Studies dealing with thionium ion promoted Mannich cyclization reactions

Article abstract of DOI:10.1021/jo991414h

Treatment of several amido-substituted thioacetals with dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF) produces synthetically useful thionium ions that are intercepted by the adjacent nitrogen atom to afford both five- and six-membered alkylthio-substituted lactams as transient intermediates. Further reaction of the alkylthio- substituted lactam with DMTSF generates an N-acyliminium ion, which undergoes cyclization with the tethered aromatic ring to produce an azapolycyclic ring system. Related cyclization sequences occur when amido thioacetals possessing simple olefinic tethers were used. The overall procedure represents an efficient one-pot approach toward various nitrogen-containing ring systems. The cyclization reaction was employed for a synthesis of the core skeleton of the erythrina alkaloid family.

Full text of DOI:10.1021/jo991414h

J . Org. Chem. 2000, 65, 235-244
235
Stu d ies Dea lin g w ith Th ion iu m Ion P r om oted Ma n n ich
Cycliza tion Rea ction s
Albert Padwa* and Alex G. Waterson
Department of Chemistry, Emory University, Atlanta, Georgia 30322
Received September 8, 1999
Treatment of several amido-substituted thioacetals with dimethyl(methylthio)sulfonium tetrafluo-
roborate (DMTSF) produces synthetically useful thionium ions that are intercepted by the adjacent
nitrogen atom to afford both five- and six-membered alkylthio-substituted lactams as transient
intermediates. Further reaction of the alkylthio-substituted lactam with DMTSF generates an
N-acyliminium ion, which undergoes cyclization with the tethered aromatic ring to produce an
azapolycyclic ring system. Related cyclization sequences occur when amido thioacetals possessing
simple olefinic tethers were used. The overall procedure represents an efficient one-pot approach
toward various nitrogen-containing ring systems. The cyclization reaction was employed for a
synthesis of the core skeleton of the erythrina alkaloid family.
Sequential transformations enable the facile synthesis
of complex target molecules from simple building blocks
in a single preparative step.1-3 Their value is amplified
if they also create multiple stereogenic centers.4-12
Moreover, the utilization of a domino sequence often
leads to a reduction in the amount of solvent, eluent, and
undesired byproducts, thereby contributing to the protec-
tion of the environment. One of the earliest examples of
a domino process reported in the literature involves
cationic cyclization chemistry.13 The synthetic potential
of this reaction is well recognized, and this sequence has
been greatly probed and extended in recent years.14-16
Many different precursors have been used to initiate the
cationic cascade. This cyclization sequence also plays an
important role in heterocyclic natural product synthesis.17
The reactions of N-acyliminium ions with tethered π-bonds
are among the most important methods for preparing
complex nitrogen-containing heterocycles.17-20 Pummerer-
based cyclizations are also finding widespread application
in both carbo- and heterocyclic syntheses.21-23 As part of
a program concerned with new methods for alkaloid
synthesis, we became interested in using a linked Pum-
merer/N-acyliminium ion cyclization sequence because
(1) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32,
131. Tietze, L. F. Chem. Rev. 1996, 96, 115.
(2) Ho, T. L. Tandem Organic Reactions; Wiley: New York, 1992.
Bunce, R. A. Tetrahedron 1995, 51, 13103. Parsons, P. J .; Penkett, C.
S.; Shell, A. J . Chem. Rev. 1995, 95, 195.
(3) Ziegler, F. E. In Comprehensive Organic Synthesis, Combining
C-C π-Bonds; Paquette, L. A., Ed.; Pergamon Press: Oxford, 1991;
Vol. 5, Chapter 7.3.
(4) Waldmann, H. Domino Reaction in Organic Synthesis Highlight
II; Waldmann, H., Ed.; VCH: Weinheim, 1995; pp 193-202.
(5) Curran, D. P. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 4; p 779.
(6) Wender, P. A., Ed.; Frontiers in Organic Synthesis. Chem. Rev.
1996, 96, 1-600.
(7) Canonne, P.; Boulanger, R.; Bernatchez, M. Tetrahedron Lett.
1987, 28, 4997. Bailey, W. F.; Ovaska, T. V. Tetrahedron Lett. 1990,
31, 627. Chamberlin, A. R.; Bloom, S. H.; Cervini, L. A.; Fotsch, C. H.
J . Am. Chem. Soc. 1988, 110, 4788. Bunce, R. A.; Dowdy, E. D.; J ones,
P. B.; Holt, E. M. J . Org. Chem. 1993, 58, 7143 and references therein.
(8) Motherwell, W. B.; Crich, D. Free Radical Reactions in Organic
Synthesis; Academic Press: London, 1991. Curran, D. P. In Compre-
hensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 4, Chapter 4.2. Mowbray, C. E.; Pattenden,
G. Tetrahedron Lett. 1993, 34, 127 and references therein. Hitchcock,
S. A.; Pattenden, G. Tetrahedron Lett. 1992, 33, 4843. Curran, D. P.;
Sisko, J .; Yeske, P. E.; Liu, H. Pure Appl. Chem. 1993, 65, 1153.
Curran, D. P.; Shen, W. Tetrahedron 1993, 49, 755. Parker, K. A.;
Fokas, D. J . Am. Chem. Soc. 1992, 114, 9688.
(9) Davies, H. M. L.; Clark, T. J .; Smith, H. D. J . Org. Chem. 1991,
56, 3817 and references therein. Padwa, A.; Fryxell, G. E.; Zhi, L. J .
Am. Chem. Soc. 1990, 112, 3100 and references therein. Kim, O. K.;
Wulff, W. D.; J iang, W.; Ball, R. G. J . Org. Chem. 1993, 58, 5571.
(10) Snider, B. B.; Vo, N. H.; Foxman, B. M. J . Org. Chem. 1993,
58, 7228 and references therein. Ali, A.; Harrowven, D. C.; Pattenden,
G. Tetrahedron Lett. 1992, 33, 2851. Grigg, R.; Kennewell, P.; Teasdale,
A. J . Tetrahedron Lett. 1992, 33, 7789 and references therein. Batty,
D.; Crich, D. J . Chem. Soc., Perkin Trans. 1 1992, 3205 and references
therein.
(11) Marko´, I. E.; Seres, P.; Swarbrick, T. M.; Staton, I.; Adams, H.
Tetrahedron Lett. 1992, 33, 5649 and references therein. Guevel, R.;
Paquette, L. A. J . Am. Chem. Soc. 1994, 116, 1776 and references
therein. J isheng, L.; Gallardo, T.; White, J . B. J . Org. Chem. 1990,
55, 5426. Wender, P. A.; Sieburth, S. M.; Petraitis, J . J .; Singh, S. K.
Tetrahedron 1981, 37, 3967 and references therein.
(12) Funk, R. L.; Vollhardt, K. P. C. Chem. Soc. Rev. 1980, 9, 41.
Danheiser, R. L.; Gee, S. K.; Perez, J . J . J . Am. Chem. Soc. 1986, 108,
806. Nicolaou, K. C.; Petasis, N. A. In Strategies and Tactics in Organic
Synthesis; Lindberg, T., Ed.; Academic Press: New York, 1984; Vol.
1, pp 155-173. Denmark, S. E.; Thorarensen, A. Chem. Rev. 1996,
96, 137.
(13) Sutherland, J . K. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 3, p 341.
(14) Taylor, S. K. Org. Prep. Proced. Int. 1992, 24, 245. Fish, P. V.,
Sudhakar, A. R.; J ohnson, W. S. Tetrahedron Lett. 1993, 34, 7849.
(15) Bartlett, P. A. In Asymmetric Synthesis; Morrison, J . D., Ed.;
Academic Press: Orlando, 1984; Vol. 3.
(16) Fish, P. V.; J ohnson, W. S. J . Org. Chem. 1994, 59, 2324.
J acobsen, E. J .; Levin, J .; Overman, L. E. J . Am. Chem. Soc. 1988,
110, 4329. J ohnson, W. S.; Fletcher, V. R.; Chenera, B.; Bartlett, W.
R.; Tham, F. S.; Kullnig, R. K. J . Am. Chem. Soc. 1993, 115, 497. Guay,
D.; J ohnson, W. S.; Schubert, U. J . Org. Chem. 1989, 54, 4731
(17) Overman, L. E.; Ricca, D. J . In Comprehensive Organic Syn-
thesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: 1991; Vol. 2,
pp 1007-1046. Overman, L. E. Acc. Chem. Res. 1992, 25, 352.
(18) Blumenkopf, T. A.; Overman, L. E. Chem. Rev. 1986, 86, 857.
(19) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41, 4367.
Hiemstra, H.; Speckamp, W. N. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2,
pp 1047-1082.
(20) Hart, D. J . J . Org. Chem. 1981, 46, 367. Hart, D. J .; Kanai, K.
J . Org. Chem. 1982, 47, 1555. Hart, D. J .; Kanai, K. J . Am. Chem.
Soc. 1983, 105, 1255.
(21) Padwa, A.; Gunn, D. E.; Osterhout, M. H. Synthesis 1997, 1353.
(22) Grierson, D. S.; Husson, H. P. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 6, pp 909-947.
(23) Kennedy, M.; McKervey, M. A. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 7, pp 193-216.
10.1021/jo991414h CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/07/2000

236 J . Org. Chem., Vol. 65, No. 1, 2000
Padwa and Waterson
Sch em e 1. Va r iou s Meth od s Utilized to Gen er a te
Th ion iu m Ion s
Sch em e 2
Sch em e 3
we felt that this combination offers unique opportunities
for the assemblage of complex target molecules.24,25
The Pummerer reaction constitutes a versatile and
effective method for the generation of thionium ions from
sulfoxide precursors.21-23 The initially formed cation is
readily trapped by a nucleophilic species present in the
reaction medium. The interaction of thionium ions with
electron-rich π-systems has proved to be extremely useful
in natural product synthesis.21 Acid anhydrides or acids
are generally employed as promoters in the majority of
synthetic applications of the Pummerer reaction.26 Thion-
ium ions have also been generated from other sulfur-
containing precursors (Scheme 1).27 A reaction that is
often compared to the Pummerer rearrangement is the
R-halogenation of sulfides.28 In 1981, Trost and Mu-
rayama reported that dimethyl(methylthio)sulfonium
tetrafluoroborate (DMTSF) exhibits a remarkably high
thiophilicity for cationic initiation reactions of thioket-
als.29 Surprisingly, this alternative method for thionium
ion generation has not been extensively exploited in
synthesis, although there are a few scattered reports
where this reagent has been used in complex target
molecule synthesis.30 The paucity of examples is some-
what surprising because thioketals are easily available
by metalation and alkylation reactions of thioacetals.31
Furthermore, the normally inert thioketal group can be
carried through a series of transformations before it is
chemoselectively unmasked to reveal the reactive thion-
ium ion.
amido annulation process based on a consecutive thionium/
Mannich ion cyclization sequence.33 A synthetic method
that combines transformations of different reaction types
significantly broadens the scope of such procedures in
synthetic chemistry. Our early studies in this area
involved a silicon-induced Pummerer reaction of ami-
dosulfoxides that possessed tethered π-bonds (Scheme
2).33 Although the sequential process proved valuable for
a number of substrates, we faced several limitations
during our attempts to extend the scope of the reaction.
