Synthesis of enantiopure mono- and disubstituted tetrahydroisoquinolines by 6-exo radical cyclizations

Article abstract of DOI:10.1016/S0040-4020(01)00274-5

2-(o-Bromophenyl)-3-allyl- and 2-allyl-3-(o-bromobenzyl)-substituted perhydrobenzoxazines, derived from (-)-8-amino menthol, readily cyclized stereoselectively by reaction with tributyltin hydride in the presence of AIBN. The cyclization compounds were transformed into enantiopure 4-alkyl tetrahydroisoquinolines by reductive ring opening of the N,O-acetal moiety with lithium aluminum hydride. Enantiopure 1,4- and 3,4-dialkyl-substituted tetrahydroisoquinolines were also prepared by reaction of the cyclized compounds with methylmagnesium iodide and subsequent elimination of the menthol appendage.

Full text of DOI:10.1016/S0040-4020(01)00274-5

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 4005±4014
Synthesis of enantiopure mono- and disubstituted
tetrahydroisoquinolines by 6-exo radical cyclizations
p
Rafael Pedrosa, Celia Andres, Jesus M. Iglesias and Manuel A. Obeso
p
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Departamento de Quõmica Organica, Facultad de Ciencias, Universidad de Valladolid, Dr. Mergelina s/n, 47011 Valladolid, Spain
Received 11 December 2000;revised 5 February 2001;accepted 22 February 2001
AbstractÐ2-(o-Bromophenyl)-3-allyl- and 2-allyl-3-(o-bromobenzyl)-substituted perhydrobenzoxazines, derived from (2)-8-amino
menthol, readily cyclized stereoselectively by reaction with tributyltin hydride in the presence of AIBN. The cyclization compounds
were transformed into enantiopure 4-alkyl tetrahydroisoquinolines by reductive ring opening of the N,O-acetal moiety with lithium
aluminum hydride. Enantiopure 1,4- and 3,4-dialkyl-substituted tetrahydroisoquinolines were also prepared by reaction of the cyclized
compounds with methylmagnesium iodide and subsequent elimination of the menthol appendage. q 2001 Elsevier Science Ltd. All rights
reserved.
1. Introduction
2. Results and discussion
In previous papers we have described the stereoselective
synthesis of pyrrolidines by 5-exo cyclization of 3-aza-5-
hexenyl radicals derived from phenylseleno allylamines1
and phenylseleno acrylamides.2,3 Stereoselective 6-exo
cyclizations of 6-heptenyl radicals, directed to the synthesis
of alkaloids4 or piperidine derivatives5 have been also
reported, although these processes are less selective because
competitive intramolecular hydrogen atom abstraction,6
ring expansion7 or neophyl rearrangements8 can appear,
especially in reactions of aryl radicals.9
The starting chiral perhydrobenzoxazines were synthesized
as summarized in Scheme 1. Compounds 3a±d were
prepared in two steps from (2)-8-aminomenthol by conden-
sation with o-bromobenzaldehyde to 1, and subsequent
alkylation with allyl-, crotyl-, prenyl-, and cinnamyl
The interest of enantiopure 4-substituted10 and disubsti-
tuted-1,2,3,4-tetrahydroisoquinolines11 lead us to consider
the stereoselective synthesis of these compounds by cycli-
zation of 4-aza-6-heptenyl aryl radicals derived from (2)-8-
amino menthol. On the other hand, we have previously
reported that the regiochemistry of the cyclization in these
substrates is dependent on the substitution at the double
bond12 or the relative position of the radical and the acceptor
double bond.13
In this paper we wish to report in full on our progress
along these lines. To this end, we studied radical cycliza-
tions on positional isomeric 2-(o-bromophenyl)-3-allyl
perhydrobenzoxazines 3a±d and 2-vinyl-3-(o-bromo-
benzyl) perhydrobenzoxazines 4a±d, promoted by tributyl-
tin hydride in the presence of AIBN as initiator.
Keywords: radical cyclizations;stereoselection;asymmetric synthesis;
isoquinolines.
Corresponding author. Tel: 1983-423211;Fax: 1983-423013;e-mail:
pedrosa@qo.uva.es
Scheme 1. Reagents and conditions. (i) o-BrC6H4CHO, CH2Cl2, rt, 4 h. (ii)
R1R2CvCHCH2Br, K2CO3, MeCN, re¯ux. (iii) NaBH4, BF3´OEt2, THF, rt,
2 h. (iv) R1R2CvCHCHO, 1208C, sealed tube, 2 h.
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00274-5

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R. Pedrosa et al. / Tetrahedron 57 ,2001) 4005±4014
Scheme 2. Reagents and conditions. (i) Bu3SnH, AIBN, benzene, re¯ux, 13±44 h.
spectroscopical properties for the known 10a.14 The cycli-
zation products were contaminated with different amounts
of N-vinyl perhydrobenzoxazines 6a±d, resulting from the
1,5-hydrogen shift in the intermediate radical.5 These
compounds were only observed in the reaction mixtures
Table 1. Radical cyclization of perhydrobenzoxazines 3a±d
Start. Mat. R1 R2 Conc. time (h) Products (%)a Ratio 5/50
3a
3a
3b
3b
3c
3c
3d
3d
H
H
H
H
H
H
0.02 M 13
0.1 M 13
1H (14):5 (71) 5a/50a(3/2)
1H (20):5 (67) 5a/50a(3/2)
1H (4):5 (76) 5b/50b(3/2)
1H (4):5 (76) 5b/50b(3/2)
1H (12):5 (70) 5c/50c(3/2)
1H (16):5 (64) 5c/50c(3/2)
1H (25):5 (68) 5d/50d(3/2)
1H (38):5 (58) 5d/50d(3/2)
1
Me 0.02 M 21
Me 0.1 M 21
by H NMR, because they were hydrolysed to 2-phenyl
perhydrobenzoxazine 1H and the corresponding aldehyde
when the reaction mixtures were subjected to puri®cation
by ¯ash chromatography on silica gel. On the other hand,
the hydrogen translocation products increased with the
concentration of the reaction, and the stabilization of the
rearranged radical. In this way, the benzylic character of
the radical forced the rearrangement in the initial inter-
mediate formed from 3d to occur in the greatest extension
(25±38%). It is also interesting to note that no direct reduc-
tion products were formed in the reactions.
Me Me 0.02 M 20
Me Me 0.1 M 20
H
H
Ph 0.02 M 44
Ph 0.1 M 44
a
Numbers in parentheses refer to the yield of products after isolation and
puri®cation.
bromides, respectively, with potassium carbonate in aceto-
nitrile at re¯ux. Compounds 4a±d were also obtained in
good yields by condensation of 8-(o-bromobenzylamino)
menthol 2, prepared by reductive ring opening of 1 with
sodium borohydride and boron tri¯uoride in THF, with
acrolein, crotonaldehyde, 3,3-dimethylacrolein and cin-
namaldehyde in a sealed tube at 1208C.
Previously we had demonstrated that the 1,5-hydrogen
migration products were not formed when the radicals
were generated at the alkyl substituent on the nitrogen
atom and the acceptor double bond was placed at the
acetallic carbon.5 On the basis of that fact, and trying to
improve both the chemical yields and the stereodifferentia-
tion of the processes, we studied the cyclization, in the
above experimental conditions, of regioisomeric 2-allyl-N-
(o-bromobenzyl) perhydrobenzoxazines 4a±d (Scheme 3
and Table 2).
The cyclization of 3a±d was carried out by slow addition
(6±8 h, syringe pump) of a solution of tributyltin hydride
(1.2 equiv.) and AIBN (0.2 equiv.) in benzene, to a solution
of the corresponding compound in boiling dry degassed
benzene, and the re¯ux was continued until the starting
perhydrobenzoxazine has been consumed. The stannane
byproducts were removed by treatment with 10% solution
of potassium ¯uoride in water and the solids were elimi-
nated by ®ltration through a pad of celite. To check the
effect of the concentration on the products distribution, the
reactions were carried out in two different concentrations
(0.02 M and 0.1 M) of the initial solution of perhydro-
benzoxazines, and the results are summarized in Scheme 2
and Table 1.
To our surprise, the parent 2-allyl-substituted derivative 4a
was regiospeci®cally transformed into the 7-endo cycliza-
tion product 8a after re¯uxing for 10 h in benzene with
tributyltin hydride (1.2 equiv.) and AIBN (0.2 equiv.),13
independently of the concentration of the reaction. The
presence of susbtituents at the outer position of the accept-
ing double bond disfavored the 7-endo cyclization,15 and in
this way, the crotyl derivative 4b yielded an equimolar
mixture of the six-membered 7b and 70b and seven-
membered derivatives 8b and 80b, whereas 4c, with two
methyl groups b in the double bond lead regiospeci®cally
to the 6-exo cyclization product 7c. The cinnamyl derivative
4d also gave the six-membered derivatives 7d and 70d
probably as a consequence of the benzylic character of the
intermediate cyclized radical. As expected, no products
resulting from 1,5-hydrogen shift were found because the
radicals formed from 4a±d are unable to adopt the chair-like
conformation required for migration.5
From these results it can be deduced that the reactions
occurred regioselectively to the 6-exo cyclization products
obtained, in good to moderate yields, as a mixture (3/2) of
diastereoisomers 5a±d and 50a±d at the newly created
stereocenter. It is noteworthy that the ratio of diastereo-
isomers is independent on both the nature of substituents
and the dilution conditions, and the major diastereoisomers
have R con®guration as determined by NOESY experiments
after isolation of the pure compounds and comparison of the

R. Pedrosa et al. / Tetrahedron 57 ,2001) 4005±4014
4007
Scheme 3. Reagents and conditions. (i) Bu3SnH, AIBN, benzene, re¯ux, 8±13 h.
