Sulfinimine-mediated asymmetric synthesis of 1,3-disubstituted tetrahydroisoquinolines: a stereoselective synthesis of cis- and trans-6,8-dimethoxy-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline.

Article abstract of DOI:10.1021/ol006654u

[reaction: see text] The highly diastereoselective addition of lateral lithiated o-tolunitriles to sulfinimines followed by treatment of the resulting sulfinamide with MeLi, hydrolysis, and reduction represents a concise new methodology for the asymmetric

Full text of DOI:10.1021/ol006654u

ORGANIC
LETTERS
2000
Vol. 2, No. 24
3901-3903
Sulfinimine-Mediated Asymmetric
Synthesis of 1,3-Disubstituted
Tetrahydroisoquinolines: A
Stereoselective Synthesis of cis- and
trans-6,8-Dimethoxy-1,3-dimethyl-
1,2,3,4-tetrahydroisoquinoline
Franklin A. Davis,* Pradyumna K. Mohanty, David M. Burns, and
Yemane W. Andemichael
Department of Chemistry, Temple UniVersity, Philadelphia, PennsylVania 19122
fdaVis@astro.ocis.temple.edu
Received September 25, 2000
ABSTRACT
The highly diastereoselective addition of lateral lithiated o-tolunitriles to sulfinimines followed by treatment of the resulting sulfinamide with
MeLi, hydrolysis, and reduction represents a concise new methodology for the asymmetric synthesis of 1,3-disubstituted tetrahydroisoquinolines.
We recently introduced methodology for the asymmetric
synthesis of 3-substituted 1(2H)-isoquinolones 2 and sug-
gested that they may be useful chiral building blocks for the
construction of tetrahydroisoquinolines 1 (Scheme 1). In this
context, a highly stereoselective asymmetric synthesis of
(3R,4S)-(-)-6-methoxy-N-methyl-3-phenyl-1,2,3,4-tetrahy-
droisoquinolin-4-ol (3) was reported.1 Isoquinolones 2 were
prepared by condensing lateral lithiated amides2 with enan-
tiopure sulfinimines (N-sulfinyl imines).3 This methodology
avoids many of the limitations of the Bischler-Napieralski
and Pictet-Spengler protocols as well as providing iso-
quinolines with substitution patterns not readily accessible
by other means.
Scheme 1
To extend the utility of 2, it is necessary to devise
procedures for the stereoselective replacement of the 1-oxo
group with other substituents (R1). Described here are studies
aimed at the asymmetric synthesis of 6,8-dimethoxy-1,3-
(1) Davis, F. A.; Andemichael, Y. W. J. Org. Chem. 1999, 64, 8627.
(2) For a reviews on lateral lithiation reactions, see: (a) Snieckus, V.
Chem. ReV. 1990, 90, 879. (b) Clark, R. D.; Jahangir, A. Org. React. 1995,
47, 5.
(3) For reviews on the chemistry of sulfinimines, see: (a) Davis, F. A.;
Zhou, P.; Chen, B.-C. Chem. Soc. ReV. 1998, 27, 13. (b) Hua, D. H.; Chen,
Y.; Millward, G. S. Sulfur Rep. 1999, 21, 211. (c) Zhou, P.; Chen, B.-C.;
Davis, F. A. Syntheses and Reactions of Sulfinimines. In AdVances in Sulfur
Chemistry; Rayner, C. M., Ed.; JAL Press: 2000; Vol 2, pp 249-282.
10.1021/ol006654u CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/08/2000

