Gallium iodide/iodine as a versatile reagent for the aza-Prins cyclization: an expeditious synthesis of 4-iodopiperidines

Article abstract of DOI:10.1016/j.tetlet.2008.03.006

4-Iodopiperidines are prepared in good yields and with high selectivity by means of aza-Prins-cyclization using a catalytic amount of gallium(III) iodide and a stoichiometric amount of iodine under mild reaction conditions. This is the first report on the preparation of 4-iodopiperidines via aza-Prins-cyclization.

Full text of DOI:10.1016/j.tetlet.2008.03.006

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3330–3334
Gallium iodide/iodine as a versatile reagent for the aza-Prins
cyclization: an expeditious synthesis of 4-iodopiperidines
J. S. Yadav *, B. V. Subba Reddy, D. N. Chaya, G. G. K. S. Narayana Kumar,
S. Aravind, A. C. Kunwar, C. Madavi
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 24 October 2007; revised 10 February 2008; accepted 3 March 2008
Available online 6 March 2008
Abstract
4-Iodopiperidines are prepared in good yields and with high selectivity by means of aza-Prins-cyclization using a catalytic amount
of gallium(III) iodide and a stoichiometric amount of iodine under mild reaction conditions. This is the first report on the preparation
of 4-iodopiperidines via aza-Prins-cyclization.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Aza-Prins-cyclization; Molecular iodine; Homoallylic amines; 4-Iodopiperidine
The piperidine ring is a common structural feature of
numerous naturally occurring alkaloids such as coniine,
sedamine, sedridine, (À)-allosedamine, (À)-allosedridine,
halosaline, and many others.1 They are very useful for
the treatment of respiratory illnesses such as asthma, bron-
chitis, and pneumonia.2 Both enantiomers of allosedridine
exhibit memory-enhancing properties and may be effective
for the treatment of Alzheimer’s disease.3 As a result, var-
ious methods have been developed for the synthesis of
substituted piperidines in a stereo- and enantioselective
manner.4 Of these, the aza-Prins cyclization is a simple
and direct method for the preparation of trans-2,4-disubsti-
tuted piperidines.5 In addition, the aza-silyl-Prins reaction
is a method for the preparation of trans-2,6-disubstituted
tetrahydropyridine derivatives.6 In spite of its potential
utility in natural product synthesis, only a few reports exist
on aza-Prins-cyclizations.5,6 Furthermore, there have been
no reports on the synthesis of iodopiperidines via the
aza-Prins-cyclization. Recently, there has been consider-
able interest in gallium-mediated transformations.7 Owing
to their unique catalytic properties, gallium halides have
been widely used for a variety of organic transformations.
In particular, gallium(III) compounds are considered as
effective Lewis acids to activate alkynes under extremely
mild conditions.8
In continuation of our research program on the Prins-
cyclization,9 we herein report an efficient method for the
synthesis of substituted piperidines from homoallylic
amines and aldehydes by means of aza-Prins-cyclization
using gallium(III) iodide/molecular iodine under mild
conditions. Accordingly, treatment of benzaldehyde with
N-tosylhomoallyl amine in the presence of 10 mol % of
GaI3 and a stoichiometric amount of molecular iodine at
ambient temperature over 6.5 h gave the corresponding
4-iodo-2-phenylpiperidine 3a in 91% yield with trans-
selectivity (Scheme 1).
I
I
GaI3/I2
CHO
+
N
N
TsHN
+
CH2Cl2, r.t.
Ts
Ts
1
2
3a (major)
Scheme 1. Preparation of 3a.
4a (trace)
*
Corresponding author. Tel.: +91 40 27193535; fax: +91 40 27160512.
E-mail address: yadavpub@iict.res.in (J. S. Yadav).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.006

