Diastereoselective tandem 6-exo carbolithiation intramolecular ring opening in (-)-8-aminomenthol-derived perhydrobenzoxazines. A new synthesis of enantiopure 4-substituted tetrahydro isoquinolines and 2-azabenzonorbornanes

Article abstract of DOI:10.1021/ja002864q

Aryllithiums prepared by bromine - lithium interchange in chiral 2-(o-bromophenyl)-substituted perhydro-1.3-benzoxazines participate in the intramolecular 6-exo carbolithiation reaction with unactivated double bonds attached to the nitrogen substituent of

Full text of DOI:10.1021/ja002864q

J. Am. Chem. Soc. 2001, 123, 1817-1821
1817
Diastereoselective Tandem 6-exo Carbolithiation Intramolecular Ring
Opening in (-)-8-Aminomenthol-Derived Perhydrobenzoxazines. A
New Synthesis of Enantiopure 4-Substituted Tetrahydro Isoquinolines
and 2-Azabenzonorbornanes
Rafael Pedrosa,* Celia Andre´s,* Jesu´s M. Iglesias, and Alfonso Pe´rez-Encabo
Contribution from the Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, UniVersidad de
Valladolid, Dr. Mergelina s/n, 47011-Valladolid, Spain
ReceiVed August 2, 2000
Abstract: Aryllithiums prepared by bromine-lithium interchange in chiral 2-(o-bromophenyl)-substituted
perhydro-1,3-benzoxazines participate in the intramolecular 6-exo carbolithiation reaction with unactivated
double bonds attached to the nitrogen substituent of the heterocycle. When the reaction time is extended or no
TMEDA is used, the cyclized lithium intermediates react intramolecularly with the N,O-acetal system leading
to 2-azabenzonorbornane derivatives. The reactions are highly stereoselective and constitute a high-yielding
synthesis of enantiopure 4-substituted tetrahydroisoquinolines or 7-substituted 2-azabenzonorbornanes.
Introduction
We have recently reported the utility of chiral perhydroben-
zoxazines derived from (-)-8-aminomenthol13 in the synthesis
of a wide variety of enantiopure compounds by nucleophilic
ring opening of the N,O-acetal system14 or intramolecular
reactions such as Diels-Alder15 or radical cyclizations.16 The
high chemical yields and stereodifferentiation of that reaction
prompted us to investigate the unprecedented diastereoselective
cyclizations of 6-heptenylaryllithiums, and now we describe the
first stereoselective, high-yielding, 6-exo carbolithiation of
unactivated double bonds affording enantiopure 4-substituted
tetrahydro isoquinolines and 2-azabenzonorbornanes.
Anionic cyclization of hexenyllithiums has been widely used
in the last years as a powerful tool for building five-membered
rings. Diversely substituted cyclopentanes,1 pyrrolidines,2 tet-
rahydrofuranes,3 and both fused1a,4 and bridged5 bicyclic
compounds have been synthesized by anionic cyclization of
1-hexenyllithium derivatives. Alkenyl vinyllithiums and alkenyl
aryllithiums have also been employed in the preparation of
alkylidenecyclopentanes,6 indanes,7 and indolines.8 However,
this method has been restricted to the formation of four- or five-
membered rings, and there are few precedents on the preparation
of six-membered rings1a,6 by carbocyclization of unactivated
double bonds, although the formation of lithiated piperidine
derivatives as a transient species by 6-endo intramolecular
addition has been recently reported.9 In addition, the asymmetric
version of this reaction has not been developed with the
exception of a few reports on intra-10,11 and intermolecular12
processes.
Results and Discussion
The development of our idea required an allylbenzylamine
system capable of generating an aryllithium species placed in a
chiral environment, and then 2-(o-bromophenyl)-substituted
perhydrobenzoxazines 2a-i, which differ in the nature of the
allylic substituent at the nitrogen atom, were prepared as
summarized in Scheme 1.
* Address correspondence to thjs author:. Phone: Int+ 983-423211.
Fax: Int+ 983-423013. E-mail: pedrosa@qo.uva.es.
(10) (a) Bailey, W. F.; Nealy, M. J. J. Am. Chem. Soc. 2000, 122, 6787.
