Ketene Dithioacetals in the Aza-Diels-Alder Reaction with N-Arylimines: A Versatile Approach to Tetrahydroquinolines, 2,3-Dihydro-4-quinolones, and 4-Quinolones

Article abstract of DOI:10.1021/ol020179d

(Matrix Presented) The first successful use of ketene dithioacetals as dienophiles in the aza-Diels-Alder reaction with N-arylimines is described. Among the ketene dithioacetals tested, 1,4-benzodithiafulveness are most effective in assembling the tetrahy

Full text of DOI:10.1021/ol020179d

ORGANIC
LETTERS
2002
Vol. 4, No. 25
4411-4414
Ketene Dithioacetals in the
Aza-Diels−Alder Reaction with
N-Arylimines: A Versatile Approach to
Tetrahydroquinolines,
2,3-Dihydro-4-quinolones, and
4-Quinolones
Dai Cheng, Jinglan Zhou, Eddine Saiah, and Graham Beaton*
Deltagen Research Laboratories, 4570 ExecutiVe DriVe, Suite 400,
San Diego, California
gbeaton@deltagen.com
Received September 4, 2002
ABSTRACT
The first successful use of ketene dithioacetals as dienophiles in the aza-Diels−Alder reaction with N-arylimines is described. Among the
ketene dithioacetals tested, 1,4-benzodithiafulvenes are most effective in assembling the tetrahydroquinoline core. Subsequent chemical
manipulations provide a concise and divergent approach to the synthesis of 2,3-tetrahydroquinolines, 2,3-dihydro-4-quinolones, and 4-quinolones.
The acid-promoted aza-Diels-Alder reaction between N-
arylimines and electron-rich alkenes has been a topic of
continuing interest for forty years.1,2 Due to its efficiency,
the ready availability of starting materials, and relatively mild
reaction conditions, this reaction constitutes the most attrac-
tive strategy for the synthesis of 1,2,3,4-tetrahydroquino-
lines.1,4 The use of a highly convergent three-component
reaction among aldehydes, anilines, and alkenes in which
the heterocycle is assembled in one pot is of particular
note2b-f and especially valuable for its potential application
in combinatorial synthesis.2e
The synthetic scope of this reaction is limited by two
factors: the generally low reactivity of imines and alkenes
and the requirement of electron-rich alkene dienophiles that
direct the electron-donating group toward the 4-position of
the tetrahydroquinoline ring.2,3,5 Because of this, the intro-
duction of substituents at the 3-position has proven to be
(1) For reviews on hetero Diels-Alder reactions, see: (a) Boger, D. L.;
Weinreb, S. M. Hetero Diels-Alder Methodology in Organic Synthesis;
Academic Press: San Diego, 1987. (b) Weinreb, S. M. ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergmon: Oxford, 1991;
Vol. 5, p 401.
(2) For leading references for aza-Diels-Alder reaction between alkenes
and N-arylimines or iminium salts, see: (a) Povarov, L. S. Russ. Chem.
ReV. 1967, 36, 656-670. (b) Grieco, P. A.; Bahsas, A. Tetrahedron Lett.
1988, 29, 5855-5858. (c) Mellor, J. M.; Merriman, G. D. Tetrahedron
1995, 51, 6115-6132 and references therein. (d) Kobayashi, S.; Ishitani,
H.; Nagayama, S. Chem. Lett. 1995, 423-424. (e) Kobayashi, S.; Nagayama,
S. J. Am. Chem. Soc. 1996, 118, 8977-8978. (f) Narasaka, K.; Shibata, T.
Heterocycles 1993, 35 (2), 1039-1053. (g) Crousse, B.; Begue, J.-P.;
Bonnet-Delpon, D. J. Org. Chem. 2000, 65, 5009-5013. (h) Sundararajan,
G.; Prabagaran, N.; Varghese, B. Org. Lett. 2001, 3, 1973-1976.
(3) For a review on the synthesis and applications of 1,2,3,4-tetrahy-
droquinolines, see: Katritzky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron
1996, 52, 15031-15070 and references therein.
(4) For the most recent developments of tetrahydroquinoline synthesis
Via other strategies, see: (a) Larock, R. C.; Yang, H.; Pace, P. Tetrahedron
Lett. 1998, 39, 1885-1888. (b) Padwa, A.; Brodney, M. A.; Liu, B.; Satake,
K.; Wu, T. J. Org. Chem. 1999, 64, 3595-3607. (c) Bunce, R. A.; Herron,
D. M.; Johnson, L. B.; Kotturi, S. J. Org. Chem. 2001, 66, 2822-2827.
10.1021/ol020179d CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/20/2002

