A modified Mannich-Type reaction catalyzed by VO(acac)2

Article abstract of DOI:10.1021/ol017229j

(Equation Presented) A fackile VO(acac)₂-catalyzed in situ generation of iminium ions from amine N-oxides and their participation in a modified Mannich-type reaction is described.

Full text of DOI:10.1021/ol017229j

ORGANIC
LETTERS
2002
Vol. 4, No. 3
463-466
A Modified Mannich-Type Reaction
Catalyzed by VO(acac)2
Der-Ren Hwang and Biing-Jiun Uang*
Department of Chemistry, National Tsing Hua UniVersity,
Hsinchu, Taiwan 300, Republic of China
bjuang@mx.nthu.edu.tw
Received December 13, 2001
ABSTRACT
A facile VO(acac)2-catalyzed in situ generation of iminium ions from amine N-oxides and their participation in a modified Mannich-type reaction
is described.
The Mannich reaction1 is an important carbon-carbon bond
formation reaction widely used in the synthesis of secondary
and tertiary amine derivatives and applied as a key step in
the synthesis of many bioactive molecules and complex
natural products.2 This reaction basically involves the addi-
tion of a carbon nucleophile to an iminium ion, resulting in
a secondary or tertiary amine derivative depending on the
nature of the substrate. Among the several methods available
for the generation of the required iminium ions, the com-
monly used procedure is the Polonovsky or modified
Polonovsky reaction3 in which a tertiary amine oxide is
treated with a promoter such as acetic anhydride, trifluoro-
acetic anhydride,4 sulfur dioxide,5 or ferrous salt6 (Scheme
1). However, these promoters are expensive or are sometimes
Scheme 1
(1) (a) Tramontini, M.; Angiolini, L. Mannich Bases: Chemistry and
Uses; CRC: Boca Raton, FL, 1994. (b) Tramontini, M. Synthesis 1973,
703. (c) Blicke, F. F. Org. React. (NY) 1942, 1, 303. (d) Overman, D. J. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 2, p 1007. (e) Arend, M.; Westermann, B.; Risch,
N. Angew. Chem., Int. Ed. 1998, 37, 1045. (f) Speckamp, W. N.; Moolenaar,
M. J. Tetrahedron 2000, 56, 3817. (g) Bur, S. K.; Martin, S. F. Tetrahedron
2001, 57, 3221.
(2) (a) Deng, W.; Overman, L. E. J. Am. Chem. Soc. 1994, 116, 11241.
(b) Ito, M.; Clark, C. W.; Mortimore, M.; Goh, J. B.; Martin, S. F. J. Am.
Chem. Soc. 2001, 123, 8003. (c) Liras, S.; Davoren, J. E.; Bordner, J. Org.
Lett. 2001, 3, 703.
(3) (a) Polonovsky, M. Bull. Soc. Chim. Fr. 1927, 41, 1190. (b) Leonard,
N. J.; Klainer, J. A. J. Heterocycl. Chem. 1971, 8, 215. (c) Leonard, N. J.;
Paukstelis. J. V. J. Org. Chem. 1963, 28, 3021.
(4) Ahond, A.; Cave´, A.; Kan-Fan, C.; Husson, H.-P.; de Rostolan, J.;
Potier, P. J. Am. Chem. Soc. 1968, 90, 5622.
(5) Edward, J. T.; Whiting, J. Can. J. Chem. 1971, 49, 3502.
(6) Ferris, J. P.; Gerwe, R. D.; Gapski, G. R. J. Am. Chem. Soc. 1967,
89, 5270.
(7) Suau, R.; Najera, F.; Rico, R. Tetrahedron 2000, 56, 9713.
(8) (a) Kuhnen, L. Chem. Ber. 1966, 99, 3384. (b) Sheng, M. N.; Zajacek,
J. G. J. Org. Chem. 1966, 33, 588.
(9) (a) Hwang, D.-R.; Chen, C.-P.; Uang, B.-J. Chem. Commun. 1999,
1207. (b) Chu, C.-Y.; Hwang, D.-R.; Wang, S.-K.; Uang, B.-J. Chem.
Commun. 2001, 980.
difficult to handle and are required in more than stoichio-
metric amounts. Recently acetyl chloride and mesyl chloride7
were used as activating agents in excess amounts in a
Polonovsky-Potier reaction of Berbine N-oxides; however,
the procedure suffered from very poor yields.
Though vanadium-catalyzed oxidation of amine to amine
oxide was previously reported,8 vanadium-mediated genera-
tion of the iminium ion from amine N-oxide was hitherto
unreported. Earlier, we investigated the vanadium-catalyzed
homo-coupling of phenols and naphthols in the presence of
an external co-oxidant.9 During the course of our studies
toward finding an ideal combination of vanadium oxidant
10.1021/ol017229j CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/09/2002