(b) Sanz Gil, G.; Groth, J. Am. Chem. Soc. 2000, 122, 6789. (c) Wakita,
H.; Matsumoto, K.; Yoshiwara, H.; Hosono, Y.; Hayashi, R.; Nishiyama,
H.; Nagase, H. Tetrahedron 1999, 55, 2449. (d) Nishiyama, H.; Sakata,
N.; Motoyama, Y.; Wakita, H.; Nagase, H. Synlett, 1997, 1147. (e)
Nishiyama, H.; Sakata, N.; Sugimoto, H.; Motoyama, Y.; Wakita, H.;
Nagase, H. Synlett 1998, 930. (f) Coldham, I.; Hufton, R.; Snowden, D. J.
J. Am. Chem. Soc. 1996, 118, 5322.
(1) (a) Bailey, W. F.; Nurmi, T. T.; Patricia, J. J.; Wang, W. J. Am.
Chem. Soc. 1987, 109, 2442. (b) Bailey, W. F.; Khanolkar, A. D.; Gavaskar,
K.; Ovaska, T. V.; Rossi, K.; Thiel, Y.; Wiberg, K. B. J. Am. Chem. Soc.
1991, 113, 5720. (c) Bailey, W. F.; Gavaskar, K. V. Tetrahedron 1994, 50,
5957. (d) Bailey, W. F.; Carson, M. W. J. Org. Chem. 1998, 63, 361. (e)
Bailey, W. F.; Carson, M. W. J. Org. Chem. 1998, 63, 9960. (f) Wei, X.;
Taylor, R. J. K. Angew. Chem., Int. Ed. 2000, 39, 409.
(2) Coldham, I.; Hufton, R. Tetrahedron Lett. 1995, 36, 2157.
(3) Broka, C. A.; Shen, T. J. Am. Chem. Soc. 1989, 111, 2981.
(4) Bailey, W. F.; Rossi, K. J. Am. Chem. Soc. 1989, 111, 765.
(5) (a) Bailey, W. F.; Khanolkar, A. D.; Gavaskar, K. V. J. Am. Chem.
Soc. 1992, 114, 8053. (b) Coldham, I.; Ferna´ndez, J. C.; Snowden, D. J.
Tetrahedron Lett. 1999, 40, 1819.
(11) Coldham, I.; Vennall, C. P. Chem. Commun. 2000, 1569.
(12) (a) Marek, I. J. Chem. Soc., Perkin Trans 1, 1999, 535. (b) Norsikian,
S.; Marek, I.; Klein, S.; Poisson, J. F.; Normant, J. F. Chem. Eur. J. 1999,
5, 2055. (c) Marek, I.; Normant, J. F. Carbometalation Reactions in Cross
Coupling Reactions; Stang, P. J., Diederich, F., Eds.; Wiley-VCH: New
York, 1998; p 322. (d) Norsikian, S.; Marek, I.; Poison, J. F.; Normant, J.
F. J. Org. Chem. 1997, 62, 4898. (e) Marek, I.; Klein, S.; Poisson, J. F.;
Normant, J. F. J. Am. Chem. Soc. 1995, 117, 8853.
(6) Chamberlin, A. R.; Bloom, S. H.; Cervini, L. A.; Fotsch, C. H. J.
Am. Chem. Soc. 1988, 110, 4788.
(7) (a) Ross, G. A.; Koppang, M. D.; Bartak, D. E.; Woolsey, N. F. J.
Am. Chem. Soc. 1985, 107, 6742. (b) Bailey, W. F.; Longstaff, S. C. J.
Org. Chem. 1998, 63, 432.
(8) (a) Zhang, D.; Liebeskind, L. S. J. Org. Chem. 1996, 61, 2594. (b)
Bailey, W. F.; Jiang, X.-L. J. Org. Chem. 1996, 61, 2596. (c) Bailey, W.
F.; Carson, M. W. Tetrahedron Lett. 1997, 38, 1329.
(13) Eliel, E.; He, X.-C. J. Org. Chem. 1990, 55, 2114.
(14) Andre´s, C.; Nieto, J.; Pedrosa, R.; Villaman˜a´n, N. J. Org. Chem.
1996, 61, 4130.
(15) (a) Andre´s, C.; Nieto, J.; Pedrosa, R.; Vicente, M. J. Org. Chem.
1998, 63, 8570. (b) Andre´s, C.; Garc´ıa-Valverde, M.; Nieto, J.; Pedrosa,
R. J. Org. Chem. 1999, 64, 5230.
(9) Barluenga, J.; Sanz, R.; Fan˜ana´s, F. J. Tetrahedron Lett. 1997, 38,
2763
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64, 4282.