difficult. Moreover, an approach to access 2,3-disubstituted
tetrahydroquinolines Via this highly efficient aza-Diels-
Alder reaction has yet to be established. We sought to address
this problem by employing cyclic6 ketene dithioacetals7 1
as dienophiles (Scheme 1). To our knowledge, ketene
Scheme 2. Conversion of Products 3 to Tetrahydroquinolines
4a,b, 2,3-Dihydro-4-quinolone 5, and 4-Quinolone 6
Scheme 1. Cycloaddition Reactions of Cyclic Ketene
Dithioacetals 1a-c with N-Phenylimine 2a
dithioacetals have not been reported in Diels-Alder reactions
with 2-azadienes despite their synthetic potential.7a,8 The
electron-donating effect of the mercapto groups of the ketene
dithioacetal should not only provide a sufficiently reactive
dienophile for the construction of the tetrahydroquinoline ring
system but also dictate placement of the R group at the
3-position of the heterocyclic core. The relatively straight-
forward preparation of ketene dithioacetals7 from aldehydes
would also provide a source of variation of the R group and
a means to conveniently modify the 3-position of tetra-
hydroquinolines. Subsequent manipulations of the dithio-
acetals 3 should provide access not only to 2,3-disubstituted
tetrahydroquinolines 4 that are inaccessible through conven-
tional [4 + 2] cycloaddition strategies but also to 2,3-dihydro-
4-quinolones 5 and 4-quinolones 6 (Scheme 2, see below),
compounds of extensive interest for their biological activi-
ties.3,9
The choice of an adequate ketene dithioacetal for this
conversion is critical.6b We first compared the reactivity of
three cyclic ketene dithioacetals shown in Table 1. Reaction
Table 1. Cycloaddition Reactions of Cyclic Ketene
Dithioacetals 1a-c with N-Phenylimine 2a (Scheme 1)
(5) For example, with styrene as a dienophile in reactions with N-
arylimines, the phenyl group would be introduced exclusively at the
4-position,2c,3 rather than at the 3-position. The ketene dithioacetal approach
described in this paper successfully places the phenyl group at the 3-position
as demonstrated on product 4a, providing a formally “reversed” substitution
pattern.
(6) (a) Using acyclic ketene dithioacetals would expose the tetrahydro-
quinoline thus formed to â-hydrogen elimination of the mercapto group
(activated by the benzene ring and the nitrogen atom) from the 4-position,
similar to using vinyl ethers as dienophiles.2a In addition, cyclic ketene
dithioacetals such as 1a-c are more sterically confined and expected to be
more reactive. (b) There has been a report2f on an unsuccessful attempt to
react an acyclic ketene dithioacetal with an N-arylimine in the presence of
BF3‚Et2O.
(7) (a) For a review on the preparations and synthetic applications of
ketene dithioacetals, see: Kolb, M. Synthesis 1990, 171-190. (b) Barbero,
M.; Cadamuro, S.; Ceruti, M.; Degani, I.; Fochi, R.; Regondi, V. Gazz.
Chim. Ital. 1987, 117, 227-235. (c) Bellesia, F.; Boni, M.; Ghelfi, F.;
Pagnoni, U. M. J. Heterocycl. Chem. 1994, 31, 1721-1723.
(8) There have been reports on ketene dithioacetals in Diels-Alder
reactions with other hetero dienes. See, for example: (a) Denmark, S. E.;
Sternberg, J. A. J. Am. Chem. Soc. 1986, 108, 8277-8279 and references
therein. (b) Tietze, L. F.; Schuffenhauer, A. Eur. J. Org. Chem. 1998, 1629-
1637.
(9) For applications of 4-quinolones, see: (a) Pesci, E. C.; Milbank, J.
B. J.; Pearson, J. P.; McKnight, S.; Kende, A. S.; Greenberg, E. P.; Iglewski,
B. H. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 11229-11234. (b) Xia, Y.;
Yang, Z.-Y.; Xia, P.; Hackl, T.; Hamel, E.; Mauger, A.; Wu, J.-H.; Lee,
K.-H. J. Med. Chem. 2001, 44, 3932-3936. (c) Cecchetti, V.; Parolin, C.;
Moro, S.; Pecere, T.; Filipponi, E.; Calistri, A.; Tabarrini, O.; Gatto, B.;
Palumbo, M.; Fravolini, A.; Palu, G. J. Med. Chem. 2000, 43, 3799-3802.
(d) Wang, J.-P.; Raung, S.-L.; Huang, L.-J.; Kuo, S.-C. Biochem. Pharmacol.
1998, 56, 1505-1514. (e) Ruiz, M.; Ortiz, R.; Perello, L.; LaTorre, F.;
Server-Carrio, F. J. Inorg. Biochem. 1997, 65, 87-96.
of 1,3-dithiolane 1a and 1,3-dithiane 1b with imine 2a in
acetonitrile in the presence of scandium triflate2d at 64 °C
for 3 h gave the corresponding cycloaddition products 3a
and 3b in 38 and 35% yields, respectively. In contrast, 1,4-
benzodithiafulvene 1c gave product 3c in a yield of 81%
under the same conditions. The increase in yield can be
rationalized by the extra electron-donating effect of the benzo
system and the aromatic nature of the corresponding car-
bocation (Figure 1),10 no matter whether the reaction mech-
anism is concerted or stepwise.11
The next study focused on the formation of the tetra-
hydroquinolines 3 from a series of substituted 1,4-benzo-
4412
Org. Lett., Vol. 4, No. 25, 2002

