A one-pot bicycloannulation method for the synthesis of tetrahydroisoquinoline systems

Article abstract of DOI:10.1021/jo991742h

A highly effective method for the synthesis of the core indolo[2,3- α]quinolizidine skeleton found in yohimbine is described. The reaction of N- monosubstituted thioamides with bromoalkenoyl chlorides furnishes thioisomunchnones as transient 1,3-dipoles that undergo ready intramolecular cycloaddition across the tethered π-bond to give thio-bicycloannulated products in a one-pot operation. The stereochemical outcome of the intramolecular reaction is the consequence of an endo cycloaddition of the neighboring π-bond across the transient thioisomunchnone dipole. A major limitation of the method is that when a hydrogen is present in the α- position of the thioamide the initially formed thio-N-acyliminium ion undergoes proton loss to produce a S,N-ketene acetal at a faster rate than dipole formation. Treatment of tetrahydro-β-carboline-1-thione with 2- bromooct-7-enoyl chloride followed by reductive removal of sulfur from the cycloadduct resulted in the formation of (±)-alloyohimbanone. Attempts to cycloadd the thioisomunchnone dipole across several nucleophilic π-bonds failed, and instead, products derived from cyclization of the π-bond onto the initially formed thio-N-acyliminium ion were formed. The resulting N,S- ketals were further converted into several tetrahydroisoquinoline alkaloids in good yield.

Full text of DOI:10.1021/jo991742h

2684
J . Org. Chem. 2000, 65, 2684-2695
A On e-P ot Bicycloa n n u la tion Meth od for th e Syn th esis of
Tetr a h yd r oisoqu in olin e System s
Albert Padwa,* L. Scott Beall,† Todd M. Heidelbaugh, Bing Liu, and Scott M. Sheehan
Department of Chemistry, Emory University, Atlanta, Georgia 30322
Received November 10, 1999
A highly effective method for the synthesis of the core indolo[2,3-a]quinolizidine skeleton found in
yohimbine is described. The reaction of N-monosubstituted thioamides with bromoalkenoyl chlorides
furnishes thioisomu¨nchnones as transient 1,3-dipoles that undergo ready intramolecular cycload-
dition across the tethered π-bond to give thio-bicycloannulated products in a one-pot operation.
The stereochemical outcome of the intramolecular reaction is the consequence of an endo
cycloaddition of the neighboring π-bond across the transient thioisomu¨nchnone dipole. A major
limitation of the method is that when a hydrogen is present in the R-position of the thioamide the
initially formed thio-N-acyliminium ion undergoes proton loss to produce a S,N-ketene acetal at a
faster rate than dipole formation. Treatment of tetrahydro-â-carboline-1-thione with 2-bromooct-
7-enoyl chloride followed by reductive removal of sulfur from the cycloadduct resulted in the
formation of (()-alloyohimbanone. Attempts to cycloadd the thioisomu¨nchnone dipole across several
nucleophilic π-bonds failed, and instead, products derived from cyclization of the π-bond onto the
initially formed thio-N-acyliminium ion were formed. The resulting N,S-ketals were further
converted into several tetrahydroisoquinoline alkaloids in good yield.
Mesoionic compounds have been known for many years
and triple-bond dipolarophiles. Mu¨nchnones (2) are gen-
erally prepared by cyclodehydration of N-acylamino acids
with reagents such as acetic anhydride.18 The Rh(II)-
catalyzed reaction of diazo imides, on the other hand,
represents the most effective method for the preparation
of isomu¨nchnones (4) (Scheme 1).19
and have been extensively utilized as substrates for 1,3-
dipolar cycloaddition chemistry.1-8 The term mesoionic
is generally restricted to five-membered heterocycles that
cannot be represented satisfactorily by normal covalent
structures and are best described as a resonance hybrid
of all possible charged forms.9,10 The peculiar structure
and reactivity of such heterocycles continue to receive
considerable attention, especially since these mesoionic
compounds have been utilized as effective synthons in
natural product synthesis.11 Perhaps the two most ex-
tensively studied mesoionic heterocycles are the
mu¨nchnones12-15 and isomu¨nchnones.16,17 These masked
1,3-dipoles readily react with a wide variety of double
Over the past several years, we have become interested
in the cycloaddition chemistry of the closely related
thioisomu¨nchnone system (7). This mesoionic betaine
contains a thiocarbonyl ylide dipole within its backbone
and is easily prepared by reaction of N-monosubstituted
thioamides with R-haloacyl halides in the presence of
Et3N (Scheme 1).20 Despite the considerable amount of
research dealing with the chemistry of thioisomu¨nch-
nones, the range of their structural variation has re-
mained somewhat narrow.21 In most of the cases studied,
at least one of the substituent groups is an aryl moiety,
presumably due to electronic stabilization of the dipole
to a sufficient degree to allow for its ready formation and
occasional isolation.21,22 To broaden the utility of this
particular class of mesoionic betaines for natural product
synthesis, we decided to investigate the reactivity of
systems where the peripheral substituents were of the
† L.S.B. is pleased to acknowledge the National Institute of Health
for a postdoctoral fellowship (CA 74500-01A1).
(1) Padwa, A. In 1,3-Dipolar Cycloaddition Chemistry; Wiley-
Interscience: New York, 1984; Vols. 1 and 2.
(2) Schoffstall, A. M.; Padwa, A. In Advances in Cycloaddition;
Curran, D. P., Ed.; J AI Press: Greenwich, CT, 1990; Vol. 2, p 1.
(3) Potts, K. T. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A.,
Ed.; Wiley-Interscience: New York, 1984.
(4) Ohta, M.; Kato, H. In Nonbenzenoid Aromatics; Snyder, J . P.,
Ed.; Academic Press: New York, 1969; pp 117-248.
(5) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 633.
(6) Ollis, W. D.; Ramsden, C. A. In Advances in Heterocyclic
Chemistry; Katritzky, A. R., Boulton, A. J ., Eds.; Academic Press: New
York, 1976; Vol. 19, p 1. Ollis, W. D.; Stanforth, S. P.; Ramsden, C. A.
Tetrahedron 1985, 41, 2239.
(17) Padwa, A.; Marino, J . P., J r.; Osterhout, M. H. J . Org. Chem.
1995, 60, 2704. Padwa, A.; Hertzog, D. L.; Nadler, W. R. J . Org. Chem.
1994, 59, 7072. Marino, J . P., J r.; Osterhout, M. H.; Price, A. T.;
Semones, M. A.; Padwa, A. J . Org. Chem. 1994, 59, 5518. Hertzog, D.
L.; Austin, D. J .; Nadler, W. R.; Padwa, A. Tetrahedron Lett. 1992, 33,
4731.
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Compounds. Vol. 45: Oxazoles; Turchi, I. J ., Ed.; Wiley: New York,
1986; p 731.
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123.
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(13) Santiago; B.; Dalton, C. R.; Huber, E. W.; Kane, J . M. J . Org.
Chem. 1995, 60, 4947.
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(15) Turchi, I. J .; Dewar, M. J . S. Chem. Rev. 1975, 75, 389. Dewar,
M. J . S.; Turchi, I. J . J . Chem. Soc., Perkin Trans. 2, 1976, 548.
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chi, M.; Ibata, T. Chem. Lett. 1975, 499.
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Ed. Engl. 1964, 3, 135. Huisgen, R.; Gotthardt, H.; Bayer, H. O.;
Schaefer, F. C. Chem. Ber. 1970, 103, 2611.
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(20) Potts, K. T.; Chen, S. J .; Kane, J .; Marshall, J . L. J . Org. Chem.
1977, 42, 1633.
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Synthesis 1994, 993.
10.1021/jo991742h CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/06/2000

Synthesis of Tetrahydroisoquinoline Systems
J . Org. Chem., Vol. 65, No. 9, 2000 2685
Sch em e 1
Sch em e 2
Sch em e 3
alkyl rather than aryl variety. We were specifically
interested in using thioisomu¨nchnone dipolar-cycloaddi-
tion chemistry as a key strategy for the assemblage of
the core indolo[2,3-a]quinolizidine skeleton found in the
yohimbane alkaloids.23
Members of the yohimbane alkaloid family possess a
characteristic pentacyclic indole ring system and gener-
ally exhibit a wide range of important pharmacological
properties.24 Construction of the core indolo[2,3-a]quino-
lizidine skeleton found in yohimbine (8) has presented a
formidable challenge to synthetic organic chemistry, and
several elegant methods have been developed to achieve
this goal.25-28 Key synthetic elements in some of these
approaches have included Diels-Alder cycloaddition,29
radical cyclization,30 oxy-Cope31 and amino-Claisen rear-
rangements,32 and photocyclization pathways.33 A par-
ticularly viable strategy that has been extensively uti-
lized for the construction of the polycyclic framework of
the yohimbanes is to assemble appropriately function-
alized derivatives of indoloquinolizidine and to elaborate
them further into different target compounds (Scheme
2).25-28
hydroxides (thioisomu¨nchnones).22 We envisioned that
dipole 12, derived from the reaction of thioamide 13 and
R-bromo-acyl chloride 14, would readily undergo in-
tramolecular dipolar cycloaddition. Removal of the sulfur
atom from the resulting cycloadduct followed by amide
reduction should lead to alloyohimbane.34 In this paper,
we report in full the results of our studies that show that
the reaction of indolo N-substituted thioamides with
R-bromoacyl chlorides represents a convenient method
for the synthesis of indolo[2,3-a]quinolizidines and re-
lated tetrahydroisoquinolines.
The approach we had in mind (Scheme 3) for the
synthesis of the indolo[2,3-a]quinolizidine skeleton was
based on our previous success involving the reaction of
2-substituted thiolactams with R-bromoacetyl chloride as
a method to generate anhydro-4-hydroxy-1,3-thiazolium
Resu lts a n d Discu ssion
The successful implementation of the strategy outlined
in Scheme 3 relied on the synthesis of the requisite
R-bromoacyl chloride 14. This compound and the related
homologous R-bromoacyl chloride 15 (n ) 1) were pre-
pared starting from aldehydo esters 16 and 17. Schreiber’s
ozonolysis protocol35 was used to form these terminally
differentiated aldehydic esters. Both of these compounds
were converted to the corresponding carboxylic acids 18
and 19 in good yield using a standard Wittig reaction
followed by alkaline saponification. Treatment of 18 and
19 with 2 equiv of LDA followed by reaction with carbon
tetrabromide and then oxalyl chloride according to the
Snider procedure36 delivered the desired R-bromoacyl
(23) Heidelbaugh, T. M.; Liu, B.; Padwa, A. Tetrahedron Lett. 1998,
39, 4757.
(24) Baxter, E. W.; Marino, P. S. In Alkaloids: Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; Springer-Verlag: New
York, 1992; Vol. 8, p 197.
(25) Winterfeldt, E. Fortschr. Chem. Org. Naturst. 1974, 30, 469.
(26) Do¨pke, W. The Alkaloids 1981, 20, 297.
(27) Waldmann, H.; Braun, M.; Weymann, M.; Gewehr, M. Tetra-
hedron 1993, 49, 397. Lock, R.; Waldmann, H. Liebigs Ann. Chem.
1994, 511.
(28) Kuehne, M. E.; Muth, R. S. J . Org. Chem. 1991, 56, 2701.
(29) Martin, S. F.; Grzejszczak, S.; Ruger, H.; Williamson, S. A. J .
Am. Chem. Soc. 1985, 107, 4072; 1987, 109, 6124.
(30) Stork, G. Pure Appl. Chem. 1989, 51, 439.
(31) Wender, P. A.; Schaus, J . M.; White, A. W. J . Am. Chem. Soc.
1980, 102, 6157; Heterocycles 1987, 25, 263.
(32) Baxter, E. W.; Labaree, D.; Ammon, H. L.; Mariano, P. S. J .
Am. Chem. Soc. 1990, 112, 7682.
(33) Pearlman, B. A. J . Am. Chem. Soc. 1979, 101, 6398, 6404.
Miyata, O.; Hirata, Y.; Naifo, T.; Ninomiya, I. Heterocycles 1984, 22,
1041.
(34) Wenkert, E.; Chang, C. J .; Chawla, H. P. S.; Cochran, D. W.;
Hagaman, E. W.; King, J . C.; Orito, K. J . Am. Chem. Soc. 1976, 98,
3645.
(35) Claus, R. E.; Schreiber, S. L. Organic Syntheses; Wiley: New
York, 1990; Collect. Vol. VII, p 168.

