Iron(III)-catalyzed Prins-type cyclization using homopropargylic alcohol: A method for the synthesis of 2-alkyl-4-halo-5,6-dihydro-2H-pyrans

Article abstract of DOI:10.1021/ol034568z

(Matrix presented) A new Prins-type cyclization between homopropargylic alcohol and aldehydes in the presence of FeX₃ to obtain 2-alkyl-4-halo-5,6-dihydro2H-pyrans in good yield is described. Osmium-catalyzed cis dihydroxylation provided direct

Full text of DOI:10.1021/ol034568z

ORGANIC
LETTERS
2003
Vol. 5, No. 11
1979-1982
Iron(III)-Catalyzed Prins-Type Cyclization
Using Homopropargylic Alcohol: A
Method for the Synthesis of
2-Alkyl-4-halo-5,6-dihydro-2H-pyrans
Pedro O. Miranda, David D. D´ıaz, Juan I. Padro´n, Jaime Bermejo, and
Victor S. Mart´ın*
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,
Instituto de Productos Naturales y Agrobiolog´ıa del C.S.I.C., C/Astrof´ısico Francisco
Sa´nchez 3, 38206 La Laguna, Tenerife, Spain
Vmartin@ull.es
Received April 1, 2003
ABSTRACT
A new Prins-type cyclization between homopropargylic alcohol and aldehydes in the presence of FeX to obtain 2-alkyl-4-halo-5,6-dihydro-
3
2H-pyrans in good yield is described. Osmium-catalyzed cis dihydroxylation provided direct access to trans-2-alkyl-3-hydroxy-tetrahydro-
pyran-4-ones. Anhydrous ferric halides are also shown to be excellent catalysts for the standard Prins cyclization using homoallylic alcohol.
Isolation of an intermediate acetal provides substantiation of a proposed mechanism.
Medium-sized oxacycles constitute important synthetic tar-
gets due to the fact that they form the structural cores of
numerous natural products.1 The dihydropyran skeleton of
these molecules is particularly attractive since the olefin
function is a synthetically useful handle for further func-
tionalization in obtaining polysubstituted tetrahydropyrans.2,3
The possibility of obtaining, in a single step, a functionalized
heterocyclic ring in the field of natural products is an ardently
pursued objective.
tetrahydropyran derivatives has been extensively applied to
synthesize many natural products containing cyclic polyethers
in their structures.5,6 Cyclic or mixed acetals and R-acetoxy
ethers are useful intermediates for generating the oxocarbe-
nium ions of the Prins cyclization.7
As a result of our studies directed toward the synthesis of
marine natural compounds containing six-membered oxa-
(4) (a) Arundale, E.; Mikeska, L. A. Chem. ReV. 1952, 51, 505-555 (b)
Snider, B. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.;
Pergamon Press: Oxford, 1991; Vol. 2, pp 527-561.
(5) (a) Stapp, P. R. J. Org. Chem. 1969, 34, 479-485. (b) Adams, D.
R.; Bhatnagar, S. P. Synthesis 1977, 661-672. (b) Cloninger, M. J.;
Overman, L. E. J. Am. Chem. Soc. 1999, 121, 1092-1093 and references
therein.
(6) For recent advances in the Prins reaction, see: (a) Lo´pez, F.; Castedo,
L.; Mascaren˜as, J. L. J. Am. Chem. Soc. 2002, 124, 4218-4219. (b) Camara,
C. A.; Pinto, A. C.; Vargas, M. D.; Zukerman-Schpector, J. Tetrahedron
2002, 58, 6135-6140. (c) Cho, Y. S.; Kim, H. Y.; Cha, J. H.; Pae, A. N.;
Koh, H. Y.; Choi, J. H.; Chang, M. H. Org. Lett. 2002, 4, 2025-2028. (d)
Rychnovsky, S. D.; Marumoto, S.; Jaber, J. J. Org. Lett. 2001, 3, 3815-
3818.
The coupling between olefins and aldehydes induced by
Lewis acid, known as the Prins reaction,4 to generate
(1) For comprehensive reviews, see: (a) Oishi, T.; Ohtsuka, Y. In Studies
in Natural Products Synthesis; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam
1989; Vol. 3, p 73. (b) Yet, L. Chem. ReV. 2000, 100, 2963-3007.
(2) For a review, see: Boivin, T. L. B. Tetrahedron 1987, 43, 3309-
3362.
(3) For examples of synthesis of polysubstituted tetrahydropyrans and
dihydropyrans, see: (a) Coppi, L.; Ricci, A.; Tadei, M. J. Org. Chem. 1988,
53, 913-915. (b) Li, C.-J.; Zhang, W.-C. Tetrahedron 2000, 56, 2403-
2411. (c) Schmidt, B.; Westhus, M. Tetrahedron 2000, 56, 2421-2426.
10.1021/ol034568z CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/07/2003