Thus, in every case examined, it was necessary to isolate
and purify the initially formed 2-phenylthio lactam
intermediate before subjecting it to various electrophilic
reagents so as to induce the second ring closure. In
addition, formation of the N-acyliminium ion intermedi-
ate required the use of a strong Lewis acid, and as a
result, the yield associated with the cyclization was
variable. We reasoned that by replacing the sulfoxide
functionality with a thioacetal group, it might be possible
to bring about a one-pot cascade. Indeed, we have found
that the desired reaction (Scheme 3) occurred in high
yield when DMTSF was used as the reagent to initiate
the process. In this paper we report the results of these
studies, which show that both cyclization steps can take
place without having to add any additional reagents or
catalysts. This novel transformation greatly extends the
synthetic potential of thionium promoted Mannich reac-
tions.
While developing a Pummerer approach toward the
synthesis of alkaloids,32 we recently uncovered a versatile
(24) Tamura, Y.; Maeda, H.; Akai, S.; Ishibashi, H. Tetrahedron Lett.
1982, 23, 2209. Ishibashi, H.; Sato, K.; Maruyama, K.; Ikeda, M.;
Tamura, Y. Chem. Pharm. Bull. 1985, 33, 4593. Ishibashi, H.; Sato,
T.; Takahashi, M.; Hayashi, M.; Ikeda, M. Heterocycles 1988, 27, 2787.
(25) Padwa, A.; Kappe, C. O.; Reger, T. S. J . Org. Chem. 1996, 61,
4888. Padwa, A. Chem. Commun. 1998, 1417.
(26) De Lucchi, O.; Miotti, U.; Modena, G. Organic Reactions;
Paquette, L. A., Ed.; Wiley: New York, 1991; Chapter 3, pp 157-184.
(27) Kita, Y.; Yasuda, H.; Tamura, O.; Ithoh, F.; Tamura, Y.
Tetrahedron Lett. 1984, 25, 4681. Magnus, P.; Kreisberg, J . D.
Tetrahedron Lett. 1999, 40, 451.
(28) Dilworth, B. M.; McKervey, M. A. Tetrahedron 1986, 42, 3731.
Paquette, L. A. Org. React. 1977, 25, 1.
(29) Trost, B. M.; Murayama, E. J . Am. Chem. Soc. 1981, 103, 6529.
Trost, B. M.; Sato, T. J . Am. Chem. Soc. 1985, 107, 719.
(30) Amat, M.; Linares, A.; Bosch, J . J . Org. Chem. 1990, 55, 6299.
Amat, M.; Bosch, J . J . Org. Chem. 1992, 57, 5792.
Resu lts a n d Discu ssion
We began our investigations of the thionium ion
promoted Mannich cyclization by first examining the
intramolecular thionium ion cyclization reaction of amido
thioacetal 5. This compound was prepared by a four-step
sequence involving ozonolysis of 4-pentenoic acid (3)
followed by reaction of the resulting aldehyde with 2
equiv of thiophenol to give 4,4-bis(phenylsulfanyl)butyric
acid (4) (Scheme 4). Sequential treatment of carboxylic
acid 4 with 1,1-carbonyl diimidazole followed by 3,4-
dimethoxyphenethylamine furnished thioacetal 5 in 93%
yield. With the necessary functionality in place, we tested
(31) Seebach, D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239.
(32) Padwa, A.; Hennig, R.; Kappe, C. O.; Reger, T. S. J . Org. Chem.
1998, 63, 1144.
(33) Padwa, A.; Waterson, A. G. Tetrahedron Lett. 1998, 39, 8585.

Mannich Cyclization Reactions
J . Org. Chem., Vol. 65, No. 1, 2000 237
Sch em e 4
Sch em e 5
Sch em e 6
the crucial annulation reaction. Gratifyingly, when 5 was
reacted with 2 equiv of DMTSF34,35 in CH2Cl2 at 25 °C,
the desired isoquinolinone 6 was obtained in 64% yield.
Treatment of the related ethylthio acetal 8 with DMTSF
also resulted in a one-pot cascade sequence, delivering
isoquinolinone 6 in an improved 98% yield.
The ease with which the S-S bond of dimethyl-
(methylthio)sulfonium salts are cleaved by nucleophilic
reagents was first documented by Helmkamp and co-
workers in their work on the preparation of DMTSF and
its addition to alkenes and alkynes.34 These reactions and
related studies by Meerwein35 indicate that reagents such
as DMTSF may be regarded as sulfenyl derivativates and
can function as a potential source of alkylsulfenyl ions.36,37
It was known from earlier work in the literature that
carbon-sulfur bonds of sulfides become labile on alkyl-
sulfenylation, and that the sulfonium ions so formed are
highly reactive intermediates that seldom can be iso-
lated.38 It is reasonable to assume, therefore, that the
conversion of 5 (or 8) into 6 upon treatment with DMTSF
follows the pathway outlined in Scheme 5. Methylthi-
olation of one of the thiophenyl groups with DMTSF gives
an alkylthiosulfonium salt 9 that easily dissociates to
generate thionium ion 10 and methyl phenyl disulfide.
Attack of the amido nitrogen atom onto the cationic
center produces a phenylthio-substituted lactam 11 as a
transient intermediate that reacts further with additional
DMTSF. Lactam 11 was not detected in the crude
reaction mixture, as it readily undergoes elimination of
thiophenol to produce N-acyliminium ion 12. Cyclization
of 12 with the tethered aromatic ring affords the iso-
quinolinone ring system 6. In the case of thioacetal 8,
the greater facility of transfer of CH3S+ to the more
nucleophilic ethylthio group is presumably responsible
for the higher yield of 6 (98%) relative to that obtained
with the less reactive phenylthio acetal 5 (64%).
Sch em e 7
The sequential thionium/Mannich cyclization worked
equally well with the 6,6-ring system. The required amide
precursor was readily prepared by treating excess bis-
(methylthio)methane with n-BuLi and allowing the re-
sulting lithiate to react with 4-bromobutyric acid. As
illustrated before, conversion of carboxylic acid 14 to
amide 15 took place in high yield. Treating a solution of
15 in CH2Cl2 at 25 °C for 12 h afforded lactam 16 in 99%
yield (Scheme 6).
The facile cleavage of thioacetals with DMTSF to form
sulfur-stabilized carbocation intermediates prompted us
to determine whether a similar reaction would occur with
the related amido thioketals 17-20. Indeed, we found
that the outcome of this reaction was in all respects
identical to that observed with the related thioacetals.
Thus, a similar pattern consisting of consecutive cycliza-
tion of the intermediate thionium and N-acyliminium
ions occurs with these four amido thioketals (Scheme 7).
What is surprising, however, is the fact that it was
necessary to carry out the DMTSF-induced reaction of
the thioketals at reflux in CH2Cl2 in order for the
(34) Helmkamp, G. K.; Pettitt, D. J . J . Org. Chem. 1963, 28, 2932.
Helmkamp, G. K.; Olsen, B. A.; Pettitt, D. J . J . Org. Chem. 1965, 30,
676. Helmkamp, G. K.; Cassey, H. N.; Olsen, B. A.; Pettitt, D. J . J .
Org. Chem. 1965, 30, 933. Helmkamp, G. K.; Olsen, B. A.; Kaskinen,
J . R. J . Org. Chem. 1965, 30, 1623. Helmkamp, G. K.; Owsley, D. C.;
Barnes, W. M.; Cassey, H. N. J . Am. Chem. Soc. 1968, 90, 1635.
(35) Meerwein, H.; Zenner, K. F.; Gipp, R. J ustus Liebigs Ann.
Chem. 1965, 688, 67.
(36) Benesch, R. E.; Benesch, R. J . Am. Chem. Soc. 1958, 80, 1666.
(37) Rice, J . L.; Favstritsky, N. A. J . Am. Chem. Soc. 1969, 91, 1751.
(38) Smallcombe, S. H.; Caserio, M. C. J . Am. Chem. Soc. 1971, 93,
5826. Kim, J . K.; Pau, J . K.; Caserio, M. C. J . Org. Chem. 1979, 44,
1544.

238 J . Org. Chem., Vol. 65, No. 1, 2000
Padwa and Waterson
Sch em e 8
tam 31 in 65% overall yield. A related set of reactions
occurred with amido thioacetal 30 ultimately producing
the known octahydroquinolizin-4,8-dione 3240 in 58% yield.
These two examples further demonstrate the facility with
which the thionium/iminium ion cascade can occur.
Given the success in forming azapolycyclic ring systems
from the DMTSF-initiated cyclization of amido thioacet-
als, it seemed to us that a related reaction might also
occur with amido-substituted thio-ortho esters. The extra
methylthio group present in the starting material would
add an additional element of functionality in the product
that could be further utilized for synthetic purposes. To
test this possibility, thio-ortho esters 33 and 34 were
Sch em e 9
synthesized from the appropriate carboxylic acid precur-
sors. Treatment of these substrates with DMTSF failed
to produce any characterizable material.41 However, after
some experimentation with other thiolating agents, we
found that the reaction of these amides with excess
dimethyl sulfate resulted in a clean cyclization to give
the enamido-substituted lactams 35 and 36 in 46% and
71% yield, respectively. It should be noted that the
enamido portion of the final product can also function as
an N-acyliminium ion precursor, thus presenting the
likelihood of conducting yet another Mannich-like reac-
tion. Efforts along these lines are ongoing in our labora-
tory and will be reported at a future date.
As an extension of these studies, we became interested
in knowing whether the method could be used to syn-
thesize the core skeleton of the erythrina alkaloids.42 This
family of alkaloids has received considerable attention
over the past decade. Many members of this family
possess curare-like activity, and the alkaloidal extracts
have been used in indigenous medicine. The vast majority
of naturally occurring erythrina alkaloids possess the
tetracyclic framework and substitution pattern shown in
structure 37. Numerous synthetic approaches into the
erythrina ring system have been developed,43 and a
cyclization to occur. The thioacetal cyclization, on the
other hand, proceeded smoothly at room temperature,
and the yield of cyclized product was much higher than
that encountered with the thioketal system. At first
glance this might seem unusual, because the thionium
ion derived from the thioketal should be easier to form
by virtue of its greater stability (i.e., tertiary vs second-
ary). Presumably, the less reactive cation 23 produced
by dissociation of the thioketal is long-lived enough to
react with a mono- or disulfide nucleophile present in the
reaction medium. This reversible reaction regenerates the
starting thioketal and thereby diminishes the rate of the
overall process (Scheme 8).39
Because all of the previous examples involved aromatic
π-bond cyclizations, we decided to study several systems
that possess a simple olefinic tether. We found that
treatment of the cyclohexenyl-substituted amido thio-
acetals 25 and 26 with DMTSF also caused a thionium
ion induced Mannich reaction to occur, ultimately pro-
ducing isoquinolinone derivatives 27 and 28 in 60% and
58% yield, respectively. To further explore the scope and
generality of the cyclization process, we also carried out
a study using the bromoalkenyl-substituted amido thio-
acetals 29 and 30 (Scheme 9). When 29 was subjected to
the DMTSF conditions followed by an aqueous workup,
the initially cyclized product was hydrolyzed to ketolac-
(40) Gesson, J .; J acquesy, J .; Rambaud, D. Tetrahedron 1993, 49,
2239.
