Br?nsted Acids Enable Three Molecular Rearrangements of One 3-Alkylidene-2H-1,2-oxazine Molecule into Distinct Heterocyles

Article abstract of DOI:10.1021/acs.orglett.7b03985

This work describes three different strategies to structurally rearrange one 3-alkylidene-2H-1,2-oxazine molecule into three distinct heterocycles using HOTf, propiolic acid, and silica gel, respectively. The mechanisms of these rearrangement reactions in

Full text of DOI:10.1021/acs.orglett.7b03985

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Brønsted Acids Enable Three Molecular Rearrangements of One
3‑Alkylidene‑2H‑1,2-oxazine Molecule into Distinct Heterocyles
Bhanudas Dattatray Mokar, Jinxian Liu, and Rai-Shung Liu*
Department of Chemistry, National Tsing-Hua University, Hsinchu 30013, Taiwan, ROC
S
* Supporting Information
ABSTRACT: This work describes three different strategies to structurally
rearrange one 3-alkylidene-2H-1,2-oxazine molecule into three distinct heterocycles
using HOTf, propiolic acid, and silica gel, respectively. The mechanisms of these
rearrangement reactions involve three independent routes, including (i) Brønsted
acid catalysis, (ii) a synergetic action of Brønsted acids and anions, (iii) a surface-
directed chemoselectivity.
rønsted acids (H+X−) are versatile at mediating numerous
rearrangement reactions via carbocation intermediates,1
products.4 To expand the utility of this renowned system, we
report three new rearrangements of a closely related family, 3-
alkylidene-2H-1,2-oxazines, using HOTf, propiolic acid, and
SiO2, respectively, furnishing new useful heterocycles, including
Z-configured N-phenyl pyran-3(6H)-imine 4 (P1), pyrrolidin-2-
one 6 (P2), and Z-configured 3-(1H-indol-2-yl)prop-2-en-1-ol 5
(P3). Mechanistically, the HOTf reaction (3 → 4, eq 4) follows a
typical Brønsted acid catalysis, and the SiO2 reaction (3 → 5, eq
5) is implemented by silica surface. Particularly notable is the
internal redox rearrangement (3 → 6, eq 3), activated by a
synergetic action of H+/X−.5
B
including the well-known pinacol, Wagner−Meervein, Nazorav,
Mannich−aza-Cope, and epoxide/carbonyl rearrangement. A
recent advance in Brønsted acid catalysis is to employ chiral
anions X− to induce high enantioselectivity by ion pairing.2 In the
context of acid-catalyzed rearrangements, the reaction efficiency,
chemoselectivity, and stereoselectivity rely largely on the cation
centers (eq 1). Anions typically alter the chemoselectivity
Regioselective [4 + 2]-cycloadditions of alkenylallenes with
nitrosoarenes in 1:1 molar ratio proceeded smoothly in THF (25
°C, 5−60 min). In a typical operation, the solution were
evaporated to dryness, followed by washing with hexane to afford
pure 3-alkylidene-2H-1,2-oxazines 3a−r in 74−99% yields (see
Table S1). The reactions proceeded also well in other solvents;
compound 3a (R1 = Ph, R2 = R3 = Me) was obtained in
satisfactory yields in CH3CN (99%), dichloromethane (DCM,
99%), toluene (87%) and CHCl3 (99%). The structure of
compound 3a was confirmed by X-ray diffraction to reveal a Z-
olefin configuration. This regioselectivity is consistent with a 1,4-
diradical path, according to our recent investigation.6
through an interception or deprotonation of carbocations (eq 2).
This work assesses anion- and surface-directed chemoselectivity,
in addition to a traditional route. Herein, anions catalyze the
transformation of initial cations ([H-S′]+X−) into new
carbocations [H-S′′]+X− (eq 3), whereas catalyst surface
controls the conformation of the ion pair ([H-S′]+X−) to
activate a new chemoselectivity.
