Dehydrative Re2O7-Catalyzed Approach to Dihydropyran Synthesis

Article abstract of DOI:10.1021/acs.orglett.0c03526

Monoallylic 1,3- and 1,5-diols undergo Re2O7-mediated ionization to form allylic cations that engage in cyclization reactions to form dihydropyran products. The reactions give the 2,6-trans-stereoisomer as the major products as a result of minimizing steric interactions in a boat-like transition state. The results of these studies are consistent with cationic intermediates, with an intriguing observation of stereochemical retention in one example.

Full text of DOI:10.1021/acs.orglett.0c03526

pubs.acs.org/OrgLett
Letter
Dehydrative Re2O7‑Catalyzed Approach to Dihydropyran Synthesis
Jean-Marc I. A. Lawrence and Paul E. Floreancig*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c03526
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Monoallylic 1,3- and 1,5-diols undergo Re2O7-
mediated ionization to form allylic cations that engage in
cyclization reactions to form dihydropyran products. The reactions
give the 2,6-trans-stereoisomer as the major products as a result of
minimizing steric interactions in a boat-like transition state. The
results of these studies are consistent with cationic intermediates,
with an intriguing observation of stereochemical retention in one example.
atalytic dehydrative routes to prepare heterocycles provide
efficient access to important units from structurally simple
monoallylic 1,3- or 1,5-diols, the observation of 2,6-trans
stereoisomers as the major products,7 and the demonstration
of a unique SNi cyclization pathway.
This process was initially demonstrated through the
cyclization of monoallylic 1,3-diol 6, prepared as a mixture of
diastereomers, to dihydropyran 7 in the presence of 5 mol %
Re2O7·SiO2 (Scheme 2). The reaction proved to be sensitive to
C
starting materials with minimal waste generation. Numerous
approaches have been developed to achieve this objective from
allylic alcohol substrates, based on both soft1 and hard2 Lewis
acids. As part of our exploration of the synthetic utility of
oxorhenium catalysis,3 we have developed catalytic, dehydrative
routes to a number of heterocyclic structures from allylic
alcohols in the presence of Re2O7 or HOReO3.4 These
processes, as exemplified by the conversion of 1 to 2 in Scheme
1, proceed through ionization of the allylic alcohol followed by
Scheme 2. Demonstration of Concept
Scheme 1. Re2O7-Catalyzed Dehydrative Cyclizations
solvent. Employing CH2Cl2, the solvent that was utilized for
previous tetrahydropyran-forming reactions, provided a low
yield of 7 with substantial diene formation through an E1
pathway being observed. Hexafluoroisopropyl alcohol (HFIP),
which we have used for other dehydrative processes, led to a
more efficient transformation though the yield was still
moderate. Inspired by Hall’s use of HFIP/MeNO2 mixtures in
dehydrative processes,8 we ultimately found that the reaction
proceeded in 71% yield as a 3.3:1 mixture of trans- and cis-
trapping by a tethered nucleophile at the proximal terminus of
the resulting allylic cation (3), resulting in the formation of an
alkenyl-substituted heterocycle. An alternative reaction pathway
is illustrated by the conversion of 4 to 5, in which the nucleophile
reacts with the distal end of the allylic cation to form a
heterocycle with an endocyclic alkene. The dihydropyrans that
can be accessed through this transformation are subunits in
several natural products5 and have frequently been used as
precursors to functionalized tetrahydropyrans.6 This manuscript
describes the development of dihydropyran syntheses from
Received: October 22, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03526
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
a
isomers in a 9:1 mixture of HFIP and MeNO2 within 5 min at rt.
An explanation for the reproducible improvement that results
from the addition of a small amount of MeNO2 remains elusive.