10.1021/ja002864q CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/06/2001

1818 J. Am. Chem. Soc., Vol. 123, No. 9, 2001
Pedrosa et al.
Scheme 1
Scheme 2
This difference in reactivity could be attributed to the benzylic
character of the final lithium intermediate, or to the formation
of an ion pair and extra stabilization of the anion by the phenyl
group. On the basis of this hypothesis, we tested the cyclization
of compounds 2h-i, bearing an aromatic ring attached to the
acceptor double bond capable of stabilizing the cyclized lithium
intermediate. Reactions of these compounds with t-BuLi in the
described conditions lead to debrominated H-2h and H-2i as
the only reaction products. It is specially noteworthy that the
presence of a donor group at the aromatic ring in 2h inhibited
the cyclization process, and that an additional methyl substituent
at the inner position of the acceptor double bond in 2i had the
same effect.3It has been described17 that a leaving group attached
R to the accepting double bond favors the formation of five-
membered rings, and we tested this fact in the reaction of
benzyloxy derivative 2f with t-BuLi in the described conditions.
After hydrolysis, the debrominated compound H-2f (33%) and
a mixture (3/1) of cyclic epimeric compounds 5f and 5′f (66%)
were isolated from the reaction mixture. These isomers result
from the 6-exo cyclization-elimination of the starting com-
pound, and the configuration at the newly created stereocenter
for the major isomer (5f) was assigned as R on the basis of 1H
NMR NOESY experiments. Finally, the reaction of 2g with an
additional phenyl group at the external position of the double
bond led to a mixture of a single stereoisomer (5g) formed by
6-exo cyclization, in 45% yield, and aminomenthol derivatives
6 (20%) and 7 (20%). The formation of 6 could be explained
as a result of the metalation of one of the phenyl groups,
followed by intramolecular nucleophilic opening of the N,O-
acetal, whereas 7 will be formed in the same way from a lithium
derivative at the allylic position on the nitrogen substituent
(Scheme 3).
The results described until now point to the fact that the
formation of the aryllithium by bromine-lithium interchange
was a fast reaction, but as described,11 the 6-exo cyclization is
a slow process. The study was continued by changing the
reaction conditions to force the cyclization. To this end, 2a-c
and 2h-i were treated with t-BuLi (2.2 equiv) at -90°C and
then TMEDA (2 equiv) was added at the same temperature,
and the reaction mixture was allowed to warm to room
temperature and the stirring continued for extended periods of
time. In these conditions, 2a,b,i lead to the corresponding
uncyclized debrominated perhydrobenzoxazines H-2 even after
being stirred for 48 h at room temperature.
On the contrary, we were pleased to find that compound 2h
led to the 7-aryl-substituted 2-azabenzonorbornane 8h, as a
single diasteroisomer, in 81% isolated yield, in the above
experimental conditions after being stirred for 15 h at room
tmeperature. It is also noteworthy that when the reaction mixture
Table 1. Synthesis of Starting Compounds 2a-i
compd
R
R1
R2
yield (%)a
2a
2b
2c
2d
2e
2f
2g
2h
2i
H
H
Me
H
H
H
H
Ph
H
H
H
H
H
Me
H
H
H
Me
88
83
91
89
63
65
72
74
72
Me
Ph
Me
H
CH2OBn
Ph
2-(OMe)Ph
Ph
H
a Yields refer to pure and isolated compounds.
Compounds 2a-e were prepared, in two steps, from (-)-8-
aminomenthol by condensation with o-bromobenzaldehyde
leading quantitatively to 1 which was converted into 2a-e by
alkylation with commercially available allyl, prenyl, crotyl,
methallyl, and cinnamyl bromide, respectively, in 63-91%
yield. Perhydrobenzoxazines 2f-i were obtained in three steps
by condensation of the amino alcohol with the corresponding
aldehyde to 3f-i, which were reduced to (-)-8-amino menthol
derivatives 4f-i by treatment with sodium borohydride. These
compounds were converted into the final perhydrobenzoxazines
in 65-74% total yield (Table 1) by heating at 120 °C with
o-bromobenzaldehyde in a sealed tube.
