Prins spirocyclization for the synthesis of spiro[isobenzofuran-pyran] derivatives

Article abstract of DOI:10.1002/ejoc.201402157

A Prins cascade process was developed for the synthesis of tetrahydro-3H-spiro[isobenzofuran-pyran] derivatives in good yields and selectivity by the condensation of 3-[2-(hydroxymethyl)phenyl]but-3-en-1-ols with aldehydes or ketones. The reaction proceeds smoothly in the presence of indium(III) trifluoromethanesulfonate (30 mol-%) in dichloroethane at 80 C. This is the first report on the synthesis of tetrahydro-3H-spiro[isobenzofuran- pyran] scaffolds through a Prins cascade reaction. Copyright

Full text of DOI:10.1002/ejoc.201402157

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402157
Prins Spirocyclization for the Synthesis of Spiro[isobenzofuran-pyran]
Derivatives
B. V. Subba Reddy,*[a] Harish Kumar,[a] P. Sivaramakrishna Reddy,[a] and
Kiran Kumar Singarapu[b]
Keywords: Spiro compounds / Cyclization / Lewis acids / Aldehydes / Ketones
A Prins cascade process was developed for the synthesis of
tetrahydro-3H-spiro[isobenzofuran-pyran] derivatives in good
yields and selectivity by the condensation of 3-[2-(hydroxy-
methyl)phenyl]but-3-en-1-ols with aldehydes or ketones. The
reaction proceeds smoothly in the presence of indium(III) tri-
fluoromethanesulfonate (30 mol-%) in dichloroethane at
80 °C. This is the first report on the synthesis of tetrahydro-
3H-spiro[isobenzofuran-pyran] scaffolds through a Prins cas-
cade reaction.
stereoselective construction of fused tetrahydropyran sys-
tems.[4] In spite of its potential application in natural prod-
ucts synthesis,[5,6] the scope of the Prins cascade process has
not yet been explored for the synthesis of spiro[isobenzofur-
an-pyrans] from a readily accessible trifunctional substrate,
that is, 3-[2-(hydroxymethyl)phenyl]but-3-en-1-ol and alde-
hydes or ketones. In addition, isobenzofuran derivatives are
privileged scaffolds in medicinal chemistry (Figure 1).[7]
Introduction
The “Prins cyclization” is one of the most versatile ap-
proaches for the synthesis of the tetrahydropyran ring sys-
tem, which is a core structure in many natural products.[1]
Prins bicyclization is a cascade process that provides a wide
range of heterobicycles such as bicyclo[3.3.1]nonanes, oxa-
spirobicycles, azaspiro[4,4]nonanes, bicyclo[3,2,1]octanes,
and dioxaspirodecanes.[2,3] Therefore, the Prins cascade pro-
cess has emerged as a powerful synthetic route for the
Results and Discussion
Following our interest in Prins and related cyclizations
for the synthesis of tetrahydropyran scaffolds,[8] we herein
report a novel strategy for the stereoselective synthesis of
spiro[isobenzofuran-pyran] derivatives through a Prins cas-
cade reaction. At first we attempted the spirocyclization of
3-[2-(hydroxymethyl)phenyl]but-3-en-1-ol (1x) with benz-
aldehyde (2) in the presence of an acid catalyst. To optimize
the reaction conditions, the above reaction was performed
with various acid catalysts, and the results are presented
in Table 1. Of the various catalysts screened, indium(III)
trifluoromethanesulfonate (InCl3) or BF3·OEt2 (20 mol-%)
at 80 °C gave desired product 3a in 25 and 30% yield,
respectively (Table 1, entries 1 and 2). Similarly, Sc(OTf)3
(10 mol-%) in dichloroethane at 80 °C also gave product 3a
only in 30% yield (Table 1, entry 3). To our surprise, no
cyclization was observed with para-toluenesulfonic acid
(TsOH, 1 equiv.; Table 1, entry 4). Furthermore, the combi-
nation of Sc(OTf)3 (10 mol-%) and a stoichiometric amount
of TsOH also gave required product 3a in low yield (42%;
Table 1, entry 5). To our delight, the yield was slightly im-
proved with the use of In(OTf)3 (20 mol-%; Table 1, en-
Figure 1. Biologically active isobenzofuranyl derivatives.
