Iron(III)-catalyzed consecutive aza-cope-mannich cyclization: Synthesis of trans -3,5-dialkyl pyrrolidines and 3,5-dialkyl-2,5-dihydro-1 H-pyrroles

Article abstract of DOI:10.1021/ol102372c

An efficient alkene aza-Cope-Mannich cyclization between 2-hydroxy homoallyl tosylamine and aldehydes in the presence of iron(III) salts to obtain 3-alkyl-1-tosyl pyrrolidines in good yields is described. The process is based on the consecutive generation of a γ-unsaturated iminium ion, 2-azonia-[3,3]-sigmatropic rearrangement, and further intramolecular Mannich reaction. Iron(III) salts are also shown to be excellent catalysts for the new aza-Cope-Mannich cyclization using 2-hydroxy homopropargyl tosylamine.

Full text of DOI:10.1021/ol102372c

ORGANIC
LETTERS
2010
Vol. 12, No. 22
5334-5337
Iron(III)-Catalyzed Consecutive
Aza-Cope-Mannich Cyclization: Synthesis
of trans-3,5-Dialkyl Pyrrolidines and
3,5-Dialkyl-2,5-dihydro-1H-pyrroles
Rube´n M. Carballo,†,§ Mart´ın Purino,† Miguel A. Ram´ırez,† V´ıctor S. Mart´ın,*,† and
Juan I. Padro´n*,†,‡
Instituto UniVersitario de Bio-Orga´nica “Antonio Gonza´lez”, Departamento de
Qu´ımica Orga´nica, UniVersidad de La Laguna, C/Astrof´ısico Francisco Sa´nchez 2,
38206 La Laguna, Tenerife, Spain, and Instituto de Productos Naturales y Agrobiolog´ıa,
CSIC, C/Astrof´ısico Francisco Sa´nchez 3, 38206 La Laguna, Tenerife, Spain
Vmartin@ull.es; jipadron@ipna.csic.es
Received October 1, 2010
ABSTRACT
An efficient alkene aza-Cope-Mannich cyclization between 2-hydroxy homoallyl tosylamine and aldehydes in the presence of iron(III) salts to obtain
3-alkyl-1-tosyl pyrrolidines in good yields is described. The process is based on the consecutive generation of a γ-unsaturated iminium ion, 2-azonia-
[3,3]-sigmatropic rearrangement, and further intramolecular Mannich reaction. Iron(III) salts are also shown to be excellent catalysts for the new
aza-Cope-Mannich cyclization using 2-hydroxy homopropargyl tosylamine.
Five-membered ring heterocycles containing nitrogen are
structural motifs of particular interest in synthetic and medicinal
chemistry, as they are present in a large number of bioactive
compounds.1 Considerable efforts have been devoted to the
synthesis of this type of heterocycles.2
The aza-Cope-Mannich is a tandem chemical process
between a cationic 2-aza-Cope rearrangement (2-azonia-[3,3]-
sigmatropic rearrangement) and Mannich reaction.3-5 It was
discovered by Overman and co-workers in 1979,6 and applied
successfully in numerous alkaloid syntheses.7
They found that the direct reaction of aldehydes and
tetrafluoroborate salts of homoallylic amine containing hydroxyl
or alkoxyl substituents at the allylic site afforded, after heating
under reflux, substituted 3-acylpyrrolidines. In addition, it was
necessary to use sulfonic acid to promote this reaction when
hydroxy or alkoxy homoallylic amine was used.6
The preparation of 3-formylpyrrolidines4a,6f,8 was especially
challenging for these authors. In this case the aza-Cope-
Mannich afforded formylpyrrolidine dimethyl acetals in low
yield together with material from the polymerization reaction.6a,f
† IUBO, Departamento de Qu´ımica Orga´nica, ULL.
‡ Instituto de Productos Naturales y Agrobiolog´ıa, CSIC.
