Green chemistry: Solvent- and metal-free Prins cyclization. Application to sequential reactions

Article abstract of DOI:10.1039/c1cc16501a

Prins cyclization between a homoallylic alcohol and an aldehyde, promoted by trimethylsilyl halide, afforded 4-halo-tetrahydropyrans with good to excellent yields. Thanks to the absence of the solvent and metal, the THP thus obtained have been implicated

Full text of DOI:10.1039/c1cc16501a

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Green chemistry: solvent- and metal-free Prins cyclization. Application to
sequential reactionsw
´
Damien Clarisse, Beatrice Pelotier, Olivier Piva and Fabienne Fache*
Received 19th October 2011, Accepted 21st October 2011
DOI: 10.1039/c1cc16501a
Prins cyclization between a homoallylic alcohol and an aldehyde,
promoted by trimethylsilyl halide, afforded 4-halo-tetrahydropyrans
with good to excellent yields. Thanks to the absence of the solvent
and metal, the THP thus obtained have been implicated without
purification in several other reactions, in a sequential way, affording
in particular new indole derivatives.
The tetrahydropyran ring (THP) is present in numerous
natural products and therefore considerable efforts have been
made to develop methods which give access to this structure,1
such as oxa-Michael reactions2 or radical cyclizations.3 Among
them, the Prins cyclization has a major impact4 as confirmed by
the continuous flow of articles which were published, and are still
published in the literature on the subject.5–7 In the course of our
study on the synthesis of THP-containing natural products,8,9 we
examined the possibility of using the Prins approach. Several
types of metals have been successfully applied as catalysts such as
Fe,10 In,11 Sc,12 salts. Ionic liquids derived from Lewis13 or
Fig. 1 Solvent- and metal-free Prins cyclisation.
carbon–halogen bond formation under solvent free conditions.
We thus examined the possibility of working under neat conditions
and our first results showed that neither the solvent (usually
CH2Cl2) nor the catalyst were necessary (Fig. 1).
Bronsted acids14 have also been developed. A proper choice of
¨
In a typical procedure, 1 mmol of homoallylic alcohol,
1 mmol of aldehyde and 1.5 mmol of trimethylsilyl halide were
stirred at room temperature for the required time (20 min–2 h).
Column chromatography on silica allowed the isolation of the
pure product with good isolated yields (Table 1).
the metal salts or the presence of an additive such as a
trimethylsilyl halide allowed the introduction of a halogen at
the 4-position of the THP ring,15,16 leading to the formation of
one C–C bond, one heteroatom–carbon bond and one halogen–
carbon bond starting from homoallylic alcohols and aldehydes.
Interested by all the concepts which allow the development of
green organic chemistry, we especially turn our attention to
sequential reactions which avoid intermediate purifications.17,18
One of the major problems to overcome is the choice of the
solvent, which has to be efficient in different reactions, solventless
conditions being the ideal case. There are only a few examples of
solvent-free Prins reaction in the literature: Borah et al. used the
SiO2 p-TSA catalyst under solventless microwave irradiation
conditions for the synthesis of 1,3-dioxanes19 and Dos Santos
et al. reported the use of the same catalyst for the synthesis of
THP odorants.20 Prins reaction of styrenes with formalin was
also described using HPA salts leading also to 1,3-dioxane
derivatives,21 but to our knowledge there is no report of
3-Buten-1-ol combined with different aldehydes, aliphatic
(Table 1, entries 1–4) or aromatic (Table 1, entries 6–14), gave
good to excellent isolated yields of the corresponding THP
derivatives. It is to be noticed that working under classical
solvent conditions led only to recovered starting materials
(Table 1, entry 5). In the case of aliphatic aldehydes, only
the cis adducts were observed. With aromatic aldehydes,
mixtures of stereoisomers were obtained, with a cis/trans ratio
in favour of the cis isomers. Most of the time, the two isomers
can be separated by column chromatography. The formation
of the trans isomer is not usually reported under classical
diluted conditions (most of the time CH2Cl2 as a solvent).
Nevertheless, Rychnovsky et al.22 observed axial-selective
Prins cyclization in the case of homoallylic ethers by solvolysis
of bromoether intermediates when TMSBr was used, invoking
the formation of an intimate ion pair followed by a possible
proximal addition of the bromide, leading to the axial adduct.
Our particularly concentrated conditions could be in favour of
the formation of this intimate ion pair and thus explain this
unusual formation.
Universite´ de Lyon, Universite´ Lyon 1, ICBMS, e´quipe SURCOOF,
CNRS, UMR 5246, Baˆt. Raulin, 43 Bd du 11 Nov. 1918, 69622
Villeurbanne cedex, France. E-mail: fache@univ-lyon1.fr;
Fax: +33 472448136; Tel: +33472448521
w Electronic supplementary information (ESI) available: Complete
synthetic procedures, characterization data, 1H and 13C NMR spectra
of all new compounds. See DOI: 10.1039/c1cc16501a
c
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Chem. Commun., 2012, 48, 157–159 157