Table 2. Radical cyclization of perhydrobenzoxazines 4a±d
Start. Mat. R1 R2 Conc. time (h) Prod (%)a Ratio 7,8/70,80
created in the cyclization reaction is coincident for both
regioisomers. Aminomenthols 9a±d were converted into
tetrahydroisoquinolines 10a±d by oxidation to the 8-amino-
menthone derivatives with a buffered (sodium acetate) solu-
tion of PCC in CH2Cl2, followed by elimination of the
menthol appendage by treatment with a solution of KOH
in H2O/MeOH/ THF at room temperature. When the oxida-
tion was carried out in the absence of sodium acetate vari-
able amounts of 3,4-dihydro isoquinolines were obtained.
The sequential reductive ring opening-oxidation-elimina-
tion on 8b gave tetrahydrobenzazepine 11b in 71% overall
yield.
4a
4a
4b
H
H
H
H
H
0.02 M 10
8a (70)
8a (70)
7b (34)
8b (34)
7b (34)
8b (34)
7c (70)b
7c (70)b
7d (75)
7d (75)
0.1 M
10
9
Me 0.02 M
(7b/70b: 3/1)
(8b/80b: 3/1)
(7b/70b: 3/1)
(8b/80b: 3/1)
4b
H
Me 0.1 M
9
4c
4c
4d
4d
Me Me 0.02 M
Me Me 0.1 M
H
H
8
8
Ph 0.02 M 13
Ph 0.1 M 13
(7d/70d: 2/1)
(7d/70d: 2/1)
a
Numbers in parentheses refer to the yield of products after isolation and
puri®cation.
The easy stereoselective ring opening of perhydrobenzoxa-
zines by organometallics18 opens the possibility to obtain
enantiopure dialkyl substituted tetrahydro isoquinolines
from cyclization products. In fact, 5a and 5d reacted with
methylmagnesium iodide in Et2O, at room temperature,
yielding quantitatively 12a and 12d as single diastereo-
isomers. Oxidation of these aminomenthol derivatives
with buffered solution of PCC in methylene chloride, and
elimination with a solution of KOH lead to 1,4-disubstituted
tetrahydroisoquinolines, which were isolated as tosylates
13a and 13d in 57% and 59% overall yield by reaction
with tosyl chloride in the presence of diisopropyl amine
(Scheme 5).
b
The corresponding epimeric compound 70c was not detected by 1H NMR
on the reaction mixture.
The stereochemical outcome of the cyclization of 4a±d is
also noteworthy. The major cyclization stereoisomers also
had R con®guration at the created stereocenter as demon-
strated by NOESY experiments, but the facial discrimina-
tion was better than for 3a±d, and the diastereomeric
excesses depend on the substituents at the double bond.
The formation of the major diastereoisomer can be
explained because the cyclization occurs in a chair-like tran-
sition state where the substituent lies on a pseudoequatorial
conformation.16 The formation of 7c as a single diastereoi-
somer is a consequence of the 1,3-allylic strain acting in the
radical formed from 4c (as shown in Fig. 1).17
Major diastereoisomers 5a±d, 7b±d, and 8b were isolated
by ¯ash chromatography and transformed into enantiopure
(R)-4-alkyl substituted tetrahydroisoquinolines 10a±d or
(R)-5-methyl tetrahydro-2-benzazepine 11b, respectively,
in 66±72% yield as summarized in Scheme 4.
To this end, cyclized products 5a±d were reacted with
lithium aluminum hydride and aluminum chloride in THF
at 08C yielding quantitatively the amino menthol derivatives
9a±d. The same reductive treatment on 7b±d lead to 9b±d
demonstrating that the con®guration at the stereocenter
Scheme 4. Reagents and conditions. LiAlH4, AlCl3, THF, 2208C, 0.5 h.
Ê
(ii) PCC, NaOAc, 3A molecular sieves, CH2Cl2, rt, 2 h., then KOH, MeOH/
THF/H2O.
Figure 1. T.E. proposed for the formation of major and minor 7b±d
and 70b±d.

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R. Pedrosa et al. / Tetrahedron 57 ,2001) 4005±4014
3. Experimental
All solvents employed were distilled prior to use. Benzene
was dried by distillation over sodium/benzophenone. All
commercially available products were used without puri®-
cation. TLC was performed on silica gel 60 F254 plates.
Flash chromatography was conducted using 240±300
mesh silica gel. Melting points were determined on capillary
open tubes, and are uncorrected. Optical rotations were
measured on a Perkin±Elmer 241 polarimeter with a sodium
lamp (254 nm). Proton and carbon magnetic resonance
spectra were recorded on a Bruker AC-300 or Bruker
ARX-300 (300 MHz for proton, 75.2 MHz for carbon)
using CDCl3 as solvent;chemical shifts ( d) are given in
ppm related to tetramethylsilane (TMS) as internal refer-
ence (dˆ0 for TMS). Mass spectra were obtained on a
Hewlett±Packard 5988 A spectrometer by chemical ioniza-
tion. Infrared spectra were registered on a Philips PU9706
apparatus, neat or as a nujol dispersion.
3.1. 2a-.o-Bromophenyl)-4,4,7a-trimethyl-trans-octa-
hydro-1,3-benzoxazine 1
A solution of (2)-8-aminomenthol (5 g, 29.2 mmol) and
2-bromobenzaldehyde (6 g, 32.2 mmol) in CH2Cl2 (50
mL) was stirred at room temperature until the starting
aminoalcohol had disappeared (by TLC). Then sodium sul-
fate was added to the solution and the mixture was stirred
for 10 min, the solid was ®ltered off and the solvent was
removed under vacuum. The resulting perhydrobenzoxazine
was puri®ed by recrystallization. 98% yield. White solid
(from ethanol);mp 74±76 8C. [a]2D5ˆ163.7 (cˆ0.9,
Scheme 5. Reagents and conditions. (i) MeMgI, OEt2, 08C, then, NH4Cl,
Ê
H2O. (ii) PCC, NaOAc, 3A molecular sieves, CH2Cl2, rt, 2 h., then KOH,
MeOH/THF/H2O, then TsCl, (i-Pr)2NH. (iii) NaBH4, EtOH, rt, then TsCl,
(i-Pr)2NH.
1
CHCl3). H NMR (d): 0.90±1.05 (2H, m);0.93 (3H, d,
Jˆ6.5 Hz);1.10 (3H, s);1.10±1.20 (1H, m);1.24 (3H, s);
1.45±1.60 (2H, m);1.65±1.80 (2H, m);1.92±2.02 (1H, m);
3.61 (1H, td, Jˆ4.1 Hz, 10.4 Hz);5.64 (1H, s);7.08±7.60
(4H, m). 13C NMR (d): 19.4;22.3;25.2;29.8;31.3;35.0;
41.6;51.6;52.2;76.7;83.4;122.5;127.1;127.6;129.4;
132.8;139.8. IR (nujol): 3300, 2920, 750 cm 21. MS (m/z,
%): 338 (M11, 100), 340 (M13, 94). Anal. Calcd for
C17H24BrNO: C, 60.36;H, 7.15;N. 4.14. Found: C, 60.48;
H, 7.09;N. 4.03.
The stereochemistry of ®nal 1,4-disubstituted tetrahydroiso-
1
quinolines was established on the basis of their H NMR
data. The values of the measured and calculated19,20
coupling constants between protons at C-3 and C-4 showed
a cis relationship of substituents at C-1 and C-4, and conse-
quently S con®guration for C-1. This fact was also in agree-
ment with the stereochemical outcome in the ring opening
reaction of the N,O-acetal moiety by magnesium
derivatives.18
3.2. N-.o-Bromobenzyl)-8-aminomenthol 2
To a cooled (08C) suspension of sodium borohydride
(1.90 g, 50 mmol) and BF3´OEt2 (100 mL, 1 M solution)
in dry THF (60 mL) was slowly added a solution of per-
hydrobenzoxazine 1 (8.45 g., 25 mmol) in THF (30 mL).
The reaction mixture was stirred at room temperature for
two hours and then quenched by slow addition of methanol
(20 mL), and stirred for additional 30 minutes. The volatiles
were eliminated in a rotavapor and the resulting solid was
treated with a 20% solution of NaOH (20 mL) and solid
NaOH (2 g) and re¯uxed for 1 h. The mixture was cooled
and extracted with chloroform (5£75 mL), washed with
brine, dried over sodium sulfate and the solvent removed.
