A new catalytic prins cyclization leading to oxa- and azacycles

Article abstract of DOI:10.1021/ol802593u

(Chemical Equation Presented) A new Prins cyclization process that builds up one carbon-carbon bond, one heteroatom-carbon bond, and one halogen-carbon bond, (in an oxa- and azacycle) relies on an iron catalyst system formed from Fe(acac)₃ and

Full text of DOI:10.1021/ol802593u

ORGANIC
LETTERS
2009
Vol. 11, No. 2
357-360
A New Catalytic Prins Cyclization
Leading to Oxa- and Azacycles
Pedro O. Miranda,† Rube´n M. Carballo,† 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@ull.es
Received November 10, 2008
ABSTRACT
A new Prins cyclization process that builds up one carbon-carbon bond, one heteroatom-carbon bond, and one halogen-carbon bond, (in an
oxa- and azacycle) relies on an iron catalyst system formed from Fe(acac)3 and trimethylsilyl halide. The method displays a broad substrate
scope and is economical, environmentally friendly, and experimentally simple. This catalytic method permits the construction of chloro, bromo
and iodo heterocycles, by the suitable combination of iron(III) source, the corresponding trimethylsilyl halide and the solvent, in high yields.
The six membered ring heterocycles of nitrogen and oxygen
are structural motifs of particular interest in synthetic and
medicinal chemistry, as they are present in a large number
of bioactive compounds.1 Among existing methodologies,
the Prins cyclization has emerged as a powerful tool in the
synthesis of this type of heterocycles.2
starting materials, being used in the production of a large
number of organic compounds.3 On the other hand, there
has been an increasing demand for environmentally friendly
and sustainable chemical processes.4 This inspired us to
develop alkyne-Prins and aza-alkyne-Prins cyclizations using
stoichiometric iron (III) halides as the promoter, generating
in situ the acetal intermediates leading to the corresponding
halo-heterocycles.5 These methods are distinguished by the
low cost, readily availability of components, and environ-
mentally benign character of the iron salts used, in combina-
tion with the high reaction rates observed and mild condi-
Typically, the Prins cyclization requires the use of sto-
ichiometric amounts of a Lewis acid and mixed acetals as
† IUBO, Departamento de Qu´ımica Orga´nica, ULL.
‡ Instituto de Productos Naturales y Agrobiolog´ıa, CSIC.
(1) Kishi, Y. Pure Appl. Chem. 1998, 70, 339–344. Baliah, V.; Jeyarama,
R.; Chandrasekaran, L. Chem. ReV. 1983, 83, 379–423. Faulkner, D. J. Nat.
Prod. Rep. 2002, 19, 1–48, and references cited therein. Buffat, M G. P.
Tetrahedron 2004, 60, 1701–1729and references cited therein Larrosa, I.;
Romea, P.; Urp´ı, F. Tetrahedron 2008, 64, 2683–2723, and references cited
therein. Tsukamoto, H.; Kondo, Y. Angew. Chem., Int. Ed. 2008, 47, 4851–
4854.
(3) Lee, C.-H. A.; Loh, T.-P Tetrahedron Lett. 2006, 47, 1641–1644.
Custar, D. W.; Zabawa, T. P.; Scheidt, K. A J. Am. Chem. Soc. 2008, 130,
804–805. Woo, S. K.; Kwon, M. S.; Lee, E. Angew. Chem., Int. Ed. 2008,
47, 3242–3244. Wender, P. A.; DeChristopher, B. A.; Schrier, A. J. J. Am.
Chem. Soc. 2008, 130, 6658–6659. Bannck, K. B.; Rychnovsky, S. D. J. Am.
Chem. Soc. 2008, 130, 13177–13181.
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M. J.; Zablocki, J. J. Am. Chem. Soc. 1996, 118, 9073–9082. Metais, E.;
Overman, L. E.; Rodr´ıguez, M. I.; Stearn, B. A. J. Org. Chem. 1997, 62,
9210–9216. Dobbs, A. P.; Guesne´, S. J. J.; Hursthouse, M. B.; Coles, S. J.
Synlett 2003, 11, 1740–1742. Dobbs, A. P.; Guesne´, S. J. J.; Martinove, S.;
Coles, S. J.; Hursthouse, M. B. J. Org. Chem. 2003, 68, 7880–7883.
Hanessian, S.; Tremblay, M.; Petersen, F. W. J. Am. Chem. Soc. 2004,
126, 6064–6071, and references cited therein. Pastor, I. M.; Yus, M. Curr.
Org. Chem. 2007, 11, 925–957.