(3) (a) Cooke, A.; Bennett, J.; McDaid, E. Tetrahedron Lett. 2002, 43,
903–905. (b) Royer, J.; Bonin, M.; Micouin, L. Chem. ReV. 2004, 104,
2311–2352. (c) Garc´ıa-Cuadrado, D.; Barluenga, S.; Winssinger, N. Chem.
Commun. 2008, 4619–4621.
§ Current address: Laboratorio de Qu´ımica Farmace´utica, Facultad de Qu´ımica,
Universidad Auto´noma de Yucata´n (UADY), Me´rida, Yucata´n, Me´xico.
(1) (a) Lewis, J. R. Nat. Prod. Rep. 2000, 18, 95–128. (b) Bellina, F.;
Rossi, R. Tetrahedron 2006, 62, 7213–7256.
(4) For brief reviews, see: (a) Overman, L. E. Acc. Chem. Res. 1992,
25, 352–359. (b) Overman, L. E. Aldrichimica Acta 1995, 28, 107–120.
(5) (a) Agami, C.; Cases, M.; Couty, F. J. Org. Chem. 1994, 59, 7937–
7940. (b) Cooke, A.; Bennett, J.; McDais, E. Tetrahedron Lett. 2002, 43,
903–905. (c) Johnson, B. F.; Marrero, E. L.; Turley, W. A.; Lindsay, H. A.
Synlett 2007, 893–896.
(2) (a) Michael, J. P. Nat. Prod. Rep. 2004, 21, 625–649. (b) Coldham,
I.; Hufton, R. Chem. ReV. 2005, 105, 2765–2810. (c) Wolfe, J. P. Eur. J.
Org. Chem. 2007, 571–582. (d) Herna´ndez, J. N.; Ram´ırez, M. A.; Rodr´ıguez,
M. L.; Mart´ın, V. S. Org. Lett. 2008, 10, 2349–2352. (e) Paderes, M. C.;
Chemler, S. R. Org. Lett. 2009, 11, 1915–1918.
10.1021/ol102372c  2010 American Chemical Society
Published on Web 10/22/2010

This polymerization was minimized when the reaction was
carried out under acetalizing conditions or when employing
a vinyloxazolidine was used as the starting material.
We have focused on a direct synthesis of five-membered
azacycles considering two possibilities. The first is the direct
reaction through a Prins cyclization between ꢀ,γ-unsaturated
tosylamines and aldehydes (Scheme 1, A). Unfortunately, the
reason, we decided to reduce the aldehyde before it was
purified.12 In this case the trans-5-isobutyl-1-tosylpyrrolidin-
3-yl)methanol (4a) resulting from the aza-Cope-Mannich and
further aldehyde reduction was obtained in 72% yield.
Table 1 summarizes the results obtained in this study using
two iron(III) salts as catalysts.
Table 1. Iron-Catalyzed Alkene-Aza-Cope-Mannich of
2-Hydroxy Homoallyl Tosylamine (1) with Isovaleraldehyde (2a)a
Scheme 1. Strategies to Five-Membered Azacycles Synthesis
cyclizations of the allyl tosylamine and propargyl tosylamine
with aldehydes (5-endo-trig cyclization) catalyzed by iron(III)
salts were fruitless.9 As an alternative, we focused our efforts
on the aza-Cope-Mannich cyclization (Scheme 1, B).
Herein, we report that iron(III) catalyzes the direct aza-
Cope-Mannich cyclization of 2-hydroxy homoallyl tosyl
amine and aldehydes to afford 3-formylpyrrolidines. Iron(III)
salts also catalyze a new alkyne aza-Cope-Mannich reaction
between 2-hydroxy homopropargyl tosylamine and aldehydes
to obtain 3-formyl-R,ꢀ-unsaturated pyrrolidines (7). To the
best of our knowledge, this is the first report on the use of
iron(III) salts catalyzing the aza-Cope-Mannich.
