Azadiene Diels-Alder cycloaddition of fulvenes: A facile approach to the [1]pyrindine system

Article abstract of DOI:10.1021/ol048762c

(Chemical Equation Presented) Regioselective and stereoselective inverse-electron-demand Diels-Alder reaction of N-sulfonyl-1-aza-1,3-butadiene with fulvenes are described. The methodology provides an efficient and novel route to tetrahydro-[1]pyrindine s

Full text of DOI:10.1021/ol048762c

ORGANIC
LETTERS
2004
Vol. 6, No. 20
3453-3456
Azadiene Diels−Alder Cycloaddition of
Fulvenes: A Facile Approach to the
[1]Pyrindine System
Bor-Cherng Hong,* Jian-Lin Wu, Arun Kumar Gupta,
Mahanandeesha Siddappa Hallur, and Ju-Hsiou Liao
Department of Chemistry and Biochemistry, National Chung Cheng UniVersity,
Chia-Yi, 621, Taiwan, R.O.C.
chebch@ccunix.ccu.edu.tw
Received June 29, 2004
ABSTRACT
Regioselective and stereoselective inverse-electron-demand Diels−Alder reaction of N-sulfonyl-1-aza-1,3-butadiene with fulvenes are described.
The methodology provides an efficient and novel route to tetrahydro-[1]pyrindine systems.
Inverse-electron-demand Diels-Alder chemistry has attracted
much attention over the past two decades,1 and many natural
products have been prepared in this manner from N-sulfonyl-
1-aza-1,3-butadienes.2 Cycloadditions of fulvenes (e.g., [4
+ 3],3 [2 + 2],4 [4 + 2],5 [2 + 4],6 [6 + 4],7 [6 + 2],8 [6 +
3]9) provide versatile and powerful approaches to various
polycyclic systems and natural products. However, to the
best of our knowledge, preparation of tetrahydro-[1]pyrindine
systems from azadienes and fulvene has never been re-
ported.10
Recently, we reported a new type of reaction: a formal
[6 + 3] cycloaddition of fulvenes and 2H-azirine11 and
N-alkylidene glycine esters12 that yields [2]pyrindines. In
conjunction with our continuing efforts in fulvene chemis-
(1) For recent reviews, see: (a) Jayakumar, S.; Ishar, M. P. S.; Mahajan,
M. P. Tetrahedron 2002, 58, 379. (b) Behforouz, M.; Ahmadian, M.
Tetrahedron 2000, 56, 5259. (c) Boger, D. L. Chemtracts: Org. Chem.
1996, 9, 149.
(2) For examples, see: (a) Boger, D. L.; Zhang, M. J. Org. Chem. 1992,
57, 3974. (b) Boger, D. L.; Hu¨ter, O.; Mbiya, K.; Zhang, M. J. Am. Chem.
Soc. 1995, 117, 11839. (c) Boger, D. L.; Corbett, W. L.; Curran, T. T.;
Kasper, A. M. J. Am. Chem. Soc. 1991, 113, 1713. (d) Boger, D. L.; Cassidy,
K. C.; Nakahara, S. J. Am. Chem. Soc. 1993, 115, 10733. (e) Boger, D. L.;
Nakahara, S. J. Org. Chem. 1991, 56, 880.
(3) (a) Rawson, D. I.; Carpenter, B. K.; Hoffmann, H. M. J. Am. Chem.
Soc. 1979, 101, 1786. (b) Noyori, R.; Hayakawa, Y.; Takaya, H.; Murai,
S.; Kobayashi, R.; Sonoda, N. J. Am. Chem. Soc. 1978, 100, 1759.
(4) (a) Imafuku, K.; Arai, K. Synthesis 1989, 501. (b) Paquette, L. A.;
Colapret, J. A.; Andrews, D. R. J. Org. Chem. 1985, 50, 201.
(5) (a) Harre, M.; Raddatz, P.; Walenta R.; Winterfeldt, E. Angew. Chem.,
Int. Ed. Engl. 1982, 21, 480. (b) Gleiter R.; Borzyk, O. Angew. Chem., Int.
Ed. Engl. 1995, 34, 1001.
(8) (a) For an example of an intermolecular [6 + 2] cycloaddition, see:
Hong, B. C.; Shr, Y. J.; Wu, J. L.; Gupta, A. K.; Lin, K. J. Org. Lett. 2002,
4, 2249. (b) For an example of an intramolecular [6 + 2] cycloaddition,
see: Suda, M.; Hafner, K. Tetrahedron Lett. 1977, 2453. (c) Wu T. C.;
Houk, K. N. J. Am. Chem. Soc. 1985, 107, 5308.
(9) Barluenga, J.; Martinez, S.; Sua´rez-Sobrino, A. L.; Toma´s, M. J. Am.
Chem. Soc. 2001, 123, 11113.
(10) (a) Theoretically, the Diels-Alder reaction of isoxazole with alkenes
should not proceed; see: Gonza˜lez, J.; Taylor, E. C.; Houk, K. N. J. Org.
Chem. 1992, 57, 3753. (b) A low-yielding [4 + 2] cycloaddition of isoxazole
has been reported; see: Nesi, R.; Giomi, D.; Papaleo, S.; Turchi, S. J. Org.
Chem. 1992, 57, 3713. (c) A low-yielding [4 + 2] cycloaddition of triazine
has been reported; see: Diaz-Ortiz, A.; Hoz, A.; Prieto, P.; Carrillo, J. R.;
Moreno, A.; Neunhoeffer, H. Synlett 2001, 236.
(6) (a) Himeda, Y.; Yamataka, H.; Ueda I.; Hatanaka, M. J. Org. Chem.
1997, 62, 6529. (b) Nair, V.; Nair, A. G.; Radhakrishnan, K. V. Nanda-
kumar, M. V.; Rath, N. P. Synlett 1997, 767.
(7) (a) Gupta, Y. N.; Doa, M. J.; Houk, K. N. J. Am. Chem. Soc. 1982,
104, 7336. (b) Yoshida, Z.-I.; Shibata, M.; Ogino, E.; Sugimoto, T. Angew.
Chem., Int. Ed. Engl. 1985, 24, 60.
(11) Hong, B.-C.; Gupta, A. K.; Wu, M.-F.; Liao, J.-H. Tetrahedron Lett.
2004, 45, 1663.
(12) Hong, B.-C.; Gupta, A. K.; Wu, M.-F.; Liao, J.-H.; Lee, H.-H. Org.
Lett. 2003, 5, 1689.
10.1021/ol048762c CCC: $27.50
© 2004 American Chemical Society
Published on Web 08/31/2004