2686 J . Org. Chem., Vol. 65, No. 9, 2000
Padwa et al.
Sch em e 4a
Sch em e 5
Sch em e 6
aReagents: (a) Ph3PdCH2; (b) KOH/MeOH; (c) LDA/CBr4; (d)
(COCl)2.
chlorides 14 and 15 in 54% and 70% yield, respectively.
To test the viability of Scheme 3 as an entry into the
yohimbane skeleton, we decided to first examine the
intramolecular cycloaddition reaction of the thioiso-
mu¨nchnone dipoles generated by treating these R-bro-
moalkenoyl chlorides with simple cyclic thioamides. We
were gratified to discover that the reaction of thioamides
20 and 21 with R-bromoacyl chloride 15 and triethy-
lamine (1.5 equiv) in toluene at 110 °C resulted in the
formation of cycloadducts 22 and 23 in 67% and 74%
yield, respectively (Scheme 4). The depicted stereochem-
istry is the result of endo cycloaddition with regard to
the dipole. This assignment is based on our related work
dealing with intramolecular isomu¨nchnone cycloaddition
chemistry, for which X-ray crystallographic analysis had
been performed.37 When a hydrogen atom is present in
the R-position of the thioamide (i.e., 24), the initially
formed N-acyliminium ion undergoes proton loss (vide
infra) to produce the S,N-acetal 25 at a faster rate than
thioisomu¨nchnone formation.
Given the success in forming intramolecular thioiso-
mu¨nchnone cycloadducts, it seemed to us that selective
modification of the cycloadduct skeleton would allow
application of the method toward the synthesis of more
complex polyheterocyclic systems. In particular, a clean
reductive cleavage of the sulfur bridge is necessary if the
method is to be useful for the preparation of various ring
skeletons found in the alkaloid kingdom. Raney nickel
seemed to be an ideal reagent to induce this reduction,
since it has been extensively utilized for desulfurization
chemistry.38 Tri-n-(butyl)tin hydride is also known to be
an effective and selective reducing agent for various
unsymmetric sulfides.39 We found that cycloadduct 26,
derived from the reaction of N-methylthiobenzamide with
acid chloride 15, gave the unsaturated lactam 28 upon
treatment with Raney nickel in ethanol.40 In contrast,
the reaction of 26 as well as the closely related cycload-
duct 27 (see the Experimental Section) with n-Bu3SnH
and AIBN afforded the saturated lactams 29 and 30 in
40
81% and 75% yield, respectively (Scheme 5).
The above results clearly demonstrate that this two-
step sequence involving an intramolecular 1,3-dipolar
cycloaddition of a thioisomu¨nchnone dipole followed by
desulfurization constitutes a simple and straightforward
route for the preparation of various azapolycyclic rings.
The facility of the process prompted us to use the method
for the preparation of alloyohimbane (11) as outlined in
Scheme 3. Treatment of the unprotected thiocarboline 31
with R-bromoacyl chlorides 14 and 15 afforded cycload-
ducts 33 and 32 in 75% and 62% yield, respectively
(Scheme 6). Raney-Ni reduction of 32 gave the pentacyclic
analogue 34 in 85% yield as the major diastereomer.40
A
short synthesis of (()-alloyohimbane (11) was achieved
in 42% yield by subjecting cycloadduct 33 to the Raney-
Ni conditions followed by further reduction using lithium
aluminum hydride. We also examined the cycloaddition
chemistry of thioamide 31 with R-bromoacyl chloride 35,
since this would allow for the introduction of oxygen
functionality onto the E-ring of the yohimbine skeleton
(e.g., 8).
(36) Snider, B. B.; Kulkarni, Y. S. J . Org. Chem. 1987, 52, 307.
(37) Padwa, A.; Hertzog, D. L.; Nadler, W. R.; Osterhout, M. H.;
Price, A. T. J . Org. Chem. 1994, 59, 1418.
(38) Luh, T. Y.; Ni, Z. J . Synthesis 1990, 89. Ho, K. M.; Lam, C. H.;
Luh, T. Y. J . Org. Chem. 1989, 54, 4474. Alper, H.; Blais, C. J . Chem.
Soc., Chem. Commun. 1980, 169. Pettit, G. R.; van Tamelen, E. E. Org.
React. 1962, 12, 356.
(39) Gutierrez, C. G.; Summerhays, L. R. J . Org. Chem. 1984, 49,
5206.
(40) The relative stereochemistry drawn is assumed and is primarily
based on the fact that the cis-ring junction is lower in energy according
to molecular mechanics calculations.

Synthesis of Tetrahydroisoquinoline Systems
J . Org. Chem., Vol. 65, No. 9, 2000 2687
Sch em e 7
Sch em e 9
π-cyclizations despite the ease with which they can be
formed.41 It is well-known that carbon-carbon bond-
forming reactions involving N-acyliminium ions play an
extremely important role in the synthesis of many
nitrogen heterocycles.42 These cyclizations have been
utilized as the key step in the preparation of several
different alkaloid families, including the tetrahydroiso-
quinoline, â-carboline, and lycopodium classes.43 By
incorporating an activated π-nucleophile as a tether on
the thioamide, cyclization followed by further manipula-
tion of the resulting S,N-ketal (i.e., 39) would also allow
for the construction of the skeletal framework of several
classes of alkaloids. We specifically thought it worthwhile
to examine the behavior of thioamides such as 41 that
contain a tethered indolo ring since this particular system
could react by either of two pathways (Scheme 9).
Cycloaddition of the thioisomu¨nchone dipole derived from
41 across the pendant indole π-system44 would represent
an attractive route toward the pentacyclic skeleton found
in the eburnamnine alkaloids.45 On the other hand, the
latent enamine functionality contained within the electron-
rich heteroaromatic ring could also undergo π-cyclization
with the initially formed thio N-acyliminium ion 42 prior
to the deprotonation step. In fact, we observed that when
thiolactam 41 was subjected to the standard conditions
used for dipole formation, no product derived from
thioisomu¨nchnone cycloaddition across the indole π-bond
could be detected in the reaction mixture. Instead, S,N-
ketal 43 was isolated in 85% yield. Compound 43 is
derived by cyclization of the dipole precursor 42 onto the
2-position of the indole ring. Apparently, attack by the
nucleophilic π-bond of the indolo ring onto the N-
acyliminium ion present in intermediate 42 occurs at a
Sch em e 8
Indeed, when this reaction was carried out in the
presence of NEt3, cycloadduct 36 was isolated in 57%
yield. The assignment of stereochemistry was based
(NMR) on related substrates previously synthesized in
these laboratories.17 As was the case with related iso-
mu¨nchnone cycloadditions, formation of the dipolar cy-
cloadduct is the consequence of endo-cycloaddition with
respect to the thiocarbonyl ylide dipole.17 This is in accord
with molecular mechanics calculations, which show a
large ground-state energy difference between the two
diastereomers. We assume that the benzyloxy group is
syn to the thio-bridge as this would place this substituent
in the less sterically demanding equatorial position.
Raney-nickel reduction resulted in the formation of the
unsaturated lactam 37 as a 2:1 mixture of diastereomers
(Scheme 7). The two diastereomers of 37 could be
interconverted by stirring in a basic methanolic solution.
The above studies suggest that formation of the thioi-
somu¨nchnone dipole from the reaction of N-monosubsti-
tuted thioamides with R-bromoacyl chlorides proceeds by
the initial formation of a thio N-acyliminium ion (i.e., 38).
Proton abstraction from the activated R-position occurs
readily in the presence of base to furnish the mesoionic
betaine 40, which undergoes subsequent dipolar cycload-
dition with the available π-bond (Scheme 8). Thio N-
acyliminium ions such as 38 have received very little
attention as potential electrophilic partners in cation
(41) Sheehan, S. M.; Beall, L. S.; Padwa, A. Tetrahedron Lett. 1998,
39, 4761.
(42) Hiemstra, H.; Speckamp, W. N. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991;
Vol. 2, p 1047. Hiemstra, H.; Speckamp, W. N. In The Alkaloids; Brossi,
A., Ed.; Academic Press: New York, 1988; Vol. 32, p 271. Hart, D. J .
In Alkaloids; Chemical and Biological Perspectives; Pelletier, S. W.,
Ed.; Wiley: New York, 1988; Vol. 6, p 227.
(43) Kametani, T.; Fukumoto, K. The Chemistry of Heterocyclic
Compounds, Isoquinoline Part 1; Grethe, G., Ed.; Wiley: New York; p
170. J ones, G. Comprehensive Heterocyclic Chemistry; Katritzky, A.
R., Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 2, p 438.
(44) For some examples involving 4 + 2-cycloaddition across an
indolo π-bond, see: Dehaen, W.; Hassner, A. J . Org. Chem. 1991, 56,
896. Padwa, A.; Price, A. T. J . Org. Chem. 1998, 63, 556. Benson, S.
C.; Lee, L.; Snyder, J . K. Tetrahedron Lett. 1996, 37, 5061. Wan, Z.
K.; Snyder, J . K. Tetrahedron Lett. 1998, 39, 2487.
(45) Lounasmaa, M.; Tolvanen, A. In The Alkaloids; Cordell, G. A.,
Ed.; Academic Press: New York, 1992; Vol. 42, p 1. Taylor, W. I. The
Alkaloids 1968, 11, 125.

2688 J . Org. Chem., Vol. 65, No. 9, 2000
Padwa et al.
Sch em e 10
Sch em e 11
tion of the iminium ion onto the tethered aromatic ring.
With this system, loss of a proton to give 55 also competes
with π-cyclization since the attacking aromatic ring is
not highly activated toward electrophilic substitution as
was the case with thioamides 41, 45, and 46. In a closely
related process, the reaction of the dimethyloctenyl
substituted thioamide 56 with bromoacetyl chloride
furnished iminium ion 57, and this was followed by
consecutive cyclization and deprotonation to give S,N-
ketal 58 in 63% yield. Unfortunately, all of our attempts
to induce cyclization with a 1,1-disubstituted alkene such
as 59 under a variety of conditions failed to produce any
characterizable products.
As an extension of these studies, the reaction of
thioamide 60 with bromoacetyl chloride was investigated
so as to evaluate the effect of placing an electron-rich
aromatic ring on the thioamide functionality. The pres-
ence of an aryl group possessing an electron-donating
substituent positioned para to the thio-N-acyliminium ion
not only allows for cation stabilization by extended charge
delocalization but also creates additional sites for cy-
clization. This reaction proved to be an extremely efficient
one affording phenanthridine 62 in 77% yield. Desulfu-
rization of 62 with Raney-nickel gave the acetylated
phenanthridine 63 in 83% yield (Scheme 12).
Given the success of this cyclization method for forming
the phenanthridine skeleton, it seemed to us that this
sequence of reactions could also be used for the synthesis
of various isoquinoline ring systems. The tetrahydroiso-
quinoline skeleton is widely represented in many plant
families and provides a challenging target for synthesis.47
The great majority of the published syntheses are
plagued by the harsh experimental conditions necessary
for ring closure that limit their use with precursor
compounds containing sensitive functional groups.48 The
π-cyclization procedure outlined in VIII represents an
efficient and mild approach toward this important class
of nitrogen heterocycles. To highlight this new strategy,
the synthesis of the alkaloid salsolidine (67) was carried
out. When thioamide 64 was treated with bromoacetyl
faster rate than dipole formation even in the presence of
triethylamine. By taking advantage of the newly formed
and highly functionalized S,N-ketal 43, we were able to
indirectly effect the desired 1,3-dipolar cycloaddition in
a stepwise fashion. Thus, oxidation of 43 to the corre-
sponding sulfoxide followed by a Pummerer-induced
cyclization46 gave the thio-bridged compound 44 in 65%
overall yield. Compound 44 is formally the product
derived from cycloaddition of a thioisomu¨nchnone across
the indole π-bond but in a higher oxidation state.
To further study the N-acyliminium ion generation/
π-cyclization sequence, both the five- (45) and six-
membered (46) cyclic thiolactams containing a 3,4-
dimethoxyphenethyl tether were prepared. In the absence
of Et3N, treatment of either 45 or 46 with bromoacetyl
chloride provided the cyclized S,N-ketals 47 or 48 in 88%
and 95% yields, respectively. Reductive cleavage of the
sulfur bridge using Raney nickel gave imine 51 (91%)
starting from 47 and amine 52 (90%) when S,N-ketal 48
was used. Both products can be rationalized by sulfur
atom extrusion to first produce the N-acetylated iminium
ions 49 and 50. Deacylation of 49 provides 51, whereas
the deacylation reaction of 50 was followed by further
air oxidation to form the fully aromatic tetrahydroiso-
quinoline 52 (Scheme 10).
So that a cross section of additional information could
be obtained in regard to the cationic π-cyclization step,
a series of N-monosubstituted thioamides containing a
variety of different π-bonds were required. Compounds
ranging from simple aromatics to alkenyl tethered sys-
tems were considered. Ultimately, substrates 53, 56, and
59 were studied as these thioamides contain easily
attainable π-bond functionality (Scheme 11). Treatment
of 2-phenethylpiperidine-2-thione (53) with bromoacetyl
chloride afforded a 2:1 mixture of N,S-ketal 54 and
thiazolo[3,2-a]pyridone 55. These two products are de-
rived from competitive pathways of the initially formed
thio N-acyliminium ion. Ketal 54 comes about by cycliza-
(47) Shamma, M. The Isoquinoline Alkaloids; Academic Press: New
York, 1978. Lundstrom, J . In The Alkaloids; Brossi, A., Ed.; Academic
Press: New York, 1983; Vol. 21, p 255.
(46) Padwa, A.; Gunn, D. E.; Osterhout, M. H. Synthesis 1997, 1353.
(48) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41, 4367.