We explored new rearrangements of nitroxy species 3a using
varied Brønsted acids (see Table S2); selected examples are
provided in Table 1. A strong acid such as HOTf (1.0 equiv, 25
°C, 5 min) afforded of Z-configured N-phenylpyran-3(6H)-
imine (4a) in 83% yield (entry 1), but moderate acids such as 4-
nitrobenzoic acid, trifluoroacetic acid, N-triflateproline, and
Metal-catalyzed [4 + 2]-cycloadditions of dienes with
nitrosoarenes deliver 5,6-dihydro-4H-1,2-oxazines3 that are
powerful building units to access many naturally occurring
Received: December 22, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03985
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Table 1. Acidity versus Chemoselectivity
Scheme 1. HOTf-Mediated Rearrangement of Nitroxy Species
3
a
b
3 = 0.025 M. Product yields are reported after purification from a
a
b
silica column.
3a = 0.025 M. Acetic acid, benzoic acid and proline were inactive
c
catalysts to give 3a in 95−98% recovery. Silica gel was obtained from
Silicycle (silicaflash G60) and Merck (Geduran Si 60) respectively.
d
82−90% yields (entries 8 and 9). We observed no reaction for
species 3k bearing R2 = R3 = H (entry 10). We varied the R1
group with methyl, isopropyl and cyclohexyl as in compounds 3l-
3n, rendering compounds 4l−n in 80−85% yields (entries 11−
13). Various nitrosoarenes (X = Me, OMe, Cl, and CO2Et) were
applicable to these reactions to afford desired products 4o−r in
high yields (81−92%, entries 14−17).
A silica-mediated rearrangement proceeded well with all
nitroxy species 3b−r to yield Z-configured indole products 5b−r
smoothly (Scheme 2). This new rearrangement was applicable to
additional 4-phenyl 3b−e (X = OMe, Me, Cl, CF3) and 3-phenyl
3f,g (X = OMe, Cl) and 2-naphthyl 3h analogues, affording the
desired indole analogues 5b−e, 5f,g, and 5h with yields
exceeding 52% (entries 1−7). The molecular structure of the
acyl derivative of species 5c was characterized with X-ray
diffraction to reveal a Z-configured allylic alcohol. This indole
Silica gel (Silicycle) was treated with Et3N (2 mol %) in THF (8 h)
before filtration and washing with hexane.
propiolic acid preferably gave the distinct pyrrolidin-2-one 6a in
41−61% yields, with propiolic acid being the most effective
(entries 2−5, Table 1). Weak acids, including acetic acid, benzoic
acid, and proline (1 equiv) in hot DCE (60 °C, 36 h), led to only
a 95−98% recovery of initial 3a (Table S2). Astonishingly, silica
gel (10 equiv, Silicycle) in DCE enabled another new
rearrangement of species 3a to furnish Z-configured 3-(1H-
indol-2-yl)prop-2-en-1-ol (5a) in 67% yield. Silica gel from a
different source (Merck) showed a similar result (entry 6).
Notably, Et3N-pretreated silica gel became inactive (entry 7). In
the case of compound 4a, its treatment with silica gel (10 equiv)
and propiolic acid (20 mol %) in DCE (25 °C, 10 h) did not yield
the other two heterocycles, but afford the its hydration product.
Accordingly, Brønsted acid (H+) alone was responsible for the
formation of N-phenyl pyran-3(6H)-imine (4a) whereas
pyrrolidin-2-one 6a requires a cooperative action of Brønsted
acid and carboxylate anion. For indole derivative 5a, its formation
is presumably relevant to the surface structure of silica gel with its
very weak acidity being indispensable.