The resulting solid was recrystallized from hexanes to afford
2 in 98% yield. White solid (from hexanes);mp 90±91 8C.
[a]2D5ˆ225.2 (cˆ1.2, CHCl3). 1H NMR (d): 0.85±1.12 (3H,
m);0.91 (3H, d, Jˆ6.5 Hz);1.21 (3H, s);1.26 (3H, s);1.27±
1.52 (2H, m);1.63±1.73 (2H, m);1.89±1.98 (1H, m);3.65
(1H, dt, Jˆ4.1 Hz, 10.4 Hz);3.84 (1H, d AB, Jˆ11.8 Hz);
Compounds 7c and 7d were also transformed into 3,4-di-
substituted tetrahydroisoquinolines in the same way.
Reaction with methylmagnesium iodide yielded amino-
menthol derivatives 14c and 14d, which were subjected
to oxidation with a buffered solution of PCC in CH2Cl2
leading directly to 3,4-disubstituted-3,4-dihydro iso-
quinolines 15c and 15d. Reaction of dihydroderivatives
with sodium borohydride in ethanol lead to the ®nal
3,4-disubstituted tetrahydro isoquinolines isolated as
tosylates 16c and 16d by treatment with tosyl chloride and
diisopropylamine. The stereochemistry of the ®nal tera-
hydro isoquinolines was also established by 1H NMR
data, because the 0 Hz coupling constant for hydrogens at
C-3 and C-4 points to that the dihedral angle between
these protons is 908 only possible if both are in a trans
relationship. The con®guration at C-3 was then established
to be S.

R. Pedrosa et al. / Tetrahedron 57 ,2001) 4005±4014
4009
3.86 (1H, dAB, Jˆ11.8 Hz);7.08±7.52 (4H, m). 13C NMR
25.5;27.0;29.7;31.3;35.0;41.5;47.6;57.6;76.1;87.3;
123.3;126.9;128.5;129.1;130.5;132.3;139.0. IR
(d): 21.2;22.1;25.7;26.0;31.0;35.0;44.3;45.8;49.9;57.2;
72.4;123.9;127.9;128.9;130.7;132.6;138.3. IR (nujol):
3200, 2920, 740 cm21. MS (m/z, %): 340 (M11, 100), 342
(M13, 94). Anal. calcd. for C17H26BrNO: C, 60.00;H, 7.70;
N, 4.12. Found: C, 59.87;H, 7.89;N, 4.26.
(nujol): 3050, 2940, 760 cm21. MS (m/z, %): 406 (M11,
100), 408 (M13, 73). Anal. Calcd for C22H32BrNO: C,
65.02;H, 7.94;N, 3.45. Found: C, 64.89;H, 7.89;N, 3.51.
3.3.4. N-Cinnamyl-2a-.o-bromophenyl)-4,4,7a-trimethyl-
trans-octahydro-1,3-benzoxazine 3d. 91% yield. Oil.
[a]2D5ˆ131.5 (cˆ0.9, CHCl3). 1H NMR (d): 0.90±1.05
(2H, m);0.95 (3H, d, Jˆ6.5 Hz);1.10±1.20 (1H, m);1.39
(6H, s);1.45±1.60 (2H, m);1.65±1.75 (2H, m);1.95±2.05
(1H, m);3.17 (1H, dd, Jˆ5.2 Hz, 17.7 Hz);3.42 (1H, m);
3.67 (1H, dt, Jˆ4.1 Hz, 10.5 Hz);5.85 (1H, m);5.88 (1H,
s);6.07 (1H, d, Jˆ15.9 Hz);6.98±7.52 (9H, m). 13C NMR
(d): 18.9;22.4;25.1;27.1;31.4;35.1;41.6;45.1;47.1;57.6;
3.3. N-Alkylation of perhydrobenzoxazine 1. General
method
A mixture of perhydrobenzoxazine 1 (1.69 g, 5.0 mmol),
potassium carbonate (0.69 g, 7 mmol) and the correspond-
ing allyl bromide (7.5 mmol), in acetonitrile (8 mL) was
re¯uxed with stirring until the reaction was ®nished (12±
48 h) (TLC). When the reaction was completed, the solid
was separated by ®ltration, the solid was washed with hot
EtOAc (25 mL), and the solvents were eliminated on rota-
vapor. The residue was puri®ed by recrystallization in the
appropriate solvent.
76.4;87.0;123.4;126.6;127.0;127.5;128.3;129.3;130.3;
132.4;137.8;138.8. IR (neat): 3050, 2940, 755, 695 cm
21
.
MS (m/z, %): 454 (M11, 100), 456 (M13, 88). Anal. Calcd
for C26H32BrNO: C, 68.72;H, 7.10;N, 3.08. Found: C,
68.79;H, 7.06;N, 3.17.
3.3.1. N-Allyl-2a-.o-bromophenyl)-4,4,7a-trimethyl-trans-
octahydro-1,3-benzoxazine 3a. 78% yield. White solid
(from ethanol);mp 78±79 8C. [a]2D5ˆ123.4 (cˆ1.0,
3.4. Synthesis of perhydrobenzoxazines 4a±h. General
procedure
1
CHCl3). H NMR (d): 0.90±1.05 (2H, m);0.94 (3H, d,
Jˆ6.4 Hz);1.10±1.25 (1H, m);1.16 (3H, s);1.36 (3H, s);
1.43±1.58 (2H, m);1.62±1.77 (2H, m);1.92±1.98 (1H, m);
3.00 (1H, dd, Jˆ5.4 Hz, 17.5 Hz);3.28 (1H, dd, Jˆ5.4 Hz,
17.5 Hz);3.64 (1H, dt, Jˆ4.1 Hz, 10.5 Hz);4.60 (1H, dd,
Jˆ1.8 Hz, 9.3 Hz);4.77 (1H, dd, Jˆ1.8 Hz, 17.1 Hz);5.39±
5.52 (1H, m);5.83 (1H, s);7.08±7.66 (4H, m). 13C NMR
(d): 18.8;22.3;25.0;27.0;31.3;35.1;41.5;45.5;47.0;57.6;
76.3;86.9;112.8;123.4;126.9;129.0;130.2;132.3;139.2;
140.0;IR (nujol): 3060, 2920, 750 cm 21. MS (m/z, %): 378
(M11, 100), 380 (M13, 92). Anal. Calcd for C20H28BrNO:
C, 63.49;H, 7.46;N, 3.70. Found: C, 63.63;H, 7.42;N,
3.78.
A mixture of aminoalcohol 2 (0.51 g, 1.5 mmol) and the
corresponding aldehyde (3 mmol) were heated at 1208C in
an oil bath in a sealed tube without solvent. When the reac-
tion is ®nished (TLC) the mixture was dissolved in ethanol
(50 mL) and the solvents were distilled under vacuum. The
residues were puri®ed by ¯ash chromatography (silica gel,
hexane/EtOAc: 10/1) or by recrystallization.
3.4.1. N-.o-Bromobenzyl)-2a-vinyl-4,4,7a-trimethyl-trans-
octahydro-1,3-benzoxazine 4a. 76% yield. Oil. [a]2D5ˆ
1
236.6 (cˆ2.0, CHCl3). H NMR (d): 0.94 (3H, s);0.95±
1.05 (2H, m);0.95 (3H, d, Jˆ6.5 Hz);1.11±1.23 (1H, m);
1.26 (3H, s);1.40±1.80 (4H, m);1.91±2.02 (1H, m);3.57
(1H, dt, Jˆ4.1 Hz, 10.6 Hz);3.81 (1H, d AB, Jˆ10.4 Hz);
3.86 (1H, dAB, Jˆ10.4 Hz);5.08 (1H, d, Jˆ10.5 Hz);5.14
(1H, d, Jˆ3.9 Hz);5.38 (1H, d, Jˆ17.3 Hz);5.62 (1H, ddd,
Jˆ4.4 Hz, 10.5 Hz, 17.3 Hz);7.00±7.83 (4H, m). 13C NMR
(d): 19.5;20.3;25.0;26.3;31.4;34.9;41.4;46.6;47.4;56.7;
76.7;87.3;117.9;122.0;126.8;127.3;130.0;131.9;136.8;
142.3. IR (neat): 3020, 2900, 740 cm21. MS (m/z, %): 378
(M11, 100), 380 (M13, 82). Anal. Calcd for C20H28BrNO:
C, 63.49;H, 7.46;N, 3.70. Found: C, 63.65;H, 7.29;N,
3.57.