Synthesis of Tetrahydroisoquinoline Systems
J . Org. Chem., Vol. 65, No. 9, 2000 2689
Sch em e 12
Sch em e 14
Sch em e 13
In summary, we have shown that a range of novel
heterocyclic compounds can be rapidly and convergently
assembled from the reaction of N-monosubstituted thioa-
mides with bromoalkenoyl chlorides. Intramolecular
dipolar cycloaddition of the thioisomu¨nchnone dipole
followed by desulfurization results in the formation of a
structurally diverse group of heterocyclic compounds.
Thio-N-acyliminium ions have also been generated from
the reaction of thioamides with bromoacetyl chloride. In
the presence of tethered π-nucleophiles, cyclization occurs
to produce S,N-ketals which can be further converted into
various alkaloid skeletons. We are continuing to explore
the synthetic applications of thioisomu¨nchnone cycload-
dition chemistry and will report additional findings at a
later date.
chloride, the cyclized S,N-ketal 65 was obtained in 98%
yield. Removal of the sulfur atom with Raney nickel gave
66 (71%) (Scheme 13).
This sequence represents a formal synthesis of (()-
salsolidine (67), since compound 66 had been previously
hydrogenated in an enantioselective manner and then
deacetylated to produce salsolidine.49
The successful synthesis of the salsolidine precursor
66 by the thio N-acyliminium ion cyclization route
prompted us to use a similar method for the preparation
of the alkaloid tetrahydropapaverine (72).49 In this case,
the reaction of thioamide 68 with bromoacetyl chloride
in refluxing toluene provided the S,N-ketene acetal 69
as the exclusive product in 84% yield (Scheme 14).
Having the double bond in conjugation with the aromatic
ring undoubtedly facilitates deprotonation of the initially
formed thio-N-acyliminium ion. We found, however, that
treatment of 69 with trifluoroacetic acid at 25 °C induced
a Mondon-type cationic cyclization50 to give the desired
N,S-ketal 70 in 93% yield. Raney-nickel reduction of 70
furnished N-acyltetrahydropapaveroline 71 in 68% yield.
Deacetylation of 71 according to the procedure of Kita-
mura and co-workers afforded tetrahydropapaverine
(72).49
Exp er im en ta l Section
Melting points are uncorrected. Mass spectra were deter-
mined at an ionizing voltage of 70 eV. Unless otherwise noted,
all reactions were performed in flame dried glassware under
an atmosphere of dry argon. Solutions were evaporated under
reduced pressure with a rotary evaporator and the residue was
chromatographed on
a silica gel column using an ethyl
acetate-hexane mixture as the eluent unless specified other-
wise. Solid samples were recrystallized from an ethyl acetate/
hexane solvent combination unless specified.
2-Br om ooct-7-en oic Ch lor id e (14). A mixture of 2.2 g (15
mmol) of 7-octenoic acid (18)36 and 10 mL of HMPA in 50 mL
of THF at -10 °C was treated with 70 mL of a 0.5 M LDA
solution in THF. After being stirred for 2 h at -10 °C, the
mixture was cooled to -78 °C and was treated with a solution
of 12 g (35 mmol) of carbon tetrabromide in 3 mL of THF. The
solution was allowed to warm to room temperature over 1 h,
and stirring was continued for an additional 1 h at room
temperature. The solution was quenched with brine and
acidified with 2 N HCl, and the product was extracted with
ether. The combined extracts were dried over magnesium
sulfate and concentrated under reduced pressure. Chroma-
tography of the residue on silica gel afforded 2.2 g (64%) of
2-bromooct-7-enoic acid, which was immediately used in the
next step.
(49) Kitamura, M.; Hsiao, Y.; Ohta, M.; Tsukamoto, M.; Ohta, T.;
Takaya, H.; Noyori, R. J . Org. Chem. 1994, 59, 297.
(50) Mondon, A.; Hansen, K. F.; Boehme, K.; Faro, H. P.; Nestler,
H. J .; Vilhuber, H. G.; Bo¨ttcher, K. Chem. Ber. 1970, 103, 615. Mondon,
A.; Seidel, P. R. Chem. Ber. 1971, 104, 2937. Mondon, A.; Nestler, H.
J . Chem. Ber. 1979, 112, 1329.
To a solution of 2.2 g (10 mmol) of the above acid in 20 mL
of benzene was added 7.9 mL (16 mmol) of oxalyl chloride (2.0
M solution in CH2Cl2) followed by a drop of DMF. After the

2690 J . Org. Chem., Vol. 65, No. 9, 2000
Padwa et al.
mixture was stirred for 2 h at room temperature, the solvent
was removed under reduced pressure to give 2.2 g (85%) of 14
as a pale yellow oil that was sufficiently pure to be used in
the next step without further purification: IR (neat) 2930,
2856, 1777, 1455, and 912 cm-1; 1H NMR (CDCl3, 300 MHz) δ
1.35-1.99 (m, 4H), 2.01-2.05 (m, 4H), 4.41 (t, 1H, J ) 6.7
Hz), 4.86-4.95 (m, 2H), and 5.64-5.73 (m, 1H); 13C NMR
(CDCl3, 75 MHz) δ 26.2, 27.9, 33.2, 34.6, 54.0, 115.0, 137.9,
and 170.1. Anal. Calcd for C8H12OBrCl: C, 40.34; H, 5.05.
Found: C, 40.15; H, 5.02.
2-Br om oh ep t-6-en oyl Ch lor id e (15). A mixture of 3.0 g
(23 mmol) of 6-heptenoic acid (19)36 and 1 mL of HMPA in 50
mL of THF at -10 °C was treated with 100 mL of a 0.5 M
LDA solution in THF. After being stirred for 2 h at -10 °C,
the mixture was cooled to -78 °C and was treated with a
solution of 18 g (54 mmol) of carbon tetrabromide in 3 mL of
THF. The solution was allowed to warm to room temperature
over 1 h, and stirring was continued for an additional 1 h at
room temperature. The solution was quenched with brine and
acidified with 2 N HCl, and the product was extracted with
ether. The combined extracts were dried over magnesium
sulfate and concentrated under reduced pressure. Chroma-
tography of the residue on silica gel followed by distillation at
110-115 °C (2 mm) gave 3.8 g (78%) of 2-bromohept-6-enoic
acid as a light yellow oil: IR (neat) 2923, 1710, 1422, 1281,
and 912 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.42-1.68 (m, 2H),
1.93-2.38 (m, 4H), 4.24 (t, 1H, J ) 7.6 Hz), 4.97-5.06 (m, 2H),
5.70-5.84 (m, 1H), and 10.10 (s, 1H); 13C NMR (CDCl3, 75
MHz) δ 25.8, 33.0, 45.4, 77.5, 115.0, 137.1, and 175.4. Anal.
Calcd for C7H11O2Br: C, 40.60; H, 5.35. Found: C, 40.48; H,
5.27.
34.9, 36.6, 36.7, 50.7, 72.2, 89.6, and 178.5. Anal. Calcd for
C14H21NOS: C, 66.89; H, 8.42; N, 5.57. Found: C, 66.81; H,
8.40; N, 5.57.
7-Meth yl-2-p en t-4-en yl-2,5,6-tr ih yd r oth ia p yr r olizin -3-
on e (25). To a stirred solution containing 0.1 g (1.0 mmol) of
3-methylpyrrolidine-2-thione (24)51 in 10 mL of toluene was
added 0.2 g (1.0 mmol) of acid chloride 15 at room temperature.
After being stirred for 10 min at room temperature, the
mixture was heated at 110 °C for 45 min. A 0.3 mL (2.0 mmol)
sample of triethylamine was added, and the reaction mixture
was heated at reflux for an additional 30 min. The solvent was
removed under reduced pressure, and the residue was sub-
jected to flash silica gel chromatography to give 0.18 g (80%)
of 25 as a light yellow oil: IR (neat) 3069, 2920, 1689, 1423,
1
and 1126 cm-1; H NMR (CDCl3, 300 MHz) δ 1.34-1.53 (m,
4H), 1.56 (s, 3H), 1.70-1.83 (m, 1H), 1.97-2.09 (m, 3H), 2.77
(t, 1H, J ) 8.6 Hz), 3.64 (t, 1H, J ) 8.6 Hz), 4.26-4.30 (m,
1H), 4.88-4.97 (m, 2H) and 5.64-5.76 (m, 1H); 13C NMR
(CDCl3, 75 MHz) δ 11.7, 25.8, 33.0, 33.4, 36.8, 41.5, 55.9, 106.5,
114.9, 129.8, 137.7, and 167.1. Anal. Calcd for C12H17NOS: C,
64.54; H, 7.68; N, 6.28. Found: C, 64.43; H, 7.61; N, 6.12.
8-Meth yl-7-ph en yl-10-th ia-8-azatr icyclo[5.2.1.01,5]decan -
9-on e (26). To a solution of 0.05 g (0.3 mmol) of N-methylth-
iobenzamide in 5 mL of toluene was added 0.08 g (0.4 mmol)
of acid chloride 15 at room temperature under N2. The reaction
mixture was stirred at room temperature for 30 min and
heated at 90 °C for 1 h, and then 0.07 g (0.7 mmol) of
triethylamine was added. The mixture was heated at reflux
for an additional 2 h, cooled to room temperature, concentrated
under reduced pressure, and chromatographed on a silica gel
column to give 0.05 g (53%) of cycloadduct 26 as a white solid:
mp 99-100 °C; IR (neat) 1700, 1448, 1360, and 1035 cm-1; 1H
NMR (CDCl3, 400 MHz) δ 1.77-1.87 (m, 1H), 1.99-2.16 (m,
4H), 2.32-2.39 (m, 1H), 2.42 (s, 3H), 2.48-2.62 (m, 3H), and
7.38-7.53 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ 23.6, 26.1,
27.6, 31.6, 40.9, 50.1, 74.1, 84.2, 128.5, 128.6, 129.2, 134.7, and
176.5. Anal. Calcd for C15H17NOS: C, 69.46; H, 6.61; N, 5.40.
Found: C, 69.49; H, 6.64; N, 5.42.
To a solution of 0.9 g (4.3 mmol) of the above acid in 10 mL
of benzene was added 4.4 mL (8.7 mmol) of oxalyl chloride (2.0
M solution in CH2Cl2) followed by a drop of DMF. After the
mixture was stirred for 2 h at room temperature, the solvent
was removed under reduced pressure to give 0.9 g (90%) of
bromoacid chloride 15 as a clear oil that was sufficiently pure
to be used in the next step without further purification: IR
9-Me t h yl-8-p h e n yl-11-t h ia -9-a za t r icyclo[6.2.1.01,6]-
u n d eca n -10-on e (27). To a solution containing 0.05 g (0.3
mmol) of N-methylthiobenzamide in 10 mL of toluene was
added 0.1 g (0.4 mmol) of acid chloride 14 in 5 mL of toluene.
The mixture was stirred at 40 °C for 24 h, and then 0.09 g
(0.8 mmol) of triethylamine was added and the solution heated
at reflux for 2 h. The solvent was removed under reduced
pressure, and the residue was purified by silica gel chroma-
tography to give 0.05 g (52%) of 27 as a white solid: mp 94-
1
(neat) 2932, 1785, 1443, 990, and 915 cm-1; H NMR (CDCl3,
300 MHz) δ 1.40-1.55 (m, 2H), 1.93-2.15 (m, 4H), 4.42 (t,
1H, J ) 6.4 Hz), 4.90-4.99 (m, 2H), 5.63-5.72 (m, 1H); 13C
NMR (CDCl3, 75 MHz) δ 25.8, 32.6, 33.9, 53.9, 115.7, 137.0,
and 169.9.
5-Aza -2,2-d im e t h yl-13-t h ia t e t r a cyclo[5.5.1.01,5.07,11]-
tr id eca n -6-on e (22). To a stirred solution containing 0.2 g
(1.6 mmol) of thioamide 2022 in 20 mL of toluene was added
0.4 g (1.7 mmol) of acid chloride 15 at room temperature. After
being stirred for 15 min at room temperature, the mixture was
heated at 60 °C for 1 h. A 0.5 mL (3.5 mmol) sample of
triethylamine was added, and the reaction mixture was heated
at reflux for 1.5 h. The mixture was filtered, and the solvent
was removed under reduced pressure. The residue was sub-
jected to flash silica gel chromatography to give 0.25 g (67%)
of 22 as a white solid: mp 67-68 °C; IR (KBr) 2954, 1716,
1460, 1346, and 1203 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.09
(s, 3H), 1.13 (s, 3H) 1.68-2.14 (m, 9H), 2.28-2.36 (m, 1H),
2.46-2.49 (m, 1H), 3.10-3.20 (dt, 1H, J ) 7.5 and 4.3 Hz),
and 3.45-3.52 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 23.2, 24.3,
24.9, 26.1, 32.1, 39.8, 40.4, 41.0, 41.7, 48.4, 76.1, 94.1, and
178.2. Anal. Calcd for C13H19NOS: C, 65.78; H, 8.07; N, 5.90.
Found: C, 65.89; H, 8.04; N, 5.92.
95 °C; IR (neat) 1700, 1448, 1369, and 763 cm-1 1H NMR
;
(CDCl3, 400 MHz) δ 1.31-1.45 (m, 2H), 1.67-1.83 (m, 3H),
1.96-2.05 (m, 2H), 2.13-2.23 (m, 2H), 2.29-2.37 (m, 1H), 2.43
(s, 3H), 2.62 (dd, 1H, J ) 12 and 7.2 Hz), and 7.39-7.54 (m,
5H); 13C NMR (CDCl3, 100 MHz) δ 22.4, 25.6, 25.7, 27.2, 31.6,
41.2, 43.1, 66.5, 81.7, 128.5, 128.7, 129.2, 134.7, and 177.4.
Anal. Calcd for C16H19NOS: C, 70.29; H, 7.01; N, 5.12.
Found: C, 70.21; H, 7.00; N, 5.05.
3-Aza -3-m et h yl-4-p h en ylb icyclo[4.3.0]n on -4-en -2-on e
(28). A suspension of 1.2 g of Raney nickel in 10 mL of acteone
was heated at reflux for 2 h. After being cooled to room
temperature, the mixture was decanted, and 10 mL of ethanol
and 0.12 g (0.46 mmol) of cycloadduct 26 were added. The
resulting mixture was heated at reflux for 1 h, cooled to room
temperature, filtered through Celite, and concentrated under
reduced pressure. The residue was purified by silica gel
chromatography to give 0.08 g (80%) of 28 as a colorless oil:
6-Aza -2,2-d im e t h yl-14-t h ia t e t r a cyclo[6.5.1.01,6.08,12]-
tetr a d eca n -7-on e (23). A stirred solution of 0.14 g (1 mmol)
of thioamide 2122 in 20 mL of toluene was treated with 0.25 g
(1.1 mmol) of acid chloride 15 at room temperature. After being
stirred for 30 min, the mixture was heated at 90 °C for 1.5 h.
A 0.3 mL (2.2 mmol) sample of triethylamine was added, and
the mixture was heated at reflux for an additional 2 h. The
solvent was removed under reduced pressure, and the residue
was purified by silica gel chromatography to give 0.19 g (74%)
of 23 as a white solid: mp 90-92 °C; IR (KBr) 2948, 2859,
1702, 1442, and 1353 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.04
(s, 3H), 1.09 (s, 3H), 1.43-1.50 (m, 2H), 1.50-2.18 (m, 10H),
1
IR (neat) 1666, 1445, 1366, and 766 cm-1; H NMR (CDCl3,
400 MHz) δ 1.54-1.64 (m, 2H), 1.86-2.06 (m, 4H), 2.70 (q,
1H, J ) 8.4 Hz), 2.83 (s, 3H), 2.86-2.88 (m, 1H), 4.87 (dd, 1H,
J ) 3.2 and 0.8 Hz), 7.16-7.20 (m, 2H), and 7.26-7.31 (m,
3H); 13C NMR (CDCl3, 100 MHz) δ 23.1, 29.6, 32.3, 33.1, 37.3,
45.3, 112.0, 127.8, 128.1, 128.3, 136.6, 140.5, and 173.9; HRMS
calcd for C15H17NO 227.1310, found 227.1304.
3-Aza-3-m eth yl-4-ph en ylbicyclo[4.3.0]n on an -2-on e (29).
A solution containing 0.13 g (0.5 mmol) of cycloadduct 26, 0.44
2.32-2.45 (m, 2H), and 3.77 (dd, 1H, J ) 7.8 and 5.5 Hz); 13
NMR (CDCl3, 75 MHz) δ 19.2, 26.1, 26.4, 27.7, 31.1, 33.4, 34.8,
C
(51) Zhang, Z. J .; Padwa, A. Heterocycles 1994, 37, 41.

