Iron(III)-promoted aza-prins-cyclization: Direct synthesis of six-membered azacycles

Article abstract of DOI:10.1021/ol061448t

A new iron(III) halide-promoted aza-Prins cyclization between γ,δ-unsaturated tosylamines and aldehydes provides six-membered azacycles in good to excellent yields. The process is based on the consecutive generation of γ-unsaturated-iminium ion and further nucleophilic attack by the unsaturated carbon-carbon bond. Homoallyl tosylamine leads to trans-2-alkyl-4-halo-1-tosylpiperidine as the major isomer. In addition, the alkyne aza-Prins cyclization between homopropargyl tosylamine and aldehydes gives 2-alkyl-4-halo-1-tosyl-1,2,5,6-tetrahydropyridines as the only cyclic products.

Full text of DOI:10.1021/ol061448t

ORGANIC
LETTERS
2006
Vol. 8, No. 17
3837-3840
Iron(III)-Promoted Aza-Prins-Cyclization:
Direct Synthesis of Six-Membered
Azacycles
Rube´n M. Carballo, Miguel A. Ram´ırez, Mat´ıas L. Rodr´ıguez,†
V´ıctor S. Mart´ın,* and Juan I. Padro´n*
Instituto UniVersitario de Bio-Orga´nica “Antonio Gonza´lez”,
UniVersidad de La Laguna, C/Astrof´ısico Francisco Sa´nchez 2,
38206 La Laguna, Tenerife, Spain
jipadron@ull.es; Vmartin@ull.es
Received June 13, 2006
ABSTRACT
A new iron(III) halide-promoted aza-Prins cyclization between
in good to excellent yields. The process is based on the consecutive generation of
by the unsaturated carbon carbon bond. Homoallyl tosylamine leads to trans-2-alkyl-4-halo-1-tosylpiperidine as the major isomer. In addition,
γ
,
δ
-unsaturated tosylamines and aldehydes provides six-membered azacycles
γ
-unsaturated-iminium ion and further nucleophilic attack
−
the alkyne aza-Prins cyclization between homopropargyl tosylamine and aldehydes gives 2-alkyl-4-halo-1-tosyl-1,2,5,6-tetrahydropyridines as
the only cyclic products.
The piperidine ring is widely distributed throughout Nature,
e.g., in alkaloids,1 and is an important scaffold for drug
discovery, being the core of many pharmaceutically signifi-
cant compounds.2,3 The syntheses of these type of compounds
have been extensively studied in the development of new
drugs containing six-membered-ring heterocycles.4
Reactions between N-acyliminium ions and nucleophiles,
also described as amidoalkylation or Mannich-type conden-
sations, have been frequently used to introduce substituents
at the R-carbon of an amine.5 There are several examples
that involve an intramolecular attack of a nucleophilic olefin
into an iminium cation for the construction of a heterocyclic
ring system.6 Traditionally, the use of hemiaminals or their
derivatives as precursors of N-acyliminium intermediates has
been a common two-step strategy in these reactions.6a Among
this type of cyclization is the aza-Prins cyclization,7 which
uses alkenes as intramolecular nucleophile. However, cy-
(5) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3187-
3856 and references therein.
(6) (a) Hiemstra, H.; Speckamp, W. N. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, O., Heathcock, C. H., Eds.; Pergamon:
New York, 1991; Vol. 2, pp 1047-1081. (b) Speckamp, W. N.; Hiemstra,
H. Tetrahedron 1985, 41, 4367-4416.
(7) (a) Dobbs, A. P.; Guesne´, S. J. J.; Hursthouse, M. B.; Coles, S. J.
Synlett 2003, 11, 1740-1742. (b) Dobbs, A. P.; Guesne´, S. J. J.; Martinove,
S.; Coles, S. J.; Hursthouse, M. B. J. Org. Chem. 2003, 68, 7880-7883.
