Domino Prins Cyclization of Enynols: Stereoselective Synthesis of Bicyclic Vinyl Fluorides

Article abstract of DOI:10.1002/ejoc.201500689

A fluoride-induced termination of Prins cyclization has been observed using a tethered alkyne and stoichiometric amounts of AgSbF₆ and found to generate a novel series of 6-fluoro-1-aryl-hexahydro-1H-isochromene derivatives in good yields with

Full text of DOI:10.1002/ejoc.201500689

FULL PAPER
DOI: 10.1002/ejoc.201500689
Domino Prins Cyclization of Enynols: Stereoselective Synthesis of Bicyclic
Vinyl Fluorides
Anipireddy Venkateswarlu,[a] Marumudi. Kanakaraju,[b] Ajit C. Kunwar,[b]
Yellala V. Rami Reddy,[c] and Basi V. S. Reddy*[a]
Keywords: Domino reactions / Cascade process / Cyclization / Acid catalysis / Alkynes / Fluorine
A fluoride-induced termination of Prins cyclization has been good yields with excellent selectivity. This is the first report
observed using
amounts of AgSbF6 and found to generate a novel series of
6-fluoro-1-aryl-hexahydro-1H-isochromene derivatives in
a
tethered alkyne and stoichiometric
of the synthesis of fluoro-substituted oxabicycles. In this tan-
dem process, three reactions occur in one-pot to leading to
installation of three contiguous stereocenters.
is a highly diastereoselective process, in which the geometry
of the olefin determines the stereochemical outcome of the
reaction. It is also a cascade process, in which the Prins
cyclization can be terminated by tethered nucleophiles.
Consequently, different nucleophiles have been used to in-
tramolecularly terminate the Prins cyclization thus produc-
ing unique fused or bridged oxacycles.[9,10] Inspired by this
cascade process, we recently reported a novel series of oxa-
cycles from homoallylic substrates bearing pendant nucleo-
philes such as hydroxy, thiol, sulfonamide, alkene and arene
groups.[11] However, there are no reports of Prins cycliza-
tion termination with pendent alkyne moieties leading to
functionalized oxabicycles.
Introduction
Fluorine-containing molecules play an important role in
agrochemicals, pharmaceuticals, biomedical imaging agents,
and chemically resistant materials due to their unique phys-
ical and chemical properties.[1] Among them, monofluoro-
alkenes[2] are of particular interest because of their potential
applications in medicinal chemistry and materials sci-
ence.[3–5] More specifically, the fluorooctahydro-1H-iso-
chromene ring is a core structure of different sesquiterpenes
like artemisin derivatives[6] as shown Figure 1.
Results and Discussions
In this article, we report a novel strategy for stereoselec-
tive synthesis of fluorooxabicycles from (E/Z)-oct-3-en-7-
yn-1-ol and aldehydes through the application of a sequen-
tial Prins/alkynylation/fluorination domino process.
Figure 1. Biologically active fluoro-containing natural product de-
rivatives.
In this process, AgSbF6 plays a dual role as i) a catalyst
first activating the terminal alkyne, and ii) secondly, as a
source of fluoride ion that traps the transient vinyl cation;
fulfilling these two roles, AgSbF6 readily enables vinyl
fluoride production. In a test reaction, we attempted cross-
coupling of (E)-oct-3-en-7-yn-1-ol (1a) with 4-nitrobenzal-
Generally speaking, fluoro-substituted tetrahydropyrans
are prepared by Prins cyclization.[7] Recently, a domino
Prins cyclization has become a popular strategy for the
stereoselective synthesis of fused or bridged oxacycles.[8] It
[a] Natural Products Chemistry, Indian Institute of Chemical dehyde (2) in the presence of 1.1 equiv. BF3·OEt2. The reac-
Technology,
tion was initially carried out in dichloroethane at –10 °C
Hyderabad 500007, India
and then the temperature was slowly raised to 25 °C. After
12 h stirring at the same temperature, corresponding fluoro-
hexahydro-1H-isochromene 3a was obtained in 30% yield
(Table 1, Entry a). To identify conditions that might en-
hance the yield the reaction was performed using various
reagents such as HBF4, InF3, AgSbF6 and AgBF4. The use
of 1.1 equiv. of AgSbF6 in dichloroethane gave the desired
E-mail: basireddy@iict.res.in
http://www.iictindia.org
[b] Centre for NMR and Structural Chemistry, CSIR – Indian
Institute of Chemical Technology,
Hyderabad 500007, India
[c] Department of Chemistry, Sri Venkateswara University,
Tirupati 517502, India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500689.
Eur. J. Org. Chem. 2015, 5389–5392
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5389