Synthesis of Tetrahydroisoquinoline Systems
J . Org. Chem., Vol. 65, No. 9, 2000 2691
g (1.5 mmol) of tributyltin hydride, and 0.05 g of AIBN in 10
mL of anhydrous toluene was heated at reflux for 24 h. The
mixture was cooled and concentrated under reduced pressure,
and the residue was chromatographed on silica gel to give 0.09
g (81%) of 29 as a white solid: mp 107-108 °C; IR (KBr) 1639,
1389, 1323, and 764 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.27-
1.37 (m, 1H), 1.48-1.85 (m, 6H), 2.22-2.34 (m, 2H), 2.59 (s,
3H), 2.66-2.69 (m, 1H), 4.31 (dd, 1H, J ) 11.4 and 4.0 Hz),
7.10-7.12 (m, 2H), 7.20-7.24 (m, 1H), and 7.26-7.30 (m, 2H);
13C NMR (CDCl3, 100 MHz) δ 22.7, 29.8, 31.8, 32.8, 35.8, 37.6,
45.9, 64.3, 126.1, 126.6, 127.7, 128.6, 128.8, 141.9, and 174.2.
Anal. Calcd for C15H19NO: C, 78.56; H, 8.36; N, 6.11. Found:
C, 78.50; H, 8.33; N, 6.05.
3-Aza -3-m eth yl-4-p h en ylbicyclo[4.4.0]d eca n -2-on e (30).
A solution containing 0.09 g (0.3 mmol) of cycloadduct 27, 0.3
mL (1.0 mmol) of tributyltin hydride, and 10 mg of AIBN in
10 mL of toluene was heated at reflux for 3 h. The mixture
was concentrated under reduced pressure, and the residue was
chromatographed on silica gel to give 0.06 g (75%) of 30 as a
white solid: mp 141-142 °C; IR (KBr) 1661, 1451, and 760
cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.00-1.88 (m, 10H), 1.99-
2.04 (m, 1H), 2.36-2.40 (m, 1H), 2.59 (s, 3H), 4.28 (dd, 1H, J
) 10.6 and 5.6 Hz), and 7.11-7.30 (m, 5H); 13C NMR (CDCl3,
100 MHz) δ 25.4, 26.1, 27.4, 32.9, 37.0, 41.7, 46.8, 64.2, 126.3,
127.6, 128.8, 142.8, and 173.1. Anal. Calcd for C16H21NO: C,
78.97; H, 8.70; N, 5.76. Found: C, 78.87; H, 8.77; N, 5.69.
removed under reduced pressure. Chromatography of the
residue on silica gel gave 0.12 g (85%) of 34 as a white solid:
mp 222-224 °C; IR (KBr) 1602, 1438 and 734 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 1.40-1.93 (m, 5H), 2.10-2.41 (m, 4H),
2.63-2.84 (m, 4H), 4.68 (d, 1H, J ) 7.5 Hz), 4.95 (d, 1H, J )
9.9 Hz), 6.96-7.06 (m, 2H), 7.26 (d, 1H, J ) 7.8 Hz), and 7.37
(d, 1H, J ) 7.8 Hz); 13C NMR (CDCl3, 75 MHz) δ 20.4, 22.4,
29.4, 31.9, 33.4, 34.4, 39.5, 45.1, 53.7, 107.4, 110.5, 117.4, 118.5,
121.0, 125.9, 132.9, 136.2 and 173.2. Anal. Calcd for
C
18H20N2O: C, 77.11; H, 7.19; N, 9.99. Found: C, 76.86; H,
7.20; N, 9.74.
(()-Alloyoh im ba n -21-on e. A 0.1 g (0.3 mmol) sample of
33 was treated with 0.8 g of Raney nickel in 50 mL of EtOH.
Standard workup afforded 0.08 g (90%) of (()-alloyohimban-
21-one53 as a white solid: mp 240-242 °C; IR (KBr) 3253,
2925, 1602, 1438, and 727 cm-1; 1H NMR (CDCl3, 400 MHz) δ
1.26-1.32 (m, 2H), 1.46-1.51 (m, 2H), 1.61-1.72 (m, 3H),
1.96-2.00 (m, 1H), 2.00-2.18 (m, 2H), 2.30 (dd, 1H, J ) 8.4
and 4.0 Hz), 2.56 (dt, 1H, J ) 11.8 and 5.2 Hz), 2.77-2.88 (m,
3H), 4.79 (t, 1H, J ) 8.0 Hz), 5.15 (dd, 1H, J ) 8.0 and 3.6
Hz), 7.14 (t, 1H, J ) 8.0 Hz), 7.19 (t, 1H, J ) 8.0 Hz), 7.35 (d,
1H, J ) 7.6 Hz), 7.51 (d, 1H, J ) 7.6 Hz), and 8.50 (s, 1H); 13
C
NMR (CDCl3, 100 MHz) δ 20.9, 21.1, 25.6, 26.4, 29.7, 30.1,
30.5, 40.1, 43.2, 54.1, 108.9, 110.9, 118.3, 119.7, 122.0, 126.7,
133.7, 136.2, and 172.9. Anal. Calcd for C19H22N2O: C, 77.51;
H, 7.54; N, 9.52. Found: C, 77.48; H, 7.50; N, 9.32. Reduction
of this amide with LAH according to the literature procedure53
gave (()-alloyohimbane (11) in 42% yield, whose spectral
properties were identical in all respects with those listed in
the literature.34
3,13-Dia za -21-t h ia h exa cyclo[13.5.1.01,13.02,10.04,9.015,19]-
h en icosa -2(10),4(9),5,7-tetr a en -14-on e (32). A mixture of
0.6 g (3.1 mmol) of thioamide 31 in 40 mL of toluene was
treated with 0.7 g (3.2 mmol) of acid chloride 15 at room
temperature. After being stirred for 15 min at room temper-
ature, the solution was heated at 100 °C for 1 h. The mixture
was treated with 0.5 mL (3.6 mmol) of triethylamine, and
heating was continued for an additional 1 h. The solvent was
removed under reduced pressure, and the residue was purified
by silica gel chromatography to give 0.64 g (62%) of 32 as a
light yellow solid: mp 225-226 °C; IR (KBr) 3274, 1680, 1452,
5-Ben zyloxy-7-octen oic Acid . To a solution containing 5.2
g (40 mmol) of methyl 5-oxohexanoate35 in 100 mL of CH2Cl2
was added 20 mL of a TiCl4 solution (1.0 M in CH2Cl2) at -78
°C, followed by dropwise addition of 6.3 mL (40 mmol) of
allyltrimethylsilane. After the addition was complete, the cold
bath was removed, and the solution was warmed to room
temperature and was stirred for 1 h. The mixture was poured
onto 100 g of ice, and the aqueous phase was extracted with
CH2Cl2. The combined organic phase was washed with brine,
dried over Na2SO4, and concentrated under reduced pressure
to give 3.7 g (66%) of 5-allyl-δ-valerolactone as a colorless oil
that was used in the next reaction without further purifica-
1
1403, and 727 cm-1; H NMR (CDCl3, 400 MHz) δ1.18-2.11
(m, 5H), 2.31-2.47 (m, 3H), 2.83-2.96 (m, 4H), 4.17 (dd, 1H,
J ) 6.7 and 1.5 Hz), 7.03 (t, 1H, J ) 7.0 Hz), 7.13 (t, 1H, J )
7.0 Hz), 7.30 (d, 1H, J ) 7.9 Hz), 7.45 (d, 1H, J ) 7.9 Hz), and
9.90 (brs, 1H); 13C NMR (CDCl3, 100 MHz) δ 22.1, 24.9, 27.1,
32.7, 32.8, 38.8, 46.3, 50.9, 77.0, 111.0, 112.4, 119.7, 120.7,
123.7, 127.1, 129.4, 137.8, and 176.7. Anal. Calcd for C18H18N2-
OS: C, 69.65; H, 5.85; N, 9.03. Found: C, 69.51; H, 5.64; N,
9.24.
tion: IR (neat) 1735, 1644, 1243 and 1047 cm-1 1H NMR
;
(CDCl3, 400 MHz) δ 1.41-1.50 (m, 1H), 1.74-1.88 (m, 3H),
2.25-2.53 (m, 4H), 4.25-4.30 (m, 1H), 5.02-5.09 (m, 2H), and
5.71-5.77 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 18.2, 27.0,
29.3, 39.8, 79.6, 118.4, 132.5, and 171.6.
3,13-Dia za -21-t h ia h exa cyclo[13.5.1.01,13.02,10.04,9.015,19]-
h en icosa 2(10),4(9),5,7-tetr a en -14-on e (33). To a stirred
solution of 0.19 g (1 mmol) of the known thioamide 3152 in 15
mL of toluene was added 0.26 g (1 mmol) of acid chloride 14
at room temperature. After being stirred for 15 min at room
temperature, the solution was heated at 100 °C for 1 h. To
this mixture was added 0.14 mL (1.0 mmol) of triethylamine,
and the solution was heated at reflux for an additional 2 h.
The solvent was removed under reduced pressure, and the
residue was purified by silica gel chromatography to give 0.24
g (75%) of cycloadduct 33 as a pale yellow solid: mp 200-201
A mixture containing 3.7 g (26 mmol) of the above lactone,
6.1 g (109 mmol) of KOH, and 7.5 mL (65 mmol) of benzyl
chloride in 100 mL of anhydrous toluene was heated at reflux
for 20 h. The reaction was quenched with 100 mL of water,
and the aqueous phase was washed twice with ether, acidified
with HCl, and extracted with ether. The ether extracts were
dried over Na2SO4 and concentrated under reduced pressure,
and the residue was purified by flash silica gel chromatography
to give 3.8 g (59%) of the title compound as a colorless oil: IR
(neat) 3568-2521 (br), 1710, 1641, and 738 cm-1 1H NMR
;
1
°C; IR (KBr) 1680, 1445, 1403, 1260, and 734 cm-1; H NMR
(CDCl3, 400 MHz) δ 1.55-1.82 (m, 4H), 2.30-2.39 (m, 4H),
3.46-3.48 (m, 1H), 4.49 (d, 1H, J ) 11.6 Hz), 4.59 (d, 1H, J )
11.6 Hz), 5.06-5.13 (m, 2H), 5.79-5.87 (m, 1H), and 7.26-
7.35 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ 20.5, 33.0, 33.9,
38.1, 70.9, 77.9, 117.2, 127.5, 127.7, 128.3, 134.5, 138.5, and
179.8; HRMS calcd for C15H20O3 248.1412, found 248.1411.
(CDCl3, 300 MHz) δ 1.37-1.46 (m, 2H), 1.73-1.83 (m, 3H),
1.99-2.34 (m, 5H), 2.44-2.50 (m, 1H), 2.93-3.96 (m, 3H),
4.23-4.28 (m, 1H), 7.16 (t, 1H, J ) 7.6 Hz), 7.25 (t, 1 H, J )
7.6 Hz), 7.38 (d, 1 H, J ) 7.9 Hz), 7.55 (d, 1H, J ) 7.9 Hz),
and 8.36 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 20.8, 22.5, 25.6,
25.9, 31.7, 37.3, 41.0, 47.9, 68.9, 73.5, 110.9, 111.3, 118.9, 120.1,
123.1, 128.4, 136.5, 150.0, and 175.8. Anal. Calcd for C19H20N2-
OS: C, 70.34; H, 6.22; N, 8.64. Found: C, 70.29; H, 6.34; N,
8.57.
10,20-Dia za p en ta cyclo[11.7.0.02,10.04,8.014,19]icosa -1(13),-
14(19),15,17-tetr a en -9-on e (34). A 0.15 g (0.50 mmol) sample
of cycloadduct 32 in 80 mL of ethanol was treated with 0.9 g
of W-2 Raney nickel for 15 min at 50 °C. The mixture was
filtered through a short pad of Celite, and the solvent was
2-Br om o-5-ben zyloxyoct-7-en oyl Ch lor id e (35). To a 3.7
g (15.0 mmol) sample of the above acid in 5 mL of THF and 5
mL of HMPA at -15 °C was added 30 mL of an LDA solution
(1.0 M in THF). After being stirred at -15 °C for 2 h, the
solution was cooled to -78 °C, and 12.6 g (38 mmol) of carbon
tetrabromide in 10 mL of THF was added. The resulting
mixture was stirred at -78 °C for 2 h and then quenched with
brine. The solution was acidified and filtered through a short
(53) Yamaguchi, R.; Hamasaki, T.; Sasaki, T.; Ohta, T.; Utimoto,
K.; Kozima, S.; Takaya, H. J . Org. Chem. 1993, 58, 1136.
(52) Abramovitch, R. A. J . Chem. Soc. 1956, 4589.