(c) Hanessian, S.; Tremblay, M.; Petersen, F. W. J. Am. Chem. Soc. 2004,
126, 6064-6071 and references therein. (d) Dobbs, A. P.; Guesne´, S. J.
Synlett 2005, 13, 2101-2103.
† X-ray analysis. E-mail address: malopez@ull.es.
(1) (a) Fodor, G. B.; Colasanti, B. Alkaloids: Chemical and Biological
PerspectiVes; Pelletier, S. W., Ed.; Wiley: New York, 1985; Vol. 23, pp
1-90. (b) Baliah, V.; Jeyarama, R.; Chandrasekaran, L. Chem. ReV. 1983,
83, 379-423.
(2) Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679-3681.
(3) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003, 103,
893-930.
(4) Buffat, M. G. P. Tetrahedron 2004, 60, 1701-1729 and references
therein.
10.1021/ol061448t CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/26/2006

clization reactions of alkynes with weak electrophiles such
as iminium ions have received less attention. Intramolecular
reactions of alkynes have been reported by Speckamp and
co-workers,6,8 throughout N-acyliminium ions. Also, Over-
man and co-workers discovered that Mannich cyclizations
of alkynes are possible in the presence of reactive external
nucleophiles throughout formaldiminium ions.9
The aza-Prins cyclization works well with either aliphatic
or aromatic aldehydes. In all the cases, the trans-diastereomer
was obtained as the major product. The trans stereochem-
istry, was confirmed by nOe experiments of 2-alkyl-4-halo-
5,6-dihydro-2H-pyrans16 and X-ray analysis of 2a (R ) i-Bu,
X ) Cl and R ) PhCH2, X ) Cl) (Figure 1).
In this paper, we explore the use of iron(III) halides to
generate a γ,δ-unsaturated-iminium intermediate which
further cyclization, through aza-Prins reaction, leads to six-
membered azacycles. The method uses homoallyl and
homopropargyl tosylamines and takes into account the similar
chemical reactivity of the sulfonamide nitrogen and the
alcohol (Scheme 1).10,11
Scheme 1. Similar Chemical Reactivity of the Nitrogen in
Sulfonamides and the Oxygen in Alcohols
Figure 1. X-ray crystallographic structures of 4-chloro-2-isobutyl-
1-tosylpiperidine (A) and 2-benzyl-4-chloro-1-tosylpiperidine (B).
To account for the stereochemical course of the reaction,
ab initio theoretical calculations at the B3LYP/6-31G(d) level
were performed for some cases of 2a and 2b, and their
N-sulfonyl iminium intermediates (Scheme 2 and Table 2).
First, to check the catalytic behavior of FeX3 in the aza-
Prins cyclization, we carried out the reaction between N-(but-
3-enyl)-4-methylbenzenesulfonamide12 (1) and several al-
dehydes using FeCl3 and FeBr313 as promoters.14 Such Lewis
acids showed that the cyclization proceeded in good yields,
affording the corresponding trans-4-halo-2-alkyl tosylpip-
eridine 2a as the major product. Table 1 summarizes the
results obtained in this study.15
Scheme 2. Proposed Intermediates in the Aza-Prins
Cyclization to 2-Alkyl-4-halo-1-tosylpiperidines
Table 1. Cyclization of Homoallyl Tosyl Amine and
Aldehydes with FeX3 as Promoter
entry
R
X
2a/2b
yield (%)
The calculations showed that the E-iminium ion, precursor
of trans stereoisomers 2a, is always more stable than the
corresponding Z-iminium ion, precursor of the cis-isomers
1
2
3
4
5
6
7
8
9
c-C6H11
i-Bu
n-C7H15
Ph
PhCH2
H
c-C6H11
i-Bu
n-C7H15
Ph
PhCH2
H
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
Br
98:2
99:1
97:3
90:10a
83:17b
68
82
88
46
78
91
82
96
90
82
94
90
(8) (a) Dijkink, J.; Schoemaker, H. E.; Speckamp, W. N. Tetrahedron
Lett. 1975, 4043-4046. (b) Dijkink, J.; Speckamp, W. N. Tetrahedron Lett.
