz, N=CH).
13C NMR (75 MHz, C6D6): d = 34.2, 61.4, 126.9, 127.2, 127.3,
127.5, 127.6, 128.5, 128.9, 130.9, 136.4, 145.0, 159.7.
13C NMR (100 MHz, C6D6): d = 20.9, 23.7, 27.9, 34.6, 52.5, 58.5,
60.7, 62.2, 66.4, 67.3, 68.3, 68.8, 70.2, 77.6, 89.8, 126.7, 128.8,
130.9, 132.3, 134.4, 136.3, 161.9.
MS (EI): m/z (%) = 208 (17), 207 (M+, 100), 206 (78), 180 (5), 179
(7), 178 (7), 130 (M+ – C6H5), 103 (6), 102 (7), 90 (6), 89 (11).
All other analytical data correspond with those of the literature.35
MS (EI): m/z (%) = 459 (21), 458 (M+, 69), 414 (16), 413 (M+ –
CH3OCH2, 55), 347 (14), 346 (21), 345 (83), 344 (25), 343 (48),
342 (5), 329 (6), 280 (18), 279 (30), 278 (100), 277 (6), 276 (7) 263
(20), 262 (9), 254 (7), 251 (5), 249 (5), 237 (5), 236 (8), 235 (16),
222 (5), 214 (8), 213 (6), 207 (7), 200 (17), 199 (88), 197 (7), 194
(6), 186 (19), 180 (23), 179 (49), 178 (19), 167 (11), 166 (13), 165
(31), 153 (5), 152 (8), 149 (12), 129 (10), 121 (43), 113 (7), 112 (6),
101 (5), 97 (6), 91 (5), 85 (7), 83 (8), 82 (5), 71 (11), 70 (14), 69 (7),
68 (5), 57 (16), 56 (14), 55 (13), 45 (18).
(3R)-3-Ferrocenyl-3,4-dihydroisoquinoline [(R)-4d]
Compound (2S,3R)-3d (200 mg, 0.45 mmol) was reacted according
to the general procedure GP 3 using lithium in liquid ammonia. Af-
ter purification by column chromatography (Et2O–hexanes, 2:1 +
0.5% Et3N), (R)-4d (57 mg, 40%) was obtained as a red-brown oil
which decomposed slowly even at –25 °C.
ee ≥96% (1H NMR with (R)-(–)-anthr-9-yl-2,2,2-trifluoroethanol).
Rf = 0.70 (Et2O).
Anal. Calcd for C26H30FeN2O2: C, 68.13; N, 6.11; H, 6.60. Found:
C, 67.84; N, 6.08; H, 6.55.
IR (KBr): 3431, 3116, 3077, 2926, 2864, 2183, 1624, 1583, 1489,
1436, 1378, 1278, 1143, 1104, 1005, 905, 885, 831, 812, 756, 497
cm–1.
1H NMR (400 MHz, C6D6): d = 2.70–2.79 (m, 2 H, NCHCH2),
4.02–4.05 (m,
N–N Bond Cleavage with Lithium in Liquid Ammonia to Af-
ford 3,4-Dihydroisoquinolines 4a and 4d; General Procedure
(GP 3)
2
H, NCHC5H4), 4.17 [m,
5
H,
In a two-neck flask filled with Ar, liquid ammonia (50 mL/mmol
hydrazine) was condensed at –78 °C. Freshly cut lithium (4.5–10
equiv), washed successively with MeOH and Et2O, was added to the
solution and a persisting deep blue color developed. After 5 min at
–78 °C, the hydrazine 3a or 3d (1.0 equiv) in absolute THF (20 mL/
mmol hydrazine) was added. The cooling bath was removed and the
reaction mixture was stirred for 5 min at reflux (–33 °C) before be-
ing cooled again to –78 °C. The reaction was quenched by slowly
adding solid NH4Cl (1 g/mmol hydrazine). After evaporation of the
ammonia, the residue was diluted in H2O and extracted 3 times with
CH2Cl2. The combined organic layers were dried over MgSO4, fil-
tered and concentrated under reduced pressure.
