Transformation of N, N-Dimethylaniline N-Oxides into Diverse Tetrahydroquinoline Scaffolds via Formal Povarov Reactions

Article abstract of DOI:10.1021/acs.orglett.8b02318

A one-pot protocol for the assembly of diversely functionalized tetrahydro-, hexahydrofuro-, hexahydropyrano-, and tetrahydrobenzofuroquinolines from N,N-dimethylaniline N-oxides and various electron-rich olefins in a tandem Polonovski-Povarov sequence is reported. Following activation of the N-O bond with Boc₂O, an exocyclic iminium ion is unveiled upon exposure to tin(IV) chloride. A formal inverse-electron-demand aza-Diels-Alder cyclization generates the tetrahydroquinoline core of 29 examples in up to 92% yield.

Full text of DOI:10.1021/acs.orglett.8b02318

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Transformation of N,N‑Dimethylaniline N‑Oxides into Diverse
Tetrahydroquinoline Scaffolds via Formal Povarov Reactions
Timothy S. Bush, Glenn P. A. Yap, and William J. Chain*
Department of Chemistry & Biochemistry, University of Delaware, Newark, Delaware 19716, United States
S
* Supporting Information
ABSTRACT: A one-pot protocol for the assembly of diversely functionalized
tetrahydro-, hexahydrofuro-, hexahydropyrano-, and tetrahydrobenzofuroqui-
nolines from N,N-dimethylaniline N-oxides and various electron-rich olefins
in a tandem Polonovski−Povarov sequence is reported. Following activation
of the N−O bond with Boc2O, an exocyclic iminium ion is unveiled upon
exposure to tin(IV) chloride. A formal inverse-electron-demand aza-Diels−Alder cyclization generates the tetrahydroquinoline
core of 29 examples in up to 92% yield.
he tetrahydroquinoline scaffold lies at the heart of
1). The tandem hydroamination−hydrogenation of alkynyl
Tcountless natural products, biologically active materials, anilines is achieved under gold catalysis4 (and often