1975, 4047-4050. (c) Boer-Terpstra, T.; Dijkink, J.; Schoemaker, H. E.;
Speckamp, W. N. Tetrahedron Lett. 1977, 939-942.
(9) (a) Overman, L. E.; Sharp, M. J. J. Am. Chem. Soc. 1988, 110, 612-
614. (b) Lin, N.-H.; Overman, L. E.; Rabinowitz, M. H.; Robinson, L. A.;
Sharp, M. J.; Zablocki, J. J. Am. Chem. Soc. 1996, 118, 9062-9072. (c)
Caderas, C.; Lett, R.; Overman, L. E.; Rabinowitz, M. H.; Sharp, M. J.;
Zablocki, J. J. Am. Chem. Soc. 1996, 118, 9073-9082. (d) Metais, E.;
Overman, L. E.; Rodr´ıguez, M. I.; Stearn, B. A. J. Org. Chem. 1997, 62,
9210-9216.
(10) (a) Mukai, C.; Sugimoto, Y.-I.; Miyazawa, K.; Yamaguchi, S.;
Hanaoka, M. J. Org. Chem. 1998, 63, 6281-6287. (b) Davis, F. A.; Song,
M.; Augustine, A. J. J. Org. Chem. 2006, 71, 2779-2786.
98:2
97:3
98:2
92:8a
86:14b
10
11
12
a The stereoisomers were isolated by silica chromatography. b The
stereoisomers were isolated by HPLC, using a semipreparative column.
3838
Org. Lett., Vol. 8, No. 17, 2006

using the Ohira methodology.17 With the exception of
benzaldehyde, the alkyne aza-Prins methodology tolerates a
wide range of aldehydes.15 In all the cases, the desired six-
membered ring is obtained in 63-96% yield. Other alde-
hydes containing aromatic rings although located at a distal
position (entries 5 and 11) relative to the carbonyl group
proceeded satisfactorily.
From the different solvents screened (THF, CH3CN,
EtOAc, CHCl3, CCl4, CH3NO2, CH2Cl2, and 1,2-dichloro-
ethane) we found the best conditions using CH2Cl2 and 1,2-
dichloroethane. A similar solvent effect to the oxa-alkyne
Prins cyclization was observed. When FeBr3 was used as
catalyst and the reaction run with CH2Cl2 as solvent, the
corresponding chlorovinyl derivative was obtained in a
mixture with the bromovinyl compound (Scheme III).11a
Table 2. Ab Initio Calculations of Some trans- and
cis-2-Alkyl-4-chloro-1-tosylpiperidine and Its
N-Sulfonyliminium Intermediate
EΕ-iminium-E·-iminium
Etrans-Ecis
entry
R
(kcal/mol)
(kcal/mol)
1
2
3
4
5
Me
Et
i-Pr
s-Bu
CH2Ph
-0.78
-1.77
-1.25
-1.56
+0.37
-1.25
-2.12
-0.41
-0.74
-2.12
2b, when R is an alkyl group (entries 1-4). However, the
Z-iminium ion becomes a more stable intermediate when R
bears an aromatic ring (entry 5). This fact could explain the
increase of cis-isomer when aromatic aldehydes are being
used (Table 1, entries 4, 5, 10, and 11). Interestingly, all the
trans-compounds are also more stable than their correspond-
ing cis-isomers.
Scheme 3. Participation of the Solvent as the Source of the
Halogen in the Alkyne Aza-Prins Cyclization
In both cis- (2b) and trans-isomers (2a) (R ) alkyl, entries
1-4), the most stable conformer has the N-tosyl group endo
over the piperidine ring like a “sunshade”. This conformer
matches with the X-ray crystallographic structure found
(Figure 1A). The N-tosyl group displays an exo disposition
with respect to the piperidine ring if R has an aromatic ring
(R ) CH2Ph, entry 5) (Figure 1B).