NCH(C5H4)Fe(C5H5)], 4.29–4.34 (m, 2 H, NCHC5H4), 4.36–4.43
(m, 1 H, NCHCH2), 6.70–6.82 (m, 2 H, CHarom), 6.94–7.00 (m, 1 H,
CHarom), 7.01–7.06 (m, 1 H, CHarom), 8.32 (d, 1 H, J = 2.8 Hz,
N=CH).
13C NMR (100 MHz, C6D6): d = 33.0, 56.4, 67.1, 67.4, 67.7, 67.8,
68.9, 126.9, 127.0, 127.4, 128.9, 130.6, 136.3, 158.2.
MS (EI): m/z (%) = 316 (23), 315 (M+, 100), 314 (35), 313 (M+ –
H2, 86), 311 (5), 250 (11), 249 (42), 248 (30), 186 (6), 166 (5), 165
(11), 121 (6).
A correct elementary analysis could not be obtained for this com-
pound.
N–N Bond Cleavage with Calcium in Liquid Ammonia to Af-
ford 3,4-Dihydroisoquinolines 4a, 4d and 4e; General Proce-
dure (GP 3)
(3S)-3-Furan-2-yl-3,4-dihydroisoquinoline [(S)-4e]
Compound (2R,3S)-3e (155 mg, 0.48 mmol) was reacted according
to the general procedure GP 3 using calcium in liquid ammonia. Af-
ter purification by column chromatography (Et2O–hexanes, 6:4),
(S)-4e (30 mg, 32%) was obtained as a colorless oil.
In a two-neck flask filled with Ar, liquid ammonia (50 mL/mmol
hydrazine) was condensed at –78 °C. Freshly cut calcium (2.2–3.5
equiv) was added to the solution and a persisting deep blue color
slowly developed. The cooling bath was then removed to afford the
ammonia solution to reflux (–33 °C) resulting in the formation of a
metallic mirror on the flask wall. The reaction mixture was cooled
again to –78 °C. The hydrazine 3a, 3d or 3e (1.0 equiv) in absolute
THF (20 mL/mmol hydrazine) was then slowly added. The cooling
Rf = 0.32 (Et2O–hexanes = 2:1).
1H NMR (400 MHz, C6D6): d = 2.71–2.84 (m, 2 H, NCHCH2),
4.68–4.74 (m, 1 H, NCHCH2), 6.14 (dd, 1 H, J = 1.8, 3.2 Hz,
OCH=CH), 6.39–6.41 (m, 1 H, OC=CH), 6.69–6.73 (m, 1 H,
Synthesis 2004, No. 18, 2980–2990 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of Substituted Isoquinolines and Isoquinolinones
2987
CHarom), 6.77–6.80 (m, 1 H, CHarom), 6.88–6.99 (m, 1 H, CHarom),
7.14–7.16 (m, 1 H, OCH=CH), 8.27 (d, 1 H, J = 2.7 Hz, N=CH).
13C NMR (100 MHz, C6D6): d = 30.3, 55.8, 106.0, 110.4, 127.1,
128.6, 130.9, 135.6, 141.5, 157.2, 159.7 (the two missing signals are
under the solvent residual peak).
MS (EI): m/z (%) = 224 (13), 223 (M+, 75), 222 (8), 194 (5), 146 (6),
145 (5), 119 (12), 118 (M+ – NH2Bn, 100), 90 (26), 89 (10).