Extending the reaction time to 24 h resulted in a moderate
increase in the trans to cis ratio, indicating that the trans-isomer is
preferred both kinetically and thermodynamically, providing a
stereochemical complement to our previously reported
tetrahydropyran-forming reactions. Perrhenic acid (HOReO3)
proved to be a competent catalyst for the prolonged exposure
study, indicating that it is likely to be the true catalyst in these
processes. This catalyst, being a liquid, is easier to handle than
Re2O7 under humid conditions. The kinetic stereochemical
outcome for this reaction arises from the requirement that it
proceed through a boat-like transition state due to the need to
generate the cis-alkene in the product. Intermediate 8, leading to
trans-7, is preferred over 9, the precursor of cis-7, because of the
lower degree of torsional strain. This can be seen in the Newman
projections of the intermediates. The slight thermodynamic
preference for the trans-isomer can be attributed to the
moderate degree of A1,2-strain9 between a pseudoequatorial
alkyl group and the alkenyl hydrogen of cis-7. This reaction can
be conducted on >1 mmol scale with only a moderate decrease
in yield (58%). Notably, the results of this reaction contrast the
BF3·OEt2-catalyzed cis-selective processes of similar substrates
reported by Hanessian.2c We exposed 6 to BF3·OEt2 and
observed only a low yield of 7 with the trans-isomer again being
favored. Additionally we exposed trans-7 to BF3·OEt2 and did
not observe isomerization.10 A closer examination of the
substrates in the Hanessian work revealed the presence of a
benzyloxy group adjacent to the nucleophilic hydroxy group that
we propose can engage in an electrostatic attraction, rather than
a steric repulsion, with the allylic cation in cis-selective transition
states related to 9.
Table 1. Scope Studies
The hypotheses regarding the kinetic and thermodynamic
preferences for the formation of the trans-isomer were examined
as shown in Scheme 3. The assumption that torsional strain
Scheme 3. Tests of Kinetic and Thermodynamic Control
a
The reactions were conducted with the substrate in HFIP and
MeNO2 (9:1, 0.1 M) and Re2O7·SiO2 (5 mol %) at rt for 10 min,
mitigation is the source of the difference in transition state
energies was tested by increasing the bulk of the side chain on
the nucleophilic alcohol group. Isopropyl-containing substrate
10 reacted with Re2O7·SiO2 to form 11 in 73% yield as a 5:1
mixture favoring the trans-isomer after 10 min. This is consistent
with an enhanced gauche interaction between the branched
chain and the incipient ring. The thermodynamic preference was
explored by increasing the A1,2-strain that would be encountered
in the cis-isomer. This was achieved by exposing trisubstituted
alkene substrate 12 to Re2O7·SiO2 to produce 13. The trans-
isomer was favored in a 5:1 ratio at a reaction time of 10 min, and
in a 17:1 ratio after 24 h.
b
unless otherwise noted. Schemes for the syntheses of starting
materials and spectral data are available in the Supporting
c
d
Information. Combined yield of both stereoisomers. Determined
by integrating the ratios of peaks in crude 1H NMR spectra.
Stereoisomers were assigned based on analogy to observed chemical
shifts and coupling constants in 7 or through NOESY analyses.
e
f
g
Reaction was run with HOReO3. Reaction was run for 24 h. No
h
loss of enantiomeric purity was observed. A single stereoisomer was
isolated.