To test the cyclization process, a solution of compounds 2a
or 2b in diethyl ether was treated with 2.2 equiv of t-BuLi at
-90 °C for 5 min, 2 equiv of TMEDA was added, and the
mixture was allowed to reach room temperature slowly over
30 min. Under these conditions no cyclization occurred, and
debrominated N-allyl- (H-2a from 2a) or 2-phenyl-N-prenyl
perhydro-1,3-benzoxazine (H-2b from 2b) were obtained as the
only compounds. The same compounds were obtained when
the reaction mixtures were stirred for 5 h at -90° C and
hydrolyzed. This fact indicated that the bromine-lithium
exchange had quickly occurred, but the aryllithium was unable
to react in these conditions. Fortunately, a very different
behavior was observed from N-cinnamyl derivative 2c. In the
above experimental conditions 2c was totally transformed into
6-exo cyclization products, as a mixture (77/23) of diastereoi-
somers 5c and 5′c isolated in 98% yield, and no reduction
product was observed.
(17) Broka, C. A.; Lee, W. J.; Shen, T. J. Org. Chem. 1988, 53, 1336.

(-)-8-Aminomenthol-DeriVed Perhydrobenzoxazines
J. Am. Chem. Soc., Vol. 123, No. 9, 2001 1819
Scheme 3
Figure 1. X-ray structure for compound 8h.
the intermediates.18 In this way, a solution in diethyl ether of
perhydrobenzoxazines 2a-e and 2h-i was treated with t-BuLi
(2.2 equiv) at -90 °C, and after 10 min at this temperature, the
mixture was allowed to reach room temperature and stirred until
the reaction was finished (TLC). In these experimental condi-
tions, 2b (with two methyl groups at the end of the double bond)
did not cyclize and only gave debrominated compound H-2b
after 15 h of reaction, and the crotyl derivative (2d) gave the
reduction product H-2d in 95% yield and 2-azabenzonorbornane
8d (5%) after 24 h of stirring. On the contrary, the methallyl
derivative 2e led to a mixture of H-2e (65%) and 2-azaben-
zonorbornane 8e (35%) after 24 h of reaction. 2a, after 8 h of
stirring at room temperature, furnished a mixture of debromi-
nated 2-phenyl-substituted perhydrobenzoxazine H-2a (12%),
6-exo cyclization compound 5′a (8%), and 2-azabenzonorbor-
nane 8a (80%) as the only diastereoisomer. Moreover, 2c
immediately cyclizes (0.3 h.) to a mixture of diastereoisomers
8c and 8′c in a 77/23 ratio and 90% total yield, and 2h led to
2-azabenzonorbornane 8h as a single diastereoisomer in 95%
yield, after 1 h of reaction. In this case, compound 2i also
participates in the cyclization process giving, after 2 h, a mixture
of 5i (11%) and diastereomeric 2-azabenzonorbornanes 8i and
8′i in a 73/11 ratio and 80% yield; the formation of traces (1H
NMR) of an isomeric azabicyclic system was observed from
the reaction mixture in this case.
Scheme 4
Table 2. Cyclization of Compounds 2a,c,d,e,h,i
compd
R
R1 R2 method time (h) products (%)a
2a
2c
2c
2d
2e
2h
2h
2i
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
B
A
B
B
B
A
B
B
8
10
0.3
24
24
15
1
8a (80)
Ph
Ph
Me
H
2-(OMe)Ph
2-(OMe)Ph
Ph
8c (75), 8′c (22)
8c (69), 8′c (21)
8d (5)
8e (35)
8h (81)
8h (95)
8i (60), 8′i (9)
The stereochemistry of the stereocenters created in the
reaction, C-4 at the tetrahydroisoquinoline system for 6-exo
carbocyclization and C-1, C-4, and C-7 at the 2-azabenzonor-
bornane derivatives, was established by NOESY experiments
and confirmed by X-ray diffraction analysis for compound 8h
(Figure 1) and 8d, 8e, and 11c.19 In this respect, the major 6-exo
cyclization compounds 5c,f,g have configuration R at C-4 in
the THIQ system, which is maintained in the 2-azabenzonor-
bornane derivatives (C-4). Furthermore, the configurations of
the stereocenters are 1S, 4R for 8a and 8e, 1S, 4R, 7R for 8c,
8h, and 8i, and 1S, 4R, 7S for 8d (the change of the configuration
at C-7 in this case is due to the change of the priority of the
substituents).