2692 J . Org. Chem., Vol. 65, No. 9, 2000
Padwa et al.
pad of Celite. The mixture was extracted with ether, dried over
Na2SO4, and concentrated under reduced pressure, and the
residue was purified by silica gel chromatography to give 3.0
g (60%) of 2-bromo-5-benzyloxy-7-octenoic acid as a pale oil:
IR (neat) 3592-2348 (br), 1717, 1641, and 738 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 1.60-2.44 (m, 6H), 3.49-3.52 (m, 1H),
4.22 (m, 1H), 4.47-4.62 (m, 2H), 5.09-5.15 (m, 2H), 5.79-
5.86 (m, 1H), 7.29-7.38 (m, 5H), and 8.66 (brs, 1H); 13C NMR
(CDCl3, 100 MHz) δ 30.5, 31.1, 37.9, 45.6, 65.3, 70.9, 117.6,
127.1, 127.8, 128.4, 134.1, 138.2, and 175.0; HRMS calcd for
NMR (CDCl3, 300 MHz) δ 1.40-1.53 (m, 1H), 1.63-1.88 (m,
3H), 2.15 (quin, 1H, J ) 7.5 Hz), 2.60-2.72 (m, 2H), 3.18-
3.27 (m, 2H), 4.37 (t, 2H, J ) 7.2 Hz), 6.52 (d, 1H, J ) 3.0
Hz), 7.09-7.25 (m, 2H), 7.21 (d, 1H, J ) 3.0 Hz), 7.45-7.48
(m, 1H), 7.63-7.66 (m, 1H), and 9.32 (s, 1H); 13C NMR (CDCl3,
75 MHz) δ 19.5, 25.6, 35.3, 43.7, 44.2, 44.3, 101.1, 109.0, 118.5,
120.7, 121.3, 127.6, 128.4, 135.8, and 205.5. Anal. Calcd for
C
15H18N2S: C, 69.72; H, 7.02; N, 10.84; S, 12.41. Found: C,
69.81; H, 7.02; N, 10.79; S, 12.51.
To a solution containing 0.2 g (0.8 mmol) of 41 in 20 mL of
dry CH2Cl2 was added 0.07 mL (0.9 mmol) of bromoacetyl
chloride under N2, and the mixture was stirred at 25 °C for
1.5 h. The solution was treated with 0.2 mL (1.5 mmol) of
triethylamine and heated at reflux for 2 h. The solution was
cooled to 25 °C, and the solvent was removed under reduced
pressure. The residue was subjected to flash silica gel chro-
matography to give 0.15 g (65%) of 43 as a white solid: mp
C
15H19BrO3 326.0518, found 326.0521.
A solution containing 2.9 g (8.9 mmol) of the above bro-
moacid and 1.2 mL (13 mmol) of oxalyl chloride in 40 mL of
benzene was heated at reflux for 2 h. The mixture was
concentrated under reduced pressure to give 3.0 g (99%) of 35
as a pale yellow oil that was immediately used in the next
step without further purification: IR (neat) 1783, 1641, 1451,
and 738 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.60-2.44 (m, 6H),
3.49-3.54 (m, 1H), 4.22 (m, 1H), 4.46-4.64 (m, 2H), 5.11-
5.16 (m, 2H), 5.81-5.86 (m, 1H), and 7.26-7.44 (m, 5H); 13C
NMR (CDCl3, 100 MHz) δ 30.6, 30.8, 37.8, 54.3, 70.3, 70.9,
117.6, 127.7, 128.3, 128.8, 133.9, 138.1, and 170.1.
1
151-152 °C; IR (neat) 1685, 1470, and 1410 cm-1; H NMR
(CDCl3, 300 MHz) δ 1.40 (dt, 1H, J ) 13.0 and 2.6 Hz), 1.50-
1.68 (m, 1H), 1.70-1.82 (m, 2H), 2.14 (dt, 1H, J ) 14.3 and
3.9 Hz), 2.30-2.42 (m, 1H), 2.48-2.62 (m, 1H), 2.81 (dt, 1H, J
) 12.5 and 3.1 Hz), 3.66 (d, 1H, J ) 15.6 Hz), 3.86 (d, 1H, J
) 15.6 Hz), 3.81-3.92 (m, 1H), 4.20-4.27 (m, 2H), 6.29 (s, 1H),
7.10-7.31 (m, 3H), and 7.55-7.58 (m, 1H); 13C NMR (CDCl3,
75 MHz) δ 24.3, 25.1, 25.6, 32.5, 37.7, 40.2, 42.3, 68.0, 97.3,
109.5, 120.5, 120.8, 122.0, 128.0, 136.9, 137.5, and 170.3. Anal.
Calcd for C17H18N2OS: C, 68.43; H, 6.08; N, 9.39; S, 10.73.
Found: C, 68.24; H, 6.08; N, 9.41; S, 10.82.
17-Ben zyloxy-3,19-epi-th ioyoh im ba n e (36). The reaction
of 1.0 g (5.0 mmol) of thioamide 31 and 1.7 g (5.0 mmol) of the
above acid chloride in the presence of 1 mL (7.2 mmol) of
triethylamine afforded 1.2 g (57%) of cycloadduct 36 as a pale
yellow solid after silica gel chromatography: mp 259-260 °C;
IR (KBr) 3280, 1679, 1398, and 735 cm-1 1H NMR (CDCl3,
;
400 MHz) δ 1.53-1.57 (m, 1H), 1.86-1.95 (m, 1H), 2.18-2.48
(m, 7H), 2.90-3.06 (m, 3H), 3.42-3.48 (m, 1H), 4.18-4.23 (m,
1H), 4.55-4.63 (AB, 2H, J ) 18.6 and 11.6 Hz), 7.13 (t, 1H, J
) 7.4 Hz), 7.20-7.37 (m, 7H), 7.51 (d, 1H, J ) 7.4 Hz), and
8.35 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 20.8, 24.0, 28.5,
37.4, 37.5, 40.8, 47.7, 67.9, 70.2, 73.9, 76.4, 110.8, 111.3, 118.8,
120.0, 123.1, 126.2, 127.7, 127.9, 128.4, 136.6, 138.3, and 175.3.
Anal. Calcd for C26H26N2O2S: C, 72.53; H, 6.09; N, 6.51.
Found: C, 72.38; H, 6.14; N, 6.42.
17-Ben zyloxy-3,14-d id eh yd r oyoh im ba n e (37). The reac-
tion of 0.3 g (0.7 mmol) of 36 with W-Raney nickel according
to the procedure used above afforded a mixture of two
stereoisomers. The minor diastereomer 37a contained 0.08 g
(27%) of a white solid: mp 257-258 °C; IR (KBr) 3304, 1641,
1394, 1221, and 738 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.24-
1.37 (m, 4H), 1.98-2.04 (m, 1H), 2.23-2.37 (m, 3H), 2.78-
2.82 (m, 1H), 2.85-2.90 (m, 1H), 3.09 (t, 1H, J ) 12.0 Hz),
3.37-3.42 (m, 1H), 4.53 (q, 2H, J ) 12.0 Hz), 4.92-4.97 (m,
1H), 5.23 (d, 1H, J ) 4.8 Hz), 7.04 (t, 1H, J ) 7.2 Hz), 7.15 (t,
1H, J ) 7.2 Hz), 7.21-7.31 (m, 6H), 7.44 (d, 1H, J ) 7.2 Hz)
and 8.07 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 20.7, 24.3, 31.4,
34.0, 38.0, 39.5, 44.6, 70.3, 76.5, 104.4, 111.0, 112.3, 119.0,
120.1, 123.6, 126.6, 127.5, 127.7, 128.4, 130.4, 137.1, 138.7,
and 171.3. Anal. Calcd for C26H26N2O2: C, 78.36; H, 6.58; N,
7.03. Found: C, 78.11; H, 6.46; N, 6.94.
The major diasteromer 37b contained 0.15 g (55%) of a clear
oil: IR (KBr) 3303, 1669, 1641, 1401, 1227, and 741 cm-1; 1H
NMR (CDCl3, 400 MHz) δ 1.31-1.41 (m, 2H), 1.48-1.58 (m,
1H), 1.84-1.94 (m, 2H), 2.44-2.48 (m, 2H), 2.61 (q, 1H, J )
4.8 Hz), 2.75-2.86 (m, 2H), 3.33-3.43 (m, 2H), 4.46 (q, 2H, J
) 12.0 Hz), 4.61 (brs, 1H), 5.45 (d, 1H, J ) 7.0 Hz), 7.03 (dt,
1H, J ) 8.0 and 0.8 Hz), 7.11-7.27 (m, 7H), 7.42 (d, 1H, J )
8.0 Hz), and 8.20 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 20.6,
22.6, 28.5, 31.7, 34.1, 39.4, 40.8, 69.6, 76.0, 103.3, 110.9, 111.8,
118.9, 119.9, 123.4, 126.9, 127.4, 127.9, 128.3, 129.7, 137.1,
138.8, and 170.6; HRMS calcd for C26H26N2O2 398.1994, found
398.1995.
10,17-Diaza-20-th iah exacyclo[11.7.01,17.02,10.03,19.04,9]icosa-
2(3),4(9),5,7-tetr a en -18-on e (44). To a solution of 1.9 g (6.3
mmol) of N,S-ketal 43 in 45 mL of MeOH and 15 mL of dioxane
at 0 °C was added 1.8 g (8.2 mmol) of sodium periodate as a
solution in 20 mL of water. After being warmed to room
temperature, the mixture was allowed to stir for 24 h. Water
was added, and the mixture was extracted with chloroform.
The organic extracts were dried, and the solvent was removed
under reduced pressure. Flash silica gel chromatography of
the residue gave 1.4 g (71%) of indolo[1,2-a]octahydro-1-
thiaoxy-3a-azacyclopenta[d]naphthylen-3-one as a pale yellow
solid: mp 179-181 °C; IR (KBr) 2926, 1684, 1059, and 749
cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.60-1.70 (m, 2H), 1.75-
1.80 (m, 1H), 1.90-1.95 (m, 1H), 2.17 (d, 1H, J ) 14.8 Hz),
2.54-2.69 (m, 2H), 2.75 (t, 1H, J ) 12.4 Hz), 3.38 (dd, 1H, J
) 4.4 and 17.2 Hz), 3.89-3.96 (m, 2H), 4.00-4.32 (m, 2H),
6.25 (s, 1H), 7.15 (t, 1H, J ) 8.0 Hz), 7.28 (t, 1H, J ) 8.4 Hz),
7.34 (d, 1H, J ) 8.4 Hz), and 7.54 (d, 1H, J ) 8.0 Hz); 13C
NMR (CDCl3, 100 MHz) δ 23.3, 24.4, 24.5, 29.5, 37.5, 40.3,
51.3, 79.9, 102.0, 109.7, 120.7, 120.8, 123.0, 127.3, 128.8, 137.7,
and 167.3. Anal. Calcd for C17H18N2O2S: C, 64.94; H, 5.77; N,
8.91. Found: C, 64.89; H, 5.79; N, 8.91
To a solution containing 5 mL (54 mmol) acetic anhydride
and 50 mg (0.3 mmol) of p-toluenesulfonic acid in 90 mL of
toluene at reflux was slowly added 0.85 g (2.7 mmol) of the
above sulfoxide. After being stirred for 1 h, the solution was
cooled to room temperature and the solvent was removed
under reduced pressure. The residue was purified by silica gel
chromato-graphy to give 0.7 g (92%) of 44 as a yellow solid:
mp 231-233 °C; IR (KBr) 2927, 1651, and 1140 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 1.91-1.96 (m, 2H), 2.39 (t, 2H, J ) 6.8
Hz), 2.61 (brs, 3H), 3.64 (brs, 2H), 4.00 (brs, 3H), 7.07-7.11
(m, 1H), 7.22-7.25 (m, 2H), and 7.45 (d, 1H, J ) 8.0 Hz); 13C
NMR (CDCl3, 100 MHz) δ 23.4, 29.1, 29.2, 38.0, 40.0, 42.8,
106.0, 108.9, 119.0, 119.9, 122.4, 123.3, 126.7, 126.9, 127.3,
135.5, and 169.6. Anal. Calcd for C17H16N2OS: C, 68.89; H,
5.44; N, 9.45. Found: C, 68.90; H, 5.48; N, 9.49.
P r ep a r a tion of In d olo[1,2-a ]-octa h yd r o-1-th ia -3a -a za -
cyclop en ta [d ]n a p h th ylen -3-on e (43). To a solution contain-
ing 3.0 g (12 mmol) of 3-(2-indol-1-yl)ethylpiperidin-2-one22 in
50 mL of toluene was added 2.5 g (6 mmol) of Lawesson’s
reagent, and the mixture was heated at reflux for 45 min. The
clear yellow solution was cooled to 25 °C, and the solvent was
removed under reduced pressure. The resulting residue was
subjected to flash silica gel chromatography to give 2.0 g (63%)
of 3-(2-indol-1-yl)ethylpiperidine-2-thione (41) as a light yellow
3-[2-(3,4-D i m e t h o x y p h e n y l)e t h y l]p y r r o li d i n e -2-
th ion e (45). To a solution of 1 mL (7 mmol) of diisopropy-
lamine in 10 mL of THF at 0 °C was added 3 mL (7.5 mmol)
of 2.5 M n-butyllithium. The solution was allowed to stir at 0
°C for 30 min and was cooled to -78 °C. To this solution was
added a solution of 1.2 g (6.2 mmol) of N-tert-butyldimethyl-
silylpyrrolidin-2-one54 in 10 mL of THF. The reaction mixture
was allowed to warm to 25 °C over a period of 1 h and was
recooled to -78 °C. A 2.0 g (7 mmol) sample of 3,4-dimethox-
solid: mp 79-80 °C; IR (neat) 1577, 1551, and 1472 cm-1
;

