Asymmetric synthesis of 1,4-disubstituted tetrahydroioquinolines

Article abstract of DOI:10.1002/1099-0690(200004)2000:7<1319::AID-EJOC1319>3.0.CO;2-J

Bischler-Napieralski cyclisation of optically active β-substituted phenylethylamines 4a-c followed by diastereoselective reduction led to 1,4- disubstituted tetrahydroisoquinolines 6a-c and 8a-c. The same methodology afforded the 4-benzyl pyrroloisoquinolines 10.

Full text of DOI:10.1002/1099-0690(200004)2000:7<1319::AID-EJOC1319>3.0.CO;2-J

FULL PAPER
Asymmetric Synthesis of 1,4-Disubstituted Tetrahydroioquinolines
Valerie Jullian,[a] Jean-Charles Quirion,*[b] and Henri-Philippe Husson[a]
Keywords: Asymmetric synthesis / Tetrahydroisoquinolines / Bischler-Napieralski reaction / Diastereoselective alkylation
of Amides / Phenylglycinol
Bischler-Napieralski cyclisation of optically active β-substi-
6a–c and 8a–c. The same methodology afforded the 4-benzyl
tuted phenylethylamines 4a–c followed by diastereoselective pyrroloisoquinolines 10.
reduction led to 1,4-disubstituted tetrahydroisoquinolines
Introduction
As part of our ongoing program investigating the use of
optically pure phenylglycinol as a source of nitrogen and
chirality[1] we were particularly interested in the synthesis
Scheme 1. Retrosynthetic scheme
of tetrahydroisoquinolines bearing substituents on the non-
aromatic moiety. Indeed, a large variety of natural and un-
natural derivatives in these series exert considerable phar-
macological activity. Much attention has been paid to the
synthesis of the C-1 substituted aporphine and related al-
kaloids in either racemic or optically pure fashions.[2]
Amongst the biologically interesting polysubstituted tetra-
hydroisoquinolines three substitution patterns are notable:
1,3; 1,4 and 1,3,4. However, very few asymmetric syntheses
have been reported for these structures.[3]
Our approach to the development of a general synthetic
methodology for the construction of 1,3-disubstituted tetra-
hydroisoquinolines with the CN(R,S) method[4] was the
first to give access to the enantiomeric C-1 substituted com-
pounds and the four isomers of the 1,3-disubstituted tetra-
hydroisoquinolines in an optically pure form without lim-
itation for the alkyl substituents. As far as we know there
are no reports of the asymmetric synthesis of 1,4-disubsti-
tuted tetrahydroisoquinolines; the nearest relevant work be-
ing a synthesis of pyrroloisoquinolines bearing an aliphatic
or aryl substituent at C-4.[5]
In this paper we provide an answer to the problem of the
asymmetric synthesis of 1,4-disubstituted tetrahydroisoqui-
nolines based upon a Bischler-Napieralski reaction of β-
substituted phenylethylamines. The latter could be easily
prepared following our method[6] of diastereoselective al-
kylation of amides derived from R-(–)phenylglycinol, fol-
lowed by the reduction and removal of the chiral append-
age (Scheme 1).
Results and Discussion
Most of the biologically active structures bear substitu-
tions in several positions of the condensed benzene ring of
tetrahydroisoquinolines. Thus we prepared amides 1a–c de-
rived from N-methyl (R)-phenylglycinol (or its benzyl deriv-
ative) and 3,4-disubstituted phenylacetyl chloride to exem-
plify our methodology (Scheme 2).
The synthetic route followed was similar to that reported
from this laboratory,[6] i.e. alkylation of the anion of 1a–
c (sBuLi, HMPA or DMPU) with iodomethane or benzyl
bromide followed by reduction of the carbonyl group with
LiAlH4 in refluxing THF and hydrogenolysis of the chiral
auxiliary. A single diastereomer was obtained for the al-
kylated amides 2a and 2c but, curiously, a 9:1 mixture was
formed in the case of 2b. However, the major diastereomer
can be easily isolated and amine 4b obtained in an optically
pure form. Obtaining primary amines in excellent yield re-
quired special conditions in the case of 3c [cyclohexene,
Pd(OH)2] to prevent incomplete deprotection as observed
in our earlier studies.
Two general routes to tetrahydroisoquinolines have been
devised from phenylethylamines. The first common ap-
proach is via an iminium salt which is cyclised according to
a Pictet-Spengler reaction.[7]The second is the cyclization of
an amide according to the Bischler-Napieralski reaction,[8]
followed by the reduction of the resultant iminium salt. In
both cases it was expected that the first stereogenic centre
at C-4 would have an effect upon the outcome of the cyc-
lization reaction (Pictet-Spengler) or the iminium reduction
(Bischler-Napieralski).
[a]
´
´
Laboratoire de Chimie Therapeutique associe au CNRS,
´
Faculte des Sciences Pharmaceutiques et Biologiques,
´
Universite Paris V,
4, Avenue de l’Observatoire, F-75270 Paris Cedex 6, France
E-mail: Husson@pharmacie.univ-paris5.fr
Laboratoire d’Heterochimie Organique associe au CNRS,
[b]
´ ´
´
IRCOF-INSA,
As far as the Pictet-Spengler reaction was concerned, the
formation of the desired product has not been observed
from the secondary amines 4a and 4b, whatever the nature
Pl. E. Blondel, B. P. 8, F-76131 Mont-Saint-Aignan Cedex,
France
E-mail: quirion@ircof.insa-rouen.fr
Eur. J. Org. Chem. 2000, 1319Ϫ1325
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0407Ϫ1319 $ 17.50ϩ.50/0
1319

V. Jullian, J.-C. Quirion, H.-P. Husson
FULL PAPER
Scheme 2. Synthesis of β-phenylethylamines
of the aldehydes (CH3CHO, PhCHO) and the experimental
conditions (pTSA, toluene, reflux TFA, CH2Cl2, reflux
HCl, CH3OH, room temp.). This lack of reactivity was sur-
prising since it is well-known that the Pictet-Spengler reac-
tion is quite a common method for the preparation of tetra-
hydroisoquinolines. Very recently, similar frustrating results
have been reported in the attempted synthesis of 1,3-dis-
usbstituted tetrahydroisoquinolines from the reaction of
secondary amines with acetaldehyde.[9] However, condensa-
tions of formaldehyde and acetaldehyde occurred easily
with primary amines. There is no explanation for this unex-
pected behaviour.
We then turned our attention to the Bischler-Napieralski
conditions. We were pleased to observe a high diastereose-
lectivity for the reduction of the iminium intermediate in
the (3,4-methylenedioxy)phenyl series 5 a–c independently
of the C-1 substituent (Scheme 3).