Fe(acac)3 FeCl3 TMSCl
t
yield
entry (mol %)b (mol %) (equiv) (h) trans:cisc (%) (4a)d
1
2
3
4
5
6
7
8
9
100
30
0.5
24
72
99:1
99:1
99:1
98:2
98:2
98:2
98:2
72
70
65
65
60
50
45
e
7.5
10
5
1.0
1.0
1.0
1.0
0.7
2
5
5
10
20
50
100
e
a Reaction conditions: (i) 1 (1.0 equiv), 2a (1.0 equiv), [Fe], CH2Cl2, rt,
2-12 h; (ii) NaBH4 (2.1 equiv), MeOH, 0 °C to rt. b acac ) acetylacetonate.
c The ratio trans:cis was determined by 1H NMR d Yield of the pure product
after silica gel chromatography. e The starting material was recovered.
As a model study, we chose the reaction between 2-hydroxy
homoallyl tosylamine (1)10 and isovaleraldehyde (2a) with
iron(III) chloride as catalyst in a sustainable chemical context.
The hydroxy tosylamine 1 reacted with the aldehyde 2a in dry
methylene chloride at room temperature using one full equiva-
lent of iron(III) chloride. It was observed that the desired
reaction proceeded within 30 min under open atmosphere to
give 5-isobutyl-1-tosylpyrrolidine-3-carbaldehyde (3a, a 40:60
cis:trans mixture of formyl epimers) in 30% yield. However,
we had observed a unique trans pyrrolidine-carbaldehyde from
the reaction crude.11 We assumed that the low stability of the
carbaldehyde under chromatographic conditions was responsible
for the mixture of diastereomers and the low yield. For this
The reaction works equally well using stoichiometric or
catalytic amounts of FeCl3 (Table 1, entries 1 and 3).13 In both
cases, we obtained a stereoselective reaction (>97% of trans
stereoisomer) with similar yields but at different rates, being
slower with the catalytic version. The addition of chlorotrim-
ethylsilane (TMSCl) improved the reaction rate in the catalytic
version, with similar or slightly lower yields (Table 1, entries
4 and 5). With respect to the catalyst loading, 10 mol % of the
iron salt was found to be optimal (Table 1, entry 4). The use of
5 mol % of the iron salt furnished 4a with lower yield and
higher reaction time (60%, 2 h, Table 1, entry 5). Other iron(III)
source, as Fe(acac)3 only catalyzed the aza-Cope-Mannich in
combination with TMSCl13a but with lower yields (Table 1,
entries 6 and 7). When Fe(acac)3 was used as the possible catalyst
no reaction was observed and the starting material was recovered
(Table 1, entries 8 and 9). In general, the process is higly
stereoselective with respect to iron(III) salts (Table 1, entries 1-7).
Control experiments, using TMSCl as the promoter, con-
firmed that in the absence of the iron(III) salts no 5-isobutyl-
1-tosylpyrrolidine-3-carbaldehyde (3a) was obtained. In this
case, the corresponding isobutylvinyl oxazolidine (5) was the
only product isolated (Scheme 2).14,15 In the presence of FeCl3
(6) (a) Overman, L. E.; Kakimoto, M. J. Am. Chem. Soc. 1979, 101,
1310–1312. (b) Overman, L. E.; Kakimoto, M. Tetrahedron Lett. 1979,
21, 4041–4044. (c) Overman, L. E.; Mendelson, L. T. J. Am. Chem. Soc.
1981, 103, 5579–5581. (d) Overman, L. E.; Mendelson, L. T.; Flippin, L. A.
Tetrahedron Lett. 1982, 23, 2733–2736. (e) Overman, L. E.; Jacobsen, J.
Tetrahedron Lett. 1982, 23, 3733–2740. (f) Overman, L. E.; Kakimoto,
M.; Okazaki, M. E.; Meier, P. J. Am. Chem. Soc. 1983, 105, 6622–6629.
(7) (a) Brueggemann, M.; McDonald, A. I.; Overman, L. E.; Rosen,
M. D.; Schwink, L.; Scott, J. P. J. Am. Chem. Soc. 2003, 125, 15284–
15285. (b) Earley, W. G.; Jacobsen, J. E.; Madin, A.; Meier, G. P.;
O’Donnell, C. J.; Oh, T.; Old, D. W.; Overman, L. E.; Sharp, M. J. J. Am.