[a] Natural Products Chemistry, CSIR – Indian Institute of
Chemical Technology,
Hyderabad 500007, India
E-mail: basireddy@iict.res.in
www.indiaiict.org
[b] Center for Nuclear Magnetic Resonance, CSIR – Indian
Institute of Chemical Technology,
Hyderabad 500007, India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402157.
4234
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 4234–4238

Prins Spirocyclization
try 6). Remarkably, In(OTf)3 (30 mol-%) gave 3a in excel-
lent yield (85%; Table 1, entry 7). Under the optimized con-
ditions, the reaction proceeded smoothly in the presence of
In(OTf)3 (30 mol-%) at 80 °C in dichloroethane (DCE).
Under the above conditions, product 3a was obtained with
high selectivity (96:4; Table 2, entry 1). Though In(OTf)3 is
known to give the dihydropyran as a side product in the
Prins cyclization,[9] no such product was detected in the
present reaction because intramolecular cyclizations are
highly favourable. The starting material was recovered for
cases in which the yields were low (Table 1). Furthermore,
no incorporation of F was observed if the reaction was per-
formed with BF3·OEt2 (Table 1, entry 2).
Figure 2. Characteristic NOEs of 3c.
sponding 3H-spiro[isobenzofuran-1,4Ј-pyran] derivatives
were obtained in good yields, and the results are presented
in Table 2. The substituents present on the aromatic system
showed some effect on the conversion. In the case of elec-
tron-deficient aldehydes, the yields gradually increased as
the electron-withdrawing ability of the substituents in-
creased. For instance, p-nitrobenzaldehyde gave 3i in excel-
lent yield (92%; Table 2, entry 10). Furthermore, chloro-
and bromobenzaldehydes also afforded the respective prod-
ucts in high yields (Table 2, entries 2, 4, and 8). Similarly,
alkyl-substituted aryl aldehydes gave spiro[isobenzofuran-
pyran] derivatives 3c and 3e in 84 and 85% yield, respec-
tively (Table 2, entries 3 and 5). This method was equally
effective with aliphatic aldehydes to provide corresponding
alkyl-substituted spirocycles 3j and 3k in good yields
(Table 2, entries 10 and 11). Remarkably, a sterically hin-
dered naphthaaldehyde also participated well in this reac-
tion (Table 2, entry 7). Thus, the present method works not
only with aromatic aldehydes but also with aliphatic alde-
hydes. In contrast, aromatic aldehydes gave the products in
higher yields than their aliphatic counterparts. Further ex-
ploration of the substrate scope revealed that the reaction
took slightly longer for cyclohexanone (Table 2, entry 6),
but the desired product was obtained in good yield. There-
Table 1. Screening of various acid catalysts in the formation of
3a.[a]
[a] Reaction was performed on 0.5 mmol scale. [b] Yield refers to
the pure product after chromatography.
The ratio of products was determined by analysis of the fore, Prins spirocyclization was successful with all kinds of
1
crude mixture by H NMR spectroscopy. The relative ste- carbonyl compounds in good yields.