(41) For a DMTSF-promoted cyclization from a tris(phenylthio)alkyl
derivative via a bis(phenylthio)carbocation, see: Bin Manas, A. R.;
Smith, R. A. J . Tetrahedron 1987, 43, 1847.
(42) Boekelheide, V. Alkaloids 1960, 7, 201. Hill, R. K. In The
Alkaloids; Manske, R. H. F., Ed.; Academic Press: New York, 1967;
Vol. 9, p 483. Dyke, S. F.; Quessy, S. N. In The Alkaloids; Rodrigo, R.
G. A., Ed.; Academic Press: New York, 1981; Vol. 18, p 1. J ackson, A.
H. In The Chemistry and Biology of Isoquinoline Alkaloids; Phillipson,
J . D., Roberts, M. F., Zenk, M. H., Eds.; Springer: Berlin, 1985; p 62.
Deulofeu, V. In Curare and Curarelike Agents; Bovet, D., Bovet-Nitti,
F., Marini-Bettolo, G. B., Eds; Elsevier: Amsterdam, 1959; p 163.
(43) Mondon, A. Chem. Ber. 1959, 92, 1461 and 1472. Mondon, A.;
Hansen, K. F. Tetrahedron Lett. 1960, 5. Mondon, A.; Nestler, H. J .
Angew. Chem., Int. Ed. Engl. 1964, 3, 588. Sano, T.; Toda, J .;
Kashiwaba, N.; Oshima, T.; Tsuda, Y. Chem. Pharm. Bull. 1987, 35,
479. Sano, T. J . Org. Chem. 1985, 50, 5667. Ahmad-Schofiel, R.;
Mariano, P. S. J . Org. Chem. 1987, 52, 1478. Ishibashi, H.; Sato, T.;
Takahashi, M.; Hayashi, M.; Ikeda, M. Heterocycles 1988, 27, 2787.
Belleau, B. Can. J . Chem. 1957, 35, 651. Prelog, V.; Langemann, A.;
Rodig, O.; Ternmah, M. Helv. Chim. Acta 1959, 42, 1301. Sugasawa,
S.; Yoshikawa, H. Chem. Pharm. Bull. 1960, 8, 290. Mu¨ller, M.;
Grossnickle, T. T.; Boekelheide, V. J . Am. Chem. Soc. 1959, 81, 3959.
(39) Another possibility suggested by one of the reviewers is that
the lower rate of the overall cascade process from thioketals can be
accounted for in terms of steric factors, both in the closure of the lactam
ring and in the generation of the quaternary carbon present in 21 and
22.

Mannich Cyclization Reactions
Sch em e 10
J . Org. Chem., Vol. 65, No. 1, 2000 239
Sch em e 12
Sch em e 11
group could be used as a nucleophilic center to trap the
N-acyliminium ion derived from the transient alkylthio-
substituted lactam (i.e., 45) (Scheme 12). Our eventual
goal is to utilize this sequence for a synthesis of elaeo-
carpidine (49).45 This particular alkaloid possesses a 1,3-
diazapentacyclic ring system and represents one of the
few indole alkaloids that contain three nitrogen atoms.
We were gratified to find that heating a sample of 43 or
44 with DMTSF in CH2Cl2 gave rise to the desired
pyrimidine-2,6-diones 46 and 47 in 60% and 73% yield,
respectively. Further efforts to streamline this protocol
and to utilize the sequence to complete the synthesis of
elaeocarpidine are in progress and will be reported in due
course.
In conclusion, this paper describes a versatile new
approach to azapolycyclic ring systems with various
substitution patterns that can be applied toward the
synthesis of the core skeleton of several alkaloids. The
synthetic procedure described here involves the reaction
of an amido-substituted thioacetal with dimethyl(meth-
ylthio)sulfonium fluoroborate (DMTSF). The initially
formed thionium ion is attacked by the adjacent amido
nitrogen atom to produce a transient alkylthio-substi-
tuted lactam. Further reaction of the lactam with DMTSF
generates an N-acyliminium ion, which undergoes sub-
sequent cyclization with the tethered aromatic ring. This
reaction sequence was used for the synthesis of the
azapentacyclic skeleton of the erythrina alkaloid family.
Further studies of the thionium initiated Mannich reac-
tion are in progress and will be reported in due course.
prominent theme for elaborating the fully substituted
carbon center at the BC ring fusion has been trapping of
N-acyliminium ion intermediates with electron-rich aryl
rings.44 The retrosynthetic analysis to which we were
attracted involved the use of an amido thioacetal such
as 38 (Scheme 10). The central feature of this approach
consists of a DMTSF-initiated Pummerer/Mannich ion
cyclization. This sequence of reactions allows for a rapid
entry into the erythrinane skeleton, where the key ABC
ring system would be assembled in a single operation.
As a target to test the feasibility of this approach
toward the erythrinane skeleton, we chose to study the
DMTSF-induced reaction of amido thioacetal 41 as a
model system. Acyclic thioketal 40 was obtained from the
known ketoacid 39 and was easily converted to amide
41 in excellent yield. We were pleased to find that
treatment of 41 with 2 equiv of DMTSF proceeded
smoothly at reflux in CH2Cl2 to give the desired indolo-
isoquinolinone 42 in 71% yield (Scheme 11). The short
number of steps to prepare 42 from easily available
starting material suggests that this approach will be
useful for the synthesis of some of the more highly
oxygenated members of the erythrina family of alkaloids.
Work along these lines will be forthcoming in future
publications.
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. All solids were recrystallized from ethyl acetate/hexane
for analytical data.
Sta n d a r d P r oced u r e for th e P r ep a r a tion of Am i-
d od ith ia n es. To a solution containing 1.0 mmol of the
appropriate carboxylic acid in 15 mL of CH2Cl2 was added 1.1
mmol of 1,1′-carbonyl diimidazole. The mixture was stirred
for 1 h at room temperature, and 1.1 mmol of the amine was
added. After stirring for an additional 30 min at 25 °C, the
To further explore the scope and utility of the amido
thioacetal cyclization sequence and its potential use in
alkaloid synthesis, we also chose to study the DMTSF-
promoted reaction of thioketals 43 and 44. These systems
offer the opportunity to test whether a tethered amido
(44) Tsuda, Y.; Sano, T. In Studies in Natural Product Chemistry;
Rahman, A. U., Ed.; Elsevier: Amsterdam, 1989; Vol. 3, Part B, p 455.
(45) Gribble, G. W.; Switzer, F. L.; Soll, R. M. J . Org. Chem. 1988,
53, 3164.

240 J . Org. Chem., Vol. 65, No. 1, 2000
Padwa and Waterson
solution was quenched by the addition of water and was
extracted with CH2Cl2. The combined extracts were dried over
MgSO4, and the solvent was removed under reduced pressure.
The residue was subjected to silica gel chromatography to give
the amidodithiane.
stirred at 25 °C for 5 h, and then 13 mL (180 mmol) of
ethanethiol was added followed by 9.0 mL (71 mmol) of BF3‚
Et2O. The reaction mixture was allowed to stir at 25 °C for 45
min, quenched with water, and extracted with CH2Cl2. The
combined organic layer was dried over MgSO4, and the solvent
was removed under reduced pressure. The residue was sub-
jected to silica gel chromatography to give 8.8 g (59%) of 7 as
4,4-Bis(p h en ylsu lfa n yl)bu tyr ic Acid (4). A solution con-
taining 2.5 mL (36 mmol) of 4-pentenoic acid in 150 mL of
CH2Cl2 was cooled to -78 °C and was treated with a stream
of ozone for 1 h. The ozonide was quenched by the addition of
5.2 mL (71 mmol) of dimethyl sulfide, and the solution was
allowed to warm to room temperature and stirred for an
additional 6 h. To this solution was added 9 mL (89 mmol) of
thiophenol followed by 4.5 mL (36 mmol) of BF3‚OEt2. The
reaction mixture was stirred for 20 min, quenched by the
addition of water, and extracted with CH2Cl2. The combined
organic layers were dried over MgSO4, and the solvent was
removed under reduced pressure. The residue was subjected
to silica gel chromatography to give 5.5 g (51%) of 4 as a white
1
a yellow oil: IR (neat) 3106, 1710, and 1437 cm-1; H NMR
(CDCl3, 400 MHz) δ 1.26 (t, 6H, J ) 7.2 Hz), 2.12 (q, 2H, J )
7.2 Hz), 2.58-2.71 (m, 6H), 3.86 (t, 1H, J ) 7.2 Hz), and 11.75
(brs, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.7, 24.5, 30.7, 31.8,
50.4, and 179.6. Anal. Calcd for C8H16S2O2: C, 46.12; H, 7.74.
Found: C, 46.18; H, 7.73.
N-[2-(3,4-Dim eth oxyph en yl)eth yl]-4,4-bis(eth ylsu lfan yl)-
bu tyr a m id e (8). Using the standard procedure, a 0.5 g (2.4
mmol) sample of acid 7, 0.4 g (2.6 mmol) of 1,1′-carbonyl
diimidazole, and 0.5 mL (2.6 mmol) of 3,4-dimethoxyphen-
ethylamine in 30 mL of CH2Cl2 gave 0.77 g (86%) of 8 as a
white solid: mp 59-60 °C; IR (CHCl3) 3305, 1644, and 1258
solid:46 mp 89-90 °C; IR (CHCl3) 3059, 1710, and 1431 cm-1
;
1
cm-1; H NMR (CDCl3, 400 MHz) δ 1.24 (t, 6H, J ) 7.2 Hz),
1H NMR (CDCl3, 400 MHz) δ 2.15 (q, 2H, J ) 7.2 Hz), 2.72 (t,
2H, J ) 7.2 Hz), 4.47 (t, 1H, J ) 7.2 Hz), 7.29-7.33 (m, 6H),
7.46-7.49 (m, 4H), and 11.42 (brs, 1H); 13C NMR (CDCl3, 100
MHz) δ 30.6, 31.4, 57.5, 128.2, 129.2, 133.1, 133.7, and 179.0.
Anal. Calcd for C16H16S2O2: C, 63.13; H, 5.30. Found: C, 63.41;
H, 5.34.