Scheme 4. Determination of the relative configuration of com-
pound 6c
The C-4 substituent clearly adopted an axial position as
indicated by the values for JH-3–H-4 (3.3 Hz). A NOESY ex-
periment revealed correlations between C3–Hax and C1–H,
indicative of an axial position for C1–H. This conclusion
was confirmed by the chemical shifts of C1–H (δ ϭ 4.04)
and C10–H (δ ϭ 6.12) which are in complete agreement
with those previously reported.[10] So, the C-1 and C-4 sub-
stituents are mutually cis in the major diastereomer. In the
1H NMR spectrum of the minor isomer, the C3–H axial
proton appeared as a doublet (δ ϭ 2.13, J ϭ 10.6 and
11.3 Hz) indicative of an axial position for C4–H. The
chemical shifts of C1–H (δ ϭ 4.24) and C10-H (δ ϭ 6.1)
are in agreement with an equatorial position for the C-1
aromatic ring confirming the trans relationship between the
two substituents.
Unexpectedly, the diastereoselectivity of the reduction
step of the same reaction sequence was poor when applied
to amides 7a and 7b, whereas it was satisfactory in the case
of amide 7c in the same (3,4-dimethoxy)phenyl series. The
relative stereochemistry in the latter series was deduced
from the results obtained for 6a–c. This diastereoselectivity
can be best explained considering the intermediate iminium
moiety in which the C-4 substituent could adopt a pseudo-
axial position to minimise steric interactions with C3–H
and C10–H (Scheme 5).
Scheme 3. Synthesis of tetrahydroisoquinolines 8a–c
Yields related to the purified major diastereomer are low
owing to degradation of the compound during the purifica-
1
tion by flash chromatography on silica. The H and 13C
NMR spectra of the crude product indicate only a mixture
of two diastereomers and no other side product. The relat-
ive cis configuration of the newly created stereogenic centre
was deduced from 1H NMR studies of compound 6c
(Scheme 4).
Scheme 5. Preferential attack in the reduction of intermediate
iminium
1320
Eur. J. Org. Chem. 2000, 1319Ϫ1325

Asymmetric Synthesis of 1,4-Disubstituted Tetrahydroioquinolines
FULL PAPER
Scheme 6. Synthesis of pyrroloisoquinoline 10
ture was cooled to 0 °C and 1.2 equiv. of acyl chloride was added
dropwise. After stirring for between 30 min and 3 h. at 0 °C, a
saturated aqueous solution of K2CO3 was added. The organic layer
was separated and the aqueous layer extracted twice with dichloro-
methane. The combined organic extracts were dried with MgSO4
and the solvent was removed. The amide was purified by flash col-
umn chromatography on silica gel.
Consequently the hydride ion approach (opposite to the
C-4 substituent) is under stereoelectronic control. The dif-
ferences observed between the benzyl and methyl series
could be due to a modification in the hindrance of these
substituents which could slightly modify the conformation
of the intermediate iminium and subsequently the selectiv-
ity of the hydride approach.
Synthesis of Amides 2a–c (GP2): To a solution of 1 equiv. of amide
1 in dry tetrahydrofuran (15 mL/mmol) under nitrogen was added
5 equiv. of DMPU. The solution was then cooled to –78 °C and a
solution of 2.5 equiv. of sec-butyllithium (1  in cyclohexane) was
added. After stirring for 15 min at –78 °C, 3 equiv. of electrophile
were added, and the solution was stirred for 2 h. at –78 °C. A satur-
ated aqueous solution of NH4Cl was added for hydrolysis. The or-
ganic layer was separated and the aqueous layer extracted 3 times
with ethyl acetate. The combined organic layers were dried with
MgSO4 and the solvent was removed. The amide was purified by
column chromatography on silica gel.
A final application of this methodology was conducted
for the synthesis of a benzyl-substituted pyrroloisoquino-
line, a series which was extensively investigated.[11]
Lactam 9 was obtained following a method previously
described by us.[12] The NaBH4 reduction of the Bischler-
Napieralski reaction iminium afforded an 80:20 diastereom-
1
eric mixture (Scheme 6). In the H-NMR spectrum of 10
C3–Hax appeared as a broad doublet at δ ϭ 2.34, indicative
of an equatorial position for C4–H as observed previously
for the major isomer 6c. A cis relationship was assigned
for the C-1 and C-4 substituents of the major diastereomer
according to the above mentioned mechanism of iminium
reduction.
Synthesis of Amines 3a–c (GP3): To a suspension of 10 equiv. of
LiAlH4 in dry THF, under nitrogen, was added dropwise at ambi-
ent temperature a solution of 1 equiv. of amide 2 in dry THF
(4.8 mL/mmol). The mixture was refluxed for 3 h. and then cooled
to 0 °C. For each gram of LiAlH4 was added carefully 1 mL of
water followed by 1 mL of a 15% solution of NaOH in water and
3 mL of water. The mixture was allowed to warm to room temper-
Conclusion
We have described the asymmetric Bischler-Napieralski
synthesis of 1,4-disubstituted tetrahydroisoquinolines, in- ature and then filtered through a Celite bed. The solid was washed
with diethyl ether, and the solvent was removed. The amine was
purified by column chromatography (silica or alumina gel).
cluding one example in the pyrroloisoquinoline series. Dur-
ing the reduction of the intermediate iminium, a moderate
to good diastereoselectivity was observed. The synthetic
pathway described above provides a general entry into a
new series of tetrahydroisoquinolines. The ease of synthesis
of enantiomerically pure β-substituted amines 4, combined
with the ability to vary the nature of the substituents,
should enjoy a wide application in the preparation of en-
antiomerically pure polysubstituted isoquinolines.
Synthesis of Amines 4a–b (GP4): To 1 g of amine in 30 mL of meth-
anol was added 500 mg of Pearlman’s catalyst. The resulting mix-
ture was stirred for 1.5 h under hydrogen. The mixture was then
filtered through a Celite bed. The catalyst was washed with meth-
anol and 2 mL of a 2  solution of HCl in methanol was added to
the filtrate. The solvent was removed. The solid crude mixture was
washed several times with diethyl ether and then diluted in a satur-
ated aqueous solution of K2CO3. This aqueous layer was extracted
three times with diethyl ether. The combined organic layers were
dried with MgSO4 and the solvent was removed to give the free
amine.
Experimental Section
1
General Remarks: H (300 MHz) and 13C (75 MHz) was recorded
Synthesis of Tetrahydroisoquinolines 6a–c, 8a–c and 10 (GP5): To a
solution of 1 equiv. of amide 6, 8 or 10 in toluene (16 mL/mmol)
was added dropwise 10 equiv. of phosphorus oxychloride. The mix-
ture was heated at reflux for 3 h and then allowed to cooled to 0
°C. Water was added for hydrolysis. The organic layer was separ-
ated and the aqueous layer extracted three times with chloroform.
The pH of the aqueous layer was adjusted to 6 with sodium hydrox-
ide. The aqueous layer was concentrated and the residue washed
with acetonitrile. This layer was added to the previous organic
layers. The solvent was removed. The crude mixture was diluted in
methanol (10 mL/mmol) and cooled to 0 °C. Sodium borohydride
(20 equiv.) was added to the solution. After stirring for 30 min at
0 °C, water was added for hydrolysis and the mixture was extracted
with a AC-300 Bruker spectrometer. Mass spectra (CI) were re-
corded at 30 eV with a Nermag R10-10 spectrometer. Optical rota-
tions were recorded with a Perkin–Elmer 141MC polarimeter. TLC
was carried out on Merck silica gel 60 PF254. Flash column chro-
matography was carried out on silica 60, 70–200 µm (SDS, France)
or aluminium oxide 90, activity II–III (Merck). THF was dried
using sodium/benzophenone and LiAlH4 before use.