15 (entry 1), though the diastereoselectivity is somewhat lower
in comparison to the cyclization of the corresponding secondary
alcohol. Prolonging the reaction time to 24 h, as before, led to
moderately higher diastereocontrol (entry 2). The substituent at
These results provided the basis for an examination of the
scope of the reaction (Table 1). Tertiary alcohols are suitable
substrates for the process, as shown by the conversion of 14 to
B
https://dx.doi.org/10.1021/acs.orglett.0c03526
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
the 4-position appears to inhibit stereochemical equilibration by
utilizing steric interactions to induce a conformation that
promotes rapid reclosure from cationic intermediates. Interest-
ingly, this trisubstituted alkene substitution pattern did not show
an increase in kinetic diastereocontrol when the propyl group
was replaced by an isopropyl group, though the yield was
improved (entry 3). We postulate that the cation can form so
readily from this substrate due to its enhanced stability that the
cisoid allylic cation can be formed competitively, leading to an
alternate pathway 2,6-cis-stereoisomer formation. This addi-
tional cation stabilization allows for the synthesis of mono-
substituted tetrahydropyrans, as seen in the conversion of 18 to
19 (entry 4). Exposing enantiomerically enriched 18 to the
reaction conditions did not result in a loss of stereochemical
integrity in 19. Benzylic alcohols are suitable substrates for the
process as seen in the conversion of diol 20 to isochroman 21
(entry 5). Functionalized side chains can be incorporated into
the substrates, as seen in the cyclization of 22 to 23 (entry 6),
though the reactions proceed somewhat less efficiently due to
inductive mitigation of the alcohol’s nucleophilicity and allow
E1 to become a competitive pathway. The conversion of 24 to
25 (entry 7) shows that exo-cyclizations of the allylic cation
intermediate are faster than endo-cyclizations, even when the
nucleophile for the exo-cyclization is protected as a silyl ether.
Multiple stereocenters can be incorporated into cyclization
substrates. These stereocenters, when matched to form a
diequatorial relationship in the product, can deliver products
with exceptional diastereoselectivity, as seen in the conversions
of 26 and 28 to 27 and 29, respectively, in entries 8 and 9.
The allylic cation intermediates in this study could, in
principle, be formed from four different precursors that arise
from two alcohol regioisomers and two alkene geometries. We
sought to determine if the efficiency of the cyclization reactions
was influenced by the starting material isomer. Therefore, we
prepared compounds 30−32 as diastereomeric mixtures and
subjected them to the standard cyclization conditions to yield 7.
The results were compared to those from the cyclization of 6
(Scheme 4). These studies showed that the cyclization yields
from 6, 30, and 31 were very similar and that the
diastereoselectivity was identical, though the cyclization of 32
was significantly more efficient and moderately more stereo-
selective. Therefore, accessing the requisite cis-geometry for the
allylic cation is equally facile from either alkene isomer for 1,3-
diol substrates and for the trans-1,5-diol. The superior efficacy of
cis-1,5-diol 32 in the process, however, suggests that the
mechanism for this substrate might be unique, and proceed
through either an SN2 pathway or, more likely, an SN1 pathway
via a tight ion pair11 due to its preorganization for cyclization.
We tested the ion pairing hypothesis by preparing individual
diastereomers of 32. This was achieved by conducting
stereocomplementary Noyori reductions12 on ketone 33,
prepared from enantiomerically pure epichlorohydrin, followed
by alkyne reduction13 and deprotection to form substrates 36
and 37 (Scheme 5). The absolute stereochemical orientation of
Scheme 5. Cyclization Reactions of 1,5-Diol Diastereomers
all stereocenters was confirmed by Mosher ester analysis,14
showing that the reaction outcomes were consistent with
literature precedents. We observed that the cyclization reactions
of both isomers proceeded very efficiently but gave different
stereochemical outcomes, with 37 being much more selective
than 36.