All other analytical data correspond to those of the literature.5e
X-ray Crystallographic Study of (3R)-3-Phenyl-3,4-dihydroiso-
quinolin-1(2H)-one [(R)-5a]
N–N Bond Cleavage to Afford 3,4-Dihydroisoquinolin-1(2H)-
ones 5a, 5d and 5e; General Procedure (GP 4)
Method A
Single crystals of (R)-5a were obtained by recrystallization from
Et2O. The compound crystallizes in the monoclinic space group P21
(Nr. 4) with two symmetrically independent molecules in the asym-
metric unit (2 × C15H13NO, Mr = 446.55). The cell dimensions are
a = 9.087(1), b = 6.126(1), c = 20.915(3) Å, and b = 91.176(5)°. A
cell volume of V = 1164.0(3) Å3 and Z = 2 result in a calculated
density of rcalc. = 1.274 gcm–3. 4959 reflections have been collected
in the w/2Q mode at T = 298 K on an Enraf-Nonius CAD4 diffrac-
tometer employing graphite monochromated CuKa-radiation
(l = 1.54179 Å). Data collection covered the range –11£h£11,
–7£k£7, and –25£l£25 (Friedel pairs) up to Qmax = 72.77°; m = 0.63
mm–1, no absorption correction. The structure has been solved by
directs methods as implemented in the Xtal3.7 suite of crystallo-
graphic routines36 where GENSIN has been used to generate the
structure-invariant relationships and GENTAN for the general tan-
gent phasing procedure. 3768 observed reflections (I>2s(I)) have
been included in the final full matrix least-squares refinement on F
involving 316 parameters and converging at R(Rw) = 0.089 (0.11,
w = 1/[18.0s2(F)], S = 1.277, and a residual electron density of
–0.36/0.50 eÅ–3. Due to a large standard deviation the result of an
attempted determination of the absolute configuration using Flack’s
method37 turned out to be insignificant. However, based on chemi-
cal evidence the absolute configuration of the molecule could be as-
signed as shown in Figure 1. The nitrogen-bonded hydrogen atoms
could be located and have been refined isotropically. All other hy-
drogen positions have been calculated in idealized positions, and
their Us have been fixed at 1.5 times U of the relevant heavy atom
without refinement of any parameters.
MeOH (60 mL/mmol hydrazine) and acetyl chloride (6.0 mL/mmol
hydrazine) were mixed at 0 °C. This mixture was added to 3,4-di-
hydroisoquinolin-1(2H)-ones 3a, 3d or 3e and the solvent was re-
moved in vacuum. The residue was diluted with AcOH (75 mL/
mmol hydrazine) and zinc powder (2.2 g/mmol hydrazine) and 6 N
HCl (3 drops/mmol hydrazine) were successively added. After son-
icating for 15 min, the reaction mixture was heated to reflux for 36
h, while new zinc powder was added every 12 h (3.0 g/mmol hydra-
zine). After allowing the reaction mixture to cool to r.t., the solid
was filtered off and washed with H2O and AcOH. The liquid was
concentrated under reduced pressure. Sat. aq Na2CO3 was added to
the residue until evolution of gas has ceased. The mixture was then
extracted 3 times with Et2O. The combined organic phases were
dried over MgSO4, filtered and the solvent evaporated in vacuum.
Method B
A solution of 3a, 3d or 3e (1.0 equiv) and MMPP·6H2O (2.0–2.5
equiv) in MeOH (13 mL/mmol hydrazine) was stirred at r.t. until the
hydrazine was consumed (24–96 h, TLC control). If necessary,
more MMPP·6H2O was added to the reaction mixture. The reaction
mixture was diluted with Et2O (60 mL/mmol hydrazine) and sat. aq
NaHCO3 (43 mL/mmol hydrazine) was added. The layers were sep-
arated and the aqueous phase was extracted 3 times with CHCl3 or
CH2Cl2. The combined organic phases were dried over MgSO4, fil-
tered and the solvent were evaporated in vacuum.
Method C27
(3S)-3-Ferrocenyl-3,4-dihydroisoquinolin-1(2H)-one [(S)-5d]
According to the general procedure GP 3 (2R,3S)-3d (125 mg, 0.28
mmol) was reacted with calcium in liquid ammonia. After purifica-
tion by column chromatography (Et2O–hexanes, 2:1) (S)-5d (41
mg, 44%) was obtained as a orange-red solid.