Synthesis of Tetrahydroisoquinoline Systems
J . Org. Chem., Vol. 65, No. 9, 2000 2693
yphenethyl iodide55 was added, and the reaction was allowed
to warm to 25 °C over a period of 2 h. The mixture was
quenched with a saturated solution of NH4Cl and extracted
with ethyl acetate. The combined organic extracts were
concentrated under reduced pressure, and the residue was
taken up in 10 mL of THF. A large excess of a 1.5 M
tetrabutylammonium fluoride solution in THF was added at
room temperature, and the mixture was allowed to stir at 25
°C for 2 h. The mixture was concentrated under reduced
pressure, and the residue was subjected to flash silica gel
chromatography to give 1.05 g (68%) of 3-[2-(3,4-dimethoxy-
phenyl)ethyl]-pyrrolidin-2-one as a white solid: mp 76-77 °C;
jected to flash silica gel chromatography to give 0.4 g (87%) of
46 as a white solid: mp 98-99 °C; IR (CH2Cl2) 1561, 1359,
1
and 1325 cm-1; H NMR (400 MHz, CDCl3) δ 1.63-1.97 (m,
5H), 2.55-2.81 (m, 4H), 3.34-3.36 (m, 2H), 3.86 (s, 3H), 3.89
(s, 3H), 6.76-6.81 (m, 3H), and 8.31 (brs, 1H); 13C NMR (100
MHz, CDCl3) δ 19.4, 24.7, 32.6, 36.8, 44.9, 45.7, 55.8, 55.9,
111.1, 111.6, 120.2, 134.1, and 208.0. Anal. Calcd for C15H21
-
NO2S: C, 64.49; H, 7.58; N, 5.02. Found: C, 64.58; H, 7.63;
N, 4.93.
6,7-D im e t h o x y -2,2a ,3,4-t e t r a h y d r o -1H -9-t h ia -11a -
a za p en ta len o[6a ,1a ]n a p h th a len -11-on e (47). To a solution
of 1.0 g (3.7 mmol) of thioamide 45 in 30 mL of CH2Cl2 at room
temperature was added 0.4 mL (4.2 mmol) of bromoacetyl
chloride, and the mixture was heated at reflux for 2 h. The
reaction mixture was cooled to 0 °C, quenched with water, and
extracted with CH2Cl2. The combined organic extracts were
dried over Na2SO4, filtered, and concentrated under reduced
pressure. The resulting residue was subjected to flash silica
gel chromatography to give 1.0 g (88%) of 47 as a white solid:
1
IR (CH2Cl2) 1655, 1510, and 1254 cm-1; H NMR (400 MHz,
CDCl3) δ 1.64-1.68 (m, 1H), 1.82-1.87 (m, 1H), 2.19-2.22 (m,
1H), 2.31-2.38 (m, 2H), 2.64-2.74 (m, 2H), 3.31-3.63 (m, 2H),
3.85 (s, 3H), 3.88 (s, 3H), 5.53 (brs, 1H), and 6.73-6.80 (m,
3H); 13C NMR (100 MHz, CDCl3) δ 29.0, 33.1, 34.5, 47.1, 52.3,
55.7, 55.8, 111.0, 111.6, 121.3, 134.2, 147.0, 148.3, and 175.3.
Anal. Calcd for C14H19NO3: C, 67.43; H, 7.69; N, 5.62. Found:
C, 67.78; H, 7.41; N, 5.53.
1
mp 153-154 °C; IR (CH2Cl2) 1680, 1510, and 1254 cm-1; H
NMR (400 MHz, CDCl3) δ 1.80-1.91 (m, 2H), 2.08-2.25 (m,
2H), 2.52-2.59 (m, 1H), 2.65-2.83 (m, 2H), 2.95-3.01(m, 1H),
3.75 (d, 1H, J ) 15.6 Hz), 3.80-3.85 (m, 1H), 3.86 (s, 3H),
3.87 (s, 3H), 4.23 (d, 1H, J ) 15.6 Hz), 6.51 (s, 1H), and 6.93
(s, 1H); 13C NMR (100 MHz, CDCl3) δ 20.5, 23.8, 27.1, 36.6,
42.1, 46.0, 55.7, 55.9, 74.6, 109.3, 110.3, 127.9, 129.3, 148.2,
148.9, and 172.0. Anal. Calcd for C16H19NO3S: C, 62.93; H,
6.28; N, 4.59. Found: C, 62.89; H, 6.23; N, 4.58.
To a solution of 1.0 g (4.0 mmol) of the above amide in 40
mL of toluene was added 0.8 g (2.0 mmol) of Lawesson’s
reagent. The mixture was heated at reflux for 4 h and was
cooled to room temperature. The solution was concentrated
under reduced pressure, and the resulting residue was sub-
jected to flash silica gel chromatography to give 0.97 g (91%)
of 45 as a white solid: mp 125-126 °C; IR (CH2Cl2) 3310, 1517,
1
and 1261 cm-1; H NMR (400 MHz, CDCl3) δ 1.65-1.74 (m,
14-Aza -4,5-d im eth oxy-17-th ia tetr a cyclo[8.7.0.01,14.02,7]-
h ep ta d eca -2(7),3,5-tr ien -15-on e (48). To a solution of 0.3 g
(1.0 mmol) of thioamide 46 in 5 mL of CH2Cl2 at room
temperature was added 0.1 mL (1.2 mmol) of bromoacetyl
chloride, and the mixture was heated at reflux for 2 h. The
solution was cooled to 0 °C, quenched with water, and
extracted with CH2Cl2. The combined organic extracts were
dried over Na2SO4, filtered, and concentrated under reduced
pressure. The resulting residue was subjected to flash silica
gel chromatography to give 0.3 g (95%) of 48 as a colorless
1H), 1.83-1.93 (m, 1H), 2.35-2.43 (m, 1H), 2.45-2.54 (m, 1H),
2.58-2.65 (m, 1H), 2.70-2.78 (m, 2H), 3.50-3.61 (m, 2H), 3.86
(s, 3H), 3.88 (s, 3H), 6.74-6.80 (m, 3H), and 8.72 (brs, 1H);
13C NMR (100 MHz, CDCl3) δ 28.5, 32.9, 34.9, 47.2, 51.5, 55.7,
55.8, 111.0, 111.6, 120.1, 133.8, 147.1, 148.7, and 209.0. Anal.
Calcd for C14H19NO2S: C, 63.37; H, 7.22; N, 5.28. Found: C,
63.42; H, 7.14; N, 5.23.
3-[2-(3,4-Dim eth oxyp h en yl)eth yl]p ip er id in e-2-th ion e
(46). To a solution of 0.9 mL (6.3 mmol) of diisopropylamine
in 10 mL of THF at 0 °C was added 2.7 mL (7 mmol) of 2.5 M
n-butyllithium. The solution was allowed to stir at 0 °C for 30
min and was cooled to -78 °C. To this mixture was added a
solution of 1.0 g (6 mmol) of N-trimethylsilylvalerolactam56 in
5 mL of THF. The reaction mixture was allowed to warm to
room temperature over a period of 1 h and was recooled to
-78 °C. A 2.0 g (7 mmol) sample of 3,4-dimethoxyphenethyl
iodide55 was added, and the solution was allowed to warm to
room temperature over a period of 2 h. The mixture was
quenched with a saturated solution of NH4Cl and extracted
with ethyl acetate. The combined organic extracts were
concentrated under reduced pressure, and the resulting resi-
due was dissolved in 10 mL of THF. An excess of a 1.5 M
tetrabutylammonium fluoride solution in THF was added at
room temperature, and the mixture was allowed to stir for 2
h. The solution was concentrated under reduced pressure, and
the resulting residue was subjected to flash silica gel chroma-
tography to give 1.2 g (79%) of 3-[2-(3,4-dimethoxyphenyl)-
ethyl]piperidin-2-one as a white solid: mp 75-76 °C; IR
solid: mp 138-139 °C; IR (CH2Cl2) 1676, 1401, and 1264 cm-1
;
1H NMR (400 MHz, CDCl3) δ 1.51-1.72 (m, 4H), 1.79-1.86
(m, 1H), 2.11-2.17 (m, 1H), 2.26-2.35 (m, 1H), 2.55-2.85 (m,
3H), 3.71 (d, 1H, J ) 15.6 Hz), 3.81 (s, 3H), 3.84 (d, 1H, J )
15.6 Hz), 3.85 (s, 3H), 4.20-4.25 (m, 1H), 6.54 (s, 1H), and
6.58 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 23.8, 24.7, 25.0,
25.9, 33.2, 40.2, 43.8, 55.8, 56.1, 72.1, 107.4, 111.1, 127.7, 128.7,
148.6, 148.9, and 170.3. Anal. Calcd for C17H21NO3S: C, 63.92;
H, 6.63; N, 4.39. Found: C, 63.89; H, 6.65; N, 4.31.
7,8-Dim e t h oxy-3,3a ,4,5-t e t r a h yd r o-2H -b e n zo[g]in -
d ole (51). To a solution of 0.1 g (0.3 mmol) of 47 in 5 mL of
EtOH was added 1 mmol of excess of Raney nickel. The
reaction mixture was heated at 80 °C for 12 h and was cooled
to room temperature. The mixture was filtered through Celite
and concentrated under reduced pressure. The resulting
residue was subjected to flash silica gel chromatography to
give 0.07 g (91%) of 51 as a clear oil: IR (CH2Cl2) 1603, 1503,
1
and 1270 cm-1; H NMR (400 MHz, CDCl3) δ 1.55-1.65 (m,
(CH2Cl2) 1652, 1510, and 1254 cm-1 1H NMR (400 MHz,
;
2H), 2.25-2.32 (m, 2H), 2.80-2.86 (m, 2H), 2.95-2.99 (m, 1H),
3.66-3.75 (m, 1H), 3.84 (s, 3H), 3.91 (s, 3H), 4.10-4.16 (m,
1H), 6.66 (s, 1H), and 7.56 (s, 1H); 13C NMR (100 MHz, CDCl3)
δ 29.8, 29.9, 31.1, 46.7, 55.8, 55.9, 59.1, 107.1, 110.6, 122.8,
134.6, 147.7, 151.2, and 174.0. Anal. Calcd for C14H17NO2: C,
72.69; H, 7.41; N, 6.06. Found: C, 72.71; H, 7.40; N, 5.99.
6,7-D i m e t h o x y -1,2,3,4-t e t r a h y d r o -4-a z a p h e n a n -
th r en e (52). To a solution of 0.1 g (0.3 mmol) of 48 in 5 mL of
EtOH was added a 1 mmol excess of Raney nickel. The reaction
mixture was heated at 80 °C for 5 h and was cooled to room
temperature. The mixture was filtered through Celite and
concentrated under reduced pressure. The resulting crude
residue was subjected to flash silica gel chromatography to
give 0.07 g (90%) of 52 as a colorless oil: IR (CH2Cl2) 3424,
1489, and 1254 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.01-2.06
(m, 2H), 2.90 (t, 2H, J ) 6.4 Hz), 3.49 (t, 2H, J ) 5.6 Hz) 3.98
(s, 3H), 3.99 (s, 3H), 6.96 (s, 1H), 7.00 (d, 1H, J ) 8.4 Hz), and
7.06-7.08 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 22.2, 27.3,
42.7, 55.7, 55.9, 99.2, 107.3, 116.1, 116.8, 118.8, 126.8, 128.5,
CDCl3) δ 1.79-1.90 (m, 4H), 2.02-2.10 (m, 2H), 2.57-2.66 (m,
3H), 3.34 (brs, 2H), 3.85 (s, 3H), 3.87 (s, 3H), 6.33 (brs, 1H),
and 6.73-6.80 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 19.8,
29.8, 30.3, 40.9, 42.6, 44.7, 55.7, 55.8, 111.0, 111.6, 119.9, 134.9,
146.9, 148.7, and 176.4. Anal. Calcd for C15H21NO3: C, 68.40;
H, 8.04; N, 5.32. Found: C, 68.46; H, 7.98; N, 5.29.
To a solution of 0.5 g (2 mmol) of the above amide in 10 mL
of toluene was added 0.4 g (1 mmol) of Lawesson’s reagent.
The mixture was heated at reflux for 2 h and cooled to room
temperature. The crude reaction mixture was concentrated
under reduced pressure, and the resulting residue was sub-
(54) Padwa, A.; Coats, S. J .; Harring, S. R.; Hadjiarapoglu, L.;
Semones, M. A. Synthesis 1995, 8, 973.
(55) Castedo, L.; Marcos, C. F.; Monteagudo, M.; Tojo, G. Synth.
Commun. 1992, 22, 677.
(56) Hua, D. H.; Miao, S. W.; Bharathi, S. N.; Katsuhira, T.; Bravo,
A. A. J . Org. Chem. 1990, 55, 3682.