Scheme 2. Silica-Mediated Rearrangement of Cyclic Nitroxy
Species 3
Shown in Scheme 1 is the rearrangement of nitroxy
compounds 3b−r using HOTf; all of these instances gave
satisfactory results. In a standard operation, compounds 3 were
first produced from alkenylallenes and nitrosoarenes in
equilmolar proportion in DCM (25 °C, 5−60 min); the solution
was subsequently treated with HOTf (1 equiv) to afford Z-
configured N-phenyl pyran-3(6H)-imine (4b−r) in 82−92%
yields. A small loading of HOTf (20 mol %) led to the imine
hydration of products 4. We examined the rearrangement of
trisubstituted nitroxy heterocycles 3b−e bearing various 4-
phenyl groups (X = OMe, Me, Cl, CF3) that were satisfactorily
rearranged to compounds 4b−e in 82−88% yields (entries 1−4);
1H NOE confirmed a Z-configured imine of compound 3a. This
rearrangement worked well with nitroxy species 3f,g bearing 3-
phenyl groups (X = OMe, Cl) and a 2-naphthyl group to afford
desired compounds 4f−h in 80−92% yields (entries 5−7). The
reactions were applicable to species 3i and 3j bearing alterable R2
and R3 substituents, producing pyran-3(6H)-imines 4i and 4j in
a
b
3 = 0.02 M. X-ray diffraction was performed on the acyl derivative of
c
compound 5c The reaction was performed at 60 °C under standard
conditions.
B
DOI: 10.1021/acs.orglett.7b03985
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synthesis was applicable also to nitroxy species 3i−k bearing
variable R2 and R3 substituents, delivering compounds 5i−k in
high yields (entries 8−10). For species 3l−n bearing variable
alkyl substituents at the R1 position (R1 = methyl, isopropyl and
cyclohexyl), the reactions delivered indole products 5l−n in 82−
86% yields (entries 11−13). Various 4-substituted nitro-
sobenzenes allowed a substituent onto the C(5)-carbon of
indole derivatives 5o−r over a broad scope (X = Me, OMe, Cl,
CO2Et, entries 14−17).
Scheme 4. A Formal Synthesis of Fluvastatin
The rearrangement of nitroxy species 3b−r into pyrrolidin-2-
ones 6 with propiolic acid (20 mol %) is very striking; herein,
three instances were unsuccessful (entries 9, 10, and 14, Scheme
3). The propiolate anion catalyzed a redox rearrangement via a
a suitable oxidation to afford Z-7 selectively.8 The Z → E
isomerization was nearly complete when species Z-8 was
dissolved in CDCl3 for 2 days. A formal synthesis of fluvastatin
with species E-8 is well documented.9
Scheme 3. Propiolic Acid-Catalyzed Rearrangement
We added D2O in the two rearrangement reactions as depicted
in eq 7. In the cases of HOTf, the resulting products 4a and 4a′
contained no deuterium at all, but in the case of propiolic acid,
resulting compound d-6a contained three deuterium contents (X
= 0.50 D, Y = 0.33 D, and Z = 0.77 D). This information indicates
that product 4a arises from the protonation of the N−O oxygen
of species Z-3a, whereas propiolic acid preferably protonates at
the PhHC carbon, reflecting two distinct mechanisms.
The mechanism of the HOTf-mediated rearrangement likely
involves a typical N−O bond cleavage because of the high acidity
(Scheme 5).10 The resulting aza-allylic cation A undergoes a
Scheme 5. HOTf and Silica-Mediated Reactions
a
b
Three = 0.025 M. Product yields are reported after purification from
a silica column.
transfer of two OCH2 protons to the R1HCN olefin. This
rearrangement was applicable to species 3b−e bearing various R1
= 4-XC6H4 substituents, with X = Cl, CF3 being more effective
than X = OMe and Me (entries 1−4). For their 3-phenyl and 2-
naphthyl analogues 3f,g and 3h, their expected products 6f,g and
6h were obtained in 52−78% yields (entries 5−7). The
molecular structure of compound 6h was elucidated with X-ray
diffraction. We varied R2 and R3 substituents as in species 3i−k
(entries 8−10); only species 3i was an applicable substrate to
form compound 6i in 70% yield. For nitroxy species 3l−n
bearing R1 = methyl, isopropyl and cyclohexyl, their internal
redox products 6l−n were obtained in high yields (82−90%,
entries 11−13). For various nitrosobenzenes, we found that
electron-rich phenyl species 3o and 3p were less efficient than
their electron-deficient analogues; their respective yields were 0−
45% and 72−74%, respectively (entries 14−17). Based on these
data, this redox rearrangement is more favorable for those nitroxy
species bearing an electron-deficient R1HC = N bond to avoid an
N−O cleavage as for the HOTf reaction.
facile C−C rotation to form its conformer A′, which is
subsequently attacked by the hydroxyl group to form N-
phenylpyran-3(6H)-imine 4a with an observed Z-geometry. In
the case of the silica reaction, the N−O group of species 3a
interacts easily with the hydroxyl group of silica surface without a
N−O cleavage. The increasing electrophilicity of the nitroxy
oxygen induces an intramolecular cyclization as shown in state B
to generate species C and ultimately the observed indole product
Z-5a.