A THF solution of SmI2 (3.1 equiv, 0.1 M in THF) was added drop-
wise to a solution (6.9 mL/mmol hydrazine) of 3a (1.0 equiv) and
DMPU (1.75 mL/mmol hydrazine) in THF (7.3 mL/mmol hydra-
zine) at r.t. under Ar. After 30 min, the reaction mixture was
quenched with a mixture of 10% NaHCO3 (175 mL/mmol hydra-
zine) and CH2Cl2 (70 mL/mmol hydrazine), extracted 2 times with
CH2Cl2 (100 mL/mmol hydrazine), dried over MgSO4, filtered and
concentrated under reduced pressure.
ee = 95% (HPLC, Chiralpak AD, n-heptane–i-PrOH, 85:15).
Mp 128 °C; Rf = 0.49 (Et2O); [a]D23 = +61.3 (c = 0.60, CHCl3).
IR (KBr): 3447, 3221, 3074, 2945, 2843, 2198, 1661, 1603, 1578,
1463, 1402, 1385, 1320, 813, 747 cm–1.
(3R)-3-Phenyl-3,4-dihydroisoquinolin-1(2H)-one [(R)-5a]
According to the general procedure GP 4 (method B) (2S,3R)-3a
(157 mg, 0.47 mmol) was reacted with MMPP·6H2O. After purifi-
cation by column chromatography (Et2O–hexanes, 7:3) (R)-5a (74
mg, 71%) was obtained as a colorless solid.
1H NMR (400 MHz, C6D6): d = 2.62–2.77 (m, 2 H, NCHCH2),
3.83–3.86 [m, 1 H, NCH(C5H4)], 3.88–3.93 [m, 2 H, NCH(C5H4)],
4.07–4.18 [m, 7 H, NCH(C5H4)Fe(C5H5)], 6.73–6.79 (m, 1 H,
O=CCCCH), 7.05–7.13 (m, 2 H, CHarom), 8.00 (s, 1 H, NH), 8.53–
8.58 (m, 1 H, O=CCCH).
13C NMR (100 MHz, C6D6): d = 37.1, 50.6, 66.2, 66.5, 68.0, 68.1,
69.0, 90.1, 127.1, 127.3, 128.1, 129.7, 131.8, 138.1, 165.8.
MS (EI): m/z (%) = 333 (8), 332 (23), 331 (M+, 100), 330 (16), 329
(47), 328 (8), 266 (6), 265 (10), 264 (8), 263 (6), 213 (5), 186 (7),
165 (9).
ee ≥99% (HPLC, Daicel OD, n-heptane–i-PrOH, 95:5).
Mp 105 °C (lit.5e 130–131 °C); Rf = 0.67 (Et2O); [a]D23 = +195.3
(c = 1.05, CHCl3).
According to the general procedure GP 4 (method C) (2S,3R)-3a
(162 mg, 0.48 mmol) was reacted with SmI2. After purification by
column chromatography (n-pentane–Et2O, 1:3) (R)-5a (102 mg,
93%) was obtained as a colorless solid.
Anal. Calcd for C19H17FeNO: C, 68.90; N, 4.23; H, 5.17. Found: C,
68.41; N, 4.01; H, 5.30.
ee ≥98% (HPLC, Chiracel OD, n-heptane–i-PrOH, 9:1).
1H NMR (300 MHz, C6D6): d = 2.56–2.73 (m, 2 H, NCHCH2),
4.33–4.40 (m, 1 H, NCHCH2), 6.66–6.71 (m, 1 H, O=CCCCH),
6.97–7.17 (m, 7 H, CHarom), 8.14 (s, 1 H, NH), 8.28–8.35 (m, 1 H,
O=CCCH).
13C NMR (75 MHz, C6D6): d = 37.3, 55.7, 126.7, 127.3, 127.4,
128.0, 128.5, 128.8, 129.6, 132.0, 137.9, 141.9, 166.2.