B. V. S. Reddy et al.
FULL PAPER
product 3a in 90% yield with complete trans-selectivity Table 2. Synthesis of fluorooxabicycles using Prins/yne cyclization
chemistry.
(Table 1, Entry e). AgBF4 was equally effective at enabling
this conversion (Table 1, Entry m). Next, we examined the
influence of different solvents such as dichloroethane,
acetonitrile, tetrahydrofuran, benzene, toluene, 1,4-dioxane,
and nitromethane on reaction efficiency. Of these, dichloro-
ethane gave the best results in terms of conversion. The
structure and relative stereochemistry of products were es-
tablished on the basis of extensive NMR studies.[12]
Table 1. Screening different promoters and solvents for the forma-
tion of 3a.[a]
[a] Reaction was performed for 12 h. [b] Isolated yield.
Inspired by these reaction optimization results, we ex-
tended this method to different aldehydes; the results of
these efforts are exemplified in Table 2. Interestingly, several
aromatic aldehydes such as benzaldehyde, 3-fluoro-, and 4-
isopropyl benzaldehydes reacted effectively with (E)-oct-3-
en-7-yn-1-ol to afford the respective aryl-substituted trans-
fluorohexahydro-1H-isochromene derivatives 3b–3d in good
to excellent yields (Table 2, Entries b–d).
Furthermore, the coupling of (Z)-oct-3-en-7-yn-1-ol (1b)
with p-nitrobenzaldehyde (2) in the presence of 1.1 equiv. of
AgSbF6 in dichloroethane at –10 to 25 °C over the course
of 9 h gave corresponding cis-fluorohexahydro-1H-iso-
5390
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 5389–5392

Domino Prins Cyclization of Enynols
chromene (4e) exclusively in 86% yield (Scheme 1, Table 2, Table 3. Synthesis of fluorooxabicycles via Prins/yne cyclization
chemistry.
Entry e).
Scheme 1. Prins/yne cyclization of (Z)-oct-3-en-7-yn-1-ol with p-
nitrobenzaldehyde.
Similarly, other aromatic aldehydes such as 4-methoxy-,
4-chloro-, and 2-chlorobenzaldehydes also participated well
in this cascade process. Furthermore, a sterically hindered
1-naphthaldehyde gave the anticipated product in fair to
good yield (Table 2, Entry i). This method was successful
not only with aromatic aldehydes but also with aliphatic
aldehydes. However, the aliphatic aldehyde n-hexanal, af-
forded the corresponding n-pentyl fluorohexahydro-1H-
isochromene in lower yield than its aromatic counterpart
(Table 2, Entry j). On the basis of data in Table 2, it is evi-
dent that the geometry of the olefin controls the stereoselec-
tivity of the reaction.
Inspired by the results obtained with oct-3-en-7-yn-1-ol,
we extended this approach to a branched homoallylic
alcohol 2-vinylhex-5-yn-1-ol (1c). Accordingly, treatment of
1c with o-tolualdehyde in the presence of 1.1 equiv. of
AgSbF6 in dichloroethane at –10 °C to room temperature
over the course of 6 h gave corresponding fluoro-hexahy-
dro-1H-isochromene as a mixture of 5 and 6 in 85% yield
(Scheme 2, Table 2, Entry k). Similarly, other aromatic alde-
hydes like 3-fluorobenzaldehyde, p-chlorobenzaldehyde re-
acted perfectly with 2-vinylhex-5-yn-1-ol (1c) under the
present conditions to provide respective fluoro-hexahydro-
1H-isochromene derivatives with high trans-selectivity
(Table 2, Entries l–m).
[a] Yield determined on basis of pure products obtained following
column chromatography. [b] Ratio was determined on the basis of
1H NMR data analysis of crude product mixture.
product 8d as a major diastereomer (Table 3, Entry d).
However, the use of branched enynol, 2-vinylhept-6-yn-1-ol
(1f) gave trans-fused product 9 as a major isomer (Table 3,
Entries e and f).
A plausible mechanism for this cascade process is pro-
posed in Scheme 3. The reaction likely proceeds through an
Scheme 2. Prins/yne cyclization of 2-vinylhex-5-yn-1-ol (1b) with o-
tolualdehyde.
The scope of the reaction was further illustrated with oxocarbenium ion formed upon convergence of the alde-
(E/Z)-non-3-en-8-yn-1-ol and the results are presented in hyde and enynol. In this reaction, AgSbF6 activates the al-
Table 3.
dehyde thus facilitating the formation of oxonium ion A,
Accordingly, the cross coupling of (E)-nonenynol (1d) which is then attacked by an internal olefin to generate
with various aldehydes such as benzaldehyde, 3,5-dimethyl- carbocation B. Subsequent activation of the alkyne C–H
benzaldehyde and phenylacetaldehyde furnished respective bond by AgI generates the silver acetylide, simultaneous
trans-fused fluorooctahydrocyclohepta[c]pyran derivatives carbocation attack installs the bicyclic vinyl cation. Finally,
7a–c in good yields with high selectivity (Table 3, Entries a– nucleophilic attack of fluoride ion at the vinyl cation center
c), whereas the use of cis-nonenynol (1e) afforded cis-fused affords the desired product (Scheme 3).
Eur. J. Org. Chem. 2015, 5389–5392
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5391