Chem. Soc. 2005, 127, 18046–18053. (c) Martin, C. L.; Overman, L. E.;
Rohde, J. M. J. Am. Chem. Soc. 2008, 130, 7568–7569. (d) Dunn, T. B.;
Ellis, J. M.; Kofink, C. C.; Manning, J. R.; Overman, L. E. Org. Lett. 2009,
11, 5658–5661. (e) Martin, C. L.; Overman, L. E.; Rohde, J. M. J. Am.
Chem. Soc. 2010, 132, 4894–4906, and references therein. .
(12) The best results were obtained using NaBH4 as reducing agent.
LiAlH4 or DIBAL-H led to similar results but with lower yields.
(13) We have developed an iron catalyst system formed from FeX3 or
Fe(acac)3 and trimethylsilyl halide to perform Prins cyclization processes:
(a) Miranda, P. O.; Carballo, R. M.; Mart´ın, V. S.; Padro´n, J. I. Org. Lett.
2009, 11, 357–360. (b) Carballo, R. M.; Valdomir, G.; Purino, M.; Mart´ın,
V. S.; Padro´n, J. I. Eur. J. Org. Chem. 2010, 2304–2313.
(8) Overman, L. E.; Ricca, D. J. Comp. Org. Synth. 1991, 2, 1007–1046.
(9) The unfavored 5-endo-trig cyclizations are based on the generation
of a ꢀ-unsaturated iminium ion and subsequent nucleophilic attack by the
unsaturated C-C bond.
(10) This product was obtained in three steps. See Supporting Information.
1
(11) See H NMR of the reaction crude in Supporting Information.
Org. Lett., Vol. 12, No. 22, 2010
5335

5-alkyl-1-tosyl-2,5-dihydro-1H-pyrrole-3-carbaldehyde (7) in
good yields (Table 3).
Scheme 2. Oxazolidine as Intermediate of the
Aza-Cope-Mannich Reaction
Table 3. Iron-Catalyzed Alkyne Aza-Cope-Mannich Cyclization
of 2-Hydroxy Homopropargyl Tosylamine (6) with Aldehydesa
this oxazolidine evolves to the corresponding 5-isobutyl-3-
formyl pyrrolidine (3a), suggesting that it is an intermediate
in the aza-Cope-Mannich (Scheme 2).
entry FeCl3 (mol %) TMSCl (equiv)
R
yield (%)b
7
We next investigated the scope of the process regarding
to the aldehyde. We tested aliphatic and aromatic aldehydes
under the optimized reaction conditions, using 2-hydroxy
homoallyl tosylamine (1) as the unsaturated compound. In
general, the corresponding pyrrolidines (4) were obtained
in good yields under the previously optimized conditions.
This methodology works well with a wide range of aldehydes
except when benzaldehyde was used (Table 2, entries 11
1a
2
120
20
i-Bu
i-Bu
H
99
85
99
87
99
95
35
1.3
1.3
3b
4
120
20
H
5
120
120
120
120
20
n-Hex
c-Hex
t-Bu
6
7
8
CH2dCH(CH2)2-
9
1.3
1.3
CH2dCH(CH2)2-
10
11
12
120
120
20
Bn
Ph
Ph
81
a Reaction conditions: 6 (1.0 equiv), aldehyde (1.0-1.2 equiv), [Fe],
TMSCl (1.3 equiv), CH2Cl2, rt, 2-12 h. b Yield of the pure product after
silica gel chromatography.