3.3.2. N-Crotyl-2a-.o-bromopheny)-4,4,7a-trimethyl-
trans-octahydro-1,3-benzoxazine 3b. 80% yield. White
solid (from ethanol);mp 51±53 8C. [a]2D5ˆ128.8 (cˆ1.0,
1
CHCl3). H NMR (d): 0.90±1.05 (2H, m);0.95 (3H, d,
Jˆ6.5 Hz);1.08±1.25 (1H, m);1.18 (3H, s);1.33 (3H, s);
1.39 (3H, d, Jˆ4.8 Hz);1.45±1.60 (2H, m);1.62±1.78 (2H,
m);1.92±2.00 (1H, m);2.87±2.94 (1H, m);3.15±3.24 (1H,
m);3.63 (1H, dt, Jˆ4.1 Hz, 10.5 Hz);4.99±5.07 (2H, m);
5.80 (1H, s);7.06±7.70 (4H, m). 13C NMR (d): 17.6;18.2;
22.3;25.0;27.1;31.3;35.0;41.5;44.9;47.4;57.5;76.1;
87.0;123.4 (2 C);126.8;129.0;130.4;132.2;132.6;
139.2. IR (nujol): 3060, 2920, 750 cm21. MS (m/z, %):
392 (M11, 100), 394 (M13, 84). Anal. Calcd for
C21H30BrNO: C, 64.28;H, 7.71;N, 3.57. Found: C, 64.43;
H, 7.56;N, 3.65.
3.4.2. N-.o-Bromobenzyl)-2a-.10-propenyl)-4,4,7a-tri-
methyl-trans-octahydro-1,3-benzoxazine 4b. 78% yield.
Oil. [a]2D5ˆ231.1 (cˆ1.1, CHCl3). H NMR (d): 0.88±
1
0.98 (2H, m);0.94 (3H, d, Jˆ6.5 Hz);0.97 (3H, s);1.02±
1.12 (1H, m);1.20 (3H, s);1.32±1.50 (2H, m);1.49 (3H, dd,
Jˆ0.7 Hz, 6.6 Hz);1.52±1.70 (2H, m);1.85±1.95 (1H, m);
3.53 (1H, dt, Jˆ4.2 Hz, 10.6 Hz);3.75 (1H, d, Jˆ18.1 Hz);
3.85 (1H, d, Jˆ18.1 Hz);4.99 (1H, d, Jˆ5.4 Hz);5.15±5.25
(1H, m);5.73±5.85 (1H, m);6.99±7.82 (4H, m). 13C NMR
(d): 17.6;18.1;22.2;25.0;26.5;31.3;34.9;41.4;47.5;56.7;
75.4;88.0;122.1;126.8;127.2;129.5;130.2;130.4;131.7;
142.4. IR (neat): 3080, 2920, 750 cm21. MS (m/z, %): 392
(M11, 100), 394 (M13, 79). Anal. Calcd for C21H30BrNO:
C, 64.28;H, 7.71;N, 3.57. Found: C, 64.39;H, 7.58;N,
3.72.
3.3.3. N-Prenyl-2a-.o-bromophenyl)-4,4,7a-trimethyl-
trans-octahydro-1,3-benzoxazine 3c. 83% yield. White
solid (from ethanol);mp 63±64 8C. [a]2D5ˆ136.5 (cˆ1.0,
1
CHCl3). H NMR (d): 0.90±1.05 (2H, m);0.93 (3H, d,
Jˆ6.5 Hz);1.10±1.20 (1H, m);1.17 (3H, s);1.21 (3H, s);
1.25 (3H, s);1.41 (3H, s);1.45±1.60 (2H, m);1.65±1.75
(2H, m);1.90±2.00 (1H, m);2.95 (1H, dd,
Jˆ6.3 Hz,
16.8 Hz);3.20 (1H, dd, Jˆ4.1 Hz, 10.5 Hz);3.62 (1H, td,
Jˆ4.1 Hz, 10.5 Hz);4.82 (1H, t, Jˆ5.9 Hz);5.79 (1H, s);
7.03±7.69 (4H, m). 13C NMR (d): 17.3;17.8;22.3;25.1;

4010
R. Pedrosa et al. / Tetrahedron 57 ,2001) 4005±4014
3.4.3. N-.o-Bromobenzyl)-2a-.20-methyl-10-propenyl)-
4,4,7a-trimethyl-trans-octahydro-1,3-benzoxazine 4c.
3.5.2. Compound 5b. 47% yield. Oil. [a]2D5ˆ243.4 (cˆ0.8,
1
CHCl3). H NMR (d): 0.90±1.05 (2H, m);0.93 (3H, d,
1
80% yield. Oil. [a]D25ˆ222.1 (cˆ2.1, CHCl3). H NMR
Jˆ6.5 Hz);0.99 (3H, t, Jˆ10.4 Hz);1.10 (3H, s);1.10±
1.22 (1H, m);1.21 (3H, s);1.42±1.51 (2H, m);1.65±1.77
(2H, m);1.78±1.90 (2H, m);1.97±2.06 (1H, m);2.61±2.64
(1H, m);2.75 (1H, dd, Jˆ4.3;11.6 Hz);3.06 (1H, dd,
Jˆ5.5;11.6 Hz);3.64 (1H, td, Jˆ4.2, 10.6 Hz;5.29 (1H,
s);7.14±7.39 (4H, m). 13C NMR (d): 12.4;15.0;22.3;25.2;
26.7;27.4;31.4;35.0;40.5;41.4;42.4;48.1;55.5;75.7;
85.0;125.9;127.4;127.5;127.6;135.9;139.9. IR (neat)
cm21: 3085, 2950, 745. MSCI (m/z, %): 314 (M11, 100).
Anal. Calcd for C21H31NO: C, 80.46;H, 9.97;N, 4.47.
Found: C, 80.58;H, 9.85;N, 4.59.
(d): 0.90±1.08 (2H, m);0.94 (3H, d, Jˆ6.5 Hz);0.97 (3H,
s);1.08±1.22 (1H, m);1.28 (3H, s);1.47 (3H, s);1.48±1.55
(2H, m);1.60±1.80 (2H, m);1.73 (3H, s);1.91±2.02 (1H,
m);3.57 (1H, dt, Jˆ4.1 Hz, 10.5 Hz);3.79 (1H, d,
Jˆ18.1 Hz);3.88 (1H, d,
Jˆ18.1 Hz);5.00 (1H, d,
Jˆ6.6 Hz);5.32 (1H, d, Jˆ6.6 Hz);6.98±7.74 (4H, m).
13C NMR (d): 18.9;22.3;25.0;26.5;31.4;35.0;41.5;
47.5;56.9;75.7;84.5;122.0;123.8;127.0;130.2;131.7;
136.8;142.8. IR (neat): 3060, 2920, 750 cm 21. MS (m/z, %):
406 (M11, 100), 408 (M13, 79). Anal. Calcd for
C22H32BrNO: C, 65.02;H, 7.94;N, 3.45. Found: C, 65.14;
H, 7.88;N, 3.37.
3.5.3. Compound 5c. 42% yield. Oil. [a]2D5ˆ267.3 (cˆ1.1,
1
CHCl3). H NMR (d): 0.80±1.10 (3H, m);0.89 (3H, d,
3.4.4. N-.o-Bromobenzyl)-2a-styryl-4,4,7a-trimethyl-
trans-octahydro-1,3-benzoxazine 4d. 81% yield. White
solid (from ethanol) mp 86±878C. [a]2D5ˆ242.6 (cˆ1.2,
Jˆ6,8 Hz);0.93 (3H, d,
Jˆ6.5 Hz);1.02 (3H, d,
Jˆ7.0 Hz);1.12 (3H, s);1.23 (3H, s);1.40±1.55 (2H, m);
1.62±1.75 (2H, m);1.96±2.04 (1H, m);2.34±2.43 (1H, m);
2.53±2.63 (1H, m);2.74 (1H, dd, Jˆ4.4;11.5 Hz);3.16
(1H, dd, Jˆ6.5;11.5 Hz);3.65 (1H, td, Jˆ4.2;10.6 Hz);
5.32 (1H, s);7.17±7.38 (4H, m). 13C NMR (d): 16.2;
19.2;21.5;22.3;25.1;26.9;30.1;31.4;34.9;39.7;41.4;
1
CHCl3). H NMR (d): 0.92±1.08 (2H, m);0.96 (3H, d,
Jˆ6.5 Hz);1.03 (3H, s);1.12±1.25 (1H, m);1.29 (3H, s);
1.45±1.65 (2H, m);1.66±1.80 (2H, m);1.98±2.08 (1H, m);
3.62 (1H, dt, Jˆ4.0 Hz, 10.6 Hz);3.84 (1H, d, Jˆ18.1 Hz);
3.92 (1H, d, Jˆ18.1 Hz);5.26 (1H, d, Jˆ4.9 Hz);5.88 (1H,
dd, Jˆ4.9 Hz, 16,0 Hz);6.70 (1H, d, Jˆ16.0 Hz);6.98±
7.88 (9H, m). 13C NMR (d): 19.1;22.3;25.1;26.5;31.4;
35.0;41.4;46.9;47.6;56.9;75.8;87.6;122.0;126.5;126.9;
127.3;127.4;128.2;128.5;130.2;131.9;132.3;136.6;
142.2. IR (neat): 3020, 2920, 750, 690 cm21. MS (m/z,
%): 454 (M11, 100), 456 (M13, 90). Anal. Calcd for
C26H32BrNO: C, 68.72;H, 7.10;N, 3.08. Found: C, 68.81;
H, 7.18;N, 3.19.