General Procedures (GP)
Synthesis of Amides 1a–c (GP1): To a solution of 1 equiv. of amine
in chloroform (4 mL/mmol) was added a solution of 1.1 equivalents
of sodium hydroxide in water (0.23 mL/mmol). The reaction mix-
Eur. J. Org. Chem. 2000, 1319Ϫ1325
1321

V. Jullian, J.-C. Quirion, H.-P. Husson
FULL PAPER
three times with chloroform. The combined organic layers were
dried with MgSO4. The solvent was removed. The tetrahydroisoqu-
inoline was purified by column chromatography on silica gel.
NCH3), 2.57 (s, 3 Hmaj, NCH3), 2.95 (dd, J ϭ 13.1, 5.7 Hz, 1 H,
C6H6CHH), 3.45 (dd, J ϭ 13.2, 9.0 Hz, 1 H, C6H6CHH), 3.8–4.1
[m, 3 H, NCHCH2, (CO)CH], 4.37 (dd, J ϭ 7.2, 7.2 Hz, 1 H, OH),
5.20 (dd, J ϭ 9.3, 4.6 Hz, 1 Hmin, NCHCH2), 5.78 (dd, J ϭ 8.8,
5.5 Hz, 1 Hmaj, NCHCH2), 5.9 (m, 2 H, OCH2O), 6.6–7.3 (m, 8
H, aromatic H). – 13C NMR (75.43 MHz, CDCl3): δ ϭ 28.3
(NCH3), 31.0 (NCH3), 41.3 (C6H6CH2), 50.5 [(CO)CH], 50.9
[(CO)CH], 58.2 (NCHCH2), 60.3 (NCHCH2), 60.7 (CH2OH), 61.5
(CH2OH), 100.9 (OCH2O), 108.2, 108.5, 121.2, 121.6, 126.0, 126.1,
127.0, 127.4, 127.5, 128.0, 128.2, 128.4, 129.0, 129.2 (aromatic CH),
132.9, 133.6, 136.3, 136.7, 139.6, 139.8, 146.5, 146.6, 147.9 (aro-
matic C), 174.1, 174.4 (CϭO). – MS (CI, NH3); 404 (MHϩ). –
C18H19NO4 (403.5): calcd. C 74.42, H 6.24, N 3.48; found C 74.57,
H 6.47, N 3.41.
Amide 1a: (R)-N-methylphenylglycinol (2.26 g, 15 mmol) was al-
lowed to react with (3,4-methylendioxyphenyl)acetyl chloride ac-
cording to GP1, yielding 1a (3.41 g, 73%) after column chromato-
graphy on silica gel (ethyl acetate) as colourless crystals, m.p. 82
°C. – [α]2D2 ϭ –93 (c ϭ 1.05, CHCl3). – IR (film): ν˜ ϭ 3385 cm–1
1
(OH), 1620 (CϭO). – H NMR (300.13 MHz, CDCl3, TMS), two
rotamers in a 70:30 ratio: δ ϭ 2.65 (s, 3 Hmin, NCH3), 2.75 (s, 3
Hmaj, NCH3), 3.68 [s, 2 H, (CO)CH2], 3.7–4.15 (m, 3 Hmaj ϩ 2
Hmin, NCHCH2), 5.15 (m, 1 Hmin, NCHCH2), 5.60 (s, 2 Hmaj
,
OCH2O), 5.85 (s, 2 Hmin, OCH2O), 6.5–7.4 (m, 8 H, aromatic H). –
13C NMR (75.43 MHz, CDCl3): δ ϭ 28.2 (NCH3), 31.03 (NCH3),
40.5 [(CO)CH2], 41.0 [(CO)CH2], 57.9 (CH), 60.9 (CH2OH), 61.1
(CH2OH), 61.5 (CH), 100.8 (OCH2O), 108.2, 109.3, 109.6, 121.8,
122.0, 126.9, 127.5, 128.2, 128.5 (aromatic CH), 136.6, 137.0, 146.3,
147.7 (aromatic C), 172.8 (CϭO). – MS (CI, NH3); 314 (MHϩ). –
C18H19NO4(313.3): calcd. C 68.99, H 6.11, N 4.47; found C 69.05,
H 6.24, N 4.36.
Amide 2b: Compound 1b (2.61 g, 7.93 mmol) was allowed to react
with iodomethane (1.5 mL, 24.1 mmol) according to GP2, yielding
2b (1.53 g) and a 2:1 mixture of 2b and the minor diastereomer
(680 mg) after column chromatography on silica gel (ethyl acetate/
cyclohexane 50:50 then 80:20). The overall yield was 81% and the
de was 80%. – Major diastereomer: [α]2D2 ϭ –68 (c ϭ 0.95, CHCl3). –
IR (film): ν˜ ϭ 3405 cm–1 (OH), 1618 (CϭO). – 1H NMR
(300.13 MHz, CDCl3, TMS), two rotamers in a 70:30 ratio: δ ϭ
Amide 1b: (R)-N-methylphenylglycinol (1 g, 6.62 mmol) was al-
lowed to react with (3,4-dimethoxyphenyl)acetyl chloride according
to GP1, yielding 2 (1.57 g, 72%) after column chromatography on
silica gel (CH2Cl2/MeOH 98:2 then 95:5) as a colourless oil. –
[α]2D2 ϭ –102 (c ϭ 0.55, CH2Cl2). – IR (film): ν˜ ϭ 3398 cm–1 (OH),
1.46 (d, J ϭ 3.5 Hz, 3 Hmin, CHCH3), 1.48 (d, J ϭ 6.6 Hz, 3 Hmaj
,
CHCH3), 2.56 (s, 3 Hmin, NCH3), 2.66 (s, 3 Hmaj, NCH3), 3.20 (m,
1 Hmaj, OH), 3.8–4.14 [m, 9 H, 2 OCH3, (CO)CH, NCHCH2], 4.35
(m, 1 Hmin, OH), 5.30 (dd, J ϭ 8.2, 5.2 Hz, 1 Hmin, NCHCH2),
5.90 (dd, J ϭ 8.2, 5.4 Hz, 1 Hmaj, NCHCH2), 6.5–7.4 (m, 8 H,
aromatic H). – 13C NMR (75.43 MHz, CDCl3): δ ϭ 20.5 (CHCH3),
20.8 (CHCH3), 28.1 (NCH3), 30.6 (NCH3), 42.4 (CHCH3), 43.3
(CHCH3), 55.6 (OCH3), 55.7 (OCH3), 58.1 (NCHCH2), 60.3
(NCHCH2), 60.4 (CH2OH), 61.1 (CH2OH), 110.1, 110.4, 111.1,
111.4, 119.4, 119.7, 127.0, 127.6, 128.2, 128.4 (aromatic CH), 133.8,
134.9, 136.3, 136.9, 147.6, 149.0 (aromatic C), 175.5 (CϭO). – MS
(CI, NH3); 344 (MHϩ).