2.12 (q, 2H, J ) 7.2 Hz), 2.38 (t, 2H, J ) 7.2 Hz), 2.54-2.69
(m, 4H), 2.76 (t, 2H, J ) 7.2 Hz), 3.50 (dd, 2H, J ) 12.8 and
6.8 Hz), 3.81 (t, 1H, J ) 7.2 Hz), 3.87 (s, 3H), 3.88 (s, 3H),
5.55 (brs, 1H), 6.72-6.74 (m, 2H), and 6.82 (d, 1H, J ) 8.0
Hz); 13C NMR (CDCl3, 100 MHz) δ 14.7, 24.5, 31.5, 34.1, 35.5,
40.9, 50.6, 56.0, 56.1, 111.6, 112.0, 120.8, 131.5, 147.9, 149.2,
and 172.1. Anal. Calcd for C18H29NS2O3: C, 58.19; H, 7.87; N,
3.77. Found: C, 58.29; H, 7.83; N, 3.75.
N-[2-(3,4-Dim eth oxyp h en yl)eth yl]-4,4-bis(p h en ylsu lfa -
n yl)bu tyr a m id e (5). To a solution containing 1.0 g (3.3 mmol)
of the above carboxylic acid in 50 mL of CH2Cl2 was added 3.3
mL (6.6 mmol) of a 2.0 M solution of 1,1′-carbonyl diimidazole
in CH2Cl2. To this solution was added 3 drops of DMF, and
the reaction mixture was stirred at 25 °C for 2 h. The solvent
and excess oxalyl chloride were removed under reduced
pressure, and the residue was taken up in 40 mL of CH2Cl2
and cooled to 0 °C. To this solution was added 0.6 mL (3.6
mmol) of 3,4-dimethoxyphenethylamine followed by 0.5 mL
(3.6 mmol) of triethylamine. The mixture was allowed to stir
at 25 °C for 20 min, diluted with water, and extracted with
CH2Cl2. The combined organic layers were dried over MgSO4,
and the solvent was removed under reduced pressure. The
residue was subjected to silica gel chromatography to give 1.4
g (93%) of 5 as a white solid: mp 102-103 °C; IR (CHCl3) 3312,
To a solution containing 0.2 g (0.5 mmol) of 8 in 20 mL of
CH2Cl2 was added 0.2 g (1.1 mmol) of DMTSF. The reaction
mixture was allowed to stir at room temperature for 12 h, and
the solvent was removed under reduced pressure. The residue
was subjected to silica gel chromatography to give 0.13 g (98%)
of isoquinolinone 6.
5,5-Bis(m eth ylsu lfa n yl)p en ta n oic Acid (14). To a solu-
tion containing 2 mL (21 mmol) of bis(methylthio)methane in
60 mL of THF at -78 °C was added 10 mL (23 mmol) of a 2.3
M solution of n-BuLi in hexane. The solution was allowed to
warm to 0 °C, stirred for 2 h, and cooled to -78 °C. To this
solution was added 1.7 g (10 mmol) of 4-bromobutyric acid (13),
and the reaction mixture was stirred at 25 °C for 3 h. The
mixture was quenched by the addition of water, acidified with
10% HCl, and extracted with CH2Cl2. The combined organic
layer was dried over MgSO4, and the solvent was removed
under reduced pressure. The residue was subjected to silica
gel chromatography to give 1.6 g (80%) of 14 as a white solid:
mp 39-40 °C; IR (CHCl3) 3059, 1703, and 1437 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 1.78-1.90 (m, 4H), 2.10 (s, 6H), 2.40 (t,
2H, J ) 7.2 Hz), 3.65 (t, 1H, J ) 7.2 Hz), and 11.50 (brs, 1H);
13C NMR (CDCl3, 100 MHz) δ 12.5, 22.7, 33.4, 33.8, 54.0, and
180.0. Anal. Calcd for C7H14S2O2: C, 43.27; H, 7.26. Found:
C, 43.37; H, 7.29.
1
1637, and 1511 cm-1; H NMR (CDCl3, 400 MHz) δ 2.18 (q,
2H, J ) 7.2 Hz), 2.54 (t, 2H, J ) 7.2 Hz), 2.72 (t, 2H, J ) 6.8
Hz), 3.47 (dd, 2H, J ) 12.8 and 6.8 Hz), 3.85 (s, 3H), 3.86 (s,
3H), 4.51 (t, 1H, J ) 6.8 Hz), 5.42 (brs, 1H), 6.69-6.71 (m,
2H), 6.78-6.79 (m, 1H), 7.25-7.33 (m, 6H), and 7.43-7.46 (m,
4H); 13C NMR (CDCl3, 100 MHz) δ 31.6, 33.8, 35.5, 56.0, 56.1,
57.4, 111.5, 112.0, 120.8, 128.0, 129.2, 131.4, 132.8, 134.0,
147.9, 149.3, and 171.7. Anal. Calcd for C25H29NS2O3: C, 66.78;
H, 6.25; N, 3.00. Found: C, 66.60; H, 6.21; N, 2.93.
8,9-Dim eth oxy-1,5,6,10b-tetr a h yd r o-2H-p yr r olo[2,1-a ]-
isoqu in olin -3-on e (6). To a solution containing 0.09 g (0.2
mmol) of amide 5 in 15 mL of CH2Cl2 was added 0.08 g (0.4
mmol) of DMTSF. The reaction mixture was stirred for 12 h
at room temperature, and the solvent was removed under
reduced pressure. The residue was subjected to silica gel
chromatography to give 0.035 g (64%) of 6 as a white solid:
mp 97-99 °C; IR (CHCl3) 1682, 1609, and 1517 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 1.77 (m, 1H), 2.36-2.43 (m, 1H), 2.47-
2.64 (m, 3H), 2.78-2.86 (m, 1H), 2.95 (td, 1H, J ) 12.8 and
4.4 Hz), 3.80 (s, 3H), 3.81 (s, 3H), 4.23 (ddd, 1H, J ) 12.8, 6.0,
and 2.0 Hz), 4.67 (t, 1H, J ) 8.0 Hz), 6.52 (s, 1H), and 6.56 (s,
1H); 13C NMR (CDCl3, 100 MHz) δ 27.8, 28.1, 31.8, 37.0, 55.9,
56.0, 56.5, 107.6, 111.6, 125.5, 129.3, 147.8, 148.0, and 173.1.
Anal. Calcd for C14H17NO3: C, 68.00; H, 6.93; N, 5.66. Found:
C, 67.92; H, 6.85; N, 5.46.
N-[2-(3,4-Dim eth oxyp h en yl)eth yl]-5,5-bis(m eth ylsu lfa -
n yl)p en ta n a m id e (15). Using the standard procedure, a 0.2
g (1.0 mmol) sample of the above acid, 0.18 g (1.1 mmol) of
1,1′-carbonyl diimidazole, and 0.2 mL (1.0 mmol) of 3,4-
dimethoxyphenethylamine in 15 mL of CH2Cl2 gave 0.28 g
(77%) of 15 as a white solid: mp 99-100 °C; IR (CHCl3) 3312,
1637, and 1517 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.74-1.81
(m, 2H), 1.83-1.88 (m, 2H), 2.09 (s, 6H), 2.16 (t, 2H, J ) 7.2
Hz), 2.77 (t, 1H, J ) 6.8 Hz), 3.51 (dd, 2H, J ) 13.2 and 6.8
Hz), 3.62 (t, 2H, J ) 7.2 Hz), 3.87 (s, 3H), 3.88 (s, 3H), 5.44
(brs, 1H), 6.72-6.75 (m, 2H), and 6.82 (d, 1H, J ) 8.0 Hz); 13
C
NMR (CDCl3, 100 MHz) δ 12.8, 24.0, 34.3, 25.5, 36.2, 40.9,
54.3, 56.1, 56.2, 111.5, 112.0, 120.8, 131.5, 147.8, 149.2, and
172.5. Anal. Calcd for C17H27NS2O3: C, 57.11; H, 7.61; N, 3.92.
Found: C, 57.36; H, 7.68; H, 3.85.
4,4-Bis(eth ylsu lfa n yl)bu tyr ic Acid (7). A solution con-
taining 5.0 mL (70 mmol) of 4-pentenoic acid in 250 mL of
CH2Cl2 was cooled to -78 °C and was treated with a stream
of ozone for 1.5 h. The ozonide was quenched by the addition
of 10 mL (140 mmol) of dimethyl sulfide. The solution was
9,10-Dim eth oxy-1,2,3,6,7,11b-h exa h yd r op yr r id o[2,1-a ]-
isoqu in olin -4-on e (16). To a solution of 0.1 g (0.28 mmol) of
thioacetal 15 in 10 mL of CH2Cl2 was added 0.12 g (0.6 mmol)
of DMTSF. The reaction mixture was allowed to stir at room
temperature for 12 h, and the solvent was removed under
reduced pressure. The residue was subjected to silica gel
chromatography to give 0.07 g (99%) of 16 as a white solid:
mp 88-90 °C; IR (CHCl3) 1638, 1510, and 1446 cm-1; 1H NMR
(46) Cronin, J . P.; Dilworth, B. M.; McKervey, M. A. Tetrahedron
Lett. 1986, 27, 757.

Mannich Cyclization Reactions
J . Org. Chem., Vol. 65, No. 1, 2000 241
(CDCl3, 400 MHz) δ 1.58-1.69 (m, 1H), 1.76-1.87 (m, 1H),
1.88-1.96 (m, 1H), 2.29-2.38 (m, 1H), 2.48-2.63 (m, 3H),
2.74-2.91 (m, 2H), 3.84 (s, 3H), 3.85 (s, 3H), 4.58 (dd, 1H, J )
10.8 and 4.4 Hz), 4.85 (ddd, 1H, J ) 12.0, 4.4, and 2.0 Hz),
6.59 (s, 1H), and 6.65 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ
19.7, 28.6, 31.1, 32.3, 39.8, 56.0, 56.2, 56.8, 108.3, 111.6, 127.4,
129.2, 147.8, 147.9, and 169.4. Anal. Calcd for C15H19NO3: C,
68.93; H, 7.33; N, 5.36. Found: C, 68.85; H, 7.18; N, 5.26.
4,4-Bis(eth ylsu lfa n yl)p en ta n oic Acid . To a solution con-
taining 1.0 g (8.6 mmol) of leveulinic acid and 10 mL of
concentrated hydrochloric acid was added 1.6 mL (22 mmol)
of ethanethiol. The reaction mixture was stirred at room
temperature for 1.5 h and diluted with 50 mL of water. The
mixture was extracted with CH2Cl2, the combined organic
layer was washed with brine and dried over MgSO4, and the
solvent was removed under reduced pressure. The residue was
subjected to silica gel chromatography to give 1.4 g (71%) of
the title compound as a colorless oil: IR (neat) 3150, 1710,
and 1445 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.23 (t, 6H, J )
9.6 Hz), 1.53 (s, 3H), 2.06-2.12 (m, 2H), 2.58-2.65 (m, 6H),
and 10.82 (brs, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.4, 23.8,
27.8, 30.0, 36.2, 59.0, and 179.1. Anal. Calcd for C9H18O2S2:
C, 48.61; H, 8.16. Found: C, 48.87; H, 8.20.
and 1265 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.22 (t, 6H, J )
10.4 Hz), 1.53 (s, 3H), 1.70-1.75 (m, 2H), 1.78-1.87 (m, 2H),
2.14 (t, 2H, J ) 7.2 Hz), 2.60 (q, 4H, J ) 10.4 Hz), 2.77 (t, 2H,
J ) 6.9 Hz), 3.50 (dd, 2H, J ) 13.2 and 6.9 Hz), 3.87 (s, 3H),
3.88 (s, 3H), 5.43 (brs, 1H), 6.72-6.75 (m, 2H), and 6.82 (d,
1H, J ) 8.4 Hz); 13C NMR (CDCl3, 75 MHz) δ 14.4, 21.3, 23.6,
27.8, 35.6, 36.8, 40.9, 41.4, 56.1, 56.2, 59.7, 111.5, 112.0, 120.7,
131.5, 147.7, 149.1, and 172.3. Anal. Calcd for C19H31NS2O3:
C, 60.11; H, 8.32; N, 3.51. Found: C, 60.14; H, 6.32; N, 3.48.