44.6;47.4;55.7;76.1;84.9;125.9;127.1;127.7;127.9;
136.0;138.5. IR (neat) cm 21: 3085, 2950, 740. MSCI
(m/z, %): 328 (M11, 100). Anal. Calcd for C22H33NO: C,
80.68;H, 10.16;N, 4.28. Found: C, 80.57;H, 10.24;N, 4.41.
3.5.4. Compound 5d. 43% yield. Oil. [a]2D5ˆ241.9 (cˆ1.7,
1
CHCl3). H NMR (d): 0.83±1.05 (2H, m);0.95 (3H, d,
Jˆ6.5 Hz);0.99 (3H, s);1.10 (3H, s);1.10±1.21 (1H, m);
1.38±1.57 (2H, m);1.64±1.73 (2H, m);1.99±2.08 (1H, m);
2.55 (1H, dd, Jˆ3.1, 11.9 Hz);2.93 (1H, dd, Jˆ3.1,
11.8 Hz);3.03±3.10 (3H, m);3.38 (1H, dt,
Jˆ4.1,
3.5. Radical cyclizations. General method
10.6 Hz);5.21 (1H, s);7.13±7.46 (9H, m). 13C NMR (d):
13.9;22.2;25.1;26.6;31.3;34.8;40.6;41.2;41.4;42.6;
48.6;55.7;75.7;85.1;125.9;126.2;127.2;127.4;127.7;
128.2;128.4;129.0;129.2;136.0;139.0;141.2. IR (neat)
cm21: 3020, 2910, 750, 700. MSCI (m/z, %): 376 (M11,
100). Anal. Calcd for C26H33NO: C, 83.15;H, 8.86;N, 3.73.
Found: C, 83.31;H, 9.01;N, 3.59.
To a re¯uxing solution of perhydrobenzoxazine (6.0 mmol)
in dry degassed benzene (60 mL for 0.1 M and 300 mL for
0.02 M concentrations) under argon, was added for a 6±8 h
period via syringe pump a solution of tributylin hydride
(7.2 mmol) and AIBN (0.36 mmol) in the same solvent.
The heating was continued until complete disappearance
of the starting material by TLC (Tables 1 and 2) and the
solvent was removed in vacuum. The resulting oil was re-
dissolved in diethylether, and treated with 10% aqueous
solution of KF for 4 h at room temperature. The mixture
was ®ltered and the solid washed with ether. The aqueous
layer was extracted with ether (3£50 mL) and the combined
organic phases were washed with brine and dried over
sodium sulfate. The solid was ®ltered off and the solvent
removed under vacuum. The oily residue was puri®ed by
¯ash chromatography (silica gel, hexane/EtOAc: 10/1).
3.5.5. Compound 7b. 26% yield. Oil. [a]2D5ˆ249.8 (cˆ0.9,
1
CHCl3). H NMR (d): 0.80±1.05 (3H, m);0.83 (3H, d,
Jˆ6.5 Hz);0.92 (3H, t, Jˆ7.5 Hz);1.18 (3H, s);1.20 (3H,
s);1.32±1.48 (2H, m);1.50±1.71 (2H, m);1.73±1.83 (1H,
m);2.64±2.70 (1H, m);3.47 (1H, td, Jˆ4.0;10.5 Hz);3.88
(1H, d, Jˆ14.9 Hz);4.20 (1H, d, Jˆ14.9 Hz);4.76 (1H, d,
Jˆ2.3 Hz);6.94±7.20 (4H, m). 13C NMR (d): 12.0;20.6;
22.2;25.1;26.4;29.6;31.4;35.0;41.3;43.6;43.9;45.3;
55.9;76.7;84.9;125.3;125.8;126.0;128.6;133.9;135.9.
IR (neat) cm21: 3060, 2920, 750. MSCI (m/z, %): 314
(M11, 100). Anal. Calcd for C21H31NO: C, 80.46;H,
9.97;N, 4.47. Found: C, 80.34;H, 10.12;N, 4.34.
3.5.1. Compound 5a. 44% yield. Oil. [a]2D5ˆ238.6 (cˆ0.2,
1
CHCl3) H NMR (d): 0.80±1.15 (3H, m);0.94 (3H, d,
Jˆ6.5 Hz);1.16 (3H, s);1.21 (3H, s);1.32 (3H, d,
Jˆ6.5 Hz);1.45±1.55 (2H, m);1.60±1.75 (2H, m);1.92±
2.02 (1H, m);2.83±2.96 (3H, m);3.68 (1H, dt, Jˆ4.2 Hz,
10.6 Hz);5.41 (1H, s);7.12±7.36 (4H, m). 13C NMR (d):
17.6;19.4;22.3;25.2;27.0;31.4;33.5;35.0;41.4;45.4;
46.6;55.4;75.9;84.3;125.9;126.8;127.7;128.0;135.3;
140.5. IR (neat): 3020, 2920, 750 cm21. MSCI (m/z, %): 300
(M11, 100). Anal. Calcd for C20H29NO: C, 80.22;H, 9.76;
N, 4.68. Found: C, 80.36;H, 9.88;N, 4.57.
3.5.6. Compound 7c. 70% yield. Oil. [a]2D5ˆ282.6 (cˆ0.6,
CHCl3). 1H NMR (d): 0.84 (3H, d, Jˆ6.5 Hz);0.88 (3H, d,
Jˆ6.9 Hz);0.90±1.05 (3H, m);0.94 (3H, d, Jˆ7.0 Hz);
1.22 (6H, s);1.42±1.52 (1H, m);1.54±1.64 (2H, m);
1.65±1.76 (1H, m);1.79±1.88 (1H, m);1.89±2.03 (1H,
m);2.68 (1H, dd, Jˆ2.2;5.3 Hz);3.52 (1H, dt, Jˆ4.1;
10.5 Hz);3.82 (1H, d,
Jˆ14.9 Hz);4.01 (1H, d,
Jˆ14.9 Hz);4.89 (1H, d, Jˆ2.2 Hz);6.98±7.82 (4H, m).

R. Pedrosa et al. / Tetrahedron 57 ,2001) 4005±4014
4011
13C NMR (d): 19.6;20.2;21.0;22.3;25.1;26.5;31.5;33.6;
35.1;41.4;43.8;44.2;49.7;56.2;76.6;83.6;125.4;125.6;
125.9;129.1;134.9;135.0. IR (neat) cm 21: 3010, 2920, 745.
MSCI (m/z, %): 328 (M11, 100). Anal. Calcd for
C22H33NO: C, 80.68;H, 10.16;N, 4.28. Found: C, 80.84;
H, 9.98;N, 4.19.
3.6.2. Oxidation±elimination. The corresponding amino
menthol (0.05 mmol) derivative was dissolved in CH2Cl2
(7 mL) and added to a mixture of PCC (0.2 mmol),
Ê
NaOAc (0.05 mmol) and 3 A molecular sieves, and stirred
at rt for 2 h. The reaction mixture was cooled to 08C and
treated for 15 min. with 2 M NaOH solution (2 mL). The
organic layer was decanted, and the aqueous phase extracted
with CHCl3. The organics were washed with brine, dried
over anhydrous Na2SO4, and the solvents removed. The
residue was redissolved in THF (1 mL), MeOH (0.3 mL)
and 2.5 M KOH solution (0.3 mL), and the mixture was
stirred overnight. The volatiles were eliminated, and the
residue was acidi®ed with 1 N solution of HCl and extracted
with Et2O. The aqueous phase was made alkaline by addi-
tion of 2 M NaOH solution and extracted with CHCl3. The
organic phase was washed, dried and concentrated, and the
residue was puri®ed by ¯ash chromatography (silica gel,
CHCl3/EtOH). In this way were prepared the following
compounds.
3.5.7. Compound 7d. 50% yield. Oil. [a]2D5ˆ2123.2
1
(cˆ0.8, CHCl3). H NMR (d): 0.80±1.05 (3H, m);0.83
(3H, d, Jˆ6.5 Hz);1.17 (3H, s);1.27 (3H, s);1.22±1.41
(1H, m);1.52±1.78 (4H, m);2.86 (2H, d,
Jˆ7.2 Hz);
3.09±3.14 (1H, m);3.29 (1H, dt, Jˆ4.0;10.7 Hz);3.94
(1H, d, Jˆ15.0 Hz);4.16 (1H, d, Jˆ15.0 Hz);4.72 (1H, d,
Jˆ1.3 Hz);7.03±7.33 (9H, m). 13C NMR (d): 22.0;22.3;
25.2;26.6;31.5;35.2;41.3;42.9;43.6;44.0;45.8;56.2;
77.0;83.5;125.8;126.0;126.1;126.3;128.3;128.9;
129.4;133.7;135.2;140.5. IR (neat) cm 21: 3010, 2920,
750, 730, 700. MSCI (m/z, %): 376 (M11, 100). Anal.
Calcd for C26H33NO: C, 83.15;H, 8.86;N, 3.73. Found:
C, 83.28;H, 8.71;N, 3.85.
3.6.3. .R)-4-Methyl-1,2,3,4-tetrahydroisoquinoline 10a.