1
1617 (CϭO). – H NMR (300.13 MHz, CDCl3, TMS), two rota-
mers in a 70:30 ratio: δ ϭ 2.63 (s, 3 Hmin, NCH), 2.78 (s, 3 Hmaj
,
NCH3), 3.75–4.1 [m, 10 H, 2 OCH3, (CO)CH2, NCHCH2], 5.21
(dd, J ϭ 9.5, 4.4 Hz, 1 Hmin, NCH), 5.90 (dd, J ϭ 9.3, 5.2 Hz, 1
Hmaj, NCH), 6.8–7.25 (m, 8 H, aromatic H). – 13C NMR
(75.43 MHz, CDCl3): δ ϭ 28.1 (NCH3), 30.8 (NCH3), 40.4
[(CO)CH2], 40.9 [(CO)CH2], 55.6 (2 OCH3), 57.7 (CH), 60.9
(CH2OH), 61.4 (CH), 111.1, 111.6, 112.1, 120.7, 121.1, 126.8,
127.0, 127.4, 127.6, 127.7, 128.4 (aromatic CH), 136.1, 137.0, 147.6,
148.9 (aromatic C), 172.8 (CϭO).
Amide 2c: Amide 1c (2.87 g, 7.08 mmol) was allowed to react with
benzyl bromide (2.5 mL, 21 mmol) according to GP2, yielding 2c
(2.37 g, 68%) after column chromatography on silica gel (ethyl acet-
ate/cyclohexane 30:70 then 50:50) as a white foam. – [α]2D2 ϭ –18
(c ϭ 1.15, CHCl3). – IR (film): ν˜ ϭ 3412 cm–1 (OH), 1636 (Cϭ
O). – 1H NMR (300.13 MHz, CDCl3, TMS), two rotamers in a 75/
25 ratio: δ ϭ 2.86 [dd, J ϭ 13.0, 4.8, 1 Hmaj, (CO)CHCHH], 3.05
Amide 1c: (R)-N-benzylphenylglycinol (4.47 g, 19.69 mmol) was al-
lowed to react with (3,4-dimethoxyphenyl)acetyl chloride according
to GP1, yielding 2 (5.05 g, 63%) after column chromatography on
silica gel (ethyl acetate/cyclohexane 80:20 then ethyl acetate) as yel-
low crystals, m.p. 102 °C. – [α]2D2 ϭ –45 (c ϭ 0.8, CHCl3). – IR
(film): ν˜
ϭ –
3406 cm–1 (OH), 1633 (CϭO). 1H NMR
[dd, J ϭ 13.0, 5.3, 1 Hmin, (CO)CHCHH], 3.56 [m, 1H ϩ 2 Hmin
,
(300.13 MHz, CDCl3, TMS), two rotamers in a 75:25 ratio: δ ϭ
3.64 [br. s, 2 Hmaj ϩ 2 Hmin, (CO)CH2], 3.83 (m, 6 Hmaj ϩ 6 Hmin
ϩ 2 Hmin, 2 OCH3, CH2OH ), 4.05 (m, 2 Hmaj ϩ 1 Hmin, CH2OH,
NCHH), 4.42 (d, J ϭ 17.7 Hz, 1 Hmaj, NCHH), 4.46 (d, J ϭ 17.7
Hz, 1 Hmaj, NCHH), 4.82 (d, J ϭ 15.4 Hz, 1 Hmin, NCHH), 5.29
(dd, J ϭ 8.6, 5.0 Hz 1 Hmin, NCH), 5.49 (dd, J ϭ 7.5, 5.4 Hz, 1
Hmaj, NCH), 6.67–6.92 (m, 3 H, aromatic H), 7.07–7.36 (m, 5 H,
aromatic H) –13C NMR (75.43 MHz, CDCl3): δ ϭ 41.1, 41.3
[(CO)CH2], 45.5, 49.6 (NCH2), 55.7 (OCH3), 61.8, 62.1 (NCH),
62.9 (CH2OH), 111.1, 111.6, 120.8, 121.1, 125.9, 126.9, 127.4,
127.8, 128.0, 128.3, 128.5, 128.7 (aromatic CH), 136.9, 137.1, 138.9,
147.8, 148.9 (aromatic C), 173.2, 173.8 (CϭO), C25H27NO4 (405.5):
calcd. C 74.05, H 6.71, N 3.45; found C 74.12, H 6.64, N 3.46.
(CO)CHCHH, NCHH, CHHOH], 3.87 [m, 7 H ϩ 2 Hmaj, 2 OCH3,
CHHOH, (CO)CH, NCHH], 4.15 (m, 1 Hmaj, CHHOH), 4.58 [m,
1 Hmaj ϩ 1 Hmin, NCHH, (CO)CH], 4.68 (dd, J ϭ 7.6 –3.7, 1 Hmaj
,
NCH), 5.0 (d, J ϭ 15.4, 1 Hmin, NCHH), 5.35 (m, 1 Hmin, NCH),
6.5–7.5 (m, 18 H, aromatic H). – 13C NMR (75.43 MHz, CDCl3):
δ ϭ 41.9 [(CO)CHCH2], 42.0 [(CO)CHCH2], 44.9 (NCH2), 50.3
(NCH2), 50.8 [(CO)CH], 52.2 [(CO)CH], 55.6 (2 OCH3), 60.9
(NCH), 61.3 (CH2OH), 63.6 (CH2OH), 64.3 (NCH), 110.3, 110.7,
111.1, 111.2, 120.0, 120.4, 125.8–129.5 (aromatic CH), 131.3, 132.2,
136.0, 136.3, 136.7, 138.9, 139.5, 139.8, 148.0, 149.0 (aromatic C),
173.6, 174.7 (CϭO). – MS (CI, NH3); 496 (MHϩ).
