pyridines (()-1 and (-)-2 from cheap starting materials5 and
the possibility of rapid access to tetra- and pentasubstituted
piperidines from mono- and disubstituted dienophiles prompted
us to explore this route (Figure 1).
Scheme 1. Diels-Alder Reaction of 1 with Various
Dienophiles
Figure 1. Retrosynthesis for pentasubstituted piperidines.
To the best of our knowledge, the Diels-Alder reactions
of 1-N-amidine-1,3-dienes, whether acyclic or cyclic such
as 1, have not been reported. We herein communicate our
progress in this area as well as methods employed to remove
the amidine and oxidatively cleave the 2-aza-bicyclo[2.2.2]-
octene adducts to afford tetra- and pentasubstituted piperi-
dines.
The cycloaddition reaction of 1 with maleic anhydride in
CH2Cl2 gave an adduct that was directly converted to the
diester to afford 3a (dr >95:5) (Scheme 1). The cycloaddi-
tions with other doubly activated dienophiles such as
maleimide and phenyl maleimide proceeded with similar
reactivity and selectivity to give 4 (dr >95:5) and 5 (dr >95:
5), respectively. All three cycloadditions were facile, requir-
ing 1 equiv of dienophile at room temperature for >95%
conversion. The thermal cycloaddition reaction of 1 with
methyl acrylate at 50 °C in toluene gave <30% conversion
to 3b. Fortunately, the corresponding Lewis acid promoted
Diels-Alder reaction in the presence of BF3‚OEt3 at 50 °C
afforded BF3‚3b in 75% yield.6 The free amidine 3b could
be obtained in 95% yield by treatment of BF3‚3b with
aqueous NaOH (Scheme 1).7
Reactions of 3b with alane8 or Birch conditions9 both led to
complex mixtures. We envisioned an alternate strategy that
entailed changing the reactivity of the amidine moiety by
reaction with MeI to form a dimethylated iminium salt, which
could then undergo base hydrolysis to the corresponding
amide.10 Prior to alkylation with MeI, the esters 3a and 3b
were reduced with LiAlH4 to give 6a and 6b (Scheme 2).11
Scheme 2. Functional Group Interconversion of Amidine 6 to
Benzamide 7
Our results show that these cycloaddition reactions are
highly stereoselective, affording one diastereomer in each
case (i.e., highly endo-selective and high diastereofacial
selectivity of addition to diene).
With the Diels-Alder adducts in hand, the focus was
directed toward the reductive removal of the amidine moiety.
Indeed, treatment of the iminium salts derived from 6a and
6b with aqueous NaOH afforded complete conversion to
benzamides 7a and 7b, respectively (Scheme 2).
(4) (a) Maison, W.; Grohs, D. C.; Prenzel, A. H. G. P. Eur. J. Org. Chem.
2004, 1527-1543. (b) Arakawa, Y.; Murakami, T.; Ozawa, F.; Arakawa,
Y.; Yoshifuji, S. Tetrahedron 2003, 59, 7555-7563. (c) Maison, W.;
Adiwidjaja, G. Tetrahedron Lett. 2002, 43, 5957-5960. (d) Maison, W.;
Kuntzer, D.; Grohs, D. Synlett 2002, 1795-1798.
(5) Prepared from diastereoselective 1,2-nucleophilic additions of orga-
nometallic reagents to triflic anhydride activated pyridinium salts: Charette,
A. B.; Grenon, M.; Lemire, A.; Pourashraf, M.; Martel, J. J. Am. Chem.
Soc. 2001, 123, 11829-11830.
(6) For a recent example of an isolation of a BF3-imine complex, see:
Ma, Y.; Lobkovsky, E.; Collum, D. B. J. Org. Chem. 2005, 70, 2335-
2337
(8) Lemire, A.; Beaudoin, D.; Grenon, M.; Charette, A. B. J. Org. Chem.
2005, 70, 2368-2371.
(9) Lemire, A.; Charette, A. B. Org. Lett. 2005, 7, 2747-2750.
(10) For hydrolysis of dimethyliminium salts, see: (a) Manh, G. T.;
Purseigle, F.; Dubreuil, D.; Pradere, J. P.; Guingant, A.; Danion-Bougot,
R.; Danion, D.; Toupet, L. J. Chem. Soc., Perkin Trans. 1 1999, 2821-
2828. (b) Nakayama, J.; Otani, T.; Sugihara, Y.; Ishii, A. Tetrahedron Lett.
1997, 38, 5013-5016. (c) Alonso, M. A.; Ubeda, J. I.; Avendano, C.;
Menendez, J. C.; Villacampa, M. Tetrahedron 1993, 49, 10997-11008.
(d) Kantlehner, W.; Greiner, U. Synthesis 1979, 339-342. (e) Janousek,
Z.; Collard, J.; Viehe, H. G. Angew. Chem., Int. Ed. Engl. 1972, 11, 917-
918.
(7) The yield was calculated on the basis of mass recovery of 3b from
a 1:1 complex of BF3:3b.
(11) Compound 6a crystallized as monohydrate; see Supporting Informa-
tion for crystal structure.
5774
Org. Lett., Vol. 7, No. 26, 2005