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Table 1 Solvent- and metal-free Prins cyclization
Table
cyclization–Bartoli reaction
2
New indole derivatives obtained via sequential Prins
Product:
isolated yield (%) ratio
Cis/trans
Entry R1
R2
X
Isolated yield (%)
(cis/trans)
Entry Aldehyde 2
R3 Compound 5
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
i-Bu
i-Bu
n-C5H11
c-C6H11
Ph
Ph
Ph
Ph
Cl 3a: 93
Br 3b: 50a
Cl 3c: 76
Cl 3d: 90
Cl 3e: 0b
Cl 3e: 83
Br 3f: 85a
100/0
100/0
100/0
100/0
—
100/0
85/15
70/30
76/24
75/25
99/1
75/25
91/9
55/45
89/11
80/20
1
H
30 (80/20)
I
3g: 70a
9
p-NO2Ph
o-NO2Ph
p-MeOPh
Cl 3h: 84
Cl 3i: 80
Cl 3j: 70
Cl 3k: 85
10
11
12
13
14
15
16
c
R2
3-NO2,4-MePh Cl 3l: 78
2-NO2,6-ClPh Cl 3m: 88
2
H
35 (26/74)
Ph
Cl 3n: 81
Cl 3o: 87
c-C6H11 c-C6H11
a
b
c
20 min reaction. In CH2Cl2 (10 mL). In this case,
R2 = 3,4-methylenedioxy-6-nitrophenyl.
Under our conditions, trimethylsilyl chloride, bromide or
iodide can be indifferently used. Nevertheless, in the case of
aliphatic aldehydes, polymerization of the starting aldehyde
occurred when using TMSBr, explaining the relatively low
yield of cyclization (Table 1, entry 2). Substituted homoallylic
alcohols also led to good isolated yields of THP products
(Table 1, entries 15 and 16). When R1 is different from R2, a
mixture of products is obtained, due to an oxonia-Cope
rearrangement prior to Prins cyclization.
3
H
22 (60/40)
4
H
30 (80/20)
Taking advantage of the absence of both the solvent and the
catalyst, we engaged our halogeno-THP obtained via the
Prins-cyclization in different other reactions, in a sequential
way, without purification of the Prins intermediate. We first
tested the Bartoli reaction, which allowed the formation of
indoles from nitro aromatic compounds (Fig. 2).23
5
CH3
24 (70/30)
Different new indole derivatives bearing a chloro-THP
substituent were obtained with moderate yields (20–35% over
the two steps) (Table 2). Considering the good isolated yields
(around 80%) measured for the first step, the Prins cyclization,
the yields for the Bartoli reaction can be estimated around
40%, which are usual yields for this reaction.24
Radical reduction and elimination reaction under basic
conditions were also tested, leading to saturated or unsaturated
THP, depending on the reaction conditions with good overall
isolated yields (Fig. 3).
Fig. 2 Sequential Prins cyclization–Bartoli reaction.
158 Chem. Commun., 2012, 48, 157–159
Fig. 3 Sequential reactions.
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In conclusion, we proposed an efficient and mild green
method to access 4-halo THP with good to excellent isolated
yields. Both the cis and trans adducts can be obtained even if
the reaction is mainly in favour of the cis isomer. Thanks to the
absence of both the solvent and catalyst, the Prins cyclization
product can be engaged in a further reaction without purification,
as illustrated by three sequential examples described in this article:
Prins cyclization followed by Bartoli reaction, by elimination
reaction or by radical reduction. But the field of possibilities is
open and we are currently working on other sequential reactions.
7 S. N. Chavre, H. Choo, J. K. Lee, A. N. Pae, Y. Kim and
Y. S. Cho, J. Org. Chem., 2008, 73, 7467; K. Tadpetch and
S. D. Rychnovsky, Org. Lett., 2008, 10, 4839.
8 E. Bourcet, F. Fache and O. Piva, Tetrahedron, 2010, 66, 1319;
E. Bourcet, F. Fache and O. Piva, Eur. J. Org. Chem., 2010, 4075.
9 M. A. Hiebel, B. Pelotier and O. Piva, Tetrahedron, 2007, 63, 7874.
10 P. O. Miranda, D. D. Diaz, J. I. Padron, J. Bermejo and
V. S. Martin, Org. Lett., 2003, 5, 1979.
11 X. F. Yang, J. T. Mague and C. J. Li, J. Org. Chem., 2001, 66, 739;
F. Liu and T.-P. Loh, Org. Lett., 2007, 9, 2063.
12 J. S. Yadav, B. V. S. Reddy, A. V. Ganesh and G. G. K. S.
Narayana Kumar, Tetrahedron Lett., 2010, 51, 2963.
13 J. S. Yadav, B. V. S. Reddy, M. D. Reddy, N. Niranjan and
A. R. Prasad, Eur. J. Org. Chem., 2003, 1779.
Acknowledgment is made to the Ministere Franc
l’Education Superieure et de la Recherche (D. Clarisse) and
Universite Lyon 1 for financial support.
¸ ais de
14 W. Wang, L. Shao, W. Cheng, J. Yang and M. He, Catal.
Commun., 2008, 9, 337.
15 P. O. Miranda, R. M. Carballo, V. S. Martin and J. I. Padron, Org.
Lett., 2009, 11, 357.
´
´
16 G. Sabitha, K. B. Reddy, M. Bhikshapathi and J. S. Yadav,
Tetrahedron Lett., 2006, 47, 2807.
Notes and references
1 P. A. Clarke and S. Santos, Eur. J. Org. Chem., 2006, 2045;
P. A. Clarke, Tetrahedron, 2011, 67, 4959 and references cited
therein.
2 C. F. Nising and S. Brase, Chem. Soc. Rev., 2008, 37, 1218;
¨
C. F. Nising and S. Brase, Chem. Soc. Rev., 2012, DOI: 10.1039/
¨
C1CS15167C.
3 E. Lee, Pure Appl. Chem., 2005, 77, 2073.
4 C. Olier, M. Kaafarani, S. Gastaldi and M. P. Bertrand, Tetrahedron,
2010, 66, 413.
5 J. S. Yadav, M. R. Pattanayak, P. P. Das and D. K. Mohapatra,
Org. Lett., 2011, 13, 1710.
6 E. A. Crane, T. P. Zabawa, R. L. Farmer and K. A. Scheidt,
Angew. Chem., Int. Ed., 2011, 50, 9112; J. Wang, E. A. Crane and
K. A. Scheidt, Org. Lett., 2011, 13, 3086.
17 M. A. Hiebel, B. Pelotier, P. Goekjian and O. Piva, Eur. J. Org.
Chem., 2008, 713.
18 F. Batt, C. Gozzi and F. Fache, Chem. Commun., 2008, 5830.
19 K. J. Borah, M. Phukan and R. Borah, Synth. Commun., 2008, 38, 3082.
20 A. Macedo, E. P. Wendler, A. A. Dos Santos, J. Zukerman-
Schpector and E. R. T. Tiekink, J. Braz. Chem. Soc., 2010, 21, 1563.
21 W. Zhang, Y. Leng, P. Zhao, J. Wang, D. Zhu and J. Huang,
Green Chem., 2011, 13, 832.
22 R. Jasti, J. Vitale and S. D. Rychnovsky, J. Am. Chem. Soc., 2004,
126, 9904.
23 M. Bosco, R. Dalpozzo, G. Bartoli, G. Palmieri and M. Petrini,
J. Chem. Soc., Perkin Trans. 2, 1991, 657.
24 L. F. Silva, Jr and M. V. Craveiro, Org. Lett., 2008, 10, 5417;
A. Dobbs, J. Org. Chem., 2001, 66, 638.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 157–159 159