and external co-oxidant for the oxidative coupling reactions,
we performed an equimolar reaction of 2-naphthol (1a) and
N-methylmorpholine N-oxide (NMO) (2a) in the presence
of 10 mol % of V2O5 in dichloromethane under refluxing
conditions (Scheme 2). To our pleasant surprise, the corre-
Table 2. Reactions of Naphthols and Phenols with Amine
N-Oxide Catalyzed by VO(acac)2
Scheme 2
sponding Mannich adduct 3a was obtained in good yield in
this reaction. We have developed this vanadium-catalyzed
reaction into an expedient general method for the in situ
generation of iminium ions from tertiary amine N-oxides for
their subsequent application in a modified Mannich-type
reaction and the results are described in this Letter.
Catalytic profiles of vanadium(IV) and vanadium(V)
species such as VO(OiPr)3, VO(acac)2, and VOSO4‚H2O were
tested to optimize the reaction conditions (Table 1). An
Table 1. Preparation of the Mannich Base from 2-Naphthol
(1a) and NMO (2a) Using Vanadium Catalystsa
entry
catalyst
time (h)
yield (%)
1
2
3
4
V2O5
VO(OiPr)3
VO(acac)2
30
16
8
78
78
92
52
VOSO4‚2H2O
24
a Reaction conditions: catalyst (10 mol %), CH2Cl2, reflux.
a For entries 2 and 8: R ) CH3. For the remaining entries: R, R )
-(CH2CH2OCH2CH2)-; NMO ) N-methylmorpholine N-oxide, TMNO
) trimethylamine N-oxide.
excellent yield of the Mannich base could be attained in a
shorter reaction time when VO(acac)2 was used as catalyst.
The yield of the product could be further upgraded by
increasing the amount of NMO to 3 equiv.
while ester-substituted 2-naphthol (entry 5) afforded the
corresponding Mannich base in a relatively low yield.
1-Naphthol and phenols also furnished the corresponding
Mannich bases albeit in low yields. Under similar reaction
conditions, trimethylamine N-oxide (TMNO) (2b) smoothly
reacted with 2-naphthol and phenol in the presence of
VO(acac)2 to provide the corresponding Mannich adducts
3. This iminium species generated from TMNO is an
equivalent of Eschenmoser salt.10
In a preliminary assessment of the generality of this
reaction, we tested several naphthols and phenols as nucleo-
philes in this Mannich-type reaction (Scheme 3). Similar
yields and reactivities were observed with bromo- and
methoxy-substituted 2-naphthols (Table 2, entries 3 and 4),
Scheme 3
Taking the reaction of 2-naphthol (1a) and N-oxide (2a)
as an illustrative case, a plausible mechanism for this reaction
is depicted in Scheme 4. Complexation of the vanadium
(10) (a) Schreiber, J.; Maag, H.; Hashimoto, N.; Eschenmoser, A. Angew.
Chem., Int. Ed. Engl. 1971, 10, 330. (b) Bryson, T. A.; Bonitz, G. H.;
Reichel, C. J.; Dardis, R. E. J. Org. Chem. 1980, 45, 524. (c) Kinast, G.;
Tietze, L.-F. Angew. Chem., Int. Ed. Engl. 1976, 15, 239. (d) Rochin, C.;
Babot, O.; Dunogue`s, J.; Duboudin, F. Synthesis 1986, 228. (e) Reissig,
H.-U.; Lorey, H. J. Chem. Soc., Chem. Commun. 1986, 269.
464
Org. Lett., Vol. 4, No. 3, 2002