reochemistry of 3c was established by 1D and 2D NMR
Encouraged by the results obtained with the carbonyl
spectroscopy experiments. The scalar coupling constants for compounds, we next attempted the Prins bicyclization with
3
3
H2, JH2,H3(eq) = 5.5 Hz and JH2,H3Ј(ax) = 8.4 Hz, and the epoxides and acetals. Interestingly, styrene oxide underwent
presence of NOE cross-peaks between H2/H6(ax) and smooth coupling with 1x in the presence of In(OTf)3
H3(ax)/H5(ax) indicate that the six-membered ring adopts
(30 mol-%) in DCE at 80 °C to afford desired product 3l in
1
a C4 chair conformation with the substituent at C2 in the 70% yield with 9:1 selectivity. In the above reaction, the
equatorial position, as depicted in Figure 2. The stereo- epoxide initially undergoes rearrangement to give the corre-
chemistry at the spiro center (C4) was determined on the sponding phenylacetaldehyde,[10] which simultaneously par-
basis of the appearance of NOE cross-peaks between H8/ ticipates in the Prins spirocyclization. However, benzalde-
H5(ax) and H8/H3(ax), which suggests that the O atom of hyde dimethylacetal failed to give the desired product under
the five-membered ring is in the axial position and that the similar conditions.
C7 atom is in the equatorial position.
Inspired by the above results, we extended this process to
Next, we examined the effect of solvents such as tetra- the aza-Prins cyclization by using various acid catalysts, but
hydrofuran, DCE, and dimethoxyethane. Of these, DCE none of them were able to give product 4 (Table 3, entries 1–
gave the best results in terms of yield. The scope of the 6). Interestingly, the reaction was successful with FeCl3
reaction was further evaluated with respect to various alde- (30 mol-%), which is a familiar catalyst for the aza-Prins
hydes and ketones, and the results are presented in Table 2. cyclization.[11] For example, treatment of benzaldehyde (2)
Accordingly a variety of aldehydes were subjected to Prins and N-{3-[2-(hydroxymethyl)phenyl]but-3-en-1-yl}-4-meth-
spirocyclization with 3-[2-(hydroxymethyl)phenyl]but-3-en- ylbenzenesulfonamide (1y) with FeCl3 (30 mol-%) in DCE
1-ol under the influence of In(OTf)3 in DCE. The corre- in the presence of molecular sieves (4 Å) afforded 2Ј-phenyl-
Eur. J. Org. Chem. 2014, 4234–4238
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4235

B. V. S. Reddy, H. Kumar, P. S. Reddy, K. K. Singarapu
SHORT COMMUNICATION
Table 2. In(OTf)3-promoted synthesis of spiro(isobenzofuranyl) pyran derivatives.
[a] All products were characterized by NMR and IR spectroscopy and mass spectrometry. [b] Yield refers to the pure product after
chromatography. [c] Diastereomeric ratio was determined by NMR spectroscopy.
1Ј-tosyl-3H-spiro[isobenzofuran-1,4Ј-piperidine] (4) in 65%
However, thia-Prins cyclization of [2-(4-mercaptobut-1-
yield with high selectivity (Table 3, entry 7). Thus, this en-2-yl)phenyl]methanol (1z) with benzaldehyde failed to
method is simple and convenient to generate the desired give the desired product under the present reaction condi-
products in good yields with good to excellent diastereo- tions.
selectivity.
4236
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 4234–4238

Prins Spirocyclization
Table 3. Screening of various acid catalysts in the formation of 4.[a] furan-1,3Ј-pyran] derivatives. The reaction is highly dia-
stereoselective and proceeds in good yields in most cases.
This method provides direct access to the synthesis of biolo-
gically interesting 1,3-dioxaspirocycles in a single-step pro-
cess. These spirocycles may be useful for the discovery of
novel antidepressants.