9,10-Dim eth oxy-11b-m eth yl-1,2,3,6,7,11b-h exa h yd r op y-
r id o[2,1-a ]isoqu in olin -4-on e (22). A solution containing 0.1
g (0.3 mmol) of 18 and 0.1 g (0.6 mmol) of DMTSF in 10 mL
of CH2Cl2 was heated at reflux for 24 h. The mixture was
allowed to cool, and the solvent was removed under reduced
pressure. The residue was subjected to silica gel chromatog-
raphy to give 0.5 g (78%) of 22 as a white solid: mp 97-98
1
°C; IR (CHCl3) 1634, 1513, and 1253 cm-1; H NMR (CDCl3,
400 MHz) δ 1.51 (s, 3H), 2.08 (q, 1H, J ) 11.2 Hz), 2.34-2.47
(m, 2H), 2.59-2.75 (m, 2H), 2.84-2.96 (m, 1H), 3.03-3.11 (m,
1H), 3.86 (s, 3H), 3.88 (s, 3H), 3.89-3.91(m, 2H), 4.30 (dd, 1H,
J ) 13.2 and 6.8 Hz), and 6.57 (s, 2H); 13C NMR (CDCl3, 100
MHz) δ 27.4, 28.24, 30.9, 34.2, 34.8, 56.0, 56.2, 60.9, 61.1,
107.9, 111.6, 124.5, 134.7, 147.9, 148.1, and 172.4. Anal. Calcd
for C16H21NO3: C, 69.79; H, 7.69; N, 5.09. Found: C, 69.55;
H, 7.42; N, 5.01.
N-[2-(3,4-Dim eth oxyph en yl)eth yl]-3-(2-m eth yl-[1,3]dith i-
ola n e-2-yl)p r op ion a m id e (19). Using the standard proce-
dure, 0.6 g (3.0 mmol) of 3-(2-methyl-[1,3]dithiolan-2-yl)-
propionic acid,35 0.5 g (3.3 mmol) of 1,1′-carbonyl diimidazole,
and 1.1 mL (6.7 mmol) of 3,4-dimethoxyphenethylamine in 50
mL of CH2Cl2 gave 0.96 g (86%) of 19 as a colorless oil: IR
(neat) 3309, 1656, and 1265 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 1.76 (s, 3H), 2.21-2.25 (m, 2H), 2.39-2.43 (m, 2H), 2.77 (t,
2H, J ) 6.8 Hz), 3.24-3.37 (m, 4H), 3.50 (dd, 2H, J ) 12.8,
6.8 Hz), 3.87 (s, 3H), 3.88 (s, 3H), 5.60 (brs, 1H), 6.72-6.74
(m, 2H), and 6.82 (d, 1H, J ) 8.0 Hz); 13C NMR (CDCl3, 100
MHz) δ 33.0, 34.4, 35.4, 40.3, 40.5, 40.9, 56.0, 56.1, 66.5, 111.5,
112.0, 120.0, 131.5, 147.8, 149.2, and 172.5. Anal. Calcd for
4,4-Bis(eth ylsu lfa n yl)-N-[2-(3,4-d im eth oxyp h en yl)eth -
yl]p en ta n a m id e (17). Using the standard procedure, a 1.4 g
(6.0 mmol) sample of the above acid, 1.0 g (6.4 mmol) of 1,1′-
carbonyl diimidazole, and 1.1 mL (6.7 mmol) of 3,4-dimethoxy-
phenethylamine in 50 mL gave 2.1 g (90%) of 17 as a colorless
oil: IR (neat) 3298, 1650, and 1258 cm-1 1H NMR (CDCl3,
;
400 MHz) δ 1.22 (t, 6H, J ) 7.6 Hz), 1.51 (s, 3H), 2.07-2.11
(m, 2H), 2.34-2.38 (m, 2H), 2.60 (q, 4H, J ) 7.6 Hz), 2.76 (t,
2H, J ) 6.8 Hz), 3.50 (dd, 2H, J ) 13.2 and 7.2 Hz), 3.87 (s,
3H), 3.88 (s, 3H), 5.51 (brs, 1H), 6.72-6.74 (m, 2H), and 6.82
(d, 1H, J ) 8.0 Hz); 13C NMR (CDCl3, 100 MHz) δ 14.2, 23.6,
27.9, 32.2, 35.4, 36.9, 40.9, 56.0, 56.1, 59.2, 111.5, 112.0, 120.8,
131.5, 147.9, 149.2, and 172.4. Anal. Calcd for C19H31NS2O3:
C, 59.19; H, 8.10; N, 3.63. Found: C, 59.17; H, 8.11; N, 3.64.
8,9-Dim eth oxy-10b-m eth yl-1,5,6,10b-tetr ah ydr o-2H-pyr -
r olo[2,1-a ]isoqu in olin -3-on e (21). A solution containing 0.2
g (0.5 mmol) of amide 17 and 0.2 g (1.1 mmol) of DMTSF in
10 mL of CH2Cl2 was heated at reflux for 12 h. The reaction
mixture was allowed to cool, and the solvent was removed
under reduced pressure. The residue was subjected to silica
gel chromatography to give 0.1 g (76%) of 21 as a white solid:
mp 120-121 °C; IR (neat) 2965, 1519, and 1259 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 1.49 (d, 1H, J ) 8.0 Hz), 1.51 (s, 3H),
2.05-2.17 (m, 1H), 2.34-2.41 (m, 1H), 2.44 (tt, 1H, J ) 9.6
and 1.6 Hz), 2.59-2.70 (m, 2H), 2.85-2.94 (m, 1H), 3.03-3.11
(m, 1H), 3.86 (s, 3H), 3.88 (s, 3H), 4.24-4.32 (m, 1H), and 6.57
(s, 2H); 13C NMR (CDCl3, 100 MHz) δ 27.5, 28.3, 30.9, 34.2,
34.9, 56.0, 56.3, 61.2, 108.0, 111.6, 124.6, 134.8, 147.9, 148.2,
and 172.5. Anal. Calcd for C15H19NO3: C, 68.94; H, 7.33; N,
5.36. Found: C, 68.76; H, 7.36; N, 5.25.
5,5-Bis(eth ylsu lfa n yl)h exa n oic Acid . To a solution con-
taining 3.0 mL (25 mmol) of 4-acetylbutyric acid in 40 mL of
concentrated hydrochloric acid was added 4.7 mL (63 mmol)
of ethanethiol. The reaction mixture was stirred at room
temperature for 12 h and diluted with 50 mL of water. The
mixture was extracted with CH2Cl2, the combined organic
layer was washed with brine and dried over MgSO4, and the
solvent was removed under reduced pressure. The residue was
subjected to silica gel chromatography to give 3.9 g (65%) of
the title compound as a white solid: mp 27-28 °C; IR (CHCl3)
3230, 1705, and 1440 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.23
(t, 6H, J ) 7.5 Hz), 1.54 (s, 3H), 1.74-1.90 (m, 4H), 2.38 (t,
2H, J ) 6.9 Hz), 2.61 (q, 4H, J ) 7.5 Hz), and 11.0 (brs, 1H);
13C NMR (CDCl3, 100 MHz) δ 14.4, 20.3, 23.7, 27.8, 34.1, 41.2,
59.7, and 179.3. Anal. Calcd for C10H20O2S2: C, 50.81; H, 8.53.
Found: C, 51.02; H, 8.52.
C
17H25NS2O3: C, 57.44; H, 7.09; N, 3.94. Found: C, 57.29; H,
7.20; N, 3.74.
A solution containing 0.12 g (0.34 mmol) of 19, 0.15 g (0.74
mmol) of DMTSF, and 10 mL of dichloroethane was heated at
reflux for 24 h. The reaction mixture was allowed to cool, and
the solvent was removed under reduced pressure. The residue
was subjected to silica gel chromatography to give 0.07 g (76%)
of 21.
4-(2-Meth yl-[1,3]d ith iola n -2-yl)bu tyr ic Acid . A solution
containing 1.0 mL (8.4 mmol) of 4-acetylbutyric acid and 0.7
mL (8.0 mmol) of ethanedithiol was cooled to 0 °C. To this
solution was added 2.2 mL (18 mmol) of BF3‚OEt2, and the
reaction mixture was stirred at 0 °C for 5 h. The mixture was
quenched by the addition of 0.5 mL of methanol, diluted with
50 mL of water, and extracted with CH2Cl2. The combined
organic layer was washed with brine and dried over MgSO4,
and the solvent was removed under reduced pressure. The
residue was subjected to silica gel chromatography to give 1.6
g (92%) of the title compound as a colorless oil: IR (neat) 3199,
1708, and 1265 cm-1 1H NMR (CDCl3, 400 MHz) δ 1.78 (s,
;
3H), 1.86-1.93 (m, 2H), 1.95-2.00 (m, 2H), 2.40 (t, 2H, J )
6.8 Hz), 3.30-3.37 (m, 4H), and 10.32 (brs, 1H); 13C NMR
(CDCl3, 100 MHz) δ 22.6, 32.6, 34.1, 40.2, 45.1, 66.5, and 179.5.
Anal. Calcd for C8H14O2S2: C, 46.57; H, 6.84. Found: C, 46.62;
H, 6.82.
N-[2-(3,4-Dim eth oxyph en yl)eth yl]-4-(2-m eth yl-[1,3]dith i-
ola n -2-yl)bu tyr a m id e (20). Using the standard procedure,
a 0.5 g (2.4 mmol) sample of the above carboxylic acid, 0.4 g
(2.5 mmol) of 1,1′-carbonyl diimidazole, and 0.5 mL (2.7 mmol)
of 3,4-dimethoxyphenethylamine in 20 mL of CH2Cl2 gave 0.85
g (96%) of 20 as a colorless oil: IR (neat) 3305, 1640, and 1270
5,5-Bis(eth ylsu lfa n yl)-N-[2-(3,4-d im eth oxyp h en yl)eth -
yl]h exa n a m id e (18). Using the standard procedure, a 0.5 g
(2.0 mmol) sample of the above carboxylic acid, 0.4 g (2.0 mmol)
of 1,1′-carbonyl diimidazole, and 0.4 mL (2.0 mmol) of 3,4-
dimethoxyphenethylamine in 20 mL of CH2Cl2 gave 0.8 g (95%)
of 18 as a white solid: mp 60-61 °C; IR (CHCl3) 3298, 1637,
cm-1 1H NMR (CDCl3, 400 MHz) δ 1.75 (s, 3H), 1.82-1.94
;
(m, 4H), 2.18 (t, 2H, J ) 7.2 Hz), 2.77 (t, 2H, J ) 7.2 Hz),
3.25-3.37 (m, 4H), 3.50 (dd, 2H, J ) 12.8 and 6.8 Hz), 3.86 (s,
3H), 3.87 (s, 3H), 5.62 (brs, 1H), 6.72-6.74 (m, 2H), and 6.82
(d, 1H, J ) 7.6 Hz); 13C NMR (CDCl3, 100 MHz) δ 23.6, 32.5,
35.4, 36.6, 40.1, 40.8, 45.2, 56.0, 56.1, 60.5, 66.6, 111.4, 111.9,

242 J . Org. Chem., Vol. 65, No. 1, 2000
Padwa and Waterson
120.8, 131.5, 147.8, 149.1, and 172.5. Anal. Calcd for C18H27
NS2O3: C, 58.51; H, 7.36; N, 3.79. Found: C, 58.49; H, 7.34;
N, 3.85.