(4) Warner, J. C.; Cannon, A. S.; Dye, K. M. EnViromental Impact
Assesment ReView 2004, 24, 775–799. Clarke, P. A.; Santos, S.; Martin,
W. H. C. Green Chem. 2007, 9, 438–440.
(5) Miranda, P. O.; Diaz, D. D.; Padro´n, J. I.; Bermejo, J.; Mart´ın, V. S.
Org. Lett. 2003, 11, 1979–1982. Miranda, P. O.; D´ıaz, D. D.; Padro´n, J. I.;
Ram´ırez, M. A.; Mart´ın, V. S. J. Org. Chem. 2005, 70, 57–62. Carballo,
R. M.; Ram´ırez, M. A.; Rodr´ıguez, M. L.; Mart´ın, V. S.; Padro´n, J. I. Org.
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10.1021/ol802593u CCC: $40.75
Published on Web 12/18/2008
2009 American Chemical Society

Table 1. Iron-Catalyzed Alkyne-Prins Cyclization of
Table 2. Iron-Catalyzed Construction of Chloro and Bromo
Heterocycles
Homopropargylic Derivatives (1) with Isovaleraldehyde (2a)a
TMSCL
(equiv)
yield
(%)a
FeCl3
(mol %)
Fe(acac)3
(mol %)b
TMSCl
(equiv)
yield
(%)c
entry
Z
X
R
entry
Z
1
2
3
4
5
6
7
8
9
10
11
12
13
14
O or NTs
O or NTs
O
NTs
NTs
NTs
NTs
NTs
NTs
O
Cl
Br
Cl
Cl
Cl
Cl
Br
Br
Br
Cl
Cl
Cl
Br
Br
i-Bu
i-Bu
i-Bu
i-Bu
c-C6H11
Bn
i-Bu
c-C6H11
Bn
CH2dCH(CH2)2-
AcO(CH2)3-
Bn
i-Bu
i-Bu
1.0
1.0
1.2
1.5
1.5
1.5
1.5
1.5
1.5
1.0
1.0
1.5
1.5
1.0
0b
0b
1
2
3
4
5
6
7
8
9
10
11
12
13
O or NTs
O
O
O
O
O
O
O
0
10
10
10
7
5
0
0
0
0
0
0
0
0
0
10
7
5
0
1.0
0.5
1.0
1.2
1.2
1.2
1.2
1.2
1.2
1.0
1.0
1.0
1.5
0
70
88
90
90
80
85
90
78
70
80d
50e
80d
90c
80c
79c
65c
87c
81c
88c
30d
37d
70d
85d
85d
O
NTs
NTs
NTs
NTs
10
10
0
O
0
10
7.5
NTs
NTs
O
0
a Reaction conditions: 1 (1.0 equiv), 2 (1.0 equiv), [Fe] (0.07 equiv),
TMSCl (1.2 equiv), CH2Cl2, rt, 2-12 h. b acac ) acetylacetonate. c Yield
of the pure product after silica-gel chromatography. d 1.5 equiv of 2.
e Conversion of 80%.
a Yield of the pure product after silica-gel chromatography. b Control
experiment without iron source. c FeCl3 (0.07 equiv) as iron source.
d Fe(acac)3 (0.07 equiv) as iron source.
tions. Encouraged by these results, we have made considerable
efforts to replace stoichiometric methods by catalytic pro-
cesses, being the halide source our first concern.
homopropargyl derivatives (1) and isovaleraldehyde (2a) to
give the unsaturated six membered ring heterocycles 3a. We
tested tetrabutylammonium chloride and TMSCl as the halide
source in the presence of catalytic FeCl3 (10 mol %) in
CH2Cl2 at room tempereature and found, that the Prins
cyclization was possible only with TMSCl providing the
desired product 3a in good yield (Table 1, entry 2). Control
experiments confirmed that in the absence of the iron salts
no product was obtained (Table 1, entry 1).10 We found that
using 1.2 equivalents of TMSCl it was possible to obtain
better yields (Table 1, compare entries 2, 3 and 4). When
only 0.5 equivalents of TMSCl were used, 3a was formed
in lower yield (Table 1, entry 2), and no significant
improvement was observed with 1.5 equivalents. With
respect to the catalyst loading, 7 mol % of the iron salt was
found to be optimal. The use of 5 mol% of the iron salt
furnished 3a with lower yield (80%, Table 1, entry 6). After
these good results, Fe(acac)3 was chosen for further inves-
tigations as it is less hygroscopic and easier to handle than
FeCl3. Interestingly, the related iron species was as efficient
as FeCl3 (Table 1, entries 7, 8 and 9).11
It has been reported that silicon is one of the most
oxyphilic elements, and it has been used as additive in several
catalytic process.6 On the other hand, Baba and co-workers
reported that a combination of InCl3 and chlorotrimethylsi-
lane (TMSCl) acts a catalyst for the Sakurai-Hosomi reac-
tion.7 More recently, Loh et al. have reported the synthesis
of 4-halo tetrahydropyran rings using trimethylsilyl halides
as additives and indium salts as catalyst.8 Herein, we report
the first iron-catalyzed Prins- and aza-Prins cyclizations. The
catalytic system, which is obtained by combining readily
available iron salts with trimethylsilyl halides,9 is widely
applicable and promotes the construction of substituted six
membered oxa- and aza-cycles.