Reductive ring opening of compound 5a yielded quantita-
tively 9a, which was transformed, without isolation, into
3.5.8. Compound 8a. 70% yield. Oil. [a]2D5ˆ267.2 (cˆ0.5,
1
CHCl3). H NMR (d): 0.81±1.10 (3H, m);0.92 (3H, d,
1
Jˆ6.5 Hz);1.11 (3H, s);1.22 (3H, s);1.25±1.37 (1H, m);
1.38±1.46 (1H, m);1.61±1.72 (2H, m);1.78±1.95 (2H, m);
1.98±2.12 (1H, m);2.81 (1H, dd, Jˆ10.5, 14.9 Hz);
2.99 (1H, dd, Jˆ10.5, 13.9 Hz);3.50 (1H, td, Jˆ4.2,
10a. 68% from 5a. Oil. [a]2D5ˆ147.2 (cˆ0.5, CHCl3). H
NMR (d): 1.29 (3H, d, Jˆ6.7 Hz);2.51 (1H, broad s);2.81
(1H, dd, Jˆ6.1, 12.3 Hz);2.89 (1H, m);3.22 (1H, dd,
Jˆ4.6, 12.3 Hz);4.01 (2H, s);6.99±7.26 (4H, m).
13C
10.6 Hz);3.54 (1H, d,
Jˆ15.0 Hz);4.04 (1H, d,
NMR (d): 20.5;31.9;48.6;51.0;125.7;125.9;126.2;
Jˆ15.0 Hz);4.67 (1H, broad s);7.05±7.10 (4H, m). 13C
NMR (d): 22.3;25.1;27.2;27.3;28.9;31.3;33.4;34.9;
41.5;46.3;48.1;56.6;75.0;86.6;125.6;126.3;127.9;
129.1;140.3;141.5. IR (neat) cm 21: 3060, 2920, 750.
MSCI (m/z, %): 300 (M11, 100). Anal. Calcd for
C20H29NO: C, 80.22;H, 9.76;N, 4.68. Found: C, 80.34;
H, 9.64;N, 4.79.
128.1;135.4;140.0. IR (neat) cm 21: 3280, 3060, 2920,
750. MSCI (m/z, %): 148 (M11, 100). This compound
was converted into the known N-methyl derivative by reac-
tion with dimethyl pyrocarbonate and subsequent reduction
with lithium aluminum hydride.21
3.6.4. .4R)-2,4-Dimethyl-1,2,3,4-tetrahydroisoquinoline
14
Me-10a. Oil. [a]2D5ˆ134.9 (cˆ0.4, CHCl3);lit.
1
3.5.9. Compound 8b. 26% yield. Oil. [a]2D5ˆ212.6 (cˆ0.8,
[a]2D5ˆ135.5 (cˆ1.1, CHCl3). H NMR (d): 1.31 (3H, d,
1
CHCl3). H NMR (d): 0.83±1.03 (3H, m);0.91 (3H, d,
Jˆ7.0 Hz);2.32 (1H, dd, Jˆ7.0, 11.3 Hz);2.43 (3H, s);2.79
(1H, dd, Jˆ5.3;11.3 Hz);3.07 (1H, m);3.55 (1H, d,
Jˆ15.0 Hz);3.57 (1H, d, Jˆ15.0 Hz);7.00±7.24 (4H, m).
13C NMR (d): 20.6;32.9;46.2;58.6;60.8;125.5;125.9;
126.2;127.4;135.4;140.0. IR (neat) cm 21: 3020, 2920, 750.
MSCI (m/z, %): 162 (M11, 100). Anal. Calcd for C11H15N:
C, 81.94;H, 9.38;N, 8.69. Found: C, 82.09;H, 9.21;N,
8.82.
Jˆ6.5 Hz);1.04 (3H, s);1.25±1.40 (2H, m);1.30 (3H, s);
1.38 (3H, d, Jˆ7.0 Hz);1.58±1.77 (3H, m);1.83±1.94 (1H,
m);1.95±2.06 (1H, m);3.13±3.24 (1H, m);3.40±3.51 (2H,
m);3.83±3.87 (1H, m);4.45±4.47 (1H, m);7.04±7.25 (4H,
m). 13C NMR (d): 20.1;21.9;24.9;26.5;30.8;34.4;41.1;
47.1;49.1;56.7;74.0;87.8;125.6;126.7;128.5;139.2;
145.0. IR (neat) cm21: 3060, 2920, 750. MSCI (m/z, %):
314 (M11, 100). Anal. Calcd for C21H31NO: C, 80.46;H,
9.97;N, 4.47. Found: C, 80.54;H, 9.86;N, 4.36.
3.6.5. .R)-4-Ethyl-1,2,3,4-tetrahydroisoquinoline 10b.
Reductive ring opening of compounds 5b or 7b yielded
quantitatively 9b. Oil. [a]2D5ˆ17.4 (cˆ0.5, EtOAc). 1H
NMR (d): 0.85±1.20 (6H, m);0.91 (3H, d, Jˆ6.5 Hz);
0.98 (3H, s);1.35±1.55 (1H, m);1.60±2.00 (6H, m);
2.30±2.70 (2H, m);3.25±3.45 (1H, m);3.55±3.75 (1H,
m);3.60 (1H, td, Jˆ4.0;10.3 Hz);3.90±4.10 (1H, m);
7.01±7.15 (4H, m);7,80 (1H, broad s). 13C NMR (d):
12.5;17.2;20.8;21.8;25.6;28.0;30.6;34.9;40.6;44.6;
3.6. Synthesis of 4-substituted-1,2,3,4-tetrahydro-
isoquinolines. General method
3.6.1. Reductive cleavage. To a suspension of LiAlH4
(0.19 g, 5 mmol) and AlCl3 (0.23 g, 1.7 mmol) in anhydrous
THF (15 mL) was dropped a solution of the corresponding
cyclized product 5a±d, 7b±d or 8b (1 mmol) in the same
solvent (7 mL) at 08C under argon, and the solution was
stirred for 20±30 min. The reaction mixture was hydrolyzed
by addition of water, the solids were separated by ®ltration,
and the solids were washed with EtOAc (2£15 mL). The
solution was dried over anhydrous MgSO4, the solvents
were eliminated in vacuo and the amino menthol derivatives
were used in the next step without further puri®cation.
46.5;47.8;48.3;60.2;72.2;125.3;125.7;126.5;128.2;
133.9;138.6. IR (neat) cm 21: 3200, 2900, 740. MSCI
(m/z, %): 316 (M11, 100). Oxidation±elimination process
leads to 10b (72% from 5b, 70% from 7b). Oil. [a]2D5ˆ16.7
(cˆ1.1, CHCl3). 1H NMR (d)1.01 (3H, t, Jˆ7.4 Hz);1.60±
1.85 (2H, m);2.58±2.66 (1H, m);2.76 (1H, broad s);3.02
(1H, dd, Jˆ4.8;12.9 Hz);3.15 (1H, dd, Jˆ4.9, 12.9 Hz);
3.99 (2H, s);7.07±7.21 (4H, m). 13C NMR (d): 11.8;28.0;

4012
R. Pedrosa et al. / Tetrahedron 57 ,2001) 4005±4014
38.5;47.0;48.4;125.7;126.0;126.1;128.7;135.5;139.1.
IR (neat) cm21: 3300, 3060, 2920, 750. MSCI (m/z, %): 162
(M11, 100). Anal. Calcd for C11H15N: C, 81.94;H, 9.38;N,
8.69. Found: C, 82.13;H, 9.52;N, 8.54.
Jˆ14.7 Hz);7.10±7.26 (4H, m). 13C NMR (d): 20.1;37.5;
37.8;50.5;54.0;125.9;127.3;128.9;140.9;146.0. IR (neat)
cm21: 3260, 2920, 750. MSCI (m/z, %): 162 (M11, 100).
Anal. Calcd for C11H15N: C, 81.94;H, 9.38;N, 8.69. Found:
C, 81.80;H, 9.26;N, 8.53.
3.6.6. .R)-4-Isopropyl-1,2,3,4-tetrahydroisoquinoline 10c.
Reductive ring opening of compounds 5c or 7c yielded
quantitatively 9c. Oil. [a]2D5ˆ15.4 (cˆ0.6, EtOAc). 1H
NMR (d): 0.50±1.55 (20H, m);1.25 (3H, s);1.55±2.00
(4H, m);2.10±2.60 (1H, m);2.95±3.70 (4H, m);3.90±
4.15 (1H, m);6.90±7.20 (4H, m). 13C NMR (d): 16.4;
18.2;21.1;22.1;25.9;29.6;30.9;35.1;44.5;46.7;60.7;
3.7. Synthesis of 1,4-disubstituted-1,2,3,4-tetrahydro-
isoquinolines
Cyclized compounds 5a, 5d, 7c, and 7d were reacted with
methylmagnesium iodide as previously described18 yielding
aminomenthol derivatives, which were transformed into the
isoquinoline derivatives by elimination of the chiral
appendage as described above.