A solution containing 0.14 g (0.4 mmol) of 20, 0.16 g (0.8
mmol) of DMTSF, and 10 mL of dichloroethane was heated at
reflux for 36 h. The reaction mixture was allowed to cool, and
the solvent was removed under reduced pressure. The residue
was subjected to silica gel chromatography to give 0.68 g (75%)
of 22.
-
2H, J ) 6.4 Hz), 3.84 (t, 1H, J ) 7.2 Hz), 5.51 (d, 1H, J ) 2.0
Hz), 5.65-5.66 (m, 1H), and 5.75 (brs, 1H); 13C NMR (CDCl3,
100 MHz) δ 14.7, 24.5, 31.4, 34.0, 37.7, 41.2, 50.5, 119.4, 131.2,
and 172.3. Anal. Calcd for C12H22NS2OBr: C, 42.35; H, 6.52;
N, 4.12. Found: C, 42.48; H, 6.57; N, 4.13.
Hexa h yd r oin d olizin -3,7-d ion e (31). A solution containing
0.1 g (0.3 mmol) of 29 and 15 mL of CH2Cl2 was cooled to -40
°C. To this was added 0.13 g (0.65 mmol) of DMTSF. The
reaction mixture was stirred at room temperature for 3.5 h,
and the solvent was removed under reduced pressure. The
crude residue contained 7-bromo-7-fluorohexahydroindolizin-
3-one40 as a1:1 mixture of diastereomers. Without purification,
this mixture was taken up in 5 mL of 98% formic acid, and
0.14 g (0.4 mmol) of Hg(OAc)2 was added. The reaction mixture
was stirred at room temperature for 12 h, poured into water,
and extracted with CH2Cl2. The combined organic layer was
dried over MgSO4, and the solvent was removed under reduced
pressure. The residue was subjected to silica gel chromatog-
raphy to give 0.03 g (65%) of 31 as a white solid: mp: 54-55
N-((2-Cycloh ex-1-en yl)eth yl)-4,4-bis(eth ylsu lfa n yl)bu -
tyr a m id e (25). Using the standard procedure, 0.7 g (3.2 mmol)
of 4,4-bis(ethylsulfanyl)butyric acid, 0.5 g (3.4 mmol) of 1,1′-
carbonyl diimidazole, and 0.5 mL (4.0 mmol) of 2-(1-cyclohex-
enyl)ethylamine in 30 mL of CH2Cl2 gave 1.0 g (98%) of 25 as
a white solid: mp 41-42 °C; IR (CHCl3) 3305, 1650, 1444 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 1.26 (t, 6H, J ) 7.2 Hz), 1.53-
1.65 (m, 4H), 1.90-1.93 (m, 2H), 1.97-2.03 (m, 2H), 2.10-
2.16 (m, 4H), 2.41 (t, 2H, J ) 7.2 Hz), 2.56-2.73 (m, 4H), 3.33
(dd, 2H, J ) 12.4 and 7.2 Hz), 3.84 (t, 1H, J ) 7.2 Hz), 5.45-
5.49 (m, 1H), and 5.52 (brs, 1H); 13C NMR (CDCl3, 100 MHz)
δ 14.7, 22.5, 23.0, 42.5, 25.4, 28.0, 31.5, 34.1, 37.3, 37.8, 50.6,
123.8, 134.8, and 171.9. Anal. Calcd for C16H29NS2O: C, 60.91;
H, 9.26; N, 4.44. Found: C, 60.72; H, 9.12; N, 4.41.
1
°C; IR (CHCl3) 1710, 1620, and 1420 cm-1; H NMR (CDCl3,
400 MHz) δ 1.72-1.81 (m, 1H), 2.30 (dd, 1H, J ) 14.4 and
12.0 Hz), 2.35-2.53 (m, 5H), 2.62 (ddd, 1H, J ) 14.4, 10.0,
and 1.6 Hz), 2.97-3.04 (m, 1H), 3.81-3.88 (m, 1H), and 4.43
(ddd, 1H, J ) 13.2, 6.8, and 3.2 Hz); 13C NMR (CDCl3, 100
MHz) δ 25.2, 29.9, 38.2, 40.1, 48.8, 56.6, 173.9, and 206.5. Anal.
Calcd for C8H11NO2: C, 62.71; H, 7.24; N, 9.15. Found: C,
62.59; H, 7.08; N, 9.26.
1,5,7,8,9,10,10a ,10b-Oct a h yd r o-2H -p yr r olo[2,1-a ]iso-
qu in olin -3-on e (27). To a solution containing 0.1 g (0.3 mmol)
of 25 and 20 mL of CH2Cl2 was added 0.13 g (0.7 mmol) of
DMTSF. The reaction mixture was stirred at room tempera-
ture for 24 h. The solvent was removed under reduced
pressure, and the residue was subjected to silica gel chroma-
tography to give 0.03 g (48%) of 27 as a colorless oil: IR (neat)
2926, 1697, and 1418 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.40-
1.72 (m, 5H), 1.82-1.91 (m, 2H), 1.99-2.28 (m, 4H), 2.37-
2.43 (m, 2H), 2.60 (td, 1H, J ) 12.8 and 4.0 Hz), 3.07 (dt, 1H,
J ) 9.6 and 7.6 Hz), 4.15 (ddd, 1H, J ) 12.8, 5.6, and 1.2 Hz),
and 5.59-6.62 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 21.9,
24.1, 26.3, 26.8, 31.5, 34.5, 41.6, 44.6, 63.9, 124.5, 136.4, and
173.7. Anal. Calcd for C12H17NO: C, 75.35; H, 8.96; N, 7.32.
Found: C, 75.51; H, 9.01; N, 7.12.
N-(3-Br om obu t-3-en yl)-5,5-bis(m eth ylsu lfa n yl)p en ta n -
a m id e (30). Using the standard procedure, 0.6 g (3.1 mmol)
of 5,5-bis(methylsulfanyl)pentanoic acid, 0.5 g (3.1 mmol) of
1,1′-carbonyl diimidazole, and 0.46 g (3.1 mmol) of 3-bromo-
3-butenylamine in 25 mL of CH2Cl2 gave 0.9 g (91%) of 30 as
a colorless oil: IR (neat) 3284, 1653, and 1432 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 1.76-1.92 (m, 4H), 2.09 (s, 6H), 2.21 (t,
2H, J ) 6.8 Hz), 2.64 (td, 2H, J ) 6.4 and 6.8 Hz), 3.47 (q, 2H,
J ) 6.4 Hz), 3.63 (t, 1H, J ) 6.8 Hz), 5.51 (d, 1H, J ) 1.6 Hz),
1
5.65-5.66 (m, 1H), and 5.77 (brs, 1H); C NMR (CDCl3, 100
MHz) δ 12.8, 23.9, 34.2, 36.0, 37.6, 41.2, 54.2, 119.3, 131.2,
and 172.7. Anal. Calcd for C11H20NS2OBr: C, 40.49; H, 6.18;
N, 4.29. Found: C, 40.67; H, 6.22; N, 4.26.
N-(2-Cycloh ex-1-en yl)-5,5-bis(m eth ylsu lfa n yl)p en ta n -
a m id e (26). Using the standard procedure, 0.64 g (3.3 mmol)
of 5,5-bis(methylsulfanyl)pentanoic acid, 0.6 g (3.5 mmol) of
1,1′-carbonyl diimidazole, and 0.5 mL (3.7 mmol) of 2-(1-
cyclohexenyl)ethylamine in 25 mL of CH2Cl2 gave 0.95 g (95%)
of 26 as a white solid: mp 48-49 °C; IR (CHCl3) 3312, 1644,
Octa h yd r oqu in olizin -4,8-d ion e (32). A solution contain-
ing 0.1 g (0.3 mmol) of 30 and 15 mL of CH2Cl2 was cooled to
-40 °C. To this solution was added 0.14 g (0.7 mmol) of
DMTSF. The reaction mixture was stirred at room tempera-
ture for 4 h, and the solvent was removed under reduced
pressure. The residue contained 8-bromo-8-fluoro-octahydro-
quinolizin-4-one40 as a 1:1 mixture of diastereomers. This
mixture was taken up in 5 mL of 98% formic acid, and 0.15 g
(0.46 mmol) of Hg(OAc)2 was added. The reaction mixture was
stirred at room temperature for 12 h, poured into water, and
extracted with CH2Cl2. The combined organic layer was dried
over MgSO4, and the solvent was removed under reduced
pressure. The residue was subjected to silica gel chromatog-
raphy to give 0.03 g (58%) of 32 as a colorless oil: IR (neat)
1725, 1645, and 1450 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.58-
1.66 (m, 1H), 1.76-1.85 (m, 1H), 1.87-1.97 (m, 1H), 2.07-
2.15 (m, 1H), 2.42-2.50 (m, 6H), 2.88-2.95 (m, 1H), 3.71 (dq,
1H, J ) 9.2 and 6.0 Hz), and 4.91 (ddd, 1H, J ) 4.0, 6.0, and
13.2 Hz); 13C NMR (CDCl3, 100 MHz) δ 19.0, 29.8, 32.9, 40.8,
41.1, 48.3, 55.1, 169.7, and 207.1. Anal. Calcd for C9H13NO2:
C, 64.63; H, 7.84; N, 8.38. Found: C, 64.49; H, 7.68; N, 8.17.
4,4,4-Tr is(m eth ylsu lfa n yl)bu tyr ic Acid . To a solution
containing 3.8 mL (8.7 mmol) of a 2.3 M solution of n-BuLi in
hexane and 20 mL of THF at -78 °C was added 1.1 mL (8.0
mmol) of tris(methylthio)methane. The mixture was allowed
to stir at this temperature for 10 min, and 2.9 mL (32 mmol)
of methyl acrylate was added. The reaction mixture was
allowed to stir at -78 °C for 2 h, warmed to room temperature,
and quenched by the addition of water. The mixture was
extracted with CH2Cl2, and the combined organic extracts were
dried over MgSO4. The solvent was removed under reduced
pressure, and the residue was subjected to silica gel chroma-
tography to give 0.76 g (40%) of 4,4,4-tris(methylsulfanyl)-
butyric acid methyl ester as a colorless oil: IR (neat) 1736,
1
and 1431 cm-1; H NMR (CDCl3, 300 MHz) δ 1.54-1.67 (m,
4H), 1.79-1.62 (m, 6H), 1.99-2.03 (m, 2H), 2.10 (s, 6H), 2.13-
2.21 (m, 4H), 3.33 (dd, 2H, J ) 12.0 and 6.9 Hz), 3.63 (t, 1H,
J ) 9.2 Hz), 5.41 (brs, 1H), and 5.45-5.49 (m, 1H); 13C NMR
(CDCl3, 75 MHz) δ 13.0, 22.7, 23.1, 24.1, 25.6, 28.2, 34.4, 36.3,
37.3, 37.9, 54.4, 123.7, 134.7, and 172.2. Anal. Calcd for C15H27
NS2O: C, 59.73; H, 9.03; N, 4.65. Found: C, 59.92; H, 8.99;
N, 4.63.