dimethyl-1,2,3,4-tetrahydroisoquinoline (4),4 the isoquinoline
segment of the anti-HIV michellamines.5 These studies
revealed for the enantioselective synthesis of 1,3-disubstituted
isoquinolines that the addition of lateral lithiated o-tolunitriles
to sulfinimines is superior to the use of lateral lithiated
amides.
of 7 was complex because diastereomeric atropisomers were
formed due to restricted rotation about the amide C-N and
C-aryl bonds. Heating the NMR sample to ca. 90 °C failed
to resolve the spectra, so it was not possible to establish the
diastereoselectivity by this method. For the same reason,
analysis by HPLC also proved unsuccessful. Selective
removal of the sulfinyl group with TFA/MeOH gave amine
8 in 87% yield following flash chromatography. Attempts
to determine the enantiomeric purity of 8 by chiral HPLC,
using chiral shift reagents, and by making the Mosher amide
were also unsuccessful. However, chiral HPLC analysis of
9 (ChiralCel OD) indicated that the ee was 92%. Isoqui-
nolone 9 was prepared in 80% yield by cyclization of 8 with
tert-butyllithium at -78 °C.
Our first attempt at the construction of 4 is outlined in
Scheme 2 and involves generating the lateral lithiated amide
Scheme 2
With isoquinolone 9 in hand, our thought was to convert
it into the imidoyl chloride 10 followed by metal-catalyzed
coupling with methylmagnesium bromide to give dihydroiso-
quinoline 11.9 Stereoselective reduction of 11 would then
afford the target 4. Compound 9 was heated at reflux in
benzene with phosphorus oxychloride for 1.5 h, and purifica-
tion by alumina chromatography gave a 50% yield of the
hydrolytically unstable chloride 10 as indicated by the
disappearance of the amide proton. The catalyst [1,3-bis-
(diphenylphosphino)propane]dichloronickel(II) [NiCl2(dppp)]9a
was employed for coupling of 10 with methylmagnesium
bromide. Unfortunately, decomposition occurred on addition
of the Grignard reagent and none of the desired product could
be detected. It is interesting to note that in a model study
the imidoyl chloride of 3-phenyl-3,4-dihydro-2H-isoquinolin-
1-one (12)1 gave an 81% yield of 13 under similar conditions
(Scheme 3). The presence of the 8-methoxy group may
Scheme 3
of N,N-diethyl-2,4-dimethoxy-6-methylbenzamide (5)6,7 by
treatment with 2.0 equiv of LDA followed by addition of
(S)-(+)-(acetylidene)-p-toluenesulfinamide (6).8 The sulfin-
amide 7 was isolated in 68% yield by flash chromatography
and is assumed to have the (R)-configuration at the new
stereogenic center based on an empirical model developed
in our synthesis of 3 (see also below).1 The 1H NMR spectra
sterically inhibit the addition of the Grignard reagent and/or
may provide an unproductive site for coordination of the
catalyst.
Even if we had been successful in coupling the Grignard
reagent to the imidoyl chloride 10, the lateral lithiated amide
(7) Despite using normal precautions to exclude moisture and oxygen,
with an argon atmosphere about 10-15% N,N-diethyl-2-hydroxymethyl-
4,6-dimethoxybenzamide (i) was formed on generation of the lateral lithiated
amide of 5.
(4) For studies related to the synthesis of this isoquinoline and its epimers,
see: (a) Bringmann, G.; Jansen, J. R.; Rink, H.-P. Angew. Chem., Int. Ed.
Engl. 1986, 25, 913. (b) Bringmann, G.; Weirich, R.; Reuscher, H.; Jansen,
J. R.; Kinzinger, L.; Ortmann, T. Liebigs Ann. Chem. 1993, 877 (c) Upender,
V.; Pollart, D. J.; Liu, J.; Hobbs, P. D.; Olsen, C.; Chao, W.-R.; Boden, B.;
Crase, J. L.; Thomas, D. W.; Padey, A.; Lawson, J. A.; Dawson, M. I. J.
Heterocycl. Chem. 1996, 33, 1371. (d) Hoye, T. R.; Chen, M. Tetrahedron
Lett. 1996, 37, 3099. (e) Hoye, T. R.; Chen, M.; Hoang, B.; Mi, L.; Priest,
O. P. J. Org. Chem. 1999, 64, 7184.
(5) For a review, see: Bringmann, G.; Pokorny, F. The Naphthyliso-
quinoline Alkaloids. In The Alkaloids; Cordell, G. A., Ed.; Academic
Press: New York, 1995; Vol. 46, p 127.
(8) (a) Davis, F. A.; Zhang, Y. Andemichael, Y.; Fang, T.; Fanelli, D.
L.; Zhang, H. J. Org. Chem. 1999, 64, 1043. (b) Fanelli, D. L.; Szewczyk,
J. M.; Zhang, Y.; Reddy, G. V.; Burns, D. M.; Davis, F. A. Org. Synth.
1999, 77, 50.
(6) Froyen, P. Synth. Commun. 1995, 25, 959.
3902
Org. Lett., Vol. 2, No. 24, 2000