B. V. S. Reddy et al.
FULL PAPER
Acknowledgments
A. V. R. thanks Council of Scientific and Industrial Research
(CSIR), New Delhi for the award of fellowships. B. V. S. thanks
CSIR, New Delhi for the financial support as a part of XII five-
year plan program under title ORIGIN (CSC-0108).
[1] a) K. Müller, C. Faeh, F. Diederich, Science 2007, 317, 1881;
b) K. L. Kirk, Org. Process Res. Dev. 2008, 12, 305; c) S. Purser,
P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 2008,
37, 320.
[2] a) P. Jeschke, ChemBioChem 2004, 5, 570; b) T. Besset, T. Pois-
son, X. Pannecoucke, Chem. Eur. J. 2014, 20, 16830.
[3] R. Banks, B. E. Smart, J. C. Tatlow (Eds.) Organofluorine
Chemistry: Principles and Commercial Applications, Plenum
Press, New York, 1994, 1, p. 631.
[4] R. Filler, R. P. Saha, Future Med. Chem. 2009, 1, 777.
[5] a) H. J. Böhm, D. Banner, S. Bendels, M. Kansy, B. Kuhn, K.
Müller, U. Obst-Sander, M. Stahl, ChemBioChem 2004, 5, 637;
b) P. Shah, A. D. J. Westwell, Enzyme Inhib. Med. Chem. 2007,
22, 527; c) D. O’Hagan, Chem. Soc. Rev. 2008, 37, 308.
[6] K. Zhang, B. M. Shafer, M. D. Demars II, H. A. Stern, R. Fa-
san, J. Am. Chem. Soc. 2012, 134, 18695.
[7] a) E. H. Al-Mutairi, S. R. Crosby, J. Darzi, J. R. Harding,
R. A. Hughes, C. D. King, T. J. Simpson, R. W. Smith, C. L.
Willis, Chem. Commun. 2001, 835; b) P. O. Miranda, D. D.
Díaz, J. I. Padrón, J. Bermejo, V. S. Martín, Org. Lett. 2003, 5,
1979; c) S. Bondalapati, U. C. Reddy, D. S. Kundu, A. K. Sai-
kia, J. Fluorine Chem. 2010, 131, 320.
Scheme 3. A plausible reaction pathway.
[8] a) J. E. Dalgard, S. D. Rychnovsky, Org. Lett. 2005, 7, 1589;
b) J. Barluenga, A. Diéguez, A. Fernández, F. Rodríguez, F. J.
Fañanás, Angew. Chem. Int. Ed. 2006, 45, 2091; Angew. Chem.
2006, 118, 2145; c) A. N. Chavre, P. R. Ullapu, S. J. Min, J. K.
Lee, A. Pae, Y. Kim, Y. S. Cho, Org. Lett. 2009, 11, 3834; d)
A. J. Bunt, C. D. Bailey, B. D. Cons, S. J. Edwards, J. D. Els-
worth, T. Pheko, C. L. Willis, Angew. Chem. Int. Ed. 2012, 51,
3901; Angew. Chem. 2012, 124, 3967; e) B. D. Cons, A. J. Bunt,
C. D. Bailey, C. L. Willis, Org. Lett. 2013, 15, 2046; f) R. J.
Hinkle, S. E. Lewis, Org. Lett. 2013, 15, 4070.
[9] a) C. Olier, M. Kaafarani, S. Gastaldi, M. P. Bertrand, Tetrahe-
dron 2010, 66, 413; b) I. M. Pastor, M. Yus, Curr. Org. Chem.