Amine 3a: 1.9 g (4.71 mmol) of amide 2a were allowed to react
according to GP3, yielding 1.7 g of 3a (72%) after column chroma-
tography on silica gel (ethyl acetate/cyclohexane 50:50) as a colour-
Amide 2a: Amide 1a (200 mg, 0.639 mmol) was allowed to react
with benzyl bromide (228 µL, 1.91 mmol) according to GP2,
yielding 2a (187 mg, 72%) after column chromatography on silica (OH). – H NMR (300.13 MHz, CDCl3, TMS): δ ϭ 1.97 (s, 3 H,
less oil. – [α]D22 ϭ –66 (c ϭ 1.12, CHCl3). – IR (film): ν˜ ϭ 3421 cm–1
1
gel (ethyl acetate/cyclohexane 30:70 then 50:50) as colourless crys-
NCH3), 2.5–3.0 (m, 5 H, NCH2CHCH2), 3.43 (dd, J ϭ 10.2, 4.6
tals, m.p. 128 °C. – [α]D22 ϭ –102 (c ϭ 0.88, CHCl3). – IR (film): Hz, 1 H, CHHOH), 3.60 (dd, J ϭ 10.3, 4.6 Hz, 1 H, NCH), 3.74
ν˜ ϭ 3404 cm–1 (OH), 1624 (CϭO). – 1H NMR (300.13 MHz,
(dd, J ϭ 10.3, 10.3 Hz, 1 H, CHHOH), 5.90 (s, 2 H, OCH2O), 6.4–
7.3 (m, 8 H, aromatic H). – 13C NMR (75.43 MHz, CDCl3): δ ϭ
CDCl3, TMS), two rotamers in a 70:30 ratio: δ ϭ 2.51 (s, 3 Hmin
,
1322
Eur. J. Org. Chem. 2000, 1319Ϫ1325

Asymmetric Synthesis of 1,4-Disubstituted Tetrahydroioquinolines
FULL PAPER
35.4 (NCH3), 41.0 (NCH2CHCH2), 46.1(NCH2CHCH2), 60.2, 61.0 matic CH), 137.9, 147.5, 149.0 (aromatic C). – MS (CI, NH3); 210
(NCH2, CH2OH), 69.5 (NCH), 100.7 (OCH2O), 107.6, 108.0, (MHϩ). – C12H19NO2 HCl 0.25CH4O (253.7): calcd. C 57.98, H
120.8, 125.7, 127.7, 127.9, 128.1, 128.6, 128.8 (aromatic CH), 135.5,
137.1, 139.9, 145.8, 147.6 (aromatic C). – MS (CI, NH3); 390
(MHϩ).
8.34, N 5.51; found C 58.01, H 7.91, N 5.81.
Amine 4c: Amine 3c (2.196 g, 4.56 mmol) was allowed to react with
100 mL of cyclohexene and 2 g of Pearlman’s catalyst. The mixture
was refluxed during 24 h and then filtered through a Celite bed.
The catalyst was washed with methanol and 10 mL of a 2  solu-
tion of HCl in methanol was added to the filtrate. The solvent was
removed. The solid crude mixture was washed several times with
Amine 3b: Amide 2b (1.43 g, 4.17 mmol) was allowed to react ac-
cording to GP3, yielding 3b (1.213 g, 88%) after column chromato-
graphy on alumina gel (ethyl acetate) as a colourless oil. – [α]D22
ϭ
ϩ2.5 (c ϭ 1.05, CHCl3). – IR (film): ν˜ ϭ 3402 cm–1 (OH). – 1H
NMR (300.13 MHz, CDCl3, TMS): δ ϭ 1.25 (d, J ϭ 6.8 Hz, 3 H, diethyl ether and then diluted with a saturated aqueous solution of
CHCH3), 2.14 (s, 3 H, NCH3), 2.55 (m, 2 H, NCH2), 2.91 (m, 1 K2CO3. This aqueous layer was extracted three times with diethyl
H, NCH2CH), 3.55 (dd, J ϭ 10.3, 4.8 Hz, 1 H, CHHOH), 3.72 ether. The combined organic layers were dried with MgSO4 and
(dd, J ϭ 10.4, 4.7 Hz, 1 H, CHCH2OH), 3.9 (m, 7 H, 2 OCH3,
the solvent was removed to give the free amine (1.1 g, 90%) as a
CHHOH), 6.7–6.85 (m, 3 H, Har.), 7.1–7.35 (m, 5 H, Har.). – 13C pale yellow oil. Its hydrochloride salt crystallised from a methanol/
NMR (75.43 MHz, CDCl3): δ ϭ 19.9 (CHCH3), 36.1, 37.4 (NCH3, diethyl ether system, m.p. 195 °C. [α]2D2 ϭ –63 (HCl salt, c ϭ 1,
NCH), 55.8 (2 OCH3), 60.2, 61.9 (NCH2, CH2OH), 69.2 (NCH), CH3OH). – H NMR (300.13 MHz, CD3OD): δ ϭ 2.95 (m, 5 H,
1
110.5, 111.2, 118.8, 127.7, 128.0, 128.6 (aromatic CH), 135.4, 138.2,
147.4, 148.8 (aromatic C).
NCH2CHCH2), 3.84 (s, 3 H, OCH3), 3.86 (s, 3 H, OCH3), 6.8–7.4
(m, 8 H, aromatic H). – 13C NMR (75.43 MHz, CDCl3): δ ϭ 40.8
(NCH2CHCH2), 46.3 (NCH2), 50.5 (NCH2CH), 55.6 (2 OCH3)
110.9, 111.1, 119.6, 125.7, 127.9, 128.1, 128.8 (aromatic CH), 134.7,
139.7, 147.4, 148.7 (aromatic C). – MS (CI, NH3); 272 (MHϩ). –
C17H21NO2 HCl 0.5CH4O (323.8): calcd. C 64.90, H 7.46, N 4.32;
found C 64.83, H 7.37, N 4.45.
Amine 3c: Amide 2c (2.97 g, 6 mmol) was allowed to react accord-
ing to GP3, yielding 3c (2.23 g, 77%) after column chromatography
on silica gel (ethyl acetate/cyclohexane 30:70 then 50:50) as a col-
ourless oil. – [α]2D2 ϭ –91 (c ϭ 1.1, CHCl3). – IR (film): ν˜ ϭ
3447 cm–1 (OH). – 1H NMR (300.13 MHz, CDCl3, TMS): δ ϭ 2.59
(m,
NCHHCHCH2 or NCH2CHCHH), 3.03 (dd, J ϭ 13.2, 5.0 Hz, 1 cording to GP1 with benzoyl chloride, yielding 7a (427 mg, 88%). –
H, NCHHCHCH2 or NCH2CHCHH), 3.17 (d, J ϭ 13.5 Hz, 1 H,
[α]2D2 ϭ ϩ50 (c ϭ 0.8, CHCl3). – IR (film): ν˜ ϭ 1633 cm–1 (CO). –
NCHHC6H6 ), 3.61 (dd, J ϭ 10.3, 4.5 Hz, 1 H, CHHOH), 3.74 (s, 1H NMR (300.13 MHz, CDCl3, TMS), two rotamers in a 70:30
3 H, OCH3), 3.82 (s, 3 H, OCH3), 3.87 (m, 2 H, NCHHC6H6, ratio: δ ϭ 1.13 (d, J ϭ 5.7 Hz, 3 Hmin, CHCH3), 1.33 (d, J ϭ 6.9
NCH), 4.00 (dd, J ϭ 10.3, 10.3 Hz, 1 H, CHHOH), 6.4–6.9 (m, 3 Hz, 3 Hmaj, CHCH3), 2.67 (s, 3 Hmaj, NCH3), 2.98 (m, 1 Hmin
H, aromatic), 7.1–7.3 (m, 5 H, aromatic). – 13C NMR (75.43 MHz,
NCH2CH), 3.07 (s, 3 Hmin, NCH3), 3.32 (m, 1 Hmin ϩ 1 Hmaj
2
H, NCHHCHCHH), 2.90 (m,
2
H, NCH2CH, Amide 7a: Amine 4b (325 mg, 1.55 mmol) was allowed to react ac-
,
,
CDCl3): δ ϭ 41.1 (NCH2CHCH2), 46.9 (NCH2CHCH2), 55.1 NCHH, NCH2CH), 3.53 (m, 1 Hmin ϩ 1 Hmaj, NCHH), 3.87 (m,
(NCH2CHCH2 or NCH2C6H6), 55.7 (2 OCH3), 56.6 6 H ϩ 1 Hmaj, 2 OCH3, NCHH), 6.3–7.3 (m, 8 H, aromatic H) –
(NCH2CHCH2 or NCH2C6H6), 60.7 (CH2OH), 65.6 (NCH), 13C NMR (75.43 MHz, CDCl3): δ ϭ 18.3, 19.4 (CHCH3), 33.4,
111.0, 111.3, 119.5, 125.2, 125.7, 127.2, 127.8, 128.0, 128.2, 128.4,
128.9, 129.1 (aromatic CH), 135.7, 135.9, 139.3, 140.2, 147.5, 148.5
(aromatic C). – MS (CI, NH3); 482 (MHϩ).