-
1,2,3,6,8,9,11,11a ,11b-Deca h yd r op yr id o[2,1-a ]isoqu in o-
lin -4-on e (28). To a solution of 0.1 g (0.33 mmol) of 26 in 10
mL of CH2Cl2 was added 0.12 g (0.6 mmol) of DMTSF. The
reaction mixture was stirred at room temperature for 24 h.
The solvent was removed under reduced pressure, and the
residue was subjected to silica gel chromatography to give 0.03
g (49%) of 28 as a colorless oil: IR (neat) 2920, 1644, and 1444
cm-1; 1H NMR (CDCl3, 400 MHz) δ 0.84-0.91 (m, 1H), 1.05-
1.14 (m, 1H), 1.24-1.28 (m, 2H), 1.38-1.47 (m, 1H), 1.75-
1.87 (m, 2H), 1.92-2.02 (m, 3H), 2.06-2.12 (m, 1H), 2.15-
2.17 (m, 2H), 2.28-2.45 (m, 3H), 2.87-2.94 (1H), 4.81 (ddd,
1H, 12.4, 4.0, and 3.2 Hz), and 5.51-5.59 (m, 1H); 13C NMR
(CDCl3, 100 MHz) δ 19.1, 21.9, 25.3, 26.9, 27.4, 33.2, 34.6, 43.5,
62.4, 77.4, 112.8, 136.2, and 201.9. Anal. Calcd for C13H19NO:
C, 76.06; H, 9.33; N, 6.82. Found: C, 75.87; H, 9.21; N, 6.69.
N-(3-Br om ob u t -3-en yl)-4,4-b is(et h ylsu lfa n yl)b u t yr a -
m id e (29). Using the standard procedure, 0.6 g (2.9 mmol) of
4,4-bis(ethylsulfanyl)butyric acid, 0.5 g (3.0 mmol) of 1,1′-
carbonyl diimidazole, and 0.4 g (2.9 mmol) of 3-bromo-3-
butenylamine in 25 mL of CH2Cl2 gave 0.94 g (94%) of 29 as
a colorless oil: IR (neat) 3284, 1639, and 1445 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 1.26 (t, 6H, J ) 7.6 Hz), 2.13 (q, 2H, J )
7.6 Hz), 2.43 (q, 2H, J ) 7.6 Hz), 2.56-2.73 (m, 6H), 3.48 (q,
1431, and 1165 cm-1 1H NMR (CDCl3, 400 MHz) δ 2.10 (s,
;

Mannich Cyclization Reactions
J . Org. Chem., Vol. 65, No. 1, 2000 243
9H), 2.23 (t, 2H, J ) 7.8 Hz), 2.70 (t, 2H, J ) 7.8 Hz), and
3.68 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 13.1, 30.0, 32.5,
51.9, 70.8, and 173.7.
was removed under reduced pressure. The residue was sub-
jected to silica gel chromatography to give 0.36 g (90%) of 34
as a white solid: mp 83-84 °C; IR (CHCl3) 3303, 1659, and
1
To a solution containing 0.5 g (2.0 mmol) of this ester in 25
mL of Et2O was added 0.4 g (3.1 mmol) of potassium trimeth-
ylsilanoate. The reaction mixture was allowed to stir at room
temperature for 12 h, and 25 mL of 10% aqueous HCl was
added. The mixture was allowed to stir for 15 min and was
extracted with CH2Cl2. The combined organic extracts were
dried over MgSO4, and the solvent was removed under reduced
pressure. The residue was subjected to silica gel chromatog-
raphy to give 0.43 g (93%) of the title compound as a white
1517 cm-1; H NMR (CDCl3, 400 MHz) δ 1.87-2.01 (m, 4H),
2.10 (s, 9H), 2.19 (t, 2H, J ) 7.2 Hz), 2.77 (t, 2H, J ) 6.8 Hz),
3.50 (dd, 2H, J ) 6.8 and 6.0 Hz), 3.87 (s, 3H), 3.88 (s, 3H),
5.50 (brs, 1H), 6.72-6.75 (m, 2H), and 6.82 (d, 1H, J ) 7.6
Hz); 13C NMR (CDCl3, 100 MHz) δ 13.2, 21.3, 35.0, 36.1, 37.4,
40.9, 56.1, 56.2, 71.0, 111.5, 112.0, 131.5, 147.8, 149.2, and
172.4. Anal. Calcd for C18H29N1O3S3: C, 53.57; H, 7.24; N, 3.47.
Found: C, 53.67; H, 7.21; N, 3.42.
9,10-Dim eth oxy-2,3,6,7-tetr ah ydr opyr ido[2,1-a ]isoqu in -
olin -4-on e (36). A solution containing 0.1 g (0.25 mmol) of
amide 34, 0.06 mL (0.5 mmol) of dimethyl sulfate, and 10 mL
of CH2Cl2 was heated at reflux for 12 h. The reaction mixture
was allowed to cool to room temperature, and the solvent was
removed under reduced pressure. The residue was subjected
to silica gel chromatography to give 0.05 g (71%) of 36 as a
yellow solid: mp 73-75 °C; IR (CHCl3) 1664, 1604, and 1517
solid: mp 77-78 °C; IR (CHCl3) 3107, 1708, and 1403 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 2.11 (s, 9H), 2.23 (t, 2H, J ) 8.0
Hz), 2.75 (t, 2H, J ) 8.0 Hz), and 9.10 (brs, 1H); 13C NMR
(CDCl3, 100 MHz) δ 13.2, 30.2, 32.4, 70.8, and 179.2. Anal.
Calcd for C7H14O2S3: C, 37.14; H, 6.23. Found: C, 37.25; H,
6.29.
N-[2-(3,4-Dim eth oxyp h en yl)eth yl]-4,4,4-tr is(m eth ylsu l-
fa n yl)bu tyr a m id e (33). To a solution containing 0.23 g (1.0
mmol) of the above carboxylic acid and 15 mL of CH2Cl2 was
added 0.17 g (1.1 mmol) of 1,1′-carbonyl diimidazole. The
mixture was stirred for 30 min, and 0.2 mL (1.1 mmol) of 3,4-
dimethoxyphenethylamine was added. The solution was stirred
at room temperature for 30 min, and the solvent was removed
under reduced pressure. The residue was subjected to silica
gel chromatography to give 0.4 g (100%) of 33 as a white
1
cm-1; H NMR (CDCl3, 300 MHz) δ 2.38-2.45 (m, 2H), 2.57
(t, 2H, J ) 7.8 Hz), 2.77 (t, 2H, J ) 6.0 Hz), 3.88 (s, 3H), 3.89
(s, 3H), 3.90 (t, 2H, J ) 6.0 Hz), 5.68 (t, 1H, J ) 5.4 Hz), 6.61
(s, 1H), and 7.03 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 19.8,
29.1, 31.5, 38.7, 56.2, 56.3, 100.8, 106.9, 110.7, 122.5, 127.4,
135.7, 148.1, 149.2, and 169.9. Anal. Calcd for C15H17NO3: C,
69.48; H, 6.61; N, 5.40. Found: C, 69.35; H, 6.42; N, 5.21.
2-[2,2-Bis((eth ylsu lfa n yl)cycloh exyl)]a cetic Acid (40).
To a solution containing 1.0 g (6.0 mmol) of (2-oxocyclohexyl)-
acetic acid (39)47 in 20 mL of concentrated HCl was added 1.1
mL (16 mmol) of ethanethiol. The reaction mixture was stirred
for 12 h at room temperature, diluted with water, and
extracted with CH2Cl2. The combined organic layers were dried
over MgSO4, and the solvent was removed under reduced
pressure. The residue was subjected to silica gel chromatog-
raphy to give 1.1 g (68%) of 40 as a white solid: mp 99-100
solid: mp 50-51 °C; IR (CHCl3) 3293, 1648, and 1237 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 2.09 (s, 9H), 2.25 (dd, 2H, J )
8.1 and 5.4 Hz), 2.47 (dd, 2H, J ) 8.1 and 5.4 Hz), 2.77 (t, 2H,
J ) 6.9 Hz), 3.50 (dd, 2H, J ) 12.9 and 6.9 Hz), 3.87 (s, 3H),
3.88 (s, 3H), 5.56 (brs, 1H), 6.72-6.75 (m, 2H), and 6.83 (d,
1H, J ) 8.4 Hz); 13C NMR (CDCl3, 75 MHz) δ 13.3, 32.3, 32.8,
35.5, 41.0, 56.1, 56.2, 71.1, 111.4, 111.9, 120.7, 131.4, 147.7,
149.1, and 172.0. Anal. Calcd for C17H27N1O3S3: C, 52.41; H,
6.99; N, 3.60. Found: C, 52.27; H, 7.03; N, 3.59.
°C; IR(CHCl3) 3049, 1701, and 1447 cm-1 1H NMR (CDCl3,
;
8,9-Dim eth oxy-5,6-d ih yd r o-2H-p yr r olo[2,1-a ]isoqu in o-
lin -3-on e (35). A solution containing 0.08 g (0.2 mmol) of the
above amide 33, 0.05 mL (0.5 mmol) of dimethyl sulfate, and
10 mL of CH2Cl2 was heated at reflux for 36 h. The mixture
was cooled to room temperature, the solvent was removed
under reduced pressure, and the residue was subjected to silica
gel chromatography to give 0.025 g (46%) of 35 as a yellow
400 MHz) δ 1.22 (q, 6H, J ) 7.6 Hz), 1.23-1.40 (m, 1H), 1.59-
1.86 (m, 7H), 2.00-2.05 (m, 1H), 2.22 (dd, 1H, J ) 10.4 and
15.6 Hz), 2.29-2.36 (m, 1H), 2.55-2.68 (m, 4H), 3.28 (dd, 1H,
J ) 15.6 and 2.4 Hz), and 10.80 (brs, 1H); 13C NMR (CDCl3,
100 MHz) δ 14.2, 14.3, 22.3, 22.6, 22.9, 24.9, 28.2, 36.3, 36.5,
42.3, 64.3, and 180.0. Anal. Calcd for C12H22S2O2: C, 54.92;
H, 8.45. Found: C, 55.17; H, 8.53.
solid: mp 114-115 °C; IR (CHCl3) 1697, 1597, and 1517 cm-1
;
2-[2,2-Bis(eth ylsu lfa n ylcycloh exyl)]-N[(2-(3,4-d im eth -
oxyp h en yl)eth yl] Aceta m id e (41). Using the standard pro-
cedure, a 1.0 g (4.0 mmol) sample of carboxylic acid 40, 0.7 g
(4.0 mmol) of 1,1′-carbonyl diimidazole, and 0.7 mL (4.0 mmol)
of 3,4-dimethoxyphenethylamine in 50 mL of CH2Cl2 gave 1.6
g (99%) of 41 as a clear oil: IR(CHCl3) 3309, 1643, and 1519
1H NMR (CDCl3, 400 MHz) δ 2.87 (t, 2H, J ) 6.0 Hz), 3.21 (d,
2H, J ) 2.8 Hz), 3.70 (t, 2H, J ) 6.0 Hz), 3.87 (s, 3H), 3.88 (s,
3H), 5.42 (t, 1H, J ) 2.8 Hz), 6.66 (s, 1H), and 6.99 (s, 1H);
13C NMR (CDCl3, 75 MHz) δ 28.6, 37.1, 38.4, 56.2, 56.3, 94.8,
106.7, 111.1, 119.7, 126.9, 139.7, 148.5, 150.0, and 176.8. Anal.