Table 2. Cyclization of 2-Hydroxy Homoallyl Tosylamine (3)
and Aldehydes Using Iron(III) Chlorides as Catalytsa
We tested the aza-Cope-Mannich using a 2-hydroxy
homopropargyl tosylamine (6)16 as the unsaturated com-
pound. In this case, it was necessary to slightly increase the
amount of FeCl3 and TMSCl (Table 3) with respect to the
alkene aza-Cope-Mannich (Table 2). Again, the reaction
works well with most aliphatic aldehydes. This alkyne aza-
Cope-Mannich did not tolerate benzaldehyde and 4-pentenal
(Table 3, entries 8, 9, 11, and 12). In general, the corre-
sponding 3-formyl-R,ꢀ-unsaturated pyrrolidines (7) were
obtained in high yields using either stoichiometric amounts
of FeCl3 or the catalytic system FeCl3/TMSCl, although the
yields in the stoichiometric version were slightly higher.
A plausible mechanism for this aza-Cope-Mannich is
outlined in Scheme 3.17 The reaction of the 2-hydroxy-
FeCl3 TMSCl
entry (mol %) (equiv)
yield
R
trans:cisb
4
(%)c 4
1a
2
100
10
i-Bu
i-Bu
H
99:1
98:2
72
65
70
62
75
60
78
63
55
70
d
1.0
1.0
3
100
10
4
H
5
100
100
100
100
10
n-Hep
c-Hex
n-Prop
99:1
99:1
99:1
99:1
98:2
98:2
6
7
8
CH2dCH(CH2)2-
9
1.0
1.0
CH2dCH(CH2)2-
10
11
12
100
100
10
Bn
Ph
Ph
d
a Reaction conditions: (i) 1 (1.0 equiv), aldehyde (1.0 equiv), [Fe], TMSCl
(1.0 equiv), CH2Cl2, rt, 2-12 h; (ii) NaBH4 (2.1 equiv), MeOH, 0 °C to rt.
b The ratio trans:cis was determined by 1H NMR. c Yield of the pure product
after silica gel chromatography. d The starting material was recovered.
Scheme 3
.
Plausible Mechanism for the Iron-Catalyzed Alkene-
and Alkyne-Aza-Cope-Mannich Reaction
and 12). However, other aldehydes containing aromatic rings
located in a distal position relative to the carbonyl group
proceeded satisfactorily (Table 2, entry 10). The current iron-
catalyst system efficiently promoted the aza-Cope-Mannich
with slightly lower yields than the stoichiometric version.
Interestingly, the iron catalyst also proved to be efficient in
the cyclization process of aldehydes bearing functional
groups such as a double bond (Table 2, entries 8 and 9).
With these results in hand, we extended our studies to the
alkyne aza-Cope-Mannich, obtaining the corresponding
unsaturated (alkyne and alkene) tosylamine and aldehyde
catalyzed by ferric halide generates the corresponding unsatur-
ated oxazolidine (5 or 8),18 which evolves to the iminium ion
(14) The oxazolidines and the aldehyde are in an equilibrium that
depends on the aldehyde nature. In the case of isovaleraldehyde this
equilibrium was displaced almost completely toward the oxazolidine species,
but with 2-phenylacetaldehyde it was displaced toward the aldehyde.
(15) This oxazolidine was obtained as a single isomer that epimerized
(60:40) under chromatographic conditions. See Supporting Information.
(16) This product was obtained in two steps. See Supporting
Information.
5336
Org. Lett., Vol. 12, No. 22, 2010

9. This iminium ion undergoes a 2-azonia-[3,3]-sigmatropic
rearrangement to give iminium ion 10, which reacts through
an irreversible intramolecular Mannich reaction to give the
corresponding pyrrolidine derivatives (3 or 7).
To provide further evidence of the proposed mechanism,
DFT theoretical calculations at the B3LYP/6-31+G(d) level
were performed. The results of these calculations are
summarized in the energy diagrams shown in Figure 1.19
Thus, the N-tosyl pyrrolidine 4b was obtained in 62% yield
from an aza-Cope-Mannich and further reduction of the
resulting aldehyde. At this point, it was necessary to protect
the hydroxymethyl as TBDPS to carry out the N-detosylation.
Deprotection of the N-tosyl group with sodium/naphthalene
led to pyrrolidine 24. The last step was a reductive amination
with 3-methylbutanal and NaBH4 in methanol that leads to
the pyrrolidine alkaloid 25 in good yield (Scheme 4).