As a model study for the optimization of the reaction
conditions, we first chose the alkyne-Prins cyclization of
(6) Fu¨rstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 2533–2534.
Fu¨rstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 12349–12357. Fu¨rstner,
A. Chem.-Eur. J. 1998, 4, 567–570. Justicia, J.; Rosales, A.; Bun˜uel, E.;
Oller-Lo´pez, J.; Valdivia, M.; Ha¨ıdour, A.; Oltra, J. E.; Barrero, A. F.;
Ca´rdenas, D. J.; Cuerva, J. M. Chem.-Eur. J. 2004, 10, 1778–1788.
(7) Onishi, Y.; Ito, T.; Yasuda, M.; Baba, A. Eur. J. Org. Chem. 2002,
1578–1581. Onishi, Y.; Ito, T.; Yasuda, M.; Baba, A. Tetrahedron 2002,
58, 8227–8235.
Encouraged by these results, we next investigated the
scope of the process regarding the aldehyde type. We tested
aliphatic and aromatic aldehydes under the optimized reaction
conditions, using homopropargyl derivatives (1) as unsatur-
(8) Chan, K.-P.; Loh, T.-P. Org. Lett. 2005, 7, 4491–4494. Chan, K.-
P.; Seow, A.-H.; Loh, T.-P. Tetrahedron Lett. 2007, 48, 37–41. Chan, K.-
P.; Ling, Y. H.; Loh, T.-P. Chem. Commun. 2007, 939–941. Liu, F.; Loh,
T.-P. Org. Lett. 2007, 9, 2063–2066.
(9) For precedents in the literature using FeCl3/TMSCl system, see:
Cunico, R. F. Tetrahedron Lett. 1990, 31, 5607–5608. Xu, L.-W.; Xia, C.-
G.; Hu, X.-X. Chem. Commun. 2003, 2570–2571. Sreedhar, B.; Reddy,
M. A.; Reddy, P. S Synlett 2008, 13, 1949–1952. Xu, L-W.; Yang, M.-S.;
Qiu, H.-Y.; Lai, G.-Q.; Jiang, J.-X. Synth. Commun. 2008, 38, 1011–1019.
(10) Using a catalytic amount of FeCl3 (0.1 equiv), we obtained the
corresponding acetal as a single product in good yield (80%). See ref 5.
(11) When this cyclization was performed, using Fe(acac)3 and isoval-
eraldehyde, in the presence of air and moisture the target product was
obtained in a remarkable 70% yield.
358
Org. Lett., Vol. 11, No. 2, 2009

Table 3. Halogen Exchange with Halogenated Solvents in the
Table 4. Iron-Catalyzed Aza-Prins Cyclization of Homoallyl
Oxa- and Aza-alkyne Prins Cyclizationa
Tosyl Aminesa
FeX3
[mol %] [mol %]
Fe(acac)3
yield
(%)
FeBr3
3a:3b
FeCl3
3a:3b
Fe(acac)3
3a:3b
entry
X
R
5:6b
entry
Z
solvent/ TMSX
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Cl
Cl
Cl
Br
Br
Br
Cl
Cl
Br
Cl
Cl
Cl
Cl
I
10
10
10
10
10
10
0
0
0
0
0
0
0
0
0
0
0
7.5
7.5
7.5
7.5
7.5
7.5
7.5
7.5
i-Bu
c-C6H11
Bn
i-Bu
c-C6H11
Bn
i-Bu
Bn
i-Bu
CH2dCH(CH2)2-
BnO(CH2)2-
TBSO(CH2)7-
AcO(CH2)3-
i-Bu
94:6
95:5
84:16
95:5
94:6
83:17
95:5 g99
83:17 g99
94:6 g99
95:5
95:5
95:5
95
92
80
95
98
86
1
2
3
4
5
6
a
O
O
O
O
NTs
NTs
CH2Cl2 TMSCl
CH2Cl2 TMSBr
CH2Br2 TMSBr
CH2Br2 TMSCl
CH2Cl2 TMSCl
CH2Br2 TMSCl
1
80:20b
25:75
0:100
30:70
85:15
30:70
100:0
25:75
0:100
35:65
100:0
40:60
100:0
20:80
0:100
40:60
100:0
40:60
Determinated by H NMR. b Ratio 3a:3b, 85:15 at 0°
85
85
71c
0
ated compounds. In general, the corresponding heterocycles
(3) were obtained in high yields under the previously
optimized conditions. The current iron-catalyst system ef-
ficiently promoted the alkyne-Prins cyclization with different
types of aldehydes, in both the oxa- and aza- version
(30-90% yield, Table 2, entries 3-14). Importantly, the iron
catalyst also proved to be efficient in the cyclization process
of more challenging aldehydes bearing functional groups
such as double bonds and acetates, but with lower yield
(Table 2, entries 10 and 11).12 Furthermore, the method
permits the construction of bromo heterocycles by using
TMSBr as additive (Table 2, entries 7, 8, 9, 13, and 14).