With these results in hand, we extended our studies using
homopropargyl tosylamine as the unsaturated amine. We
found the corresponding 2-alkyl-4-halo-1-tosyl-1,2,5,6-tet-
rahydropyridines 4 was obtained in good yields (Table 3).
Several hypotheses could be considered: (a) some halide
exchange between the halogenated solvent and the metal,18
(b) the capture of the solvent halogen by the vinyl cation
intermediate,19 and (c) the combination of both a and b. From
the synthetic point of view, it is clear that for each halide
the corresponding halogenated solvent must be used. In
addition, we did not find any mixture of halogenated products
Table 3. Synthesis of
2-Alkyl-4-halo-1-tosyl-1,2,5,6-tetrahydropyridines from N-Tosyl
Homopropargyl Amine and Aldehydes, Using FeX3 as Catalyst
(11) For the use of iron(III) halides in oxa-Prins cyclizations from our
laboratory, see: (a) Miranda, P. O.; Diaz, D. D.; Padro´n, J. I.; Bermejo, J.;
Mart´ın, V. S. Org. Lett. 2003, 5, 1979-1982. (b) Miranda, P. O.; Diaz, D.
D.; Padro´n, J. I.; Ram´ırez, M. A.; Mart´ın, V. S. J. Org. Chem. 2005, 70,
57-62.
(12) The N-(but-3-enyl)-4-methylbenzenesulfonamide was prepared from
3-bromoprop-1-ene with 4-methylbenzenesulfonamide in 67% yield ac-
cording to: Larock, R. C.; Yang, H.; Weinreb, S. M.; Herr, R. J. J. Org.
Chem. 1994, 59, 4172-4178.
entry
R1
X
yield (%)
(13) FeCl3 and FeBr3 were purchased from the Aldrich Chemical Co.
(14) To the best of our knowledge, this is the first report on the use of
Fe(III) halides promoting this kind of reaction.
1
2
3
4
5
6
7
8
9
c-C6H11
i-Bu
n-C7H15
Ph
PhCH2
H
c-C6H11
i-Bu
n-C7H15
Ph
PhCH2
H
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
Br
74
85
91
29
63
83
84
85
90
38
67
96
(15) Typical experimental procedure for a ferric halide promoted
aza-Prins cyclization: To a solution of homoallyl tosylamine or homopro-
pargyl tosylamine (1 equiv) and aldehyde (1.5 equiv) in dry CH2Cl2 was
added anhydrous FeX3 (1.5 equiv) in one portion. The reaction was
concluded in approximately 10 min, quenched by addition of water and
extracted with CH2Cl2. The combined organic layers were dried over
magnesium sulfate, and the solvent was removed under reduced pressure.
This crude reaction mixture was purified by flash silica gel column
chromatography (n-hexane/EtOAc solvent systems).
(16) See the Supporting Information.
(17) Ohira, S. Synth. Commun. 1989, 19, 561-564.
(18) For a precedent about the halogen transfer from halogenated solvents
to a metal, see: Fu¨rstner, A.; Mathes, C.; Lehmann, C. W. Chem. Eur. J.
2001, 7, 5299-5317.
10
11
12
(19) Only a few examples of halogen abstraction by vinyl cations from
chlorinated solvents are known: (a) Cook, G. C.; Hayashi, R. Org. Lett.
2006, 8, 1045-1048. (b) Sun, J.; Kozmin, S. A. J. Am. Chem. Soc. 2005,
127, 13512-13513. (c) Balog, A.; Geib, S. V.; Curran, D. P. J. Org. Chem.
1995, 60, 345-352 and references therein.
The N-(but-3-ynyl)-4-methylbenzenesulfonamide 3 was
readily prepared from 3-aminopropan-1-ol in three steps,
Org. Lett., Vol. 8, No. 17, 2006
3839

(2, X ) Cl or Br) when the aza-Prins cyclization was
performed over homoallyl tosylamine.
chloro-1-tosyl-1,2,5,6-tetrahydropyridine from the more elabo-
rated and noncommercial aldehyde 9 (Scheme 6). The aza-
To improve yields, the amount of anhydrous ferric chloride
was also varied from substoichiometric (0.1 equiv) to 2 equiv.