Scheme 4. Synthesis of 1-(3-Methylbutyl)pyrrolidin-3-methanol
Pyrrolidine Alkaloid from Poison Glands of Leptothoracini Ants
In summary, we have developed a novel iron-catalyzed aza-
Cope-Mannich of 2-hydroxy-γ,δ-unsaturated (alkyne and
alkene) tosylamines with different aldehydes. The coupling
between 2-hydroxy homopropargyl tosylamine and aldehydes
provides 5-alkyl-1-tosyl-2,5-dihydro-1H-pyrrole-3-carbalde-
hydes in good yields. The process catalyzed by iron(III) salts
is direct, avoiding the preformation of the oxazolidine as the
starting material. It is based on the consecutive generation of
γ-unsaturated-iminium ion, 2-azonia-[3,3]-sigmatropic rear-
rangement, and further intramolecular Mannich reaction. DFT
theoretical calculations support the proposed mechanism.
Overall, this process builds up two carbon-carbon bonds,
one nitrogen-carbon bond, and a ring in a regioselective
and efficient manner.
Figure 1. Energy (kcal/mol) profile of 2-azonia-[3,3]-sigmatropic
rearrangements and Mannich reaction.
The calculations showed that the E-iminium ion (11),
precursor of trans-stereoisomer 14, is slightly more stable than
the corresponding Z-iminium ion (15), precursor of the cis-
isomer 18. The main difference between these processes could
be found in the Mannich intramolecular cyclization that was
more exothermic for the trans-isomer than for the cis-isomer.
In both cases, the aza-cope rearrangement was slightly favored.
In the alkyne aza-Cope-Mannich, the 2-azonia-[3,3]-
sigmatropic rearrangement is also favored but with a higher
activation energy. However, the strongly exothermic final
alenol-intramolecular Mannich cyclization is responsible to
drive all the tandem process. This energy profile correlates
very well with our proposed mechanism.20
Acknowledgment. This research was supported by the
Ministerio de Educacio´n y Ciencia of Spain, co-financed by
the European Regional Development Fund (CTQ2008-
06806-C02-01/BQU), the Spanish MSC (RTICC RD06/0020/
1046 and RD06/0020/0041), the Canary Islands Government
(ACIISI) (PI 2007/022), FUNCIS (REDESFAC PI 01/06),
Consejo Superior de Investigaciones Cient´ıficas (CSIC) (PIE
200880I032) and FICIC (Grant-G.I. 08/2007). M.P. is
supported by the Programme Alban, the European Union
Programme of High Level Scholarships for Latin America,
scholarship E07D402567AR.
Finally, to explore the synthetic scope of this methodology,
we synthesized the racemic 1-(3-methylbutyl)pyrrolidin-3-
methanol 25, one of the pyrrolidine alkaloids isolated from
the poison gland of ants Leptothoracini (Myrmicinae).21
1
Supporting Information Available: H NMR and 13C
NMR spectra for all new compounds and computational
calculating data. This material is available free of charge
via the Internet at http://pubs.acs.org.
(17) Based on Overman’s proposal. (a) Jacobsen, E. J.; Levin, J.;
Overman, L. E. J. Am. Chem. Soc. 1988, 110, 4329–4336. (b) Deng, W.;
Overman, L. E. J. Am. Chem. Soc. 1994, 116, 11241–11250.
(18) TMSCl also promoted the corresponding alkyne oxazolidine
formation as intermediate in the alkyne aza-Cope-Mannich.
(19) The absolute configuration of the hydroxyl group was fixed to
simplify the calculations.
OL102372C
(20) The DFT studies confirm the alkyne aza-Cope-Mannich mecha-
nism vs alkyne Prins-pinacol alternative.
(21) Reder, E.; Veith, H. J.; Buschinger, A. HelV. Chim. Acta 1995, 78,
73–79.
Org. Lett., Vol. 12, No. 22, 2010
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