Figure 1. Examples of naturally occurring [1]pyrindine.
try,13 we have now developed an efficient and general hetero
Diels-Alder cycloaddition of fulvenes with azadienes to give
tetrahydro-[1]pyrindines.
fulvene would undergo an inverse-electron-demand Diels-
Alder reaction to afford the hetero [4 + 2] cycloadduct.17 In
a model study, dimethyl fulvene (1a) and azadiene (2a) were
stirred in CH2Cl2 for 65 h to afford [1]pyrindine 3a as the
only isolable product (70% yield), Table 1, entry 1, method
A. A higher yield and a faster reaction time were achieved
under microwave conditions (30 min, 96% yield, method
Piperidine alkaloids are common constituents of plants and
possess a wide range of biological activities. For example,
streptazolin, a microbial metabolite, has antibiotic and
antifungal acitivity,14 while 5-O-(â-D-xylopyranosyl)-strepta-
zolin shows in vitro cytotoxic activity against certain human
cancer cell lines, Figure 1. The unique structural features
and promising bioactivity of streptazolins and specifically
streptazone C prompted us to explore the synthesis of this
natural product via a fulvene cycloaddition strategy.15 We
initially envisioned that an electron-deficient azadiene such
as ethyl (E)-4-[(phenylsulfonyl)imino]-2-butenoate16 and
(13) For previous papers in this series, see: (a) Hong, B.-C.; Shr, Y.-J.;
Wu, J.-L.; Gupta, A. K.; Lin, K.-J. Org. Lett. 2002, 4, 2249. (b) Hong,
B.-C.; Shr, Y.-J.; Liao, J.-H. Org. Lett. 2002, 4, 663.
(14) (a) Streptazolin, streptazon C, and streptazon A were isolated from
Streptomyces FORM5, Stain A1, Viridochromogenes and leteogriseus.
See: (i) Puder, C.; Krastel, P.; Zeeck, A. J. Nat. Prod. 2000, 63, 1258. (ii)
Puder, C.; Loya, S.; Hizi, A.; Zeeck, A. J. Nat. Prod. 2001, 64, 42. (iii)
Grabley, S.; Kluge, H.; Hoppe, H.-U. Angew. Chem. 1987, 99, 692. (b)
Abikoviromycin was isolated from Isolierung aus Streptomyces-Arten.
See: (i) Sakagami, Y.; Utahara, R.; Yagishita, K.; Umezawa, H. J. Antibiot.
1958, 11, 231. (ii) Gurevich, A. I.; Kolosov, M. N.; Korobko, V. G.;
Onoprienko, V. V. Tetrahedron Lett. 1968, 9, 2209. (iii) Maruyama, H.;
Okamoto, S.; Kubo, Y.; Tsuji, G.; Fujii, I.; Ebizuka, Y.; Furihata, K.;
Hayakawa, Y.; Nagasawa, H.; Sakuda, S. J. Antibiot. 2003, 56, 801. (c)
Pyrindicin was isolated from Streptomyces sp. SCC 2313. See: Hegde, V.
R.; Dai, P.; Patel, M. G.; Troyanovich, J. J.; Das, P.; Puar, M. S. J. Antibiot.
1994, 47, 110. (d) trans-5,7-Dimethyl-6,7-dihydro-5H-[1]pyrindine was
isolated from aus Erdoel. See: Monti, S. A.; Schmidt, R. R.; Shoulders, B.
A.; Lochte, H. L. J. Org. Chem. 1972, 37, 3834. (e) Octahydro-[1]pyrindine-
3,4,5-triol was Isolation from Rhizoctonia leguminicola. See: Guengerich,
F. P.; DiMari, S. J.; Broquist, H. P. J. Am. Chem. Soc. 1973, 95, 2055. (f)
1-Methyl-4-azafluorenone was isolated from branches of Porcelia macro-
carpa (Warm.). See: Chaves, M. H.; Santos, L. de A.; Lago, J. H. G.;
Roque, N. F. J. Nat. Prod. 2001, 64, 40.
(15) Several synthetic approaches to streptazolins have been reported.
(a) For 8R-hydroxystreptazolone, see: Izumi Nomura, I.; Mukai, C. J. Org.
Chem. 2004, 69, 1803. (b) For streptazolin, see: Kozikowski, A. P.; Park,
P. J. Am. Chem. Soc. 1985, 107, 1763.
(16) Prepared from the corresponding 4-oxo-crotonic acid ethyl ester and
benzenesulfonamide (Et3N, TiCl4, CH2Cl2; 60% yield), see: Boger, D. L.;
Curran, T. T. J. Org. Chem. 1990, 55, 5439 and ref 2c.
Figure 2. ORTEP plots for X-ray crystal structures of 4d and 5.
3454
Org. Lett., Vol. 6, No. 20, 2004