2694 J . Org. Chem., Vol. 65, No. 9, 2000
Padwa et al.
137.3, 148.7, and 148.9. Anal. Calcd for C15H17NO2: C, 74.04;
H, 7.05; N, 5.76. Found: C, 74.01; H, 6.93; N, 5.72.
Meth yl 3,7-Dim eth yloct-6-en eth ion ic Acid Am id e (56).
To a solution containing 3 mL (16 mmol) of citronellic acid in
30 mL of CH2Cl2 was added 3.2 g (20 mmol) of 1,1′-carbonyl-
diimidazole. The reaction mixture was allowed to stir for 1 h,
after which time the mixture was cannulated into a solution
of 10 mL of 40% methylamine in 20 mL of CH2Cl2 at 0 °C.
The solution was allowed to warm to room temperature over
a period of 4 h and was diluted with 50 mL of water. The
product was extracted with CH2Cl2, and the combined organic
extracts were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure to give 0.3 g (98%) of
N-methyl 3,7-dimethyloct-6-enamide as a thick oil. This mate-
rial was dissolved in 50 mL, of toluene and 3.2 g (8.0 mmol) of
Lawesson’s reagent was added. The mixture was heated at
reflux for 2 h and cooled to 25 °C, and the solvent was removed
under reduced pressure. The resulting residue was subjected
to flash silica gel chromatography to give 2.6 g (82%) of
thioamide 56 as a clear oil: IR (CH2Cl2) 1538, 1453, and 1368
3-P h en eth ylp ip er id in e-2-th ion e (53). To a solution of 0.9
mL (6.4 mmol) of diisopropylamine in 10 mL of THF at 0 °C
was added 2.8 mL (7.0 mmol) of 2.5 M n-butyllithium. The
solution was allowed to stir at 0 °C for 30 min and was cooled
to -78 °C. To this mixture was added a solution of 1.0 g (5.8
mmol) of N-trimethylsilylvalerolactam56 in 5 mL of THF. The
reaction mixture was allowed to warm to room temperature
over a period of 1 h and was recooled to -78 °C. A 1.0 mL (7.0
mmol) sample of phenethyl iodide55 was added, and the
reaction mixture was allowed to warm to room temperature
over a period of 2 h. The mixture was quenched with a
saturated solution of NH4Cl and extracted with ethyl acetate.
The combined organic extracts were concentrated under
reduced pressure and the resulting residue was dissolved in
10 mL of THF. An excess of 1.5 M tetrabutylammonium
fluoride solution in THF was added at room temperature, and
the mixture was allowed to stir for 2 h. The reaction mixture
was concentrated under reduced pressure, and the resulting
residue was subjected to flash silica gel chromatography to
give 0.9 g (77%) of 3-phenethylpiperidin-2-one as a white
1
cm-1; H NMR (400 MHz, CDCl3) δ 0.91 (d, 3H, J ) 6.4 Hz),
1.17-1.25 (m, 1H), 1.31-1.42 (m, 1H), 1.60 (s, 3H), 1.68 (s,
3H), 1.91-2.09 (m, 2H), 2.12-2.22 (m, 1H), 2.39-2.45 (m, 1H),
2.65-2.70 (m, 1H), 3.16 (d, 3H, J ) 4.8 Hz), 5.08 (t, 1H, J )
7.2 Hz), and 7.88 (brs, 1H); 13C NMR (100 MHz, CDCl3) δ 17.5,
18.7, 25.3, 25.5, 32.7, 33.4, 36.4, 54.3, 124.1, 131.4, and 205.4.
Anal. Calcd for C11H21NS: C, 66.29; H, 10.63; N, 7.03. Found:
C, 66.15; H, 10.71; N, 7.18.
solid: mp 99-100 °C; IR (CH2Cl2) 1559, 1360, and 1331 cm-1
;
1H NMR (300 MHz, CDCl3) δ 1.50-2.04 (m, 5H), 2.21-2.33
(m, 2H), 2.60-2.79 (m, 2H), 3.25-3.32 (m, 2H), 5.92 (brs, 1H),
and 7.12-7.28 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 21.4,
26.3, 33.2, 33.3, 40.5, 42.4, 125.8, 128.3, 128.4, 141.9, and
174.7. Anal. Calcd for C13H17NO: C, 76.80; H, 8.43; N, 6.89.
Found: C, 76.91; H, 8.46; N, 6.94.
6-Isopr open yl-4,9-dim eth yl-1-th ia-4-azaspir o[4.5]decan -
3-on e (58). To a solution of 0.5 g (2.5 mmol) of 56 in 20 mL of
CH2Cl2 at room temperature was added 0.3 mL (3.0 mmol) of
bromoacetyl chloride, and the mixture was heated at reflux
for 2 h. The solution was concentrated under reduced pressure,
and the resulting residue was subjected to flash silica gel
chromatography to give 0.38 g (63%) of the major diasteromer
of 58 as a colorless solid: mp 124-125 °C; IR (CH2Cl2) 1673,
To a solution of 0.8 g (4.0 mmol) of the above amide in 40
mL of toluene was added 0.8 g (2.0 mmol) of Lawesson’s
reagent. The mixture was heated at reflux for 4 h and cooled
to room temperature. The crude mixture was concentrated
under reduced pressure, and the resulting residue was sub-
jected to flash silica gel chromatography to give 0.8 g (89%) of
thioamide 53 as a white solid: mp 90-91 °C; IR (CH2Cl2) 1560,
1360, and 1325 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.62-1.69
(m, 1H), 1.74-1.82 (m, 1H), 1.87-1.98 (m, 3H), 2.54-2.71 (m,
3H), 2.77-2.84 (m, 1H), 3.28-3.36 (m, 2H), 7.16-7.20 (m, 1H),
7.23-7.30 (m, 4H), and 8.97 (brs, 1H); 13C NMR (100 MHz,
CDCl3) δ 19.3, 24.6, 33.1, 36.6, 44.7, 45.8, 125.8, 128.4, 128.5,
141.5, and 207.2. Anal. Calcd for C13H17NS: C, 71.20; H, 7.82;
N, 6.39. Found: C, 71.13; H, 7.85; N, 6.33.
1453 and 1389 cm-1 1H NMR (400 MHz, CDCl3) δ 0.93 (d,
;
3H, J ) 5.6 Hz), 1.64-1.83 (m, 10H), 2.33-2.37 (m, 1H), 2.87
(s, 3H), 3.30 (d, 1H, J ) 15.6 Hz), 3.41 (d, 1H, J ) 15.6 Hz),
and 4.89 (d, 2H, J ) 17.6 Hz); 13C NMR (100 MHz, CDCl3) δ
22.0, 22.8, 28.2, 28.8, 29.5, 32.7, 34.0, 48.4, 49.2, 76.5, 115.2,
144.1, and 171.3. Anal. Calcd for C13H21NO1S: C, 65.24; H,
8.85; N, 5.86. Found: C, 65.33; H, 8.91; N, 5.80. The stereo-
chemistry of 58 is not known.
5,6,9-Tr im e t h oxy-11b H -1-t h ia -3a -a za cyclop e n t a [l]-
p h en a n th r en -3-on e (62). To a solution of 0.5 g (1.6 mmol)
of thioamide 6057 in 30 mL of CH2Cl2 at room temperature
was added 0.2 mL (2.0 mmol) of bromoacetyl chloride, and the
mixture was heated at reflux for 2 h. The solution was
concentrated under reduced pressure, and the resulting resi-
due was subjected to flash silica gel chromatography to give
0.4 g (77%) of 62 as a yellow solid: mp 200-202 °C; IR (CH2-
14-Aza th ia tetr a cyclo[8.7.0.01,14.02,7]h ep ta d eca -2(7),3,5-
tr ien -15-on e (54). To a solution of 0.2 g (0.9 mmol) of
thioamide 53 in 5 mL of CH2Cl2 was added 0.1 mL (1.1 mmol)
of bromoacetyl chloride at room temperature. After the mixture
was stirred for 10 min, 0.4 g (2.7 mmol) of AlCl3 was added in
one portion, and the reaction was heated at reflux for 2 h. The
mixture was cooled to 0 °C, quenched with water, and
extracted with CH2Cl2. The combined organic extracts were
dried over Na2SO4, filtered, and concentrated under reduced
pressure. The resulting residue was subjected to flash silica
gel chromatography to give a 2:1 mixture of two compounds.
The major product obtained contained 0.08 g (31%) of N,S-
ketal 54 as a clear oil that exhibited the following spectral
1
Cl2) 1666, 1595 and 1510 cm-1; H NMR (300 MHz, CDCl3) δ
3.83 (s, 3H), 3.84 (s, 3H), 3.93 (s, 3H), 4.58 (s, 2H), 6.77-6.94
(m, 5H), and 7.27-7.30 (m, 1H); 13C NMR (100 MHz, CDCl3)
δ 32.6, 55.6, 56.1, 56.2, 110.4, 111.3, 115.0, 119.8, 119.9, 128.3,
130.3, 149.8, 150.2, 161.9, 163.4, 167.8, and 183.2. Anal. Calcd
for C18H17NO4S: C, 62.96; H, 4.99; N, 4.08. Found: C, 63.08;
H, 5.02; N, 4.11.
1
properties: IR (CH2Cl2) 1674, 1396, and 1268 cm-1; H NMR
1-(2,3,9-T r im e t h o x y -6H -p h e n a n t h r id in -5-y l)e t h a -
n on e (63). To a solution of 0.2 g (0.6 mmol) of 62 in 5 mL of
EtOH at room temperature was added a 3 equiv excess of
Raney nickel. The reaction mixture was heated at 80 °C for 5
h and was allowed to cool to room temperature. The mixture
was filtered through Celite and concentrated under reduced
pressure. The resulting residue was subjected to flash silica
gel chromatography to give 0.2 g (83%) of 63 as a pale yellow
oil: IR (CH2Cl2) 1648, 1511 and 1205 cm-1; 1H NMR (400 MHz,
CDCl3) δ 2.51 (s, 3H), 3.75 (s, 3H), 3.76 (s, 3H), 3.85 (s, 3H),
6.69-6.71 (m, 2H), 6.76-6.78 (m, 2H), 6.83-6.86 (m, 1H), 7.18
(s, 1H), and 7.20 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 27.2,
55.6, 56.1, 56.2, 101.2, 110.6, 111.3, 114.8, 120.0, 120.3, 128.7,
130.1, 149.7, 150.0, 162.1, 163.0, 165.8, and 170.3; HRMS calcd
for C18H19NO4 313.1314, found 313.1315.
(400 MHz, CDCl3) δ 1.43-1.74 (m, 4H), 1.83-1.89 (m, 1H),
2.16-2.33 (m, 2H), 2.52-2.58 (m, 1H), 2.75-2.91 (m, 2H), 3.69
(d, 1H, J ) 15.6 Hz), 3.84 (d, 1H, J ) 15.6 Hz), 4.20-4.25 (m,
1H), 7.09-7.14 (m, 2H), and 7.18-7.21 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 24.0, 24.6, 24.7, 26.1, 33.0, 39.9, 43.9, 71.6,
125.0, 127.2, 127.8, 129.5, 134.8, 137.4, and 170.2; HRMS calcd
for C15H17NOS 259.1030, found 259.1028.
8-P h en eth yl-6,7-d ih yd r o-5H-th ia zolo[3,2-a ]p yr id in -3-
on e (55). The minor fraction isolated from the above column
chromatography contained 0.03 g (14%) of 55 as a yellow
solid: mp 84-85 °C; IR (CH2Cl2) 1687, 1652, and 1389 cm-1
;
1H NMR (400 MHz, CDCl3) δ 1.80-1.86 (m, 2H), 2.11 (t, 2H,
J ) 6.4 Hz), 2.29 (t, 2H, J ) 7.6 Hz), 2.72 (t, 2H, J ) 7.8 Hz),
3.57 (t, 2H, J ) 6.4 Hz), 3.70 (s, 2H), 7.18-7.21 (m, 3H), and
7.26-7.31 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 20.7, 26.8,
32.6, 33.6, 35.1, 41.4, 109.3, 125.9, 127.0, 128.3, 128.4, 141.4,
and 169.5. Anal. Calcd for C15H17NOS: C, 69.47; H, 6.61; N,
5.40. Found: C, 69.44; H, 6.62; N, 5.36.
(57) Yates, P. C.; McCall, C. J .; Stevens, M. F. G. Tetrahedron 1991,
47, 6493.