The hypothesis of the reaction efficiency being dictated by a
tight ion pair intermediate15 would predict that 36 would
proceed smoothly to generate the trans-stereoisomer through a
backside approach via intermediate 38, while intermediate 39
from 37 would cyclize more slowly and lead to the solvent-
separated allylic cation that forms from 6, 30, and 31 (Scheme
6). We observed the opposite result, with 37 reacting efficiently
through a pathway to stereochemical retention, rather than
inversion, and 36 reacting in high yield but with only a moderate
preference for stereochemical inversion. The reactions were
conducted for identical 5-min intervals. Our previous equilibra-
tion studies showed that negligible epimerization proceeds at
short reaction times, indicating that these outcomes reflect
kinetic control. These results can be reconciled through
invoking an SNi pathway, as proposed in the conversion of
alcohols to alkyl chlorides by SOCl2.16 We postulate that the
mechanism proceeds through cyclic perrhenate diester for-
mation, seen in the conversion of 37 to 40. Cyclic Re(VII)
diesters have previously been proposed as intermediates in
oxidative cyclization reactions of bis-homoallylic alcohols.17
Ionization to generate 41 followed by a nucleophilic attack and
concomitant HOReO3 loss that is faster than bond rotation will
result in the formation of 7-trans, as a result of stereochemical
retention at the allylic center. HPLC analysis confirmed that no
loss of enantiomeric purity occurred in this reaction. The lower
stereocontrol for the cyclization of 36 does not invalidate the ion
pairing mechanism but most likely arises from competition from
Scheme 4. Consequences of Allylic Cation Precursor
a
Structure
a
All reactions were run for 5 min with 5 mol % catalyst.
C
https://dx.doi.org/10.1021/acs.orglett.0c03526
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Scheme 6. Mechanistic Options for 1,5-Diols
AUTHOR INFORMATION
■
Corresponding Author
Paul E. Floreancig − Department of Chemistry, University of
Pittsburgh, Pittsburgh, Pennsylvania 15260, United States;
orcid.org/0000-0001-9626-3187; Email: florean@
pitt.edu
Author
Jean-Marc I. A. Lawrence − Department of Chemistry,
University of Pittsburgh, Pittsburgh, Pennsylvania 15260,
United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03526
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Institutes of Health (R01-GM103886)
for generous funding of this project.
the SNi pathway through perrhenate diester intermediate 42,
which decomposes to form 7-cis. The high yield indicates that
the competing and stereochemically complementary ion pairing
and SNi pathways are both very efficient. The formation of cyclic
perrhenate diesters are also likely intermediates for reactions of
1,3-diol substrates, but the stereochemical information will be
lost as the intermediate cation assumes the proper conformation
for cyclization.
REFERENCES
■
(1) (a) Hirai, Y.; Watanabe, J.; Nozaki, T.; Yokoyama, H.; Yamaguchi,
S. J. Org. Chem. 1997, 62, 776. (b) Yokoyama, H.; Otaya, K.; Kobayashi,
H.; Miyazawa, M.; Yamaguchi, S.; Hirai, Y. Org. Lett. 2000, 2, 2427.
(c) Makabe, H.; Kong, L. K.; Hirota, M. Org. Lett. 2003, 5, 27.
(d) Uenishi, J.; Ohmi, M. Angew. Chem., Int. Ed. 2005, 44, 2756.
(e) Kawai, N.; Lagrange, J.-M.; Ohmi, M.; Uenishi, J. J. Org. Chem.
2006, 71, 4530. (f) Aponick, A.; Li, C.-Y.; Biannic, B. Org. Lett. 2008,
10, 669. (g) Hande, S. M.; Kawai, N.; Uenishi, J. J. Org. Chem. 2009, 74,
244. (h) Tanaka, S.; Seki, T.; Kitamura, M. Angew. Chem., Int. Ed. 2009,
48, 8948. (i) Hanessian, S.; Focken, T.; Oza, R. Org. Lett. 2010, 12,
3172. (j) Aponick, A.; Biannic, B. Org. Lett. 2011, 13, 1330.
(k) Mukherjee, P.; Widenhoefer, R. A. Org. Lett. 2011, 13, 1334.
(l) Miyata, K.; Kutsuna, H.; Kawakami, S.; Kitamura, M. Angew. Chem.,
Int. Ed. 2011, 50, 4649. (m) Unsworth, W. P.; Stevens, K.; Lamont, S.
G.; Robertson, J. Chem. Commun. 2011, 47, 7659. (n) Mukherjee, P.;
Widenhoefer, R. A. Angew. Chem., Int. Ed. 2012, 51, 1405.