Table 1. Hetero Diels-Alder Reaction of 1-Aza-1,3-butadiene
with Fulvene 1a
Table 2. Hetero Diels-Alder Reaction of 1-Aza-1,3-butadiene
with Fulvenes
a Isolated yield based on starting azadiene. b Recovered most of the
starting material. c Recovered some starting material and many complicated
mixtures. Method A: CH2Cl2, 25 °C. Method B: ClC6H5, microwave, 125
°C. Method C: toluene, TinyClave, ∼6 bar, 110 °C. Method D: EDC,
reflux, 85 °C. Method E: benzene, reflux, 80 °C. Method F: toluene, reflux,
110 °C. Method G: DMF, microwave, 110 °C. Method H: toluene,
microwave, 100 °C. Method I: 1,4-dioxane, microwave, 90 °C.
B). The reaction was also attempted in a TinyClave18 at ca.
6 bar in toluene (3.5 h, 83% yield, method C). The structure
of 3a was assigned on the basis of IR, 1H, 13C NMR, COSY,
DEPT, HMQC, MS, and HRMS analysis. The reaction also
a Isolated yield based on starting azadiene.
works in other solvents at reflux, albeit with lower yield
(entry 1, methods D-I). The exclusive regio- and diastereo-
selectivity of the reaction can be attributed to two mutually
reinforcing occurrences that stabilize the endo-head-to-head
transition state as depicted in Scheme 1: (1) secondary orbital
interactions between the azadiene and the C5-C6 double
bond of fulvene and (2) the interaction between the ester
carbonyl group and the C1-C2 double bond of fulvenes. The
first feature is noticeably absent in the corresponding exo-
head-to-head transition state, while the second interaction
Scheme 1
(17) For other regioselective [2 + 4] cycloadditions of fulvenes to
electron-deficient dienes, see: (a) Houk, K. N.; Luskus, L. J. J. Org. Chem.
1973, 38, 3836. (b) Bimanand, A. Z.; Gupta, Y. N.; Doa, M. J.; Eaton, T.
A.; Houk, K. N. J. Org. Chem. 1983, 48, 403. (c) Lewis, N. J.; Collins, W.
J.; Knight, D. B. J. Med. Chem. 1979, 22, 1505. (d) Nair, V.; Anilkumar,
G.; Radhakrishnan, K. V.; Sheela, K. C.; Rath, N. P. Tetrahedron 1997,
53, 17361.
(18) TinyClave (Bu¨chiglassuster) is a miniature laboratory autoclave for
safe small-scale experiment under pressure. It allows one to run chemical
reactions in organic media under pressure up to 10 bar and 150 °C.
Org. Lett., Vol. 6, No. 20, 2004
3455