(3R)-3-Furan-2-yl-3,4-dihydroisoquinolin-1(2H)-one [(R)-5e]
According to the general procedure GP 4 (method B) (2S,3R)-3e
(224 mg, 0.69 mmol) was reacted with MMPP·6H2O. After purifi-
cation by column chromatography (Et2O–hexanes, 7:3) and recrys-
tallization (Et2O–hexanes–CH2Cl2 mixture), (R)-5e (20 mg, 14%)
was obtained as a colorless solid.
ee ≥98% (HPLC, Daicel OD, n-heptane–i-PrOH, 97:3).
Synthesis 2004, No. 18, 2980–2990 © Thieme Stuttgart · New York

2988
D. Enders et al.
PAPER
Mp 97 °C; Rf = 0.17 (Et2O–hexanes, 2:1); [a]D25 = +30.5 (c = 0.56,
1H NMR (400 MHz, C6D6): d = 1.31 (br s, 1 H, NH), 2.72 (dd, 1 H,
J = 3.7, 15.9 Hz, NHCHCH2), 2.86 (dd, 1 H, J = 10.7, 15.9 Hz,
NHCHCH2), 3.36 (s, 3 H, OCH3), 3.60 (dd, 1 H, J = 4.0, 10.7 Hz,
NHCH), 3.84–3.95 (m, 2 H, CH2NH), 6.82–6.97 (m, 4 H, CHarom),
7.03–7.08 (m, 2 H, CHarom), 7.25–7.30 (m, 2 H, CHarom).
13C NMR (100 MHz, C6D6): d = 38.5, 49.4, 54.7, 58.1, 113.9, 125.7,
126.0, 126.2, 127.8, 129.1, 135.4, 135.6, 137.3, 159.1.
MS (EI): m/z (%) = 240 (17), 239 (M+, 100), 238 (54), 224 (16), 222
(7), 208 (11), 134 (15), 132 (9), 131 (9), 130 (12), 121 (19), 105
(13), 104 (78), 103 (15), 78 (12), 77 (7).
CHCl3).
IR (KBr): 3177, 3069, 3034, 1660, 1607, 1576, 1468, 1395, 1318,
1006, 817, 788, 736 cm–1.
1H NMR (400 MHz, C6D6): d = 2.71 (dd, 1 H, J = 5.2, 15.7 Hz,
NCHCH2), 2.84 (dd, 1 H, J = 7.7, 15.7 Hz, NCHCH2), 4.34–4.40
(m, 1 H, NCHCH2), 5.92 (dd, 1 H, J = 1.8, 3.2 Hz, OCH=CH),
6.03–6.07 (m, 1 H, OC=CH), 6.65–6.70 (m, 1 H, O=CCCCH), 6.94
(dd, 1 H, J = 0.8, 1.6 Hz, OCH=CH), 6.97–7.03 (m, 2 H, CHarom),
7.92 (m, 1 H, NH), 8.38–8.44 (m, 1 H, O=CCCH).
13C NMR (100 MHz, C6D6): d = 33.1, 49.2, 106.6, 110.3, 127.1,
127.4, 128.2, 129.2, 131.9, 137.2, 141.8, 154.3, 165.8.
HRMS: m/z calcd for C16H17NO: 239.1310; found: 239.1310.
(3R)-3-Ferrocenyl-1,2,3,4-tetrahydroisoquinoline [(R)-6d]
According to the general procedure GP 5 (2S,3R)-3d (330 mg, 0.74
mmol) was reacted with BH3·THF (14.8 mL, 14.8 mmol). After pu-
rification by column chromatography (Et2O–hexanes, 3:6) (S)-6d
(83 mg, 35%) was obtained as a orange-red solid.
MS (EI): m/z (%) = 214 (5), 213 (M+, 32), 212 (5), 196 (15), 195
(99), 184 (15), 156 (6), 128 (7), 119 (10), 118 (100), 91 (5), 90 (39),
89 (14).
Anal. Calcd for C13H11NO2: C, 73.22; N, 6.57; H, 5.20. Found: C,
73.32; N, 6.55; H, 5.43.
ee ≥97% (HPLC, Chiralpak AD, n-heptane–i-PrOH, 93:7).
Mp 80 °C; Rf = 0.13 (Et2O); [a]D25 = +69.7 (c = 1.02, CHCl3).
IR (KBr): 3419, 2807, 2770, 1495, 1448, 1312, 815, 746 cm–1.
1H NMR (400 MHz, C6D6): d = 1.58 (br s, 1 H, NH), 2.77–2.91 (m,
2 H, NHCHCH2), 3.53 (dd, 1 H, J = 5.0, 9.6 Hz, NHCHCH2), 3.91–
4.06 [m, 9 H, NHCH(C5H4)Fe(C5H5), CH2NHCHCH2], 4.16–4.21
[m, 2 H, NHCH(C5H4)Fe(C5H5)], 6.88–6.93 (m, 1 H, CHarom), 6.99–
7.03 (m, 1 H, CHarom), 7.05–7.12 (m, 2 H, CHarom).
13C NMR (100 MHz, C6D6): d = 37.2, 48.9, 52.8, 66.3, 66.8, 67.5,
67.7, 68.5, 93.0, 125.8, 126.0, 126.1, 129.2, 135.2, 136.1.
MS (EI): m/z (%) = 318 (22), 317 (M+, 100), 316 (14), 315 (17), 314
(8), 313 (16), 252 (6), 251 (25), 250 (9), 249 (16), 248 (9), 222 (6),
213 (13), 194 (5), 186 (23), 165 (8), 131 (11), 130 (22), 121 (9), 56
(8).
N–N Bond Cleavage Using BH3·THF to Afford 1,2,3,4-Tetrahy-
droisoquinolines 6a and 6c-f; General Procedure (GP 5)
In a Schlenk flask filled with Ar and fitted with a condenser was
placed a solution of the hydrazine (1.0 equiv) in absolute THF (40
mL/mmol hydrazine). BH3·THF (20 equiv, 1 M in THF) was added
and the reaction mixture was heated to reflux for 4 h. The reaction
mixture was cooled to –5 °C and a solution of 1 N HCl (7.7 mL/
mmol hydrazine) was cautiously added. After a 1 min reflux, the
solvent was removed in vacuum and sat. aq solution of NaHCO3 or
K2CO3 was added to the residue until no evolution of gas could be
observed. The mixture was extracted 3 times with CH2Cl2 or Et2O.
The combined organic phases were dried over MgSO4, filtered and
evaporated in vacuum.
(3S)-3-Phenyl-1,2,3,4-tetrahydroisoquinoline [(S)-6a]
According to the general procedure GP 5 (2R,3S)-3a (809 mg, 2.40
mmol) was reacted with BH3·THF (48.1 mL, 48.1 mmol). After pu-
rification by column chromatography (n-pentane– Et2O, 7:3) (S)-6a
(430 mg, 85%) was obtained as a pale yellow oil.
Anal. Calcd for C19H19FeN: C, 71.94; N, 4.42; H, 6.04. Found: C,
72.10; N, 4.54; H, 5.89.
(3S)-3-Furan-2-yl-1,2,3,4-tetrahydroisoquinoline [(S)-6e]
According to the general procedure GP 5 (2R,3S)-3e (100 mg, 0.31
mmol) was reacted with BH3·THF (6.2 mL, 6.2 mmol). After puri-
fication by column chromatography (Et2O–hexanes, 1:1) (S)-6e (29
mg, 47%) was obtained as a colorless oil.
ee ≥97% (HPLC, Chiralcel OJ, n-heptane–i-PrOH, 98:2).
Rf = 0.31 (Et2O–hexanes, 4:6); [a]D25 = +26.7 (c = 1.10, CHCl3).
1H NMR (400 MHz, C6D6): d = 1.18 (br s, 1 H, NH), 2.68 (dd, 1 H,
J = 3.8, 15.9 Hz, NHCHCH2), 2.81 (dd, 1 H, J = 10.7, 15.9 Hz,
NHCHCH2), 3.64 (dd, 1 H, J = 4.0, 10.7 Hz, NHCHCH2), 3.80–
3.90 (m, 2 H, CH2NH), 6.85–6.92 (m, 2 H, CHarom), 7.02–7.07 (m,
2 H, CHarom), 7.10–7.15 (m, 1 H, CHarom), 7.18–7.23 (m, 2 H,
CHarom), 7.31–7.35 (m, 2 H, CHarom).
ee ≥99% (HPLC, Daicel OJ, n-heptane–i-PrOH, 95:5).
Rf = 0.1 (Et2O–hexanes, 1:1); [a]D23 = –36.9 (c = 1.02, CHCl3).
1H NMR (300 MHz, C6D6): d = 1.38 (br s, 1 H, NH), 2.79–2.95 (m,
2 H, NHCHCH2), 3.68–3.84 (m, 2 H, CH2NH), 3.90 (dd, 1 H,
J = 5.6, 8.1 Hz, NHCHCH2), 6.03–6.06 (dt, 1 H, J = 0.8, 3.3 Hz,
OC=CH), 6.10 (dd, 1 H, J = 1.8, 3.2 Hz, OCH=CH), 6.76–6.80 (m,
1 H, CHarom), 6.88–6.94 (m, 1 H, CHarom), 6.97–7.05 (m, 2 H,
CHarom), 7.11 (dd, 1 H, J = 0.8, 1.9 Hz, OCH=CH).
13C NMR (75 MHz, C6D6): d = 34.0, 48.1, 51.8, 105.2, 110.4, 126.0,
126.2, 126.3, 129.4, 134.4, 135.8, 141.5, 157.8.
All other analytical data correspond with those of the literature.38
13C NMR (100 MHz, C6D6): d = 38.5, 49.3, 58.7, 125.9, 126.2,
126.4, 127.0, 127.4, 128.6, 129.3, 135.5, 135.7, 145.4.
All other analytical data are consistent with those reported in the lit-
erature.38
(3R)-3-(4-Methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline [(R)-
6c]
According to the general procedure GP 5 (2S,3R)-3c (118 mg, 0.32
mmol) was reacted with BH3·THF (6.4 mL, 6.4 mmol). After puri-
fication by column chromatography (Et2O–hexanes, 99:1 + 1%
Et3N) (R)-6c (58 mg, 76%) was obtained as a colorless solid.
(3R)-7-Methyl-3-ferrocenyl-1,2,3,4-tetrahydroisoquinoline
[(R)-6f]
According to the general procedure GP 5 (2S,3R)-3f (172 mg, 0.37
mmol) was reacted with BH3·THF (7.5 mL, 7.5 mmol). After puri-
fication by column chromatography (Et2O + 1% Et3N) (R)-6f (82
mg, 67%) was obtained as a orange-red solid.
ee ≥97% (HPLC, Daicel AD, n-heptane–i-PrOH, 95:5).
Mp 91 °C; Rf = 0.23 (Et2O); [a]D26 = +119.1 (c = 1.39, CHCl3).
IR (KBr): 3447, 3221, 3016, 2957, 2936, 2907, 2885, 2861, 2835,
1610, 1581, 1511, 1453, 1438, 1413, 1385, 1353, 1298, 1244, 1196,
1182, 1118, 1103, 1040, 1025, 963, 938, 914, 874, 831, 810, 778,
743 cm–1.
ee ≥97% (HPLC, Daicel AD, n-heptane–i-PrOH, 90:10).
Mp 72 °C; Rf = 0.15 (Et2O); [a]D24 = +67.8 (c = 0.61, CHCl3).
Synthesis 2004, No. 18, 2980–2990 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of Substituted Isoquinolines and Isoquinolinones
2989
IR (KBr): 3447, 2918, 2900, 2826, 2798, 2772, 1501, 1449, 1426,
1412, 1353, 1313, 1297, 1236, 1127, 1105, 1052, 1038, 1012, 999,
837, 813, 782 cm–1.
(7) Vicario, J. L.; Badía, D.; Carrillo, L.; Anakabe, E.
Tetrahedron: Asymmetry 2003, 14, 347, and references cited
therein.
(8) (a) Derdau, V.; Snieckus, V. J. Org. Chem. 2001, 66, 1992.
(b) Davis, F. A.; Mohanty, P. K.; Burns, D. M.;
Andemichael, Y. W. Org. Lett. 2000, 2, 3901. (c) Brózda,
D.; Koroniak, ; Rozwadowska, M. D. Tetrahedron:
Asymmetry 2000, 11, 3017. (d) Hanessian, S.; Demont, E.;
van Otterlo, W. A. L. Tetrahedron Lett. 2000, 41, 4999.
(e) Davis, F. A.; Andemichael, Y. W. J. Org. Chem. 1999,
64, 8627. (f) Carrillo, L.; Badía, D.; Domínguez, E.;
Anakabe, E.; Osante, I.; Tellitu, I.; Vicario, J. L. J. Org.
Chem. 1999, 64, 1115. (g) Vicario, J. L.; Badía, D.;
Domínguez, E.; Carrillo, L. J. Org. Chem. 1999, 64, 4610.
(h) Katritzky, A. R.; Cobo-Domingo, J.; Yang, B.; Steel, P.
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4999. (j) Barbier, D.; Marazano, C.; Riche, C.; Das, B. C.;
Potier, P. J. Org. Chem. 1998, 63, 1767. (k) Monsees, A.;
Laschat, S.; Dix, I.; Jones, P. G. J. Org. Chem. 1998, 63,
10018. (l) Davis, F. A.; Andemichael, Y. W. Tetrahedron
Lett. 1998, 39, 3099. (m) Gosmann, G.; Guillaume, D.;
Husson, H.-P. Tetrahedron Lett. 1996, 37, 4369. (n)Tellitu,
I.; Badí a, D.; Domínguez, E.; García, F. J. Tetrahedron:
Asymmetry 1994, 5, 1567.
1H NMR (400 MHz, C6D6): d = 1.58 (br s, 1 H, NH), 2.19 (s, 3 H,
CH3), 2.79–2.91 (m, 2 H, NHCHCH2), 3.57 (dd, 1 H, J = 5.6, 8.9
Hz, NHCHCH2), 3.93–4.09 [m, 9 H, NHCH(C5H4)Fe(C5H5),
CH2NH], 4.18–4.23 [m, 2 H, NHCH(C5H4)Fe(C5H5)], 6.73 (s, 1 H,
CHarom), 6.91–6.98 (m, 2 H, CHarom).
13C NMR (100 MHz, C6D6): d = 21.1, 36.8, 48.9, 53.0, 66.4, 66.9,
67.5, 67.7, 68.5, 93.2, 126.7, 126.9, 129.1, 132.2, 134.8, 135.9.
MS (EI): m/z (%) = 332 (26), 331 (M+, 100), 330 (14), 329 (12), 266
(8), 265 (29), 264 (10), 263 (15), 262 (6), 236 (7), 213 (29), 212 (5),
211 (5), 208 (6), 199 (8), 187 (6), 186 (36), 179 (5), 178 (5), 165 (5),
146 (6), 145 (15), 144 (31), 121 (14), 117 (5).
Anal. Calcd for C20H21FeN: C, 72.52; N, 4.23; H, 6.39. Found: C,
72.32; N, 4.21; H, 6.36.
Acknowledgment
This work was supported by the Deutsche Forschungsgemeinschaft
(Sonderforschungsbereich 380, Graduiertenkolleg 440) and the
Fonds der Chemischen Industrie. We thank Bayer AG, BASF AG
and Degussa AG for the donation of chemicals.
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