The use of anhydrous solvent and the amount of scandium
triflate were found to be crucial in order to achieve the yields
that are summarized in Table 2. Scandium triflate was used
in proportions of 1.2 equiv relative to imine 2 for the
synthesis of tetrahydroquinolines from substituted 1,4-
benzodithiafulvenes 1c-e. For the highly reactive 1,4-
benzodithiafulvene 1f, 0.2 equiv of scandium triflate was
used. The use of other Lewis acids such as boron trifluoride
diethyl etherate and trifluoroacetic acid was unsuccessful in
terms of effecting this transformation, which is consistent
with previous observations.2d
Figure 1. Resonance structures of 1,4-benzodithiafulvenes.
dithiafulvenes 1c-f and imines 2a-d as described in Table
2. The basic protocol for the transformation involved the
As summarized in Table 2, the readily prepared 1,4-
benzodithiafulvenes 1c-e7 were reacted with preformed or
in situ-generated N-phenylimines 2a-d to give the tetrahy-
droquinolines 3c-g with combinations of aliphatic or
aromatic substituents at both 2- and 3-positions. This
methodology could also be applied to the synthesis of
systems lacking the 3-substituent as exemplified by 3h and
3i by using the in situ-generated 1f. From the results in Table
2, it appears that the anti/syn stereoselectivity depends on
the steric demands of the two substituents R and R′. High
preference for anti isomers12 was observed for examples 3c,
3e, and 3g where both R and R′ were relatively bulky, while
there was little or no discrimination in relative stereochem-
istry for 3d and 3f for the less hindered iso-butyl group at
the 2-position.
Table 2. Cycloaddition Reactions of 1,4-Benzodithiafulvenes
1c-f with N-Phenylimines 2a-d
The true versatility of this method lies in the opportunity
to chemically manipulate the dithioacetal moiety within the
tetrahydroquinolines 3 (Scheme 2). Reduction of dithioacetals
3c and 3g with NiCl2/NaBH413 afforded the 2,3-disubstituted
1,2,3,4-tetrahydroquinolines 4a and 4b. These compounds
have a substitution pattern that is formally opposite to those
obtained if styrene or 3-methyl-1-butene were used as
dienophiles in the cyclization.5 Hydrolysis of the ketene
dithioacetal group, as illustrated for example 3e, occurred
readily at room temperature with mercuric oxide in tetrafluoro-
boric acid ether solution14 to yield the corresponding 2,3-
dihydro-4-quinolone 5. When the reaction was carried out
at 60 °C overnight, the oxidized 4-quinolone 6 was isolated.
The successful conversion of dithioacetal 3e to either 2,3-
dihydro-4-quinolone 5 or 4-quinolone 6 demonstrates a more
concise and mild alternative to the existing methods of
synthesis of these classes of compounds.15,16
product
protocol
yield
reaction time
anti/syn
3c
3d
3e
3f
3g
3h
3i
A
B
A
B
A
C
D
81%
64%
82%
66%
38%
92%
64%
180 min
60 min
75 min
60 min
240 min
15 min
15 min
23/1
2/1
28/1
1/1
100/0
reaction of 1,4-benzodithiafulvene with Schiff base in
acetonitrile in the presence of scandium triflate at 64 °C (see
protocol A in Supporting Information). Alternative protocols
were developed where either the imine (protocol B) or 1,4-
benzodithiafulvene (protocol C) could not be isolated. In