protocol for the synthesis of 1,3-disubstituted tetrahydroiso-
quinolines was still problematic (Scheme 2). The problem
is the difficulty in determining the diastereoselectivity in the
key addition step because of the formation of atropodiaste-
reoisomers. The presence of these rotamers makes it nearly
impossible to improve the stereoselectivity and to obtain a
diastereomerically pure product. To overcome this limitation,
an anionic species is needed that, on addition to the
sulfinimine, does not produce rotamers while still retaining
the necessary functionality for elaboration to the target. The
lateral lithiated species generated from a substituted o-
tolunitrile2,10 would appear to meet these requirements since
rotamer formation would be unlikely and the nitrile can be
considered to be a masked carbonyl for further elaboration.
However, o-tolunitrile anions are reported to dimerize2 and
the presence of the methoxy group could present problems
similar to those encountered in our first approach (Scheme
2).
Scheme 4
2-Bromo-1,5-dimethoxy-3-methylbenzene (14)11 was heated
with copper(I) cyanide in DMF to give 2,4-dimethoxy-6-
methylbenzonitrile (15) in 89% yield (Scheme 4). The nitrile
was reacted with 2 equiv of LDA in THF at -78 °C to give
the dark-red lateral lithiated species, which was treated with
(S)-(+)-6 to afford the sulfinamide 16 in 45% yield. Use of
diglyme improved the yield to 68%. The diastereoselectivity
of the addition was >97% and was easily determined by
integration of the methyl protons in 16. This selectivity
confirms the absence of atropodiastereoisomers. On treatment
with 4 equiv of MeLi, 16 was directly converted into cyclic
imine (3R)-(+)-11 on acidification. This accomplished three
operations in one-pot: (i) removal of the sulfinyl auxiliary,
(ii) installation of the 1-methyl group, and (iii) cyclization
to the imine. Although the sequence of steps leading from
16 to 11 is not known with certainty, it is reasonable to
propose that deprotonation of the acidic sulfinamide proton
occurs first followed by addition of MeLi to the cyano group
with formation of the methyllithium ketimine. Hydrolysis
removes the sulfinyl group, to afford the free amine, which
then intramolecularly cyclizes to 11.
quinonedimethane structure derived from the nitrile anion
is chelated through the lithium cation to the sulfinyl oxygen
and approaches the Si-face of the sulfinimine via a six-
membered chair-like transition state, TS-1.
Imine 11 was converted into (1R,3R)-(-)-4 in 93% yield
and >95% ee by reduction with LiAlH4/Me3Al, as described
by Bringmann,4a,b to assign the stereochemistry of the
stereogenic center. Reduction of 11 with NaBH4 gave the
cis isomer (1S,3R)-(-)-17 in 91% yield, which means that
the stereochemistry of the initially formed stereogenic centers
in 7 and 16 is (R). These results support the chiral-recognition
model developed earlier for the addition of lateral lithiated
amides to sulfinimines.1 In this representation, the o-
In summary, new methodology is presented for the
asymmetric synthesis of 1,3-disubstituted tetrahydroisoquino-
lines from lateral lithiated nitriles and chiral sulfinimines.
This new protocol is illustrated in the concise, highly
stereoselective four-step asymmetric synthesis of cis- and
trans-6,8-dimethoxy-1,3-dimethyl-1,2,3,4-tetrahydroisoquin-
olines 17 and 4 from (S)-(+)-6 in 40-41% overall yield.
Acknowledgment. We thank Dr. Bin Chao for prelimi-
nary studies. This work was supported by a grant from the
National Institutes of Health (GM 51982).
(9) For examples of metal-catalyzed Grignard coupling with imidoyl
chlorides, see: (a) Tamao, K.; Kodama, S.; Nakajima, I.; Kumada, M.;
Minato, A.; Suzuki, K. Tetrahedron 1982, 38, 3354. (b) Lin, S.-Y.; Sheng,
H.-Y.; Haung, Y.-Z. Synthesis 1991, 235. (c) Faust, R.; Gobelt, B.
Tetrahedron Lett. 1997, 38, 8071.
(10) (a) Kobayashi, K.; Uneda, T.; Takada, K.; Tanaka, H.; Kitamura,
T.; Morikawa, O.; Konishi, H. J. Org. Chem. 1997, 62, 664. (b) Beaton,
H.; Hamley, P.; Tinker, A. C. Tetrahedron Lett. 1998, 39, 1227. (c) Bunce,
R. A.; Johnson, L. B. Org. Prep. Proc. Int. 1999, 31, 407.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for compounds 5-17. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(11) Srebnik, M.; Mechoulan, R.; Yona, I. J. Chem. Soc. 1957, 1946.
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