cycles,8 we addressed our attention to the Prins cyclization
as a way of obtaining dihydropyrans (Scheme 1).9 In our
With these results in hand, we extended our studies using
homopropargylic alcohol instead of homoallylic alcohol.14
We obtained the corresponding 2-alkyl-4-halo-5,6-dihydro-
2H-pyrans 2 in good yields (Table 2).15
Scheme 1
Table 2. Synthesis of 2-Alkyl-4-halo-5,6-dihydro-2H-pyrans
from Homopropargylic Alcohol and Aldehydes Using FeX3 as a
Catalyst
approach and considering precedents found in the literature
using the intramolecular cyclization of acetals, we pondered
the possibility of the direct coupling of homopropargylic
alcohol and aldehydes10 as molecular fragments.7
Within the Lewis acid catalog, FeCl3 is an inexpensive,
environmentally friendly, and stable Lewis acid. Herein, we
report on a Prins cyclization for accessing 2-alkyl-4-halo-
5,6-dihydro-2H-pyrans that make use of the direct coupling
of homopropargylic alcohol and aldehydes induced by
anhydrous ferric halides (FeCl3 and FeBr3). We also found
that such intermediates are useful substrates, for example,
to stereoselectively obtain 2-alkyl-3-hydroxy-tetrahydro-
pyran-4-one as a single diastereoisomer after a cis dihy-
droxylation reaction.
entry
R1
H
R2
X
2:3
yield (%)
1
2
3
4
5
6
7
8
c-C6H11
i-Bu
Cl
100: 1
80
90
30
75
98
93
92
80
Ph
Bn
i-Bu
c-C6H11
Bn
Br
Cl
a
a
a
Me
n-C6H12
35:65
a Product was contaminated with the corresponding chlorovinyl derivative
(see text and Scheme 2).
First, to check the catalytic behavior of FeX3 in the Prins
cyclization, we carried out the reaction between 3-buten-1-
ol and several aldehydes using such Lewis acids as a
11
promoter. FeCl3 and FeBr3 showed that the cyclization
The methodology produced in a good yield the desired
six-membered ring with a wide range of aldehydes except
when benzaldehyde was used (entry 3).16 However, other
aldehydes containing aromatic rings, although located in a
distal position (entries 4 and 7) relative to the carbonyl group,
proceeded satisfactorily. When pent-3-yn-1-ol was used
proceeded satisfactorily, affording the corresponding cis-4-
halo-2-alkyl tetrahydropyrans 112 in good yields.3a Table 1
Table 1. Cyclization of Homoallyl Alcohol and Aldehydes
Using FeX3 as a Promoter
(8) (a) Betancort, J. M.; Mart´ın, V. S.; Padro´n, J. M.; Palazo´n, J. M.;
Ram´ırez, M. A.; Soler, M. A. J. Org. Chem. 1997, 62, 4570-4583. (b)
Ram´ırez, M. A.; Padro´n, J. M.; Palazo´n, J. M.; Mart´ın, V. S. J. Org. Chem.
1997, 62, 4584-4590. (c) Betancort, J. M.; Mart´ın, T.; Palazo´n, J. M.;
Mart´ın, V. S. J. Org. Chem. 2003, 68, 3216-3224.
(9) For the synthesis of dihydropyrans using the Prins cyclization, see:
(a) Viswanathan, G. S.; Yang, J.; Li, C.-J. Org. Lett. 1999, 1, 993-995.
(b) Dobbs, A. P.; Martinovic´, S. Tetrahedron Lett. 2002, 43, 7055-7057.
(10) For precedents in the direct coupling of aldehydes and acetylenes
yielding nitrogen heterocycles, see: 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 and references therein.
entry
R
X
yield (%)
1
2
3
4
5
6
7
8
c-C6H11
i-Bu
Cl
90
93
97
83
48
93
90
97
(11) FeCl3 and FeBr3 were purchased from the Aldrich Chemical Co.
(12) Stereochemistry was determined by NOE studies. See Supporting
Information.
Ph
p-NO2Ph
p-HOPh
c-C6H11
Ph
(13) To the best of our knowledge, this is the first report on the use of
Fe(III) halides promoting the Prins reaction.
(14) For a coupling of homopropargylic alcohol with aldehydes yielding
allylic alcohols, see: Takai, K.; Sakamoto, S. Isshiki, T. Org. Lett. 2003,
5, 653-655.
Br
1-naphthyl
(15) For precedents in the synthesis of halovinyl tetrahydropyrans, see:
(a) Melany, M. L.; Lock, G. A.; Thompson, D. W. J. Org. Chem. 1985,
50, 3925-3927. (b) Chan, T. H.; Arya, P. Tetrahedron Lett. 1989, 30,
4065-4068. (c) Tsukayama, M.; Utsumi, H.; Kunugi, A.; Nozaki, H.
Heterocycles 1997, 45, 1131-1142.
(16) Typical Experimental Procedure for a Ferric Halide Promoted
Prins Cyclization. To a solution of homoallylic alcohol or homopropargylic
alcohol (1 equiv) and aldehyde (1 equiv) in dry CH2Cl2 was added anhydrous
FeX3 (1 equiv) in one portion. The reaction was complete in approximately
1 min, quenched by addition of water with stirring for 5 min, 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).
summarizes the results obtained in this study.13 The reaction
works very well with both aliphatic and aromatic aldehydes.
A moderate yield was obtained only in the case of an
aldehyde with a hydroxy-substituted aromatic ring (entry 5).
(7) (a) Sano, T.; Oriyama, T. Synlett 1997, 6, 716-718. (b) Bunnelle,
W. H.; Seamon, D. W.; Mohler, D. L.; Ball, T. F.; Thompson, D. W.
Tetrahedron Lett. 1984, 25, 2653-2654. (c) Jaber, J. J.; Mitsui, K.;
Rychnovsky, S. D. J. Org. Chem. 2001, 66, 4679-4686, and references
therein.
1980
Org. Lett., Vol. 5, No. 11, 2003