72.4;125.5;126.2;126.7;137.3. IR (neat) cm
21: 3200,
2940, 750. MSCI (m/z, %): 330 (M11, 100). Oxidation±
elimination process lead to 10c. (66% from 5c, 72% from
1
7c). Oil. [a]2D5ˆ127.6 (cˆ0.3, CHCl3). H NMR (d): 0.83
3.7.1. .1S, 4R)-N-Tosyl-1,4-dimethyl-1,2,3,4-tetrahydro-
isoquinoline 13a. Reaction of 5a with methylmagnesium
iodide gave compound 12a, which was transformed by
oxidation±elimination, and treatment with tosyl chloride
(3H, d, Jˆ6.8 Hz);1.04 (3H, d, Jˆ6.9 Hz);2.17±2.28 (1H,
m);2.65 (1H, q, Jˆ5.7 Hz);2.90 (1H, broad s);3.07 (1H,
dd, Jˆ6.2, 13.2 Hz);3.14 (1H, dd, Jˆ5.7, 13.2 Hz);3.98
(2H, s);6.99±7.26 (4H, m). 13C NMR (d): 18.2;21.1;31.1;
42.5;44.2;48.3;125.6;125.9;126.0;128.6;136.1;137.9.
IR (neat) cm21: 3380, 2900, 740. MSCI (m/z, %): 176
(M11, 100). Anal. Calcd for C12H17N: C, 82.23;H, 9.78;
N, 7.99. Found: C, 82.12;H, 9.56;N, 8.12.
1
into 13a (57% from 5a). [a]2D5ˆ145.2 (cˆ1.7, CHCl3). H
NMR (d): 1.21 (3H, d, Jˆ6.8 Hz);1.45 (3H, d, Jˆ6.8 Hz);
2.34 (3H, s);2.81 (1H, m);3.04 (1H, dd, Jˆ11.2, 13.8 Hz);
3.86 (1H, dd, Jˆ6.1, 13.8 Hz);5.15 (1H, q, Jˆ6.8 Hz);
7.01±7.78 (8H, m). 13C NMR (d): 17.8;21.4;22.9;30.8;
45.1;52.3;115.0;126.1;126.6;126.7;126.9;127.1;129.5;
137.4;137.7;137.9;143.0. IR (neat) cm 21: 3020, 2940,
1650, 1460, 740. MSCI (m/z, %): 316 (M11, 100). Anal.
Calcd for C18H21NO2S: C, 68.54;H, 6.71;N, 4.44. Found:
C, 68.70;H, 6.82;N, 4.56.
3.6.7. .R)-4-Benzyl-1,2,3,4-tetrahydroisoquinoline 10d.
Reductive ring opening of compounds 5d or 7d yielded
quantitatively 9d. Oil. [a]2D5ˆ14.7 (cˆ0.9, EtOAc). 1H
NMR (d): 0.80±1.10 (9H, m);1.10±1.80 (9H, m);1.90±
2.40 (2H, m);2.90±3.40 (3H, m);3.50±3.80 (1H, m);3.90±
4.20 (1H, m);7.00±7.60 (9H, m);7.95 (1H, broad s). 13C
NMR (d): 17.4;21.2;22.3;25.8;30.8;35.1;40.8;41.4;
3.7.2. .1S, 4R)-N-Tosyl-4-benzyl-1-methyl-1,2,3,4-tetra-
hydroisoquinoline 13d. Reaction of 5d with methylmagne-
sium iodide gave compound 12d. Oil. [a]2D5ˆ225.8 (cˆ1.4,
EtOAc). 1H NMR (d): 0.80±1.10 (3H, m);0.82 (3H, s);0.90
(3H, d, Jˆ6.5 Hz);1.22 (3H, s);1.35±1.50 (1H, m);1.36
(3H, d, Jˆ6.7 Hz);1.50±1.60 (1H, m);1.60±1.75 (2H, m);
1.85±1.95 (1H, m);2.83 (1H, dd, Jˆ7.6;13.2 Hz);3.10±
3.30 (4H, m);3.62 (1H, td, Jˆ4.0;10.3 Hz);4.30±4.40 (1H,
m);7.02±7.35 (9H, m);8.25 (1H, broad s). 13C NMR (d):
21.3;22.1;23.3;26.0;31.0;35.0;38.5;42.1;43.3;44.4;
44.4;45.6;46.1;48.2;60.8;72.6;125.8;126.0;126.2;
126.8;128.1;128.6;129.1;129.6;134.6;137.6;141.0. IR
(neat) cm21: 3200, 2900, 740. MSCI (m/z, %): 392 (M11,
100). Oxidation±elimination process leads to 10d. (66%
from 5d, 70% from 7d). Oil [a]2D5ˆ232.9 (cˆ1.3,
1
CHCl3). H NMR (d): 1.85 (1H, broad s);2.86 (1H, dd,
Jˆ9.3, 12.7 Hz);2.94±3.00 (3H, m);3.07 (1H, dd, Jˆ4.0,
12.7 Hz);3.92 (2H, s);6.99±7.32 (9H, m). 13C NMR (d):
39.1;42.1;46.9;48.7;126.0;126.1;128.4;129.0;129.2;
135.9;138.5;140.4. IR (neat) cm 21: 3300, 3060, 3010,
2900, 1590, 750, 690. MSCI (m/z, %): 224 (M11, 100).
Anal. Calcd for C16H17N: C, 86.05;H, 7.67;N, 6.27.
Found: C, 86.23;H, 7.84;N, 6.09.
47.0;51.9;62.8;72.5;126.2;126.3;126.7;128.1;128.3;
129.3;137.5;139.6;140.6. IR (neat) cm 21: 3200, 2920,
760, 710. MSCI (m/z, %): 392 (M11, 100). 12d was
transformed by oxidation±elimination, and treatment with
tosyl chloride into 13d (59% from 5d). Oil. [a]2D5ˆ119.1
1
(cˆ0.5, CHCl3). H NMR (d): 1.52 (3H, d, Jˆ6.7 Hz);
3.6.8. .R)-5-Methyl-[1H]-2,3,4,5-tetrahydro-2-benzaze-
pine 11b. Reductive ring opening of compounds 8b yielded
quantitatively the corresponding aminomenthol derivative
as an oil. [a]2D5ˆ225.2 (cˆ0.6, EtOAc). 1H NMR (d):
0.83±1.05 (3H, m);0.92 (3H, d, Jˆ6.5 Hz);1.00 (3H, s);
1.06±1.46 (4H, m);1.35 (3H, d, Jˆ7.1 Hz);1.50±1.85 (6H,
m);2.70±2.85 (1H, m);3.05±3.15 (1H, m);3.20±3.70 (3H,
m);3.95±4.05 (1H, m);7.10±7.20 (4H, m);7.64 (1H, broad
s). 13C NMR (d): 17.9;20.5;21.6;22.1;25.9;30.9;35.2;
36.1;37.4;45.0;48.0;50.0;53.8;61.7;72.2;124.8;126.0;
2.37 (3H, s);2.67 (1H, dd, Jˆ9.7, 13.8 Hz);2.96 (1H, m);
3.20 (1H, dd, Jˆ9.5, 13.6 Hz);3.26 (1H, dd, Jˆ4.5,
13.8 Hz);3.49 (1H, dd, Jˆ5.7, 13.8 Hz);5.04 (1H, q,
Jˆ6.8 Hz);7.05±7.57 (13H, m). 13C NMR (d): 22.2;25.1;
37.5;39.5;43.5;52.6;126.3;126.5;126.6;126.8;127.1;
128.5;128.8;129.4;136.2;137.0;137.9;138.8;143.0. IR
(neat) cm21: 3040, 2920, 1640, 1460, 750, 710. MSCI
(m/z, %): 392 (M11, 100). Anal. Calcd for C24H25NO2S:
C, 73.62;H, 6.44;N, 3.58. Found: C, 73.51;H, 6.37;N,
3.69.
127.3;129.6;138.4. IR (neat) cm 21: 3200, 3040, 2920, 740.
MSCI (m/z, %): 316 (M11, 100). Oxidation±elimination
process of this intermediate leads to 11b (71% from 8b).
Oil. [a]2D5ˆ116.8 (cˆ0.6, CHCl3). 1H NMR (d): 1.30 (3H,
d, Jˆ7.1 Hz);1.43±1.60 (1H, m);1.74±1.82 (1H, m);2.30
(1H, broad s);3.08±3.26 (2H, m);3.31 (1H, ddd, Jˆ3.3;
3.7.3. .3S, 4R)-N-Tosyl-4-isopropyl-3-methyl-1,2,3,4-
tetrahydroisoquinoline 16c. Reaction of 7c with methyl-
magnesium iodide gave compound 14c. Oil. [a]2D5ˆ218.6
1
(cˆ0.9, CHCl3). H NMR (d): 0.69 (3H, d, Jˆ6.6 Hz);
0.80±1.15 (3H, m);0.92 (3H, d, Jˆ6.5 Hz);0.96 (3H, d,
Jˆ6.4 Hz);1.11 (3H, s);1.15 (3H, d, Jˆ6.3 Hz);1.38±1.55
5.8;13.9 Hz);3.95 (1H, d,
Jˆ14.7 Hz);4.00 (1H, d,

R. Pedrosa et al. / Tetrahedron 57 ,2001) 4005±4014
4013
(1H, m);1.55±1.75 (2H, m);1.80±1.97 (3H, m);2.05 (1H,
d, Jˆ10.5 Hz);3.55±3.71 (2H, m);3.78 (1H, d,
Jˆ13.2 Hz);4.00 (1H, d, Jˆ13.2 Hz);7.00±7.14 (4H, m);
7.73 (1H, broad s). 13C NMR (d): 21.3;21.9;22.1;26.5;
28.7;31.1;35.3;44.3;44.5;46.9;48.2;57.1;61.2;72.7;
cm21: 3040, 2920, 1640, 1460, 760, 700. MSCI (m/z, %):
392 (M11, 100). Anal. Calcd for C24H25NO2S: C, 73.62;H,
6.44;N, 3.58. Found: C, 73.76;H, 6.56;N, 3.49.