Me
2
a Yields refer to pure and isolated compounds.
was quenched after being stirred for 10 h, it was possible to
isolate 8h and debrominated perhydrobenzoxazine H-2h, but it
was not possible to detect the formation of the corresponding
6-exo cyclization derivative. In a similar way, after the mixture
was stirred for 15 h at room temperature, 2c gives 7-phenyl-
2-azabenzonorbornanes, as a mixture of diastereoisomers 8c
(77%) and 8′c (23%) ,which differ in the stereochemistry at
the stereocenters of the bicyclic system (Scheme 4). The
formation of bicyclic compounds is a consequence of a tandem
6-exo carbolithiation of starting perhydrobenzoxazines, followed
by stereospecific intramolecular nucleophilic N,O-acetal opening
by the lithiated intermediate.With this information in mind, a
novel set of experiences was planned in the absence of TMEDA,
although it is well-known that the cosolvent enhances the
reactivity of organolithiums by diminishing the aggregation of
Both chemical and stereochemical outcome of these reactions
could be interpreted as summarized in Scheme 5. In this respect,
it is clear that the formation of the aryllithium (A) by bromine-
lithium interchange is a fast process, but the 6-exo cyclization
(18) Knochel, P. Carbometallation of alkenes and alkynes. In Compre-
hensiVe Organic Synthesis; Trost, B. M., Fleming, I., Semmelhack, M. F.,
Eds.; Pergammon Press: New York, 1991; Vol. 4, p 865.
(19) See Supporting Information.

1820 J. Am. Chem. Soc., Vol. 123, No. 9, 2001
Pedrosa et al.
Scheme 5
Scheme 6
is slower than the 5-exo reaction,11,20 and only occurs quickly
if the terminal alkene carbon bears either a phenyl group (2c)
that is able to stabilize the alkyllithium (B in Scheme 5)
generated in the cyclization or a good leaving group that directs
the process to an SN2′ reaction.17 Interestingly, in the absence
of strong chelating TMEDA, the 6-exo cyclization followed by
nucleophilic intramolecular ring opening of the N,O-acetal
system is a fast process. This points to the fact that the reactive
species resembles more an alkyllithium than a carbanion,21 and
in this case the driving force for the initial cyclization could be
the second nucleophilic reaction leading to the 2-azabenzonor-
bornane system.
From the stereochemical standpoint the results can be
interpreted by accepting that the major or single isomer is
formed from the initial coordination of the lithium atom to the
alkene π-bond, followed by syn insertion across the double
bond22 in a chairlike transition state formed from A (Scheme
5), where the double bond is in the pseudoequatorial disposition.
In this way, alkyllithium intermediate B will be formed, leading
to the 4-substituted THIQ ring with configuration R at C-4 upon
hydrolysis. Minor diastereoisomers will be formed, also through
a chairlike transition state, from A′ where the double bond is
oriented in a pseudoaxial disposition.
The formation of the azabicyclic system is also stereochemi-
cally noteworthy. The formation of the final product as a single
diastereoisomer or as a mixture in the same ratio in which are
formed the 6-exo cyclization compounds shows that the forma-
tion of the bicyclic system accurs from alkyllithium B, by
intramolecular attack of the lithium alkyl to the early iminium
ion (C) formed during the N,O-acetal opening.14 This reaction
could occur with inversion of configuration at the organolithium
center or, most probably, through epi-B, as a result of a previous
epimerization of this carbon due to its benzylic character.12, 23
Enantiopure 4-substituted tetrahydro isoquinoline derivatives
9c,f,g were obtained from major diastereoisomers 5c,f,g isolated
from the reaction mixtures by flash chromatography. Reductive
ring opening of these compounds with a mixture of H4AlLi and
AlCl3 in THF at -20 °C led to the corresponding (8)-amino-
menthol derivatives, which were converted into 8-amino men-
thones by oxidation with a buffered (NaOAc) solution of PCC
in CH2Cl2 in the presence of molecular sieves.24 Finally, amino
menthones, without isolation, were transformed into the final
products by elimination promoted by KOH in THF/MeOH. In
this way (R)-4-benzyl tetrahydroisoquinoline 9c, (R)-4-vinyl
tetrahydroisoquinoline 9f, and (R)-4-diphenylmethyl tetrahy-
droisoquinoline 9g, isolated as tosylates 10f and 10g, respec-
tively, were obtained in 62-68%. Amino menthol derivatives
8a,c,h,i were also transformed into tosylates of 7-substituted
2-azabenzonorbornanes 11a,c,h,i in 68-74%. Oxidation of
starting aminomenthols with PCC in the above conditions
yielded 8-amino menthone derivatives, which were transformed,
without isolation, into 2-azabenzonorbornane derivatives by
elimination with KOH in THF/MeOH, and derivatized as tos-
ylates by treatment with tosyl chloride in DIPEA (Scheme 6).