provides the high regioselectivity of the product and is
disfavored in the endo-head-to-tail approach.19
monoalkylfulvenes 1h and 1i gave the two olefinic regioi-
somers in a nearly 1:1 ratio.
In summary, the above regioselective and stereoselective
hetero [4 + 2] cycloadditions emphasize a new feature of
the reactivity of fulvene and azadienes. This methodology
represents an unprecedented approach to tetrahydra-[1]-
pyrindine. Further applications of this methodology toward
total synthesis of natural products are currently under active
investigation in our laboratory, and the results will be
published in due course.
The hetero [4 + 2] cycloaddition of 4-[(phenylsulfonyl)-
imino]-2-butenoate with electron-rich alkenes is well docu-
mented, yet there is only one example of the corresponding
reaction of zimtaldehydiminotosylate.20 In our hands, zimtal-
dehydiminotosylate21 (2b) reacted with fulvene (1a) in CH2-
Cl2 at ambient temperature to yield a similar hetero Diels-
Alder adduct (4a). However, this reaction was much slower
and gave a lower yield when compared to 2a (240 h, 27%
yield, vs 65 h, 70% yield, entries 1 and 2, Method A).
Various solvents and reaction conditions were screened, and
the best yield (92%) was observed under microwave condi-
tions in ClC6H5 at 125 °C.
Acknowledgment. We are grateful to Dr. Sepehr Sarshar
for valuable discussions. Financial support from National
Science Council and National Health Research Institute are
gratefully acknowledged.
A series of homologous fulvenes were then reacted with
1-aza-1,3-butadienes 2a and 2b to afford the corresponding
[1]pyrindines (entries 1-8, Table 2).22
The structure of 4d23 and the p-bromobenzoate derivative
524 (prepared from the corresponding dibromophenylfulvene)
were unambiguously assigned by single-crystal X-ray analy-
sis, Figure 1. Interestingly, the olefinic isomers of the
Supporting Information Available: Crystallographic
information files (CIF) for 4d and 5. Experimental procedures
and characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL048762C
(23) Four independent molecules in an asymmetric unit. Crystallographic
data for 4d: C34H29NO2S, M ) 515.64, monoclinic, space group P21, T )
298 K, a ) 9.8136(10), b ) 37.446(4), c ) 15.0320(16) Å, â )
90.095(2)°, V ) 5523.9(10) Å3, Z ) 8, D ) 1.240 g/cm3, λ (Mo KR) )
0.71073 Å, 34 867 reflections collected, 20 465 unique reflections, 1374
parameters refined on F2, R ) 0.0852, wR2[F2] ) 0.1495 [13 042 data with
F2 > 2σ(F2)].
(24) Compound 5 was prepared from di-p-bromophenylfulvene with 2b,
method B; 85% yield. Crystallographic data for 5: C34H27Br2NO2S, M )
673.45, monoclinic, space group P21/n, T ) 298 K, a ) 17.5841(15), b )
9.7852(8), c ) 18.2955(15) Å, â ) 110.9240(10)°, V ) 2940.4(4) Å3, Z )
4, D ) 1.521 g/cm3, λ (Mo KR) ) 0.71073 Å, 34 131 reflections collected,
7166 unique reflections, 362 parameters refined on F2, R ) 0.0457, wR2-
[F2] ) 0.1250 [5487 data with F2 > 2σ(F2)].
(19) Selectivity may also be explained by the LUMO (azadiene) and
HOMO (fulvene) coefficients; see ref 2c.
(20) Croce, P.; Ferraccioli, R.; Rosa, C. L. J. Chem. Soc., Perkin Trans.
1 1994, 2499.
(21) Prepared from toluene-4-sulfonamide and 3-phenyl-propenal (TiCl4,
NEt3, CH2Cl2, 78%); see: Marchand, E.; Morel, G.; Sinbandhit, S. Eur. J.
Org. Chem. 1942, 7, 1729.
(22) All new compounds were fully characterized by 1H NMR, 13C NMR,
DEPT, IR, MS, and HRMS. In most cases, COSY and HMQC spectra were
also obtained. Yields refer to spectroscopically and chromatographically
homogeneous (>95%) materials.
3456
Org. Lett., Vol. 6, No. 20, 2004