(entry 8), the tetrahydrofuran 3 was the major cyclic
product.7b With other alkyne alcohols such as 4-pentyn-1-ol
and 5-hexyn-1-ol, no cyclization reaction was observed.17
From the different solvents screened (THF, CH3CN,
AcOEt, CHCl3, CCl4, CH3NO2, CH2Cl2, and 1,2-dichloro-
ethane) we found the best conditions using CH2Cl2 and
1,2-dichloroethane. However, an unexpected result was
the appearance of chlorovinyl derivatives when FeBr3, in
CH2Cl2, was used as a catalyst. In an attempt to clarify this
point, we ran a reaction using 1,2-dichloroethane as a solvent
and obtained a similar amount of the chloro dihydropyran.
Our suspicion that the chlorine atom comes from the solvent
was clarified by the use of CH2Br2 as a solvent, when the
uncontaminated bromovinyl ring was cleanly obtained. In a
similar manner, the use of FeCl3 in CH2Br2 produced the
chloro derivative contaminated with the corresponding bro-
mide (Scheme 2). In addition, we did not find any contami-
4-chloro-2-alkyl-tetrahydropyran 1 obtained by coupling
between homoallylic alcohol and aldehyde in the presence
of FeCl3. On the other hand, reductive ozonolysis of 2
provided the aldehyde 5 that supports the presence of the
six-membered ring. When the halovinyl tetrahydropyrans 2
Table 3. Cis Hydroxylation of
2-Alkyl-4-halo-5,6-dihydro-2H-pyrans
entry
R, X
time (60 °C)a
yield
1
2
3
4
5
c-C6H11, Cl
i-Bu, Cl
Ph, Cl
Bn, Cl
Bn, Br
3 days
3 days
3 days
3 days
3 days
59
56
60
60
56
Scheme 2
a At room temperature, the completion of the reaction requires 7 days
and additional OsO4 must be added at approximately 50% conversion.
were submitted to osmium-catalyzed cis hydroxylation, the
trans-2-alkyl-3-hydroxy-tetrahydro-pyran-4-ones 6 were ste-
reoselectively produced as the sole stereoisomer.12 Although
the isolated yields are modest, the procedure implies only
one step and that the reaction is clean inasmuch as only one
spot is detected by TLC.20
To optimize the reaction conditions, the amount of
anhydrous ferric chloride was also varied from catalytic to
3 equiv, and it was found that the highest yields were
obtained when 1 equiv was used. A noteworthy aspect of
the reaction is that the carbon-carbon formation is very rapid
even at 0 °C and is usually completed within 1 min.21
To check the advantage of the use of iron over other
metal halides, we performed a few runs using indium ha-
lides as catalysts (Scheme 4).22 We found that both InCl3
nation when the Prins cyclization was performed over allylic
alcohol (Table 1). Although at the moment we do not have
a clear explanation for these facts, two alternatives in
consideration are some halide exchange with the halogenated
solvent in the metal18 or the capture of the solvent halogen
by the vinyl cation intermediate.19 From the synthetic point
of view, it is clear that for each halide the corresponding
halogenated solvent must be used.
To clarify the structure of the obtained cyclic compounds,
we performed a series of chemical transformations that also
showed the synthetic versatility of such intermediates
(Scheme 3). Thus, 2 (R1 ) H, R2 ) C6H11-c) was hydro-
Scheme 4
Scheme 3
and InBr3 also induced the cyclization of propargylic alco-
hol and aldehydes to the corresponding dihydropyrans, but
(17) All compounds were satisfactorily characterized by elemental
genated using Pd/C as a catalyst to give the tetrahydropyran
4, which was also synthesized by reductive elimination of
1
analyses ((0.4% for C, H, etc.) and spectral data (IR, H NMR, and 13C
NMR). See Supporting Information.
Org. Lett., Vol. 5, No. 11, 2003
1981