0
0
0
95:5
92d
a Reaction conditions: 4 (1. 0 equiv), 2 (1.5 equiv), [Fe] (0.1 or 0.07
equiv), TMSCl (1.5 equiv), CH2Cl2, rt, 2-12 h. b Determinated by 1H NMR.
c 30% protected as TBS and 41% as alcohol. d CH3I was used as solvent.
corresponding dihydropyran (Table 3, entries 1-4) and
tetrahydropyridine (Table 3, entries 5 and 6) products with
higher halide exchange. This halide exchange ranged between
25% for CH2Cl2 (Table 3, entry 2) and 65% for CH2Br2
(Table 3, entry 4). Surprisingly, the combination FeCl3/
TMSBr/CH2Br2 led exclusively to the bromotetrahydropyran
(Table 3, entry 3). The catalytic system using Fe(acac)3 as
iron source, and the same halogen in TMSX and CH2X2
avoided the halogen exchange to give the desired product
(Table 3, entries 1, 3 and 5).
Scheme 1
.
Synthesis of Iodo-Substituted 6-Membered
Heterocycles
This catalytic method also permits the construction of iodo
heterocycles, presumably via the in situ generation of the
unstable and noncommercial available FeI3.14 The optimal
solvent for this reaction should be methylene iodide (CH2I2)
since the use of CH2Cl2 leads to a mixture of products. To
our delight methyl iodide (CH3I) could be used as the solvent
with excellent results, and thus, avoids the use of CH2I2
which has a higher boiling point (181 °C) that complicates
15
the workup (Scheme 1).
The conditions for the iron-catalyzed alkyne-Prins cy-
clization can also be applied to homoallyl N-tosyl amines
and homoallyl alcohols as unsaturated heteroatomic species
(Table 4 and Table 5, respectively). With N-(but-3-enyl)-4-
methylbenzenesulfonamide, the iron sources, FeCl3 and
Fe(acac)3 catalyzed the cyclization and afforded in both cases
A halide exchange with halogenated solvents, using
stoichiometric amounts of iron(III) halides as promoters, in
oxa- and aza-alkyne Prins cyclizations have been observed.
The process is specific for alkynes, since during the Prins
cyclization using both homoallyl N-tosyl amines and ho-
moallyl alcohols, the halide participation from the haloge-
nated solvent was absent.5,5,13 As shown in Table 3, we tested
the halogen exchange with halogenated solvents in the
current iron-catalyst process. In general, dibromomethane
was more reactive than dichloromethane and gave the
(12) The reaction does not work with other functional groups as benzyl,
THP, or TBS.
(13) Miranda, P. O.; Carballo, R. M.; Ram´ırez, M. A.; Mart´ın, V. S.;
Padro´n, J. I. ArkiVoc 2007, iV, 331–334.
(14) Yoon, K. B.; Kochi, J. K. Inorg. Chem. 1990, 29, 869–874.
(15) Sun, J.; Kozmin, S. A. J. Am. Chem. Soc. 2005, 127, 13512–13513.