Calcd for C14H15N1O3: C, 68.56; H, 6.16; N, 5.71. Found: C,
68.77; H, 6.31; N, 5.87.
1
cm-1; H NMR (CDCl3, 400 MHz) δ 1.21 (dt, 6H, J ) 8.4 and
7.6 Hz), 1.25-1.32 (m, 1H), 1.52-1.68 (m, 3H), 1.74-1.88 (m,
2H), 2.02-2.05 (m, 1H), 2.38 (tt, 1H, J ) 10.4 and 3.2 Hz),
2.47-2.70 (m, 4H), 2.75 (t, 2H, J ) 6.8 Hz), 3.50 (ddd, 1H, J
) 7.2, 6.0, and 2.8 Hz), 3.87 (s, 3H), 3.88 (s, 3H), 5.49 (t, 1H,
J ) 5.6 Hz), 6.72-6.74 (m, 2H), and 6.81 (d, 1H, J ) 8.4 Hz);
13C NMR (CDCl3, 100 MHz) δ 14.2, 22.1, 22.7, 22.9, 25.3, 28.4,
35.5, 36.5, 39.0, 40.9, 42.5, 56.0, 56.1, 64.4, 111.5, 112.0, 120.8,
131.5, 147.8, 149.2, and 172.6. Anal. Calcd for C22H35NS2O3:
C, 62.08; H, 8.29; N, 3.29. Found: C, 62.19; H, 8.27; N, 3.26.
5,5,5-Tr is(m eth ylsu lfa n yl)p en ta n oic Acid . To a solution
containing 0.3 mL (2.1 mmol) of tris(methylthio)methane and
15 mL of THF at -78 °C was added 1.0 mL (2.3 mmol) of a
2.3 M solution of n-BuLi in hexane. The reaction mixture was
allowed to stir at this temperature for 10 min, and 0.17 g (1.0
mmol) of 4-bromo butanoic acid was added. The reaction
mixture was allowed to warm to room temperature, stirred
for 3 h, quenched by the addition of 10% aqueous HCl, and
extracted with CH2Cl2. The combined organic extracts were
dried over MgSO4, and the solvent was removed under reduced
pressure. The residue was subjected to silica gel chromatog-
raphy to give 0.25 g (100%) of the title compound as a white
11,12-Dim eth oxy-1,2,3,4,4a ,5,8,9-octah ydr oin dolo[1a ,7a ]-
isoqu in olin -6-on e (42). To a solution containing 0.16 g (0.4
mmol) of amide 41 in 10 mL of CH2Cl2 was added 0.16 g (0.8
mmol) of DMTSF. The reaction mixture was heated at reflux
for 12 h, and the solvent was removed under reduced pressure.
The residue was subjected to silica gel chromatography to give
0.08 g (71%) of 42 as a white solid: mp 117-118 °C; IR(CHCl3)
1682, 1513, and 1246 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.51-
1.57 (m, 2H), 1.62-1.75 (m, 3H), 1.82-1.90 (m, 2H), 2.00-
2.09 (m, 1H), 2.35 (dd, 2H, J ) 7.6 and 3.0 Hz), 2.55-2.60 (m,
1H), 2.69 (dq, 1H, J ) 16.4 and 3.0 Hz), 3.00 (ddd, 1H, J )
16.0, 10.0, and 7.6 Hz), 3.19-3.26 (m, 1H), 3.85 (s, 3H), 3.89
solid: mp 64-65 °C; IR (CHCl3) 3119, 1697, and 1424 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 1.89-2.05 (m, 4H), 2.11 (s, 9H),
2.43 (t, 2H, J ) 6.6 Hz), and 8.10 (brs, 1H); 13C NMR (CDCl3,
75 MHz) δ 13.3, 20.5, 33.8, 37.3, 70.9, and 179.1. Anal. Calcd
for C8H16S3O2: C, 39.97; H, 6.71. Found: C, 40.05; H, 6.82.
2-(3,4-Dim et h oxyp h en yl)et h yl-5,5,5-t r is(m et h ylsu lfa -
n yl)p en ta n a m id e (34). To a solution containing 0.24 g (1.0
mmol) of the above carboxylic acid and 15 mL of CH2Cl2 was
added 0.17 g (1.1 mmol) of 1,1′-carbonyl diimidazole. The
mixture was stirred for 30 min, and 0.2 mL (1.1 mmol) of 3,4-
dimethoxyphenethylamine was added. The solution was al-
lowed to stir at room temperature for 30 min, and the solvent
(47) Sucrow, W.; Slopianka, M.; Winkler, D. Chem. Ber. 1972, 105,
1621.

244 J . Org. Chem., Vol. 65, No. 1, 2000
Padwa and Waterson
(s, 3H), 4.08-4.14 (m, 1H), 6.59 (s, 1H), and 6.88 (s, 1H); 13C
NMR (CDCl3, 100 MHz) δ 20.5, 20.9, 27.3, 27.4, 35.0, 36.0,
36.7, 37.8, 56.0, 56.3, 62.4, 108.3, 112.0, 125.9, 135.0, 147.4,
and 147.9. Anal. Calcd for C18H23NO3: C, 71.73; H, 7.69; N,
4.65. Found: C, 71.56; H, 7.61; N, 4.52.
5,5-Bis(m eth ylsu lfa n yl)-N-(2-m eth ylca r ba m oyleth yl)-
p en ta n a m id e (44). Using the standard procedure, a 0.5 g (2.6
mmol) sample of 5,5-bis(methylsulfanyl)pentanoic acid (14),
0.44 g (2.7 mmol) of 1,1′-carbonyl diimidazole, and 0.24 g (2.7
mmol) of 3-amino-N-methylpropionamide48 gave 0.5 g (75%)
of 44 as a white solid: mp 115-116 °C; IR (CHCl3) 3292, 1737,
4,4-Bis(eth ylsu lfa n yl)-N-(2-m eth ylca r ba m oyleth yl)bu -
tyr a m id e (43). Using the standard procedure, 0.1 g (0.47
mmol) of carboxylic acid 7, 0.09 g (0.5 mmol) of 1,1′-carbonyl
diimidazole, and 0.05 g (0.5 mmol) of 3-amino-N-methylpro-
pionamide48 in 10 mL of CH2Cl2 gave 0.12 g (92%) of 43 as a
white solid: mp 118-119 °C; IR (CHCl3) 3305, 1644, and 1551
1
and 1644 cm-1; H NMR (CDCl3, 300 MHz) δ 1.75-1.79 (m,
2H), 1.83-1.87 (m, 2H), 2.08 (s, 6H), 2.18 (t, 2H, J ) 7.2 Hz),
2.40 (t, 2H, J ) 6.0 Hz), 2.81 (d, 3H, J ) 4.0 Hz), 3.52 (q, 2H,
J ) 4.0 Hz), 3.62 (t, 1H, J ) 7.2 Hz), 5.78 (brs, 1H), and
6.36 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 12.8, 23.9, 26.5, 34.2,
35.5, 35.6, 36.1, 54.2, 172.3, and 172.8. Anal. Calcd for
C11H22N2O2S2: C, 47.45; H, 7.96; N, 10.06. Found: C, 47.49;
H, 7.98; N, 10.09.
1-Me t h ylh e xa h yd r op yr id o[1,2-a ]p yr im id in e -2,6-d i-
on e (47). To a solution containing 0.13 g (0.5 mmol) of
thioacetal 44 in 10 mL of CH2Cl2 was added 0.2 g (1.0 mmol)
of DMTSF. The reaction mixture was heated at reflux for 12
h, concentrated under reduced pressure, and subjected to silica
gel chromatography to give 0.06 g (73%) of 47 as a white
1
cm-1; H NMR (CDCl3, 400 MHz) δ 1.25 (t, 6H, J ) 7.6 Hz),
2.12 (q, 2H, J ) 7.6 Hz), 2.39-2.44 (m, 4H), 2.57-2.70 (m,
4H), 2.82 (d, 3H, J ) 8.0 Hz), 3.53 (q, 2H, J ) 6.0 Hz), 3.82 (t,
1H, J ) 6.8 Hz), 5.73 (brs, 1H), and 6.37 (brs, 1H); 13C NMR
(CDCl3, 100 MHz) δ 14.7, 24.5, 26.5, 31.5, 34.1, 35.6, 35.7, 50.6,
172.2, and 172.4. Anal. Calcd for C12H24N2O2S2: C, 49.28; H,
8.27; N, 9.58. Found: C, 49.08; H, 8.26; N, 9.50.
1-Me t h ylh e xa h yd r op yr olo[1,2-a ]p yr im id in e -2,6-d i-
on e (46). To a solution containing 0.3 g (1.0 mmol) of thioacetal
43 and 15 mL of CH2Cl2 was added 0.4 g (2.2 mmol) of DMTSF.
The mixture was allowed to warm to room temperature, stirred
for 12 h, concentrated under reduced pressure, and subjected
to silica gel chromatography to give 0.1 g (60%) of 46 as a white
solid: mp 75-77 °C; IR (CHCl3) 2954, 1652, and 1410 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 1.69-1.77 (m, 2H), 1.89-1.98
(m, 1H), 2.34-2.46 (m, 3H), 2.48-2.59 (m, 3H), 2.88 (ddd, 1H,
J ) 12.9, 11.1, and 5.1 Hz), 2.96 (s, 3H), 4.74 (ddd, 1H, J )
12.9, 5.4, and 2.7 Hz), and 4.85 (dd, 1H, J ) 8.1 and 5.1 Hz);
13C NMR (CDCl3, 100 MHz) δ 17.7, 29.3, 29.6, 32.3, 32.7, 37.9,
71.4, 168.7, and 168.8. Anal. Calcd for C9H14N2O2: C, 59.32;
H, 7.74; N, 15.37. Found: C, 59.17; H, 7.70; N, 15.27.
solid: mp 65-67 °C; IR (CHCl3) 2926, 1710, and 1644 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 1.89-1.95 (m, 1H), 2.43-2.54
(m, 5H), 2.93 (s, 3H), 3.03-3.11 (m, 1H), 4.28 (ddd, 1H, J )
13.2, 5.6, and 2.8 Hz), and 5.00 (t, 1H, J ) 6.0 Hz); 13C NMR
(CDCl3, 100 MHz) δ 26.4, 29.3, 29.6, 31.8, 35.4, 72.1, 167.7,
and 172.6. Anal. Calcd for C8H12N2O2: C, 57.13; H, 7.19; N,
16.66. Found: C, 57.30; H, 7.32; N, 16.71.
Ack n ow led gm en t. We gratefully acknowledge the
National Institutes of Health (GM60003-01) for their
generous support of this work.
(48) J uaristi, E.; Quintanu, D.; Lamatsch, B.; Seebach, D. J . Org.
Chem. 1991, 56, 2553.
J O991414H