Conclusions
The present work shows for the first time the synthetic utility
of anionic 6-exo cyclizations of unactivated alkenes. The
reaction easily occurs if the cyclized lithium derivative is
moderately stable or if the lithium intermediate can evolve to a
stable final compound by elimination of a good leaving group
or intramolecular ring opening of the N,O-acetallic system. On
the contrary, the cyclization of 2b with two methyl groups at
the terminal olefinic bond was not possible, and cyclization of
2d, with one methyl group at the same position, led to the
2-azabenzonorbonane derivative in only 5% yield. This fact has
been previously observed in the formation of five-membered
rings by 5-exo cyclization processes,1b,3 and could be explained
because the cyclization leads to unstable tertiary or secondary
(20) Bailey, W. F.; Patricia, J. J.; Del Gobbo, V. C.; Jarret, R. M.;
Okarma, P. J. J. Org. Chem. 1985, 50, 1999.
(21) Coldham, I. J. Chem. Soc., Perkin Trans. 1 1998, 1343 and
references therein.
(22) (a) Gawley, R. E.; Zhang, Q.; Campagna, S. J. Am. Chem. Soc.
1995, 117, 11817. (b) Coldham, I.; Hufton, R.; Snowden, D. J. J. Am. Chem.
Soc. 1996, 118, 5322.
(23) (a) Woltering, M. J.; Fro¨hlich, R.; Hoppe, D. Tetrahedron Lett. 1998,
39, 1745. (b) Oestreich; Fro¨hlich, R.; Hoppe, D. Angew. Chem., Int. Ed.
Engl. 1997, 36, 1764. (c) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed.
Engl. 1997, 36, 2282 and references therein.
(24) Modification of the method described in: Andre´s C.; Nieto J.;
Pedrosa R.; Vicente M. J. Org. Chem. 1998, 63, 8570.

(-)-8-Aminomenthol-DeriVed Perhydrobenzoxazines
J. Am. Chem. Soc., Vol. 123, No. 9, 2001 1821
Elimination of the Menthol Appendage. To a stirred solution of
the corresponding aminomenthol derivative (0.55 mmol) in dichlo-
romethane (15 mL) was added PCC (2.1 mmol) sodium acetate (0.55
mmol) and 3 Å molecular sieves (0.20 g), and the mixture was stirred
at room temperature for 2 h. The reaction was quenched with 2 M
NaOH (20 mL) in an ice bath and stirred for 15 min. The organic layer
was decanted and the aqueous extracted with chloroform (5 × 25 mL).
The organic extracts were washed with brine and dried (sodium sulfate)
and the solvents removed. The resulting slurry was redissolved in THF
(6 mL), methanol (2 mL), and 2.5 M KOH (2 mL) and stirred overnight.
The volatiles were eliminated and the residue was acidified with 1 N
HCl and extracted with ether (2 × 25 mL). The aqueous layer was
then made alkaline by careful addition of 2 M NaOH and extracted
with chloroform (5 × 25 mL). The organic phases are washed, dried
,and concentrated. The free amines were purified by chromatography
(compound 9c), or directly transformed into the N-tosylamides (com-
pounds 10f-g and 11a,c,h,i).19
cyclized lithium intermediates. Whereas the intramolecular 6-exo
carbolithiation allows the preparation of enantiopure 4-substi-
tuted tetrahydroisoquinolines, the tandem process constitutes an
unprecedented25 stereoselective synthesis of enantiopure 7-sub-
stituted 2-azabenzonorbornane derivatives.