the reactions are slower and the yields obtained are slightly
lower.
between homopropargylic alcohols and aldehydes provides
2-alkyl-4-halo-5,6-dihydro-2H-pyrans in good yields. The
reaction is applicable to both aromatic and aliphatic sub-
strates, as well as with both enolizable and nonenolizable
aldehydes. A new synthesis of trans-2-alkyl-3-hydroxy-
tetrahydro-pyran-4-ones is described. Efforts in the applica-
tion of the developed methodologies to the synthesis of
highly functionalized tetrahydropyrans are currently under-
way in our laboratory and will be published in due course.
Using a catalytic amount of FeCl3 (0.1 equiv), we obtained
the acetal 7 as a single product in a good yield (80%). The
intermediate acetal was isolated and fully characterized and,
when treated with more ferric chloride to reach 1 equiv,
yielded cleanly the halovinyl tetrahydropyran.7a A plausible
mechanism involves the acetal 7 that, via FeX3-mediated
ionization, generates the oxonium ion 8 that is intramolecu-
larly trapped by the triple bond with concomitant attack of
the halide (Scheme 5).
Acknowledgment. This research was supported by the
Ministerio de Ciencia y Tecnologia (PPQ2002-04361-C04-
02) and the Canary Islands Government. D.D. thanks the
Spanish M.E.C. for a F.P.I. fellowship. Many thanks are also
given to Dr. Sreenivas Punna for useful discussions and
suggestions.
Scheme 5
Supporting Information Available: 1H NMR and 13C
NMR spectra for all new compounds and COSY and NOE
experiments for compounds 1 (R ) C6H11-c) and 6 (R )
C6H11-c). This material is available free of charge via the
Internet at http://pubs.acs.org.
OL034568Z
(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.
(19) This alternative could explain why the halide exchange does not
occur in the homoallylic alcohols (Table 1).
(20) At the moment, we cannot determine the fate of the remainder of
the matter.
(21) Reaction has been scaled up to 5 g with no difficulty.
(22) For the use of InX3 in Prins reactions, see refs 6c and 9b. The use
of InBr3 in CH2Cl2 produces a 7:3 mixture of bromo and chloro
dihydropyran derivatives.
In conclusion, we report a novel use of iron(III) halides
as efficient catalysts for Prins cyclizations. The coupling
1982
Org. Lett., Vol. 5, No. 11, 2003