The relevant mechanism in the 3a → 6a rearrangement
became resolved with a D2O experiment (eq 7). The three
distinct contents of d-6a indicate the varied stages of the D2O
deuteration. Propiolic acid is a weak acid that cannot cleave the
N−O bond, but its carboxylic anion is a weak base to show a
synergetic effect, as depicted in state D (Scheme 6). We believe
Fluvastatin (Lescol) is an important member of the class of
statin drugs which is used for the treatment of hyper-
cholesterolemia.7 We employed our silica gel reaction on
allenylalkene 1o to synthesize an indole derivative 5s in 60%
yield (Scheme 4). This species was treated with i-PrI, followed by
C
DOI: 10.1021/acs.orglett.7b03985
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Letter
Notes
Scheme 6. Cooperative Action for Propiolic Acid
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Science Council, Taiwan, for financial
support of this work.
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REFERENCES
■
(1) (a) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev. 2014,
114, 9047. (b) Terada, M. Synthesis 2010, 2010, 1929. (c) Akiyama, T.;
Mori, K. Chem. Rev. 2015, 115, 9277.
(2) (a) Phipps, R. J.; Hamilton, G. L.; Toste, F. D. Nat. Chem. 2012, 4,
603. (b) Zi, W.; Toste, F. D. Chem. Soc. Rev. 2016, 45, 4567. (c) Brak, K.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2013, 52, 534. (d) Mahlau, M.;
List, B. Angew. Chem., Int. Ed. 2013, 52, 518. (e) Jia, M.; Bandini, M. ACS
Catal. 2015, 5, 1638. (f) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem.
Rev. 2008, 108, 3351.
(3) (a) Bodnar, B. S.; Miller, M. J. Angew. Chem., Int. Ed. 2011, 50,
5630. (b) Yamamoto, Y.; Yamamoto, H. Eur. J. Org. Chem. 2006, 2006,
2031. (c) Vogt, P. F.; Miller, M. J. Tetrahedron 1998, 54, 1317.
(d) Denmark, S. E.; Thorarensen, A. Chem. Rev. 1996, 96, 137.
(4) Carosso, S.; Miller, M. J. Org. Biomol. Chem. 2014, 12, 7445.
(5) Cooperative catalysis typically employs metal catalysts bearing a
functional ligand; see: (a) Kim, D.-S.; Park, W.-J.; Jun, C.-H. Chem. Rev.
2017, 117, 8977. (b) Afewerki, S.; Cordova, A. Chem. Rev. 2016, 116,
13512.
(6) Liu, J.; Skaria, M.; Sharma, P.; Chiang, Y.-W.; Liu, R.-S. Chem. Sci.
2017, 8, 5482.
(7) (a) Switzer, J. A.; Hess, D. C. Expert Rev. Neurother. 2006, 6, 195.
(b) Davidson, M. H. Am. J. Med. 1994, 96, 41.
(8) Liu, J.; Ma, S. Org. Lett. 2013, 15, 5150.
(9) (a) Zacharia, J. T.; Tanaka, T.; Hayashi, M. J. Org. Chem. 2010, 75,
7514. (b) Tempkin, O.; Abel, S.; Chen, C.-P.; Underwood, R.; Prasad,
K.; Chen, K.-M.; Repic, O.; Blacklock, T. J. Tetrahedron 1997, 53, 10659.
(10) Acid-catalyzed rearrangement of cyclic nitroxy species:
(a) Kulandai Raj, A. S.; Kale, B. S.; Mokar, B. D.; Liu, R.-S. Org. Lett.