Synthesis of Tetrahydroisoquinoline Systems
J . Org. Chem., Vol. 65, No. 9, 2000 2695
8,9-Dim eth oxy-10b-m eth yl-6,10b-d ih yd r o-5H-th ia zolo-
[2,3-a ]isoqu in olin -3-on e (65). To a solution of 0.5 g (2 mmol)
of thioamide 6449 in 10 mL of CH2Cl2 at room temperature
was added 0.2 mL (2.4 mmol) of bromoacetyl chloride, and the
mixture was stirred at room temperature for 18 h. The solution
was concentrated under reduced pressure, and the resulting
residue was subjected to flash silica gel chromatography to
give 0.6 g (98%) of 65 as a white solid: mp 129-130 °C; IR
149.4, and 201.9. Anal. Calcd for C20H25NO4S: C, 63.97; H,
6.72; N, 3.73. Found: C, 63.85; H, 6.68; N, 3.71.
2-(3,4-Dim eth oxyben zylid en e)-3-[2-(3,4-d im eth oxyp h e-
n yl)eth yl]th ia zolid in -4-on e (69). To a solution of 0.5 g (1.3
mmol) of 68 in 15 mL of toluene at room temperature was
added 0.1 mL (1.6 mmol) of bromoacetyl chloride, and the
mixture was heated at reflux for 18 h. The solution was
concentrated under reduced pressure, and the resulting resi-
due was subjected to flash silica gel chromatography to give
0.5 g (84%) of 69 as a pale yellow oil: IR (CH2Cl2) 1688, 1510
and 1261 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.96 (t, 2H, J )
7.6 Hz), 3.76-3.98 (m, 16H), 6.00 (s, 1H), and 6.78-6.92 (m,
6H); 13C NMR (100 MHz, CDCl3) δ 32.0, 32.3, 44.2, 55.8, 55.9,
102.2, 110.9, 111.2, 111.9, 112.0, 120.3, 120.7, 128.4, 130.3,
135.1, 147.2, 147.8, 148.7, 148.9, and 170.2. Anal. Calcd for
(CH2Cl2) 1673, 1510, and 1140 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 1.95 (s, 3H), 2.66-2.71 (m, 1H), 2.91-2.98 (m, 1H),
3.14-3.17 (m, 1H), 3.63 (d, 1H, J ) 15.6 Hz), 3.80-3.85 (m,
1H), 3.84 (s, 3H), 3.89 (s, 3H), 4.40-4.51 (m, 1H), 6.56 (s, 1H),
and 6.65 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 27.8, 32.4, 34.0,
36.7, 55.8, 56.0, 68.0, 107.7, 111.2, 123.6, 132.1, 148.2, 148.4,
and 169.1. Anal. Calcd for C14H17NO3S: C, 60.20; H, 6.14; N,
5.02. Found: C, 60.06; H, 6.09; N, 4.98.
C
22H25N O5S: C, 63.59; H, 6.07; N, 3.37. Found: C, 63.71; H,
1-(6,7-Dim eth oxy-1-m eth ylen e-3,4-d ih yd r o-1H-isoqu in -
olin -2-yl)eth a n on e (66). To a solution of 0.1 g (0.4 mmol) of
65 in 5 mL of EtOH at room temperature was added a 3 equiv
excess of Raney nickel. The reaction mixture was heated at
reflux for 15 h and was cooled to room temperature. The
mixture was filtered through Celite and concentrated under
reduced pressure. The crude residue was subjected to flash
silica gel chromatography to give 0.06 g (71%) of 66 as a white
solid: mp 106-107 °C (lit.49 mp 106-107 °C); IR (CH2Cl2)
1681, 1510, and 1261 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.23
(s, 3H), 2.83 (t, 2H, J ) 6.0 Hz), 3.88 (s, 3H), 3.92 (s, 3H), 3.98
(t, 2H, J ) 6.0 Hz), 4.97 (brs, 1H), 5.61 (brs, 1H), 6.60 (s, 1H),
and 7.09 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 22.2, 28.3, 41.4,
55.7, 55.8, 104.0, 106.5, 111.0, 123.5, 127.8, 142.9, 147.5, 149.6,
and 169.1. Anal. Calcd for C14H17NO3: C, 67.98; H, 6.93; N,
5.67. Found: C, 67.79; H, 6.87; N, 5.55.
6.04; N, 3.30.
10b-(3,4-Dim eth oxyben zyl)-8,9-d im eth oxy-6,10b-d ih y-
d r o-5H-th ia zolo[2,3-a ]isoqu in olin -3-on e (70). To a solution
of 0.15 g (0.35 mmol) of 69 in 3 mL of CH2Cl2 was added 0.3
mL (3.6 mmol) of trifluoroacetic acid, and the mixture was
allowed to stir at room temperature for 2 days. The solution
was quenched with water and extracted with CH2Cl2. The
combined organic extracts were dried over Na2SO4, filtered,
and concentrated under reduced pressure. The resulting
residue was subjected to flash silica gel chromatography to
give 0.14 g (93%) of 70 as a colorless oil: IR (CH2Cl2) 1674,
1510, and 1254 cm-1; H NMR (400 MHz, CDCl3) δ 2.59 (d,
1
1H, J ) 14.8 Hz), 2.72-2.77 (m, 1H), 2.93-3.02 (m, 1H), 3.13-
3.23 (m, 2H), 3.41 (d, 1H, J ) 14.8 Hz), 3.86-3.92 (m, 13H),
4.47-4.51 (m, 1H), 6.61 (s, 1H), 6.64 (s, 1H), 6.71-6.73 (m,
1H), 6.79 (s, 1H), and 6.81 (s, 1H); 13C NMR (100 MHz, CDCl3)
δ 28.1, 34.5, 37.0, 48.5, 55.7, 55.8, 55.9, 56.2, 71.5, 107.9, 110.6,
111.3, 114.1, 123.2, 124.0, 127.1, 131.3, 148.2, 148.4, 148.5,
and 170.0. Anal. Calcd for C22H25NO5S: C, 63.59; H, 6.07; N,
3.37. Found: C, 63.51; H, 6.04; N, 3.24.
2-(3,4-Dim eth oxyp h en yl)-N-[2-(3,4-d im eth oxyp h en yl)-
eth yl]th ioa ceta m id e (68). To a solution of 5.0 g (25 mmol)
of (3,4-dimethoxyphenyl)acetic acid in 50 mL of benzene was
added 6.7 mL (76 mmol) of oxalyl chloride, which contained 2
drops of DMF. The solution was allowed to stir for 2 h at room
temperature, after which time the excess oxalyl chloride was
removed under reduced pressure. The crude acid chloride was
taken up in 50 mL of CH2Cl2 and was cannulated into a
solution containing 4.3 mL (25 mmol) of 3,4-dimethoxyphen-
ethylamine in 150 mL of CH2Cl2 at 0 °C. The mixture was
allowed to warm to room temperature over a period of 2 h and
was quenched with water and extracted with CH2Cl2. The
combined organic extracts were washed with brine, dried over
Na2SO4, and concentrated under reduced pressure to afford
8.0 g (87%) of 2-(3,4-dimethoxyphenyl)-N-[2-(3,4-dimethoxy-
phenyl)ethyl]acetamide as a thick oil. This material was
dissolved in 50 mL of toluene, and 4.5 g (11 mmol) of
Lawesson’s reagent was added. The reaction mixture was
heated at reflux for 5 h and cooled to room temperature, and
the solvent was removed under reduced pressure. The residue
was subjected to flash silica gel chromatography to give 7.9 g
(83%) of 68 as a light amber oil: IR (CH2Cl2) 1510, 1261, and
N-Acetyltetr a h yd r op a p a ver olin e (71). To a solution of
0.1 g (0.2 mmol) of 70 in 5 mL of EtOH at room temperature
was added a 3 equiv excess of Raney nickel. The reaction
mixture was heated at reflux for 15 h and was cooled to room
temperature. The solution was filtered through Celite and then
concentrated under reduced pressure. The resulting crude
residue was subjected to flash silica gel chromatography to
give 0.06 g (68%) of 71 as a white solid: mp 135-136 °C (lit.49
135-136 °C). Anal. Calcd for C22H27NO5: C, 68.54; H, 7.06;
N, 3.64. Found: C, 68.43; H, 6.97; N, 3.41. This compound was
taken on to tetrahydropapaverine (72) according to the method
of Kitamura and co-workers.49
Ack n ow led gm en t. We gratefully acknowledge the
National Institutes of Health (GM60003-01) for their
generous support of this work.
1
1232 cm-1; H NMR (400 MHz, CDCl3) δ 2.78 (t, 2H, J ) 6.4
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for new compounds lacking elemental analyses. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Hz), 3.78 (s, 3H), 3.82-3.88 (m, 2H), 3.83 (s, 3H), 3.88 (s, 3H),
3.90 (s, 3H), 4.03 (s, 2H), 6.40 (d, 1H, J ) 8.0 Hz), 6.58 (m,
4H), 6.79 (d, 1H, J ) 8.0 Hz), and 7.02 (brs, 1H); 13C NMR
(100 MHz, CDCl3) δ 33.0, 44.6, 52.7, 55.7, 55.8, 110.9, 111.0,
111.2, 111.3, 120.3, 121.9, 126.4, 129.9, 147.7, 148.6, 149.1,
J O991742H