We found that the highest values were obtained when 1.5
equiv was used.
Scheme 6. Synthesis of a
2-Alkyl-4-chloro-1-tosyl-1,2,5,6-tetrahydropyridine Dimer-Type
To check the advantage of iron over other typical metal
halides used in the aza-Prins cyclization, we performed a
few runs using indium halides as catalysts (Scheme 4).20 We
Scheme 4. Alkyne Aza-Prins Cyclization with In(III) Halides
as Promoter
Prins cyclization with the corresponding homopropargyl
tosylamine (3) and the aldehyde 9 led the unprecedented
dimer 10, showing that this new methodology could be
applied to the synthesis of complex molecules in a highly
efficient manner.
In conclusion, we have reported on a novel use of iron-
(III) halides as efficient catalysts for aza-Prins cyclizations.
The coupling between homoallyl tosyl- and homopropargyl
tosylamines provides in good yields trans-2-alkyl-4-halo-1-
tosylpiperidine and 2-alkyl-4-halo-1-tosyl-1,2,5,6-tetrahy-
dropyridines, respectively. The reaction proceeds satisfac-
torily with aromatic and aliphatic substrates, as well as with
enolizable and nonenolizable aldehydes. It is noteworthy that
the carbon-carbon bond formation is very rapid even at 0
°C, usually being completed within 10 min.22 The method
is direct, generating N-sulfonyliminium intermediates in situ.
Ab initio theoretical calculations support the proposed
mechanism. Efforts in the application of the developed
methodology to nonterminal olefins and alkynes are currently
underway in our laboratory. In addition, the catalytic and
asymmetric version is under development and the results will
be reported in due course.
found that both InCl3 and InBr3 also induced the cyclization
of homopropargyl tosylamine and aldehydes to the corre-
sponding tetrahydropyridines. However, the reactions are
slower and the obtained yields are lower.
A plausible mechanism for this new alkyne aza-Prins
cyclization is outlined in Scheme 5. The reaction of the
Scheme 5. Plausible Mechanism of the Alkyne Aza-Prins
Cyclization
Acknowledgment. This research was supported by the
Ministerio de Educacio´n y Ciencia of Spain, co-financed by
the European Regional Development Fund (CTQ2005-
09074-C02-01/BQU) and the Canary Islands Government.
R.M.C. thanks the Spanish MEC for an FPU fellowship, and
J.I.P. thanks the Spanish MEC-FSE for a Ramo´n y Cajal
contract.
homopropargyl tosylamine and an aldehyde promoted by
ferric halide generates the N-sulfonyl iminium ion 5. This
intermediate evolves to the corresponding tetrahydropyridine
4.21
Finally, to explore the synthetic scope of this method we
decided to perform the synthesis of the dimer 2-alkyl-4-
Supporting Information Available: 1H NMR and 13C
NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(20) For the use of InX3 in silyl aza-Prins type reactions, see refs 7a and
7b. Examples of the use of InX3 in the Prins reaction are known. (a) Lee,
C.-H. A.; Loh, T. P. Tetrahedron Lett. 2006, 47, 1641-1644. (b) Chan,
K.-P.; Loh, T. P. Org. Lett. 2005, 7, 4491-4494. (c) Meiler, K.; Brimble,
M. A. Org. Lett. 2005, 7, 3497-3500. (d) Chan, K.-P.; Loh, T. P.
Tetrahedron Lett. 2004, 45, 8387-8390.
OL061448T
(21) On the basis of our previous results, we cannot discard the formation
of a vinylic carbocation as a possible intermediate.
(22) The reaction has been scaled up to 1 g with no difficulty.
3840
Org. Lett., Vol. 8, No. 17, 2006