2017, 19, 5340. (b) Sharma, P.; Liu, R.-S. Org. Lett. 2016, 18, 412.
(c) Ghorpade, S.; Jadhav, P. D.; Liu, R.-S. Chem. - Eur. J. 2016, 22, 2915.
(d) Sharma, P.; Liu, R.-S. Chem. - Eur. J. 2016, 22, 15881. (e) Kawade, R.
K.; Tseng, C.-C.; Liu, R.-S. Chem. - Eur. J. 2014, 20, 13927.
(11) For unsaturated six-membered nitroxy species, see: Sukhorukov,
A. Y.; Ioffe, S. L. Chem. Rev. 2011, 111, 5004.
(12) This ring cleavage was well documented for other nitroxy species;
see refs 10 and 11 and selected examples: (a) Ioffe, S. L.; Lyapkalo, I. M.;
Tishkov, A. A.; Danilenko, V. M.; Strelenko, Y. A.; Tartakovsky, V. A.
Tetrahedron 1997, 53, 13085. (b) Gygax, P.; Das Gupta, T. K.;
Eschenmoser, A. Helv. Chim. Acta 1972, 55, 2205. (c) Shatzmiller, S.;
Shalom, E. Liebigs Ann. Chem. 1983, 1983, 897. (d) Goldberg, I.; Saad,
D.; Shalom, E.; Shatzmiller, S. J. Org. Chem. 1982, 47, 2192.
(13) For the aza-Nazarov cyclizations, see: (a) Klumpp, D. A.; Zhang,
Y.; O’Connor, M. J.; Esteves, P. M.; de Almeida, L. S. Org. Lett. 2007, 9,
3085. (b) Ma, Z.-X.; He, S.; Song, W.; Hsung, R. P. Org. Lett. 2012, 14,
5736. (c) Zhou, A.-H.; He, Q.; Shu, C.; Yu, Y.-F.; Liu, S.; Zhao, T.;
Zhang, W.; Lu, X.; Ye, L.-W. Chem. Sci. 2015, 6, 1265. (d) Sahani, R. L.;
Liu, R.-S. Angew. Chem., Int. Ed. 2017, 56, 12736. (e) Pawar, S. K.;
Sahani, R. L.; Liu, R.-S. Chem. - Eur. J. 2015, 21, 10843.
that the weakly O-bound propiolic acid D abstracts one O−CH2
proton, whereas another propiolic acid delivers a proton to the
PhC carbon, affording a hypothetical 2H-1,2-oxazine species E
that remains unknown.11 A 6π retro-electrocyclization12 of
highly unstable species E generates 4-imino-2-en-1-al species F
that undergoes protonation to yield azapentadienyl cations G or
G′. The C(3)-methyl of species G′ can undergo a deuterium
exchange via intermediate H. A final aza-Nazarov cyclization13 of
cation G or G′ affords pyrrole product J and, ultimately, the
observed product 6a. According to this reaction sequence, the
deuterium content of compound 6a follows the decreasing order
D > D′′ > D′′′, compatible with our observed data of species d-
6a.
In summary, we have successfully developed three molecular
rearrangements of 3-alkylidene-2H-1,2-oxazines using HOTf,
silica gel and propiolic acid, affording N-phenyl pyran-3(6H)-
imine 4, pyrrolidin-2-one 6, and Z-configured 3-(1H-indol-2-
yl)prop-2-en-1-ol 5, respectively. Our experimental data suggest
that the reactions with HOTf represent a typical acid catalysis,
enabling a N−O cleavage of cyclic nitroxy species. Silica enables a
distinct rearrangement with its surface acidic sites to increase the
electrophilicity of the nitroxy oxygen. The reaction with propiolic
acid involves a synergetic action of H+ and X−.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03985.
Experimental details and spectral data of all compounds
(PDF)
Accession Codes
CCDC 1582436−1582438 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: rsliu@mx.nthu.edu.tw.
ORCID
Rai-Shung Liu: 0000-0002-2011-8124
D
DOI: 10.1021/acs.orglett.7b03985
Org. Lett. XXXX, XXX, XXX−XXX