21
125.9;126.1;127.0;130.2;134.9;137.8. IR (neat) cm
:
Acknowledgements
3200, 2940, 750. MSCI (m/z, %): 344 (M11, 100). Oxida-
tion of 14c with PCC as described above gave directly (3S,
We gratefully thank the Spanish DGESIC (Project PB98-
Â
0361) and Junta de Castilla y Leon (Projects VA67/99 and
79/99) for ®nancial support. J. M. I. thanks the Ministerio de
Â
Educacion y Cultura for a predoctoral fellowship.
4R)-4-isopropyl-3-methyl-3,4-dihydroisoquinoline
15c
1
(76% from 7c). Oil. [a]2D5ˆ2479.3 (cˆ0.7, CHCl3). H
NMR (d): 0.78 (3H, d, Jˆ6.8 Hz);0.91 (3H, d, Jˆ
6.8 Hz);1.01 (3H, d, Jˆ6.8 Hz);1.73 (1H, oct. Jˆ
6.8 Hz);2.30 (1H, d, Jˆ6.8 Hz);4.31 (1H, q, Jˆ6.8 Hz);
7.10±7.39 (4H, m);8.23 (1H, s). 13C NMR (d): 19.6;20.3;
20.6;32.8;47.8;54.0;126.7;126.9;127.3;130.1;130.5;
References
137.0;157.9. IR (neat) cm 21: 2940, 1630. MSCI (m/z, %):
188 (M11, 100). Reduction of 15c with NaBH4 as
previously described22 leads to 16c (92%). White solid
(from hexanes);mp 97±98 8C. [a]2D5ˆ29.1 (cˆ0.5,
Â
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Â
2. Andres, C.;Duque-Soladana, J. P.;Pedrosa, R. J. Org. Chem.
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1
CHCl3). H NMR (d): 0.75 (3H, d, Jˆ6.7 Hz);0.81 (3H,
Â
3. Andres, C.;Duque-Soladana, J. P.;Pedrosa, R.
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Chem.
d, Jˆ6.8 Hz);1.04 (3H, d, Jˆ6.6 Hz);1.68±1.80 (1H, m);
2.18 (1H, d, Jˆ8.3 Hz);2.41 (3H, s);4.08 (1H, d,
4. (a) Beckwith, A. L. J.;Joseph, S. P.;Mayadunne, R. T. A.
J. Org. Chem. 1993, 58, 4198. (b) Rausson, S.;Urbain, P.;
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Jˆ15.4 Hz);4.55 (1H, q,
Jˆ6.7 Hz);4.62 (1H, d,
Jˆ15.4 Hz);7.04±7.16 (4H, m);7.31 (2H, d, Jˆ8.1 Hz);
7.78 (2H, d, Jˆ8.1 Hz). 13C NMR (d): 17.0;20.8;21.4;
21.5;31.9;42.9;49.2;53.1;126.0;126.2;127.3;129.6;
130.7;131.3;135.2;136.6;143.2. IR (neat) cm
21: 3040,
 Â
5. Pedrosa, R.;Andre s, C.;Duque-Soladana, J. P.;Roso n, C.
Tetrahedron: Asymmetry 2000, 11, 2809.
2920, 1650, 1450, 750. MSCI (m/z, %): 344 (M11, 100).
Anal. Calcd for C20H25NO2S: C, 69.93;H, 7.34;N, 4.08.
Found: C, 70.06;H, 7.45;N, 4.19.
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3.7.4. .3S, 4R)-N-Tosyl-4-benzyl-3-methyl-1,2,3,4-tetra-
hydroisoquinoline 16d. Reaction of 7d with methylmagne-
sium iodide gave compound 14d. Oil. [a]2D5ˆ225.7 (cˆ1.1,
8. (a) Franz, J. A.;Barrows, R. D.;Camaioni, D. M. J. Am.
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Tetrahedron 1997, 53, 13787. (d) Curran, D. P.;Xu, J. Synlett
1997, 1102. (e) Kim, S.;Yeon, K. M.;Yoon, K. S.
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1
CHCl3). H NMR (d): 0.78±1.18 (3H, m);0.95 (3H, d,
Jˆ6.5 Hz);1.05 (3H, d, Jˆ6.4 Hz);1.07 (3H, s);1.33
(3H, s);1.35±1.54 (1H, m);1.62±1.78 (3H, m);1.92±
2.01 (1H, m);2.86±2.91 (1H, m);2.98 (1H, dd, Jˆ6.2;
14.2 Hz);3.28 (1H, dd, Jˆ8.8;14.2 Hz);3.51 (1H, q,
Jˆ14.8 Hz);3.63 (1H, td, Jˆ4.0;10.4 Hz);3.96 (1H, d,
Jˆ14.8 Hz);4.05 (1H, d, Jˆ14.8 Hz);6.90±7.35 (9H, m);
7.40 (1H, broad s). 13C NMR (d): 21.9;22.2;23.4;26.4;
31.0;35.3;41.6;43.0;44.6;47.0;49.2;49.4;61.1;73.0;
125.6;125.9;126.1;126.7;128.2;128.5;129.2;134.8;
137.1;141.0. IR (neat) cm 21: 3200, 2920, 750, 700. MSCI
(m/z, %): 392 (M11, 100). Oxidation of 14d with PCC as
described above gave directly (3S, 4R)-4-benzyl-3-methyl-
3,4-dihydroisoquinoline 15d (75% from 7d). Oil.
Â
10. Philippe, N.;Levacher, V.;Dupas, G.;Que
Bourguignon, J. Org. Lett. 2000, 2, 2185 and references
guiner, G.;
therein.
1
[a]2D5ˆ2512.3 (cˆ0.5, CHCl3). H NMR (d): 0.97 (3H, d,
Â
Â
Â
11. (a) Tellitu, I.;Badõ a, D.;Domõ nguez, E.;Garcõ a, F. J.
Tetrahedron: Asymmetry 1994, 5, 1567. (b) Jullian, V.;
Quirion, J. C.;HuÈsson, H.-P. Eur. J. Org. Chem. 2000, 1319.
Jˆ6.9 Hz);2.65±2.82 (3H, m);4.16 (1H, q, Jˆ6.9 Hz);
6.81±7.31 (9H, m);8.34 (1H, s). 13C NMR (d): 18.7;
41.7;43.8;55.1;126.1;126.6;127.2;128.2;129.1;129.3;
Â
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Â
13. Andres, C.;Duque-Soladana, J. P.;Iglesias, J. M.;Pedrosa, R.
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130.9;138.0;139.4;158.0. IR (neat) cm 21: 3040, 2940,
1630, 770, 740, 710. MSCI (m/z, %): 236 (M11, 100).
Reduction of 15d with NaBH4 as previously described22
leads to 16d (94%). White solid (from hexanes);mp 107±
14. Belvisi, L.;Gennari, C.;Poli, G.;Scolastico, C.;Salom, B.
Tetrahedron: Asymmetry 1993, 4, 273.
1
1088C. [a]2D5ˆ289.7 (cˆ0.5, CHCl3). H NMR (d): 0.71
(3H, d, Jˆ6.8 Hz);2.42 (3H, s);2.76±2.81 (2H, m);3.01
(1H, dd, Jˆ10.5;14.7 Hz);4.09 (1H, d, Jˆ15.5 Hz);4.29
(1H, q, Jˆ6.8 Hz);4.77 (1H, d, Jˆ15.5 Hz);6.95±7.80
(13H, m). 13C NMR (d): 15.5;21.5;42.5;43.0;48.6;
49.7;125.9;126.2;126.4;126.7;127.4;128.3;129.6;
15. (a) Lee, E.;Tae, J. S.;Chong, Y. H.;Park, Y. C.;Yun, M.;
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S. D.;Rancourt, J. J. Am. Chem. Soc. 1991, 113, 2335.
È
16. Giese, B.;Kopping, B.;Go bel, T.;Dickhaut, J.;Thoma, G.;
Kulicke, K. J.;Trach, F. In Radical Cyclization Reactions,
129.7;130.4;130.5;135.7;136.5;140.1;143.4. IR (neat)

4014
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