SCHEME 1. Synthesis of Pyrrolidinone-Derived
a
FIGURE 2. X-ray crystal structure of 7a. Counterion and
water molecule omitted for clarity.
SCHEME 2. Synthesis of Achiral Catalyst
a
(
a) Boc2O, NaOH, THF/H2O, 23 °C; (b) Meldrum’s acid, DMAP,
DCC, CH2Cl2, 0 °C; (c) AcOH, NaBH4, CH2Cl2, 0 °C; (d) toluene,
-
1
10 °C; (e) TFA, CH2Cl2, 0 °C; (f) Me3O+BF4 , CH2Cl2, 23 °C; (g)
phenylhydrazine or 4-(trifluoromethyl)phenylhydrazine, 23 °C; (h)
MeOH, CH(OMe)3, 80 °C or MeOH, CH(OEt)3, 110 °C.
The synthesis of enantiopure bicyclic triazolium salts
7
a and 7b began with Boc protection of phenylalanine
10
according to Meyers’ procedure (Scheme 1). With an
easy route to a large amount of N-Boc-protected phenyl-
alanine, the synthesis of the pyrrolidinone core was
realized according to literature precedent.11 Coupling of
the Boc-protected amino acid with Meldrum’s acid in the
presence of DMAP and DCC affords the desired product
that can be used without further purification. Reduction
of the ketone with slow addition of 2.5 equiv of sodium
borohydride at 0 °C over 3 h followed by stirring at 0 °C
for 24 h provides the desired product as yellow oil. Initial
attempts at using the resulting yellow oil resulted in a
complicated purification of the desired pyrrolidinone 6.
However, 5 can be recrystallized from diethyl ether,
affording an analytically pure white crystalline solid.
Cyclization of 5 in toluene at 110 °C followed by removal
of the N-Boc protecting group with trifluoroacetic acid
gives the desired pyrrolidinone 6 as a yellow solid that
can be used without further purification.12 With the
pyrrolidinone in hand, a one-pot modification of the
a
(a) (MeO) SO , MeCN, 80 °C, 12 h; (b) phenylhydrazine, 23
2
2
°C, 4 h; (c) 40% KOH; (d) HCl, MeOH; (e) o-dichlorobenzene,
CH(OMe)3, 120 °C, HCl, MeOH, 24 h.
Finally, treatment with trimethyl orthoformate in metha-
nol (7:1) at 80 °C affords triazolium salt 7a. The triazo-
lium salt could be precipitated from ethyl acetate and
then recrystallized from hot methanol, affording a white
crystalline solid. This one-pot protocol can be extended
to the synthesis of 4-(trifluoromethyl)phenylhydrazine;
however, the cyclization step was performed in triethyl
orthoformate in methanol (7:1) at 110 °C in order to
obtain clean formation of catalyst 7b. An X-ray crystal
structure of the chloride salt of 7a is shown in Figure 2.
In efforts to make a des-benzyl analogue of this catalyst
by a more economical route, amide activating agents
other than trimethyloxonium tetrafluoroborate were
investigated. For this purpose, 2-pyrrolidinone 8 was
implemented to provide the aliphatic part of the bicyclic
skeleton (Scheme 2). A variety of attempts to activate
the carbonyl through iminoyl chloride intermediates met
with no success. Fortunately, refluxing the amide in
acetonitrile with dimethyl sulfate provides the desired
amidate, which may be treated with phenylhydrazine in
situ. Counterion exchange is achieved by liberating the
free hydrazino compound with 40% KOH and treating
with methanolic HCl to provide the chloride salt. Cy-
clization in o-dichlorobenzene with trimethyl orthofor-
mate and catalytic HCl provides the achiral catalyst 13.
In addition to the pyrrolidine framework, the morpho-
line scaffold appeared attractive since it can be readily
prepared from amino alcohols.13 The synthesis of a chiral
bicyclic benzyl-substituted triazolium chloride has been
previously reported by Leeper6 and can typically be
extended to other alkyl groups on the morpholine ring.
However, this synthetic route can be problematic with
some side chains and certain aryl hydrazines.
6
Leeper synthesis was used for the three-step conversion
into triazolium salt. Methylation of 6 with Meerwein’s
reagent affords the desired amidate, which was treated
in situ with phenylhydrazine to generate a red solution
that corresponds to the desired cyclization precursor.
(
5) Korotkikh, N. I.; Rayenko, G. F.; Shvaika, O. P.; Pekhtereva, T.
M.; Cowley, A. H.; Jones, J. N.; Macdonald, C. L. B. J. Org. Chem.
2
1
1
003, 68, 5762-5765.
6) Knight, R. L.; Leeper, F. J. J. Chem. Soc., Perkin Trans. 1998,
891-1893.
7) Enders, D.; Kalfass, U. Angew. Chem., Int. Ed. 2002, 41, 1743-
(
(
745.
(8) (a) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc.
2
002, 124, 10298-10299. (b) Kerr, M. S.; Rovis, T. Synlett 2003, 1934-
1
936. For other examples of enantioselective Stetter reactions, see: (c)
Pesch, J.; Harms, K.; Bach, T. Eur. J. Org. Chem. 2004, 2025-2035.
(
d) Mennen, S. M.; Blank, J. T.; Tran-Dub e´ , M. B.; Imbriglio, J. E.;
Miller, S. J. Chem. Commun. 2005, 195-197.
(9) (a) Kerr, M. S.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 8876-
8
877. (b) Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2005, 127,
284-6289. (c) Reynolds, N. T.; Read de Alaniz, J.; Rovis, T. J. Am.
6
Chem. Soc. 2004, 126, 9518-9519.
(
10) Meyers, A. I.; Tavares, F. X. J. Org. Chem. 1996, 61, 8207-
215.
11) Smrcina, M.; Majer, P.; Majerov a´ , E.; Guerassina, T. A.;
Eissenstat, M. A. Tetrahedron 1997, 53, 12867-12874.
12) (a) Pyrrolidinone 6 was initially obtained as a yellow oil that
8
(
(
In our explorations into the asymmetric Stetter reac-
tion, we identified aminoindanol-derived catalyst 18 as
can be used in the subsequent reactions without complications. The
yellow solid is obtained after removing the excess solvent in vacuo
overnight. (b) Lebrun, S.; Couture, A.; Deniau, E.; Grandclaudon, P.
Tetrahedron: Asymmetry 2003, 14, 2625-2632. (c) Ackermann, J.;
Matthes, M.; Tamm, C. Helv. Chim. Acta 1990, 73, 122-132.
(13) Norman, B. H.; Kroin, J. S. J. Org. Chem. 1996, 61, 4990-
4998.
5726 J. Org. Chem., Vol. 70, No. 14, 2005