Experimental Section
Typical Procedure for the Prins Cascade Cyclization for the Synthe-
sis of 3a–l: To a stirred solution of 2-arylethylbut-3-en-1-ol (1x;
0.5 mmol) and aldehyde (0.6 mmol) in dry dichloroethane (2 mL)
was added In(OTf)3 (30 mol-%). The resulting mixture was stirred
at 80 °C under a nitrogen atmosphere for the specified time
(Table 2). Upon completion of the reaction as indicated by TLC,
the mixture was quenched with saturated NaHCO3 solution
(2.0 mL) and extracted with dichloromethane (2ϫ 6 mL). The or-
ganic layers were combined, washed with brine (6 mL), dried with
Na2SO4, and concentrated in vacuo. The resulting crude product
was purified by silica gel column chromatography (100–200 mesh)
by using ethyl acetate/hexane as the eluent to afford the pure prod-
uct. The same procedure was followed for the synthesis of all other
compounds reported in this work.
[a] Reaction was performed on 0.5 mmol scale. [b] Yield refers to
the pure product after chromatography. n.d. = not detected.
A plausible mechanism for the Prins cascade process is
proposed in Scheme 1. The reaction is assumed to proceed
through the formation of an oxocarbenium ion generated
in situ from the hemiacetal, which in turn is formed by the
reaction of a homoallylic alcohol with the aldehyde under
acidic conditions. The thus-formed oxocarbenium ion is at-
tacked by the internal alkene to generate the carbocation,
which is simultaneously trapped by a tethered benzylic
alcohol to give the desired tetrahydro-3H-spiro[isobenzo-
furan-1,3Ј-pyran].
Supporting Information (see footnote on the first page of this arti-
cle): General experimental procedures and spectroscopic data
(1H NMR and 13C NMR) for the corresponding products.
Acknowledgments
H. K. thanks the Council of Scientific and Industrial Research
(CSIR), New Delhi, for the award of a fellowship. B. V. S. thanks
the CSIR for financial support as a part of a XII five-year-plan
program under title ORIGIN (CSC-0108).
[1] For recent reviews on Prins reaction, see: a) C. Olier, M. Kaafa-
rani, S. S. Gastaldi, M. P. Bertrand, Tetrahedron 2010, 66, 413;
b) I. M. Yus, M. Pastor, Curr. Org. Chem. 2007, 11, 925; c) X.
Han, G. R. Peh, P. E. Floreancig, Eur. J. Org. Chem. 2013,
1193; d) O. L. Epstein, T. Rovis, J. Am. Chem. Soc. 2006, 128,
16480; e) K. Zheng, X. Liu, S. Qin, M. Xie, L. Lin, C. Hu, X.
Feng, J. Am. Chem. Soc. 2012, 134, 17564; f) S. J. Greco, R. G.
Florot, V. Lacerda Jr., R. B. dos Santos, Aldrichim. Acta 2013,
46, 59.
[2] a) Y. Kishi, H. Nagura, S. Inagi, T. Fuchigami, Chem. Com-
mun. 2008, 3876; b) X.-F. Yang, J. T. Mague, C.-J. Li, J. Org.
Chem. 2001, 66, 739.
[3] a) Y. S. Cho, H. Y. Kim, J. H. Cha, A. N. Pae, H. Y. Koh, J. H.
Choi, M. H. Chang, Org. Lett. 2002, 4, 2025; b) Z.-H. Chen,
Y.-Q. Tu, S.-Y. Zhang, F.-M. Zhang, Org. Lett. 2011, 13, 724;
c) B. V. S. Reddy, G. Narasimhulu, Y. V. Reddy, P. P. Chakrav-
arthy, J. S. Yadav, B. Sridhar, Tetrahedron Lett. 2012, 53, 3100;
d) M. Lejkowski, P. Banerjee, J. Runsink, H. J. Gais, Org. Lett.
2008, 10, 2713; e) S. N. Chavre, P. R. Ullapu, S.-J. Min, J. K.
Lee, A. N. Pae, Y. Kim, Y. S. Cho, Org. Lett. 2009, 11, 3834.
[4] a) J. D. Elsworth, C. L. Willis, Chem. Commun. 2008, 1587; b)
J. S. Yadav, P. Borkar, P. P. Chakravarthy, B. V. S. Reddy,
A. V. S. Sarma, B. Sridhar, R. Grée, J. Org. Chem. 2010, 75,
2081; c) B. V. S. Reddy, P. Borkar, J. S. Yadav, B. Sridhar, R.