Scheme 4
Table 3. VO(acac)2-Catalyzed Modified Mannich-Type
Reactions of 3° Amine Oxides with Naphthols
species with amine N-oxide 2a followed by an intramolecular
elimination through six-membered transition structure A
resulted in iminium ion B. Subsequent addition of the
naphtholate (obtained from the acidic proton abstraction of
2-naphthol (1a) by vanadium species) to the iminium ion B
results in Mannich base 3a. The protonated vanadium species
C then eliminates one molecule of water to regenerate the
oxovanadium catalyst.
R-position of the R-amino acid. Ours is the first metal-
catalyzed modified Polonovsky reaction and provides a new
entry to R-aryl-R-amino acids. Recently the Risch group
reported in situ generation of ternary iminium salts from
benzotriazole-based ethyl glyoxylate aminals by using a
stoichiometric amount of Lewis acid (AlCl3 or TiCl4) in the
synthesis of R-aryl-R-amino acid esters.11 The classical
Site selectivity in this reaction was studied by conducting
the reaction of various amine N-oxides with 2-naphthol in
the presence of a catalytic amount of VO(acac)2 (Table 3).
When pyrrolidine N-oxide (2c) was employed, C-C bond
formation took place from the endo position. On the other
hand, N-substituted-morpholine N-oxides (2a, 2d, and 2f)
afforded exo-addition products. Interestingly, N-allylmor-
pholine N-oxide (2e) gave hemiacetal 3m, whose formation
can formally be explained by a three-step sequence, 1,4-
addition of 2-naphthol (1a) to the R,â-unsaturated iminium
ion intermediate D followed by hydrolysis and subsequent
hemiacetal formation (Scheme 5). N,N-Disubstituted glyci-
nate N-oxides were found to be more reactive as they could
furnish the Mannich base even at room temperature (entries
5 and 6). It is noteworthy that these glycinate N-oxides
exibited high regioselectivity with the selective participation
of active methylene carbon (R to the ester carbonyl) in the
formation of Mannich base. Another significant feature of
this protocol is that it involves an umpolung-type reaction
facilitating the incorporation of an aryl substituent at the
Scheme 5
(11) Grumbach, H.-J.; Merla, B.; Risch, N. Synthesis 1999, 1027.
Org. Lett., Vol. 4, No. 3, 2002
465

Mannich reaction had limited applicability in the synthesis
of these amino acids.11
An interesting double alkylation reaction of the imine
carbon was witnessed when 1,3-dicarbonyl compounds such
as dibenzoylmethane (4a) and diethyl malonate (4b) were
reacted with NMO or TMNO (Scheme 6, Table 4). Initial
Table 4. Reaction of 1,3-Dicarbonyl Compounds with Amine
N-Oxides
entry
substrate
N-oxide
time (h)
product
yield (%)
1
2
3
4a
NMO
TMNO
TMNO
14
10
24
5a
56
77
54
4b
5b
Scheme 6
In conclusion, we have devised a general and convenient
VO(acac)2-catalyzed method for the facile in situ generation
of iminium ions from various amine oxides, for their usage
in Mannich-type reactions. The formation of a CdN bond
is highly regioselective, selectively involving the carbon-
bearing more acidic proton. Viability of this approach for
the conversion of different types of amine N-oxides into
iminium ions promises a wide scope to access a variety of
Mannich bases.
Acknowledgment. We are grateful to the National
Science Council, Republic of China for financial support of
this work.
Supporting Information Available: Detailed experi-
mental procedure and characterization data for new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Mannich reaction followed by a â-elimination of an amine
from the Mannich base to form an R,â-unsaturated compound
and subsequent Michael addition of a second molecule of
1,3-dicarbonyl compound would rationalize the formation
of a double alkylation product in these reactions.
OL017229J
466
Org. Lett., Vol. 4, No. 3, 2002