Org. Lett., Vol. 11, No. 2, 2009
359

Table 5. Iron-Catalyzed Prins Cyclization of Homoallyl
Scheme 2. Plausible Mechanism for the Iron-Catalyzed
Construction of Oxa- and Azacycles Through the Prins
Cyclization
Alcoholsa
entry
X
R
yield (%)
1
2
3
4
5
6
Br
Br
Cl
Cl
Cl
Cl
i-Bu
p-NO2Ph
CH2dCH(CH2)2-
AcO(CH2)3-
TBSO(CH2)7-
BnO(CH2)2-
88
78
70
60
71b
86
a Reaction conditions: 7 (1. 0 equiv), 2 (1.0 equiv), [Fe] (0.07 equiv),
TMSCl (1.0 equiv), CH2Cl2, rt, 2-12 h. b 30% protected as TBS and 41%
as alcohol
trans-4-halo-2-alkyl tosylpiperidine 5 as the major product
in very good yield (Table 4).5 The aza-Prins cyclization
works well with either aliphatic or aromatic aldehydes. The
catalysts loadings, 10 mol% of FeCl3 and 7.5 mol% of
Fe(acac)3 were found to be optimal (Table 4). The tolerance
of functional groups at the aldehyde such as alkene,
benzyloxy (BnO) and tert-butydimethyllsilyloxy (TBSO),
with Fe(acac)3 as the iron source, to the described protocol
is remarkable, and much higher than in the alkyne-Prins
cyclization (Table 4, entries 10, 11 and 12, respectively).
Surprisingly, the benzyl group was stable under the catalytic
conditions (Table 4, entry 11).16 As before the use of
Fe(acac)3 as the iron source, with a 7 mol% as catalyst
loading led the Prins cyclization of homoallyl alcohol (7)
with several aldehydes (Table 5). Consistent with the
previous results, the cyclization works very well with a wide
range of aldehydes; aliphatics, aromatics and functionalides
(Table 5). An advantage of the catalytic process, with respect
to stoichiometric version, is the tolerance of aldehydes
functionalized with double bonds, acetates, or benzyl groups
(Table 5, entries 3, 4 and 6).
halide, constitute the thermodynamic sink which drives the
conversion but demands the use of stochoichiometric or
excess amount of iron (III) salts.
Therefore an indirect way to complete a catalytic cycle
was devised relying on a ligand exchange between the iron
complex and a chlorosilane, regenerating the iron (III) halide
due to the more oxyphilic character of the silicon.
In summary, we have developed a novel iron-catalyzed
Prins cyclization of γ,δ-unsaturated (alkyne and alkene)
amines and alcohols with different substituted aldehydes. The
key finding for this protocol is the catalytic effect of a
combination of readily available and inexpensive iron source
(FeX3 or Fe(acac)3) and TMSCl. This catalytic method also
permits the construction of chloro, bromo and iodo hetero-
cycles by the suitable combination of iron(III) source, the
corresponding trimethylsilyl halide and the solvent. Overall,
this process builds up one carbon-carbon bond, one het-
eroatom-carbon bond, one halogen-carbon bond, and a ring
in a regioselective and efficient manner. Our results expand
the application of iron salts as promising cost-efficient
catalysts in organic synthesis. In addition, the asymmetric
version, the use of secondary homoallylic and homoprop-
argylic alchohols, and the synthetic application to more
structurally complex products are under development and
the results will be reported in due course.
The tentative catalytic cycle is depicted in Scheme 2. We
reasoned that a plausible catalytic cycle could be readily
initiated via an activation of the aldehyde with the iron salt.17
Its reaction with the corresponding unsaturated nucleophilic
species would lead to the acetal precursor.18 The very high
stability of the accumulating iron oxide or nitrogen coun-
terpart, and the fact that the iron salt is the only source of
Acknowledgment. This research was supported by the
Ministerio de Educacio´n y Ciencia of Spain, cofinanced by
the European Regional Development Fund (CTQ2005-
09074-C02-01/BQU), FICIC, the Spanish MSC ISCIII
(RETICS RD06/0020/1046) and the Canary Islands Govern-
ment. R.M.C. thanks the Spanish MEC for a FPU fellowship.
(16) The utilization of stoichiometric ferric chloride in CH2Cl2 at room
temperature is a suitable method to achieve debenzylations. See: Padro´n,
J. I.; Va´zquez, J. T. Tetrahedron Asymmetry 1995, 6, 857–858.
(17) It should be emphasized that the storage of R3SiX generate traces
of free acid HX by hydrolysis: Dilman, A. D.; Ioffe, S. L Chem. ReV. 2003,
103, 733–772. On the other hand, in the presence of free acid HX, Fe(acac)3
is hydrolyzed to the corresponding iron (III) halide: Miller, D. D.; Van
Campen, D Am. J. Clin. Nutr. 1979, 32, 2354–2361.
1
Supporting Information Available: H NMR and 13C
NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(18) With 0.1 equiv of FeCl3, the corresponding acetal was isolated only
when Z is oxygen.
OL802593U
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Org. Lett., Vol. 11, No. 2, 2009