J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 3330–3334
3331
The structure of 3a shown in Figure 1 was deduced from
the NMR data, where the two substituents, iodo and
phenyl, are trans to each other. Proton H4 has two large
couplings (J = 12.6 Hz) indicating it to be in an axial posi-
tion, with diaxial couplings to H3a and H5a, implying that
the iodo group adopts the equatorial position at C4. This
was further confirmed by a NOESY cross peak, H4/H6a.
The axial orientation of the Ph group was confirmed by
the NOESY cross peaks, H-ortho/H4 and also H-ortho/
H6a. In addition, the couplings and H3a/H5a NOE corre-
lation provided additional support for the structure.
H
1
5
H
3
H
6
NTs
H
I
H
4
H
2
H
H
o
m
p
This result provided incentive for further study of
reactions with other aldehydes such as cyclohexanecarbox-
aldehyde, n-decanal, isovaleraldehyde, and hydrocinnamal-
Fig. 1. Characteristic NOEs and energy-minimized structure of 3a.
Table 1
Gallium(III) iodide/iodine promoted aza-Prins cyclization
Entry
Homoallyl amine
Aldehyde
CHO
Iodopyridinea
Time (h)
6.5
Yieldb (%)
91
Trans/cisc
96:4
I
NHTs
a
N
Ts
I
CHO
NHTs
b
6.0
88
97:3
N
Ts
I
NHTs
NHTs
CHO
c
6.5
6.5
90
89
98:2
98:2
( )5
( )5
N
Ts
I
d
CHO
N
Ts
I
CHO
NHTs
NHTs
e
f
7.0
6.0
91
89
98:2
97:3
N
Ts
I
CHO
CHO
N
Ts
Br
Br
I
NHTs
NHTs
g
6.5
8.0
92
83
96:4
N
Ts
Me
MeO
Me
I
CHO
h
96:4
N
Ts
MeO
(continued on next page)

3332
J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 3330–3334
Table 1 (continued)
Entry
Homoallyl amine
Aldehyde
Iodopyridinea
Time (h)
8.5
Yieldb (%)
82
Trans/cisc
96:4
I
CHO
CHO
NHTs
i
O2N
N
Ts
O2N
I
NHTs
NHTs
j
7.5
7.5
90
86
97:3
—
N
Ts
I
k
CHO
CHO
N
H
I
NHTs
NHTs
NHTs
l
8.0
7.0
7.5
90
85
88
—
—
—
N
H
I
CHO
m
N
H
I
n
CHO
N
H
a
All products were characterized by 1H NMR, IR, and mass spectroscopy.
Yield refers to pure products after chromatography.
b
c
The diastereoselectivity was determined by HPLC.
dehyde to produce the respective trans-2-alkyl-4-iodopi-
peridines in excellent yields (Table 1, entries b–e). Aromatic
aldehydes such as p-bromobenzaldehyde, p-methylbenzal-
dehyde, p-methoxybenzaldehyde, and p-nitrobenzaldehyde
underwent smooth coupling with N-tosylhomoallylic
amine to furnish the corresponding trans-2-aryl-4-iodopi-
peridines (Table 1, entries f–i). Similarly, trans-cinnamalde-
hyde gave the corresponding trans-4-iodo-2-styryl-
piperidine in 90% yield (Table 1, entry j). The use of the
substituted homoallylic amines afforded 2,4,6-trisubsti-
tuted piperidines with all cis-configuration (Table 1, entries
k–n, Scheme 2).
H
H
H
6
H
4
5
7
I
1
H
2
NH
H
3
o
H
p
m
Fig. 2. Characteristic NOEs and energy-minimized structure of 3l.
The NMR data suggested the structure for 3l (Fig. 2),
where the three 2-, 4-, and 6-substituents are in equatorial
positions.
The H2 and H6 protons showed large couplings
(J = 11.0 Hz) whereas H4 has two large couplings (J =
12.4 Hz) indicating the axial positioning of these protons,
and thereby the equatorial orientation of the substituents
at the 2-, 4-, and 6-positions. The structure was further
confirmed by NOESY cross peaks between H4a/H6a,
H2a/H6a, and H3a/H5a. Further, the equatorial position
of the Ph group was confirmed by NOESY cross peaks,
H-ortho/H3e and H-ortho/H3a. It is important to mention
that N-tosyl deprotection was observed during the aza-
Prins-cyclization of substituted homoallylic amides (Table
I
NHTs
O
GaI3/I2
N
H
+
H
CH2Cl2, r.t.
3l
Scheme 2. Preparation of 3l.