(o) Ghebreghiorgis, T.; Biannic, B.; Kirk, B. H.; Ess, D. H.; Aponick,
A. J. Am. Chem. Soc. 2012, 134, 16307.
We have demonstrated that dihydropyrans can be prepared
through a Re2O7-catalyzed dehydrative route from monoallylic
1,3- or 1,5-diols, whereby a hydroxy group reacts with the distal
terminus of an appended allyl cation. The reactions proceed
quickly to give the 2,6-trans-isomer with moderate to good levels
of stereocontrol. The trans-isomer is the kinetic product,
resulting from a boat-like transition state, and equilibration
studies show that is also the thermodynamic product due to A1,2-
strain minimization. This stereochemical outcome is comple-
mentary to prior dehydrative cyclizations that proceed through
hydroxy groups reacting at the proximal terminus of appended
allylic cations. Primary allylic alcohols can serve as substrates,
allowing for the formation of enantiomerically enriched
monosubstituted dihydropyrans. Structural variations of cycliza-
tion substrates show that (E)- and (Z)-1,3- and (E)-1,5-
monoallylic diols form the same cation upon ionization as
determined by reaction yields and stereochemical outcomes.
(Z)-1,5-Monoallylic diols, however, react more efficiently and
with stereochemical retention being observed to an unexpect-
edly high degree, suggesting an intriguing SNi mechanism that is
unique to this substitution pattern.
́
(2) (a) Guerinot, A.; Serra-Muns, A.; Gnamm, C.; Bensoussan, C.;
́
Reymond, S.; Cossy, J. Org. Lett. 2010, 12, 1808. (b) Guerinot, A.;
Serra-Muns, A.; Bensoussan, C.; Reymond, S.; Cossy, J. Tetrahedron
2011, 67, 5024. (c) Hanessian, S.; Focken, T.; Oza, R. Tetrahedron
2011, 67, 9870. (d) Zheng, H.; Ghanbari, S.; Nakamura, S.; Hall, D. G.
Angew. Chem., Int. Ed. 2012, 51, 6187. (e) Zhang, F.-Z.; Tian, Y.; Li, G.-
X.; Qu, J. J. Org. Chem. 2015, 80, 1107. (f) Hoshiya, N.; Noda, K.;
Mihara, Y.; Kawai, N.; Uenishi, J. J. Org. Chem. 2015, 80, 7790.
(3) For reviews on Re2O7-mediated transformations, see: (a) Volch-
kov, I.; Lee, D. Chem. Soc. Rev. 2014, 43, 4381. (b) Bellemin-Laponnaz,
S. ChemCatChem 2009, 1, 357. For more specific examples: (c) Hu, J.;
Xu, D.; Zhang, Q.; Shang, Y.; Shi, M.; Huangfu, Y.; Liu, L.; Liang, R.;
Lai, Y.; He, Y.; Gao, J.-m.; Xie, W. RSC Adv. 2016, 6, 52583. (d) Yun, S.
Y.; Hansen, E. C.; Volchkov, I.; Lo, W. Y.; Lee, D. Angew. Chem., Int. Ed.
2010, 49, 4261. (e) Herrmann, A. T.; Saito, T.; Stivala, C. E.; Tom, J.;
Zakarian, A. J. Am. Chem. Soc. 2010, 132, 5962. (f) Bellemin-Laponnaz,
S.; Gisie, H.; Le Ny, J. P.; Osborn, J. A. Angew. Chem., Int. Ed. Engl.
1997, 36, 976. (g) Narasaka, K.; Kusama, H.; Hayashi, Y. Tetrahedron
1992, 48, 2059.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03526.
Schemes for substrate syntheses, cyclization protocols,
1
stereochemical determinations, and H and 13C NMR
(4) (a) Asari, A. H.; Floreancig, P. E. Angew. Chem., Int. Ed. 2020, 59,
6622. (b) Qin, Q.; Xie, Y.; Floreancig, P. E. Chem. Sci. 2018, 9, 8528.