37.4, 37.9, 38.4 (NCH3, CHCH3), 54.3 (NCH2), 55.7 (OCH3), 58.7
(NCH2), 109.6, 110.4, 111.0, 119.1, 126.5, 126.7, 128.0, 128.1,
128.9, 129.2, 129.7 (aromatic CH), 135.4, 136.7, 147.5, 148.8, 149.1,
149.3 (aromatic C), 169.8, 171.4 (CO).
Amine 4a: Amine 3a (1.3 g, 3.34 mmol) was allowed to react ac-
cording to GP4, yielding 4a as its hydrochloride salt (915 mg, 90%),
Amide 7b: Amine 4b (117 mg, 0.56 mmol) was allowed to react ac-
which can be crystallised from a methanol/diethyl ether system, cording to GP1 with acetyl chloride, yielding 7b (110 mg, 78%)
m.p. 156 °C. – [α]D22 ϭ –70 (HCl salt, c ϭ 1.16, MeOH). – 1H NMR after column chromatography on silica gel (ethyl acetate). – [α]2D2
of the HCl salt (300.13 MHz, CD3OD): δ ϭ 2.71 (s, 3 H, NCH3), ϩ79 (c ϭ 0.8, CHCl3). – IR (film): ν˜ ϭ 1633 cm–1 (CO). – 1H NMR
2.95 (dd, 13.6, 8.6 Hz, H, NCHHCHCH2 or (300.13 MHz, CDCl3, TMS), two rotamers in a 55:45 ratio: δ ϭ
ϭ
J
ϭ
1
NCH2CHCHH), 3.09 (dd, J ϭ 13.4, 6.0 Hz, 1 H, NCHHCHCH2
or NCH2CHCHH), 3.32 (m, 2 H, NCH2CH, NCHHCHCH2 or
1.15 (d, J ϭ 6.8 Hz, 3 Hmaj, CHCH3), 1.22 (d, J ϭ 7.0 Hz, 3 Hmin
CHCH3), 1.76 [s, 3 Hmin, C(O)CH3], 1.94 [s, 3 Hmaj, C(O)CH3],
,
NCH2CHCHH), 3.44 (m, 1 H, NCHHCHCH2 or NCH2CHCHH), 2.66 (s, 3 Hmaj, NCH3), 2.79 (s, 3 Hmin, NCH3), 2.92 (m, 1 Hmin
6.02 (s, 2 H, OCH2O), 6.75–6.86 (m, 3 H, aromatic H), 7.15–7.3 NCH2CH), 3.04 (m, 1 Hmaj, NCH2CH), 3.15 (dd, J ϭ 13.1, 8.4
(m, 5 H, aromatic H). – 13C NMR (75.43 MHz, CD3OD): δ ϭ 34.3 Hz, 1 Hmaj, NCHHCH), 3.30 (m, 2 Hmin, NCH2CH), 3.67 (dd, J ϭ
(NCH3), 41.7 (NCH2CHCH2), 46.2 (NCH2CHCH2), 54.9 (NCH2), 13.0, 6.9 Hz, 1 Hmaj, NCHHCH), 3.78 (s, 3 H, OCH3), 3.80 (s, 3
102.4 (OCH2O), 108.9, 109.4, 122.8, 127.3, 129.3, 130.1 (aromatic H, OCH3), 6.6–6.8 (m, 3 H, aromatic H) –13C NMR (75.43 MHz,
CH), 134.1, 139.7, 148.5, 149.6 (aromatic C). – MS (CI, NH3); 270 CDCl3): δ ϭ 18.2, 19.0 (CHCH3), 20.9, 21.7 [C(O)CH3], 33.8, 36.9,
(MHϩ). – C17H19NO2 HCl 0.5CH4O (321.8): calcd. C 65.31, H 37.5, 38.2 (NCH3, CHCH3), 54.9 (NCH2), 55.7 (OCH3), 58.5
,
6.89, N 4.35; found C 65.03, H 6.55, N 4.35.
(NCH2), 110.3, 110.4, 111.0, 111.3, 118.9 (aromatic CH), 135.7,
136.9, 147.40, 147.8, 148.7, 148.9 (aromatic C), 170.5 (CO).
Amine 4b: Amine 3b (1.16 g, 3.53 mmol) was allowed to react ac-
cording to GP4, yielding 4b (594 mg, 80%). Its hydrochloride salt
Amide 7c: Amine 4c (170 mg, 0.627 mmol) was allowed to react
crystallised from a methanol/diethyl ether system, m.p. 191 °C. – according to GP1 with benzoyl chloride, yielding 7c (170 mg,
1
[α]2D2 ϭ ϩ13 (c ϭ 1.75, CHCl3). – H NMR (300.13 MHz, CDCl3,
72%). – [α]2D2 ϭ ϩ16 (c ϭ 0.85, CHCl3). – IR (film): ν˜ ϭ 1638
TMS): δ ϭ 1.22 (d, J ϭ 6.9 Hz, 3 H, CHCH3), 2.35 (s, 3 H, NCH3), cm–1 (CO). – H NMR (300.13 MHz, CDCl3, TMS): δ ϭ 2.97 (m,
1
2.68 (m, 2 H, NCH2), 2.86 (m, 1 H, NCH2CH), 3.83 (s, 3 H, 2 H, NCH2CHCH2), 3.17 (m, 1 H, NCH2CH), 3.50 (m, 1 H,
OCH3), 3.85 (s, 3 H, OCH3), 6.7–6.8 (m, 3 H, aromatic H). – 13C
NCHH), 3.76 (s, 3 H, OCH3), 3.83 (s, 3 H, OCH3), 3.93 (m, 1 H,
NMR (75.43 MHz, CDCl3): δ ϭ 20.1 (CHCH3), 36.5, 39.5 (NCH3, NCHH), 5.94 (m, 1 H, NH), 6.5–7.5 (m, 13 H, aromatic H) –13C
CHCH3), 55.8 (2 OCH3), 59.5 (NCH2), 110.5, 111.4, 118.9 (aro-
Eur. J. Org. Chem. 2000, 1319Ϫ1325
NMR (75.43 MHz, CDCl3): δ ϭ 40.9, 44.7 (NCH2CHCH2), 46.8
1323

V. Jullian, J.-C. Quirion, H.-P. Husson
(NCH2CH), 55.7 (OCH3), 110.9, 111.1, 119.4, 126.0, 126.6, 128.1, 2.56 (dd, J ϭ 13.2, 5.7 Hz, 1 H, NCHH), 2.85 (m, 2 H, NCH,
FULL PAPER
128.3, 131.2 (aromatic CH), 134.3, 134.4, 139.4, 147.7, 148.8 (aro-
matic C), 167.2 (CO).