2012, 16, 1277; c) X. Han, G.-R. Peh, P. E. Floreancig, Eur. J.
Org. Chem. 2013, 1193.
Conclusions
In summary, we have demonstrated a highly efficient and
stereoselective approach for the synthesis of bicyclic vinyl
fluorides from enynols and aldehydes employing 1.1 equiv.
of AgSbF6. This method provides direct access to bicyclic
vinyl fluorides in good yields. The salient features of this
method include: i) high conversions, ii) mild reaction condi-
tions, iii) high selectivity, and iv) operational simplicity.
[10] a) J. Elsworth, C. Willis, Chem. Commun. 2008, 1587; b) A. J.
Bunt, C. D. Bailey, B. D. Cons, S. J. Edwards, J. D. Elsworth,
T. Pheko, C. L. Willis, Angew. Chem. Int. Ed. 2012, 51, 3901;
Angew. Chem. 2012, 124, 3967; c) A. Barbero, A. Diez-Varga,
F. J. Pulido, Org. Lett. 2013, 15, 5234; d) B. Cons, A. Bunt, C.
Bailey, C. Willis, Org. Lett. 2013, 15, 2046.
Experimental Section
Typical Procedure for Domino Prins Cyclization: To a stirred solu-
tion of an enynol (1a–1f) (0.5 mmol) and aldehyde 2 (0.525 mmol)
was added 1.1 equiv. of AgSbF6 in dichloroethane at –10 °C and
the temperature was slowly raised to room temperature for the
specified time (8–10 h). After completion of the reaction as indi-
cated by TLC, the mixture was quenched with saturated NaHCO3
solution (0.5 mL), diluted with water (2–3 mL) and extracted with
dichloromethane (2ϫ 5 mL). The combined organic phases were
washed with brine (3ϫ 2 mL), dried with anhydrous Na2SO4 and
concentrated in vacuo. The resulting crude product was purified
by silica gel column chromatography (100–200 mesh) using EtOAc/
hexane gradients to afford the pure products (see Tables 2 and 3).
[11] a) B. V. S. Reddy, A. Venkateswarlu, P. Borkar, J. S. Yadav, M.
Kanakaraju, A. C. Kunwar, B. Sridhar, J. Org. Chem. 2013, 78,
6303; b) B. V. S. Reddy, A. Venkateswarlu, P. Borkar, J. S. Ya-
dav, R. Grée, J. Org. Chem. 2014, 79, 2716; c) B. V. S. Reddy,
A. Venkateswarlu, B. Sridevi, M. Kanakaraju, A. C. Kunwar,
G. Gayathri, Org. Biomol. Chem. 2015, 13, 2669.
[12] The stereochemistry of 3c and 4e was assigned on the basis of
nOe studies (see Supporting Information).
Received: May 28, 2015
Published Online: July 20, 2015
5392
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 5389–5392