(c) Rohrs, T. M.; Qin, Q.; Floreancig, P. E. Angew. Chem., Int. Ed. 2017,
56, 10900. (d) Xie, Y.; Floreancig, P. E. Angew. Chem., Int. Ed. 2014, 53,
4926. (e) Xie, Y.; Floreancig, P. E. Angew. Chem., Int. Ed. 2013, 52, 625.
spectra (PDF)
FAIR data, including the primary NMR FID files, for
compounds 6, 7, 10−37, S1, S2, and S5 (ZIP)
D
https://dx.doi.org/10.1021/acs.orglett.0c03526
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(f) Xie, Y.; Floreancig, P. E. Chem. Sci. 2011, 2, 2423. (g) Jung, H. H.;
Seiders, J. R.; Floreancig, P. E.; II. Angew. Chem., Int. Ed. 2007, 46, 8464.
(5) For representative examples, see: (a) Kito, K.; Ookura, R.;
Namikoshi, M.; Ooi, T.; Kusami, T. Org. Lett. 2008, 10, 225−225.
(b) Williams, D. E.; Roberge, M.; Van Soest, R.; Andersen, R. J. J. Am.
Chem. Soc. 2003, 125, 5296−5297. (c) Jefford, C. W.; Bernardinelli, G.;
Tanaka, J.; Higa, T. Tetrahedron Lett. 1996, 37, 159−162.
(d) Tachibana, K.; Scheuer, P. J.; Tsukitani, Y.; Kikuchi, H.; Van
Engen, D.; Clardy, J.; Gopichand, Y.; Schmitz, F. J. J. Am. Chem. Soc.
1981, 103, 2469−2471.
(6) Jacques, R.; Pal, R.; Parker, N. A.; Sear, C. E.; Smith, P. W.;
Ribaucourt, A.; Hodgson, D. M. Org. Biomol. Chem. 2016, 14, 5875.
(7) For a conceptually related approaches, see: (a) Venegas, E. R.;
Willis, C. L. Org. Lett. 2020, 22, 2548. (b) Flamme, E. M.; Roush, W. R.
Beilstein J. Org. Chem. 2005, 1, 7.
(8) Mo, X.; Yakiwchuk, J.; Dansereau, J.; McCubbin, J. A.; Hall, D. G.
J. Am. Chem. Soc. 2015, 137, 9694.
(9) Johnson, F. Chem. Rev. 1968, 68 (4), 375.
(10) Please see the Supporting Information for details.
(11) Winstein, S.; Klinedinst, P. E., Jr.; Robinson, G. C. J. Am. Chem.
Soc. 1961, 83, 885.
(12) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1997, 119, 8738.
(13) Brown, C. A.; Ahuja, V. K. J. Org. Chem. 1973, 38, 2226.
(14) Hoye, T. R.; Jeffrey, C. S.; Shao, F. Nat. Protoc. 2007, 2, 2451.
(15) Rodriguez del Rey, F.; Floreancig, P. E. Submitted for
publication.
(16) (a) Sharkey, B. E.; Jentoft, F. C. ACS Catal. 2019, 9, 11317.
(b) Morimoto, Y.; Iwai, T.; Kinoshita, T. J. Am. Chem. Soc. 1999, 121,
6792. (c) Morimoto, Y.; Iwai, T. J. Am. Chem. Soc. 1998, 120, 1633.
(d) Tang, S.; Kennedy, R. M. Tetrahedron Lett. 1992, 33, 7823.
(17) Lewis, E. S.; Boozer, C. E. J. Am. Chem. Soc. 1952, 74, 308.
E
https://dx.doi.org/10.1021/acs.orglett.0c03526
Org. Lett. XXXX, XXX, XXX−XXX