NCH2CHCHH), 2.99 (m, 2 H, NCH2CHCHH), 3.10 (dd, J ϭ 13.2,
4.9 Hz, 2 H, NCHH), 5.89 (s, 1 H, OCHHO), 5.90 (s, 1 H,
OCHHO), 6.54 (s, 1 H, aromatic H), 6.64 (s, 1 H, aromatic H),
7.1–7.3 (m, 5 H, aromatic H). – 13C NMR (75.43 MHz, CDCl3):
δ ϭ 20.6 (CH3CHCH3), 20.8 (CH3CHCH3), 33.2 (CH3CHCH3),
35.9 (NCH3), 41.9 (NCH2CHCH2), 43.7 (NCH2CH), 51.8 (NCH2),
70.5 (NCH), 100.5 (OCH2O), 107.9, 108.5, 126.0, 128.2, 129.2 (aro-
matic CH), 131.1, 140.1 (aromatic C) – MS (CI, NH3); 324 (MHϩ).
Lactam 9: Amine 4c (240 mg, 0.88 mmol) was heated at reflux in
absolute ethanol (3 mL) with DBU (199 µL, 1.33 mmol) and
methyl 5-bomovalerate (139 mL, 0.97 mmol) during 96 h. The solv-
ent was then removed. The crude mixture was purified by column
chromatography on silica gel (ethyl acetate/methanol 98:2 then
95:5) yielding 9 (132 mg, 44%) as a colourless oil. – [α]2D2 ϭ –56
1
(c ϭ 1.18, ethyl acetate ). – IR (film): ν˜ ϭ 1680 cm–1 (CO). – H Tetrahydroisoquinoline 8a: Amide 7a (163 mg, 0.52 mmol) was al-
NMR (300.13 MHz, CDCl3, TMS): δ ϭ 1.77 (m, 2 H, NCH2CH2), lowed to react according to GP5. After preparative thin layer chro-
2.22 (m, 2 H, NCOCH2), 3.00 (m, 5 H, NCH2CHCH2, NCH2CH2), matography, 31 mg (20%) of the major diastereomer was isolated. –
1
3.49 (dd, J ϭ 13.7, 9.0, 1 H, NCHHCH), 3.63 (dd, J ϭ 13.6, 7.0, [α]2D2 ϭ ϩ52 (c ϭ 0.74, CHCl3). – H NMR (300.13 MHz, CDCl3,
1 H, NCHHCH), 6.6–6.7 (m, 3 H, aromatic H), 7.0–7.2 (m, 5 H, TMS): δ ϭ 1.50 (d, J ϭ 6.9 Hz, 3 H, CHCH3), 2.20 (s, 3 H, NCH3),
aromatic H) . – 13C NMR (75.43 MHz, CDCl3): δ ϭ 17.6 2.72 (dd, J ϭ 11.5, 4.2 Hz, 1 H, NCHH), 2.80 (dd, J ϭ 11.5, 3.0
(NCH2CH2), 30.7 (NCOCH2), 41.1 (NCH2CHCH2), 45.1 Hz, 1 H, NCHH), 2.90 (m, 1 H, CHCH3), 3.55 (s, 3 H, OCH3),
(NCH2CH), 47.2, 47.3 (CH2NCH2), 55.5 (OCH3), 55.6 (OCH3), 3.85 (s, 3 H, OCH3), 4.13 (s, 1 H, NCH), 6.09 (s, 1 H, aromatic
110.6, 119.6, 125.7, 127.9, 128.8 (aromatic CH), 134.0, 139.4, 147.3, H), 6.03 (s, 1 H, aromatic H), 7.2–7.4 (m, 5 H, aromatic H). – 13C
148.4 (aromatic C), 174.9 (CO). – MS (CI, NH3); 340 (MHϩ), 357 NMR (75.43 MHz, CDCl3): δ ϭ 23.2 (CHCH3), 33.0 (NCH3), 55.8
(MNH4ϩ).
(CHCH3), 44.4 (2 OCH3), 58.5 (NCH2), 71.2 (NCH), 110.4, 111.3,
127.3, 128.3, 129.6 (aromatic CH). – MS (IC, NH3); 298 (MHϩ). –
HR-MS (CI, CH4) calcd. for C19H24NO2 (MHϩ) 298.1807; found
298.1818.
Tetrahydroisoquinoline 6a: Amide 5a (200 mg, 0.53 mmol) was al-
lowed to react according to GP5, yielding 123 mg of 6a as a yellow
oil and 4 mg of a 1:2 mixture of major and minor diastereomer
(overall yield: 67%) after column chromatography on silica gel Tetrahydroisoquinoline 8b: Amide 7b (95 mg, 0.38 mmol) was al-
(ethyl acetate/cyclohexane 10:90). Major diastereomer: [α]D22 ϭ ϩ61 lowed to react according to GP5. A 72:28 mixture of 2 inseparable
1
1
(c ϭ 0.92, CHCl3). – H NMR (300.13 MHz, CDCl3, TMS): δ ϭ diastereomers was obtained (71 mg). – H NMR of the major dia-
2.13 (s, 3 H, NCH3), 2.50 (dd, J ϭ 11.5, 3.3 Hz, 1 H, NCHH), stereomer (300.13 MHz, CDCl3, TMS): δ ϭ 1.32 (d, J ϭ 6.8 Hz,
2.80 (dd, J ϭ 11.6, 1.8 Hz, 1 H, NCHH), 2.85 (m, 1 H, NCH2CH), 3 H, NCHCH3), 1.46 (d, J ϭ 6.5 Hz, 3 H, CH2CHCH3), 2.55 (s,
3.06 (dd, J ϭ 13.2, 5.2 Hz, 1 H, NCH2CHCHH), 3.33 (dd, J ϭ 3 H, NCH3), 2.84 (m, 1 H, NCHH), 3.01 (m, 2 H, CH2CHCH3,
13.2, 10.3 Hz, 1 H, NCH2CHCHH), 4.04 (s, 1 H, CHC6H6), 5.78 NCHH), 3.70 (q, J ϭ 6.8 Hz, 1 H, NCH), 3.85 (s, 3 H, OCH3),
(s, 1 H, OCHHO), 5.80 (s, 1 H, OCHHO), 6.11 (s, 1 H, aromatic 3.86 (s, 3 H, OCH3), 6.55 (s, 1 H, aromatic H), 6.69 (s, 1 H, aro-
H), 6.52 (s, 1 H, aromatic H), 7.2–7.4 (m, 10 H, aromatic H). – 13
C
matic H), –13C NMR (75.43 MHz, CDCl3): δ ϭ 19.6, 20.1
NMR (75.43 MHz, CDCl3): 41.7 (NCH2CH), 43.4 (NCHCH3, NCH2CHCH3 ), 29.8 (NCH3), 42.4 (NCH2CHCH3),
δ
ϭ
(NCH2CHCH2), 44.2 (NCH3), 54.7 (NCH2), 72.1 (NCH), 100.6 54.3 (NCH2), 55.8 (OCH3), 58.9 (NCH), 109.7, 110.0 (aromatic
(OCH2O), 108.0, 108.2, 126.0, 127.3, 128.3, 129.4 (aromatic CH) CH), 129.8, 130.1, 147.4, 147.7 (aromatic C). – MS (CI, NH3);
138.1, 141.0, 144.5, 145.6, 145.8 (aromatic C). – MS (CI, NH3); 236 (MHϩ).