Grée, J. Org. Chem. 2011, 76, 7677; d) A. Barbero, A. Diez-
Varga, F. J. Pulido, Org. Lett. 2013, 15, 5234.
Scheme 1. A plausible mechanism.
Conclusions
[5] a) H. M. Lee, C. N. Oberhuber, M. D. Shair, J. Am. Chem. Soc.
2008, 130, 16864; b) E. Fenster, C. Fehl, J. Aube, Org. Lett.
2011, 13, 2614; c) B. Li, Y.-C. Lai, Y. Zhao, Y.-H. Wong, Z.-
In summary, a novel Prins spirocyclization was devel-
oped for the synthesis of tetrahydro-3H-spiro[isobenzo-
Eur. J. Org. Chem. 2014, 4234–4238
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4237

B. V. S. Reddy, H. Kumar, P. S. Reddy, K. K. Singarapu
SHORT COMMUNICATION
L. Shen, T.-P. Loh, Angew. Chem. Int. Ed. 2012, 51, 10619;
Angew. Chem. 2012, 124, 10771; d) J. Lu, Z. Song, Y. Zhang,
Z. Gan, H. Li, Angew. Chem. Int. Ed. 2012, 51, 5367; Angew.
Chem. 2012, 124, 5463.
Kumar, P. Borkar, J. S. Yadav, B. Sridhar, Eur. J. Org. Chem.
2013, 1993; d) B. V. S. Reddy, A. Venkateswarlu, P. Borkar, J. S.
Yadav, M. Kanakaraju, A. C. Kunwar, B. Sridhar, J. Org.
Chem. 2013, 78, 6303.
[6] a) E. A. Crane, K. A. Scheidt, Angew. Chem. Int. Ed. 2010, 49,
8316; Angew. Chem. 2010, 122, 8494; b) X. Han, G. R. Peh,
P. E. Floreancig, Eur. J. Org. Chem. 2013, 1193.
[9] F. K. Chio, J. Warne, D. Gough, M. Penny, S. Green, S. J.
Coles, M. B. Hursthouse, P. Jones, L. Hassall, T. M. McGuire,
A. P. Dobbs, Tetrahedron 2011, 67, 5107.
[7] a) C. Trapella, C. Fischetti, M. Pela, I. Lazzari, R. Guerrini,
G. Calo, A. Rizzi, V. Camarda, D. G. Lambert, J. McDonald,
D. Regoli, S. Salvadori, Bioorg. Med. Chem. 2009, 17, 5080; b)
K. K. Soby, J. D. Mikkelsen, E. Meier, C. Thomsen, Neuro-
pharmacology 2002, 43, 95.
[8] a) B. V. S. Reddy, S. Jalal, P. Borkar, J. S. Yadav, P. P. Reddy,
A. C. Kunwar, B. Sridhar, Org. Biomol. Chem. 2012, 10, 6562;
b) P. Borkar, P. Van de Weghe, B. V. S. Reddy, J. S. Yadav, R.
Grée, Chem. Commun. 2012, 48, 9316; c) B. V. S. Reddy, H.
[10] J. S. Yadav, P. Borkar, P. P. Chakravarthy, B. V. S. Reddy,
A. V. S. Sarma, S. J. Basha, B. Sridhar, R. Grée, J. Org. Chem.
2010, 75, 2081.
[11] a) R. M. Carballo, M. A. Ramirez, M. L. Rodriguez, V. S.
Martin, J. I. Padron, Org. Lett. 2006, 8, 3837; b) P. O. Miranda,
R. M. Carballo, V. S. Martin, J. I. Padron, Org. Lett. 2009, 11,
357.
Received: March 27, 2014
Published Online: June 3, 2014
4238
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 4234–4238