these cases, the respective intermediate was generated in situ.
For the 1,4-benzodithiafulvene 1f, the reactivity of this
reagent was such that the tetrahydroquinoline formation was
performed at room temperature. A complementary protocol
(protocol D) was also established for the in situ generation
of both intermediates where neither reagent was stable. In
this way, a highly convergent approach was realized that
covered combinations of various substituents at both 2- and
3-positions.
In summary, we have successfully demonstrated the aza-
Diels-Alder reaction between N-arylimines and ketene
(12) Structure assignments were based on NOE experiments and coupling
constants.
(13) Back, T. G.; Baron, D. L.; Yang, K. J. Org. Chem. 1993, 58, 2407-
2413.
(14) Degani, I.; Fochi, R.; Regondi, V. Synthesis 1981, 51-53.
(15) For methods of 4-quinolone synthesis, see: (a) Reynolds, G.; Hauser,
C. In Organic Syntheses; Wiley & Sons: New York, 1955; Collect. Vol.
III., pp 593 and 374. (b) Heindel, N. D.; Kennewell, P. D.; Fish, V. B. J.
Heterocycl. Chem. 1969, 6, 77-81 and references therein. (c) Potts, K. T.;
Ehlinger, R.; Nichols, W. M. J. Org. Chem. 1975, 40, 2596-2600. (d) Chen,
B.-C.; Huang, X.; Wang, J. Synthesis 1987, 482-483.
(10) Soder, L.; Wizinger, R. HelV. Chim. Acta. 1959, 42, 1733-1737
and 1779-1785.
(11) For the mechanistic aspect of this type of reactions, see: (a) refs
1a (pp 258-260) and 2c,d,g. (b) Cheng, Y.-S.; Ho, E.; Mariano, P. S.;
Ammon, H. L. J. Org. Chem. 1985, 50, 5678-5686. (c) Lucchini, V.; Prato,
M.; Scorrano, G.; Stivanello, M.; Valle, G. J. Chem. Soc., Perkin Trans. 2
1992, 259-266. (d) Kobayashi, S.; Ishitani, H.; Nagayama, S. Synthesis
1995, 1195-1202. (e) Linkert, F.; Laschat, S.; Kotila, S.; Fox, T.
Tetrahedron 1996, 52, 955-970.
(16) For methods of 2,3-dihydro-4-quinolone synthesis, see: (a) Elder-
field, R. C.; Maggiolo, A. J. Am. Chem. Soc. 1949, 78, 1906-1910. (b)
Kano, S.; Ebata, T.; Shibuya, S. J. Chem. Soc., Perkin Trans. 1 1980, 2105-
2111. (c) Ongania, K.; Hohenlohe-Oehringen, K. Chem. Ber. 1981, 114,
1203-1205. (d) Donnelly, J. A.; Farrell, D. F. J. Org. Chem. 1990, 55,
1757-1761. (e) Nieman, J. A.; Ennis, M. D. J. Org. Chem. 2001, 66, 2175-
2177 and references therein.
Org. Lett., Vol. 4, No. 25, 2002
4413

dithioacetals. Construction of the tetrahydroquinoline core
is most efficiently realized through the use of substituted
1,4-benzodithiafulvenes. Subsequent chemical manipulations
provide a convenient and divergent approach to the synthesis
of substituted tetrahydroquinolines, 4-quinolones and 2,3-
dihydro-4-quinolones. To our knowledge, this represents the
first synthetic methodology that allows access to 2,3-
disubstituted tetrahydroquinolines Via a highly efficient aza-
Diels-Alder pathway.
presented, Karla Savage and Robyn Rourick for assistance
in obtaining High-Resolution Mass data, and Sabine Hadida-
Ruah, Mark Suto, and Theodore Cohen for critical review
of this manuscript.
Supporting Information Available: Experimental pro-
cedures and details of compound characterization. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank Catherine Jolivet for as-
sistance with the NMR characterization of the compounds
OL020179D
4414
Org. Lett., Vol. 4, No. 25, 2002