Experimental Section
Anionic Cyclization: General Method. To a deoxygenated solution
of the corresponding perhydrobenzoxazine 2a-i (8 mmol) in diethyl
ether (80 mL), cooled to -90 °C, was slowly added a 1.5 M solution
of t-BuLi in pentane (11.7 mL); the mixture was stirred for 10 min at
-90 °C, then TMEDA (16 mmol) was slowly added at that temperature,
the cooling bath was removed, and the reaction mixture was allowed
to reach room temperature. After being stirred for 20 min the reaction
was quenched with a saturated solution of ammonium chloride, the
phases were decanted, and the aqueous layer was extracted with EtOAc
(2 × 50 mL). The organic layer was washed with brine and dried over
anhydrous sodium sulfate, and the solvent was removed. The products
were purified by flash chromatography (silica gel, EtOAc/hexane 1/60).
In the reaction without TMEDA, the same experimental procedure,
except for the addition of the cosolvent, was followed.
(R)-4-Benzyl-1,2,3,4-tetrahydroisoquinoline 9c. 62% from 5c. Oil.
[R]D -32.86 (c 1.3, CHCl3). Lit.26 mp 179-180 °C for racemic
25
1
hydrochloride. H NMR (δ): 1.85 (1H, broad s); 2.86 (1H, dd, J )
9.3, 12.7 Hz); 2.94-3.00 (3H, m); 3.07 (1H, dd, J ) 4.0, 12.7 Hz);
3.92 (2H, s); 6.99-7.32 (9H, m). 13C NMR (δ): 39.1; 42.1; 46.9; 48.7;
126.0; 126.1 (2C); 128.4 (2C); 129.0; 129.2 (3C); 135.9; 138.5; 140.4.
IR (neat): 3300, 3060, 2900, 1590 cm-1. MS (m/z, %): 224 (M + 1,
100). Anal. Calcd for C16H17N: C, 86.05; H, 7.67; N, 6.27. Found: C,
86.19; H, 7.81; N, 6.34.
25
Cyclized Compound 5c. 77% from 2c. Oil. [R]D -41.9 (c 1.7,
CHCl3). 1H NMR (δ): 0.83-1.05 (2H, m); 0.95 (3H, d, J ) 6.5 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, J ) 3.1, 11.9
Hz); 2.93 (1H, dd, J ) 3.1, 11.8 Hz); 3.03-3.10 (3H, m); 3.38 (1H,
dt, J ) 4.1, 10.6 Hz); 5.21 (1H, s); 7.13-7.46 (9H, m). 13C NMR (δ):
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): 3020, 2910 cm-1. MS (m/z, %):
376 (M + 1, 100). Anal. Calcd for C26H33NO: C, 83.15; H, 8.86; N,
3.73. Found: C, 83.31; H, 8.99; N, 3.66.
Acknowledgment. Financial support from the DGESIC of
Spain (Project PB98-0361) and Junta de Castilla y Leo´n (Project
VA79/99) is gratefully acknowledged. J.M.I. also thanks the
Spanish Ministerio de Educacio´n y Cultura for a predoctoral
felowship.
Reductive Ring Opening of Compounds 5c,f,g. To a stirred
suspension of LiAlH4 (0.12 g, 3.2 mmol) and AlCl3 (0.17 g, 1.3 mmol)
in dry tetrahydrofuran (8 mL) at -10 °C was added the corresponding
perhidrobenzoxazine 5c,f,g (0.64 mmol) dissolved in tetrahydrofuran
(5 mL). After 20 min at that temperature the reaction was quenched
by slow addition of water and a 20% aqueous solution of NaOH. The
solid was filtered and washed with chloroform, the organic solvents
were dried over anhydrous sodium sulfate, and the solvent was removed
under vacuum. The resulting amino alcohols were employed in the next
step without further purification.
Supporting Information Available: Experimental details
for preparation and physical and spectral properties for com-
pounds 1, 2a-i, 3f-i, 4f-i, 5f-g, 8a-i, 10f-g, and 11a-i;
NOESY experiments for compounds 8a,c,h,i and X-ray dia-
grams, crystal data, and structure refinement for compounds 8d,
8e, 8h. and 11c including atomic coordinates, isotropic and
anisotropic displacement parameter,s and a listing of bond angles
and bond lengths (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
(25) A very interesting 5-exo carbolithiation approach to azanorbornanes
appeared during the redaction of this paper: Coldham, I.; Ferna´ndez, J. C.;
Price, K. N.; Snowden, D. J. J. Org. Chem. 2000, 65, 3788.
JA002864Q
(26) Clark, R. D.; Jahangir; Langston, J. A. Can. J. Chem. 1994, 72, 23.