J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 3330–3334
3333
Ts
N+
O+ Ga(III)
H
Ts
-
I
N
I
TsHN
+
..
R
R
R
E
-iminium intermediate
Scheme 3. A plausible reaction mechanism.
London, UK, 1985; Chapter 3, pp 89–183; (e) Numata, A.; Ibuka, I.
In The Alkaloids; Brossi, A., Ed.; Academic: New York, 1987; Vol. 31,
pp 193–315; (f) Angle, R. S.; Breitenbucher, J. G. In Studies in Natural
Products Chemistry; Atta-ur-Rahman, Ed.; Stereoselective Synthesis
(Part J); Elsevier: Amsterdam, The Netherlands, 1995; Vol. 16, pp
453–502.
1, entries k–n). In the absence of gallium(III) iodide, no
aza-Prins-cyclization was observed even with stoichio-
metric amounts of iodine. The use of gallium(III) iodide
alone gave the products in low yields (20–35%). Therefore,
addition of 1 equiv. of iodine was crucial to obtain high
conversion. Thus, the combination of gallium(III) iodide
and iodine worked efficiently to furnish the corresponding
di- and tri-substituted piperidines in good to high yields.
The effects of various metal iodides such as GaI3, InI3,
AlI3, and MgI2 were screened. Of these metal iodides, gal-
lium(III) iodide was found to be superior in terms of con-
version. For example, the reaction between benzaldehyde
and N-tosylhomoallyl amine in the presence of 1 equiv of
molecular iodine and 10 mol % of metal iodides such as
GaI3, InI3, AlI3, and MgI2 gave product 3a, in 91%,
75%, 69%, and 62% yields, respectively. The combination
of 10 mol % of FeCl3 and 1 equiv of iodine also gave
4-iodopiperidines along with 4-chloropiperidines. In addi-
tion, N-tosyl deprotection was observed in aza-Prins-cycli-
zation when using FeCl3/I2. As solvent, dichloromethane
gave the best results. In all cases, the reactions proceeded
readily at room temperature under mild conditions to give
the products in good yields and with high diastereoselecti-
vity. The formation of the products may be explained by
initial aminal formation and subsequent Prins-type cycli-
zation (Scheme 3). The scope and generality of this process
is illustrated in Table 1.10
2. Gershwin, M. E.; Terr, A. Clin. Rev. Allergy Immunol. 1996, 14, 241.
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Suec. 1967, 4, 97; (b) Micel, K.-H.; Sandberg, F.; Haglid, F.; Norin,
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D.; Millwood, P. A.; Smith, P. D. Chem. Commun. 1998, 633–640; (c)
Weintraub, P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R.
Tetrahedron 2003, 59, 2953–2989; (d) Felpin, F.-X.; Lebreton, J. Eur.
J. Org. Chem. 2003, 3693–3712; (e) Couty, F. Amino Acids 1999, 16,
297–320. Interscience: New York, 1972; Vol. 2, pp 1–95.
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Padron, J. I. Org. Lett. 2006, 8, 3837.
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A. P.; Guesne, S. J. J.; Hursthouse, M. B.; Coles, S. J. Synlett 2003,
1740–1742; (c) Dobbs, A. P.; Guesne, S. J. J.; Martinovic, S.; Coles, S.
J.; Hursthouse, M. B. J. Org. Chem. 2003, 68, 7880–7883.
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2002, 124, 10294; (b) Yamaguchi, M.; Tsukagoshi, T.; Arisawa, M. J.
Am. Chem. Soc. 1999, 121, 4074; (c) Asao, N.; Asano, T.; Ohishi, T.;
Yamamoto, Y. J. Am. Chem. Soc. 2000, 122, 4817.
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Biswas, S. K. Tetrahedron Lett. 2005, 46, 1161; (b) Yadav, J. S.;
Reddy, B. V. S.; Padmavani, B.; Gupta, M. K. Tetrahedron Lett.
2004, 45, 7577.
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Swamy, T. Tetrahedron Lett. 2007, 48, 2205–2208; (b) Yadav, J. S.;
Subba Reddy, B. V.; Narayana Kumar, G. G. K. S.; Reddy, M. G.
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In summary, we have developed an efficient protocol for
the synthesis of 2,4-di- and 2,4,6-trisubstituted piperidines
by means of aza-Prins-cyclization using gallium(III)
iodide/molecular iodine as a novel catalytic system. The
method is mild, selective, and convenient and the reaction
conditions are amenable to scale-up.
10. General procedure:
A mixture of homoallylic amine (1 mmol),
aldehyde (1 mmol), and gallium iodide (0.1 mmol) and iodine
(1.0 mmol) in dichloromethane (5 mL) was stirred at 23 °C for the
specified amount of time (Table 1). After completion of the reaction
as indicated by TLC, the reaction mixture was extracted with
dichloromethane (2 Â 10 mL). The combined organic layers were
dried over anhydrous Na2SO4. Removal of the solvent followed by
purification on silica gel (Merck, 60–120 mesh, ethyl acetate–hexane,
0.5–9.5) gave the pure 4-iodopiperidine. The products thus obtained
were characterized by IR, NMR, and mass spectroscopy. The spectral
data were found to be consistent with authentic samples. Compound
3a: 4-Iodo-1-(4-methylphenylsulfonyl)-2-phenylhexahydropyridine:
solid, mp 102–104 °C. IR (KBr): mmax 3029, 2924, 2870, 1598, 1494,
1448, 1336, 1285, 1156, 1091, 1059, 950, 930, 834, 701 cmÀ1. 1H NMR
(500 MHz, CDCl3): d 7.76 (d, J = 7.7 Hz, 2H, tos-o), 7.34 (m, 4H, tos-
m, Ph-m), 7.28 (m, 3H, Ph-o, p), 5.21 (br m, 1H, H2e), 4.13 (tt,
J = 12.6, 3.9, Hz, 1H, H4a), 3.74 (ddt, J = 14.8, 4.6, 2.3 Hz, 1H, H6e),
3.04 (ddd, J = 15.2, 12.6, 2.9 Hz, 1H, H6a), 2.95 (ddt, J = 13.4, 4.2,
2.1 Hz, 1H, H3e), 2.46 (s, 3H, CH3), 2.28 (dt, J = 5.4, 13.4 Hz, 1H,
H3a), 2.10 (m, 1H, H5e), 1.95 (dq, J = 4.6, ꢀ12.6 Hz, 1H, H5a). 13C
NMR (75 MHz, CDCl3): d 19.0, 21.6, 38.0, 40.6, 43.4, 57.6, 126.6,
Acknowledgements
DNC, GGKSNK and SA thank CSIR, New Delhi, for
the award of fellowships and also thank DST for the finan-
cial assistance under the J. C. Bose fellowship scheme.
References and notes
1. (a) Jones, T. H.; Blum, M. S. In Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; Wiley: New York, 1983; Vol. 1,
Chapter 2, pp 33–84; (b) Fodor, G. B.; Colasanti, B.. In Alkaloids:
Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New
York, 1985; Vol. 3, Chapter 1, pp 1–90; (c) Schneider, M. J. In
Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.;
Wiley: New York, 1996; Vol. 10, Chapter 3, pp 155–315; (d) Strunz,
G. M.; Findlay, J. A. In The Alkaloids; Brossi, A., Ed.; Academic:

3334
J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 3330–3334
127.0, 127.4, 129.0, 129.9, 137.1, 138.0, 143.6. LCMS: m/z: (M++H)
2.57 (ddt, J = 12.8, 4.2, 2.1 Hz, 1H, H3e), 2.39 (ddt, J = 12.6, 4.2,
2.1 Hz, 1H, H5e), 2.14 (q, J ꢀ 13.0 Hz, 1H, H3a), 2.01 (q,
J ꢀ 12.0 Hz, 1H, H5a), 1.81 (q, J ꢀ 6.8 Hz, 1H, H7), 0.98 (d,
J = 6.8 Hz, 3H, CH3), 0.96 (d, J = 6.8 Hz, 3H, CH3). 13C NMR
(75 MHz, CDCl3): d 18.2, 18.4, 23.4, 29.7, 32.9, 41.6, 47.5, 80.3, 83.8,
125.5, 127.4, 128.3, 141.6. LCMS: m/z (%): (M++H) 330.
442. Compound 3l: 4-Iodo-2-isopropyl-6-phenylhexahydropyridine:
liquid IR (KBr): mmax 3451, 2959, 2923, 2850, 1451, 1156, 1129, 1063,
1
1001, 754 cmÀ1. H NMR (500 MHz, CDCl3): d 7.34 (m, 2H, Ph-m),
7.28 (m, 3H, Ph-o, p), 4.43 (tt, J = 12.4, 4.2 Hz, 1H, H4a), 4.36 (dd,
J = 11.0, 2.2 Hz, 1H, H2a), 3.23 (ddd, J = 11.0, 5.9, 1.8 Hz, 1H, H6a),