358 (MHϩ). – HR-MS (CI, CH4) calcd. for C24H24NO2 (MHϩ)
358.1807; found 358.1803.
Tetrahydroisoquinoline 8c: Amide 7c (137 mg, 0.365 mmol) was al-
lowed to react according to GP5. After column chromatography
Tetrahydroisoquinoline 6b: Amide 5b (173 mg, 0.55 mmol) was al- on alumina gel (ethyl acetate/cyclohexane 50:50) 40 mg (30%) of
lowed to react according to GP5, yielding 40 mg of the major dias- the major diastereomer was obtained as a yellow oil. – [α]2D2 ϭ –36
tereomer (25%) as a yellow oil after column chromatography on (c ϭ 0.8, CHCl3) –1H NMR (300.13 MHz, CDCl3, TMS): δ ϭ 1.58
silica gel (ethyl acetate/cyclohexane 20:80 then 50:50). – [α]2D2ϭ –65 (m, 1 H, NH), 2.94 (m, 1 H, NCH2CH), 3.10 (m, 4 H,
1
(c ϭ 0.77, CHCl3) . – H NMR (300.13 MHz, CDCl3, TMS): δ ϭ NCH2CHCH2), 3.60 (s, 3 H, OCH3), 3.71 (s, 3 H, OCH3), 5.00 (s,
1.39 (d, J ϭ 6.4 Hz, 3 H, CHCH3), 2.39 (s, 3 H, NCH3), 2.41 (dd, 1 H, NCH), 6.19 (s, 1 H, aromatic H), 6.39 (s, 1 H, aromatic H),
J ϭ 11.7, 4.1 Hz, 1 H, NCHH), 2.70 (dd, J ϭ 11.7, 4.1 Hz, 1 H, 7.2–7.35 (m, 10 H, aromatic H). – 13C NMR (75.43 MHz, CDCl3):
NCHH), 2.88 (m, 1 H, NCH2CH), 2.98 (m, 2 H, NCH2CHCH2), δ ϭ 39.8 (NCH2CH), 42.7, 46.5 (NCH2CHCH2, NCH2CHCH2),
3.36 (q, J ϭ 6.3 Hz, 1 H, NCHCH3), 5.89 (s, 2 H, OCH2O), 6.55 55.6 (OCH3), 62.3 (NCH), 110.5, 111.6, 126.0, 127.4, 128.3, 128.4,
(s, 1 H, aromatic H), 6.60 (s, 1 H, aromatic H), 7.2–7.4 (m, 5 H, 128.9, 129.5 (aromatic CH), 140.6, 144.8, 147.1 (aromatic C). – MS
aromatic H). – 13C NMR (75.43 MHz, CDCl3): δ ϭ 20.6 (CHCH3), (CI, NH3); 360 (MHϩ). – HR-MS (CI, CH4) calcd. for C24H26NO2
40.6 (NCH3), 42.2 (NCH2CHCH2), 43.6 (NCH2CHCH2), 53.7 (MHϩ) 360.1963; found 360.1987.
(NCH2), 60.1 (CHCH3), 100.6 (OCH2O), 106.5, 107.9, 125.9,
Tetrahydroisoquinoline 10: Lactam 9 (132 mg, 0.39 mmol) was al-
128.2, 129.2 (aromatic CH), 131.4, 133.1, 140.8, 145.5, 145.9 (aro-
lowed to react according to GP5. After column chromatography
on alumina gel (ethyl acetate/cyclohexane 10:90) 46 mg (37%) of
matic C) – MS (CI, NH3); 296 (MHϩ). – HR-MS (CI, CH4) calcd.
for C19H22NO2 (MHϩ) 296.1650; found 296.1636.
the major isomer was obtained as a yellow oil. – [α]2D2 ϭ –105 (c ϭ
1
Tetrahydroisoquinoline 6c: Amide 5c (65 mg, 0.19 mmol) was al- 0.92, ethyl acetate). – H NMR (300.13 MHz, CDCl3, TMS): δ ϭ
lowed to react according to GP5. After preparative thin layer chro- 1.65–2.05 (m,
3
H, NCH2CH2CHH), 2.34 (m,
3
H,
matography on alumina gel (ethyl acetate/cyclohexane 10:90), NCHHCH2CHH, NCHHCH), 3.01 (m,
6
H, NCH,
20 mg (33%) of the major diastereomer was isolated. – [α]2D2 ϭ ϩ9 NCHHCHCH2, NCHHCH2), 3.74 (s, 3 H, OCH3), 3.85 (s, 3 H,
1
(c ϭ 0.77, CHCl3). – H NMR (300.13 MHz, CDCl3, TMS): δ ϭ OCH3), 6.53 (s, 1 H, aromatic H), 6.58 (s, 1 H, aromatic H), 7.20–
0.89 (d, J ϭ 6.8 Hz, 3 H, CH3CHCH3), 1.04 (d, J ϭ 7.0 Hz, 3 H, 7.32 (m, 5 H, aromatic H). – 13C NMR (75.43 MHz, CDCl3): δ ϭ
CH3CHCH3), 1.80 (m, 1 H, CH3CHCH3), 2.32 (s, 3 H, NCH3), 21.7 (NCH2CH2), 29.5 (NCHCH2), 41.2 (NCH2CHCH2), 43.6
1324
Eur. J. Org. Chem. 2000, 1319Ϫ1325

Asymmetric Synthesis of 1,4-Disubstituted Tetrahydroioquinolines
FULL PAPER
Mutter, G. W. Bemis, R. R. Whittle, R. A. Olofson, J. Org.
(NCH2CHCH2), 52.3, 53.6 (CH2NCH2), 55.7 (OCH3), 55.8
(OCH3), 64.6 (NCH), 108.2, 111.6, 125.8, 128.2, 129.4, 130.4, 131.0
(aromatic CH), 141.1, 146.9, 147.0 (aromatic C). – MS (CI, NH3);
324 (MHϩ).
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Acknowledgments
V. J. is grateful to the Ministere de l’Education Nationale, de la
`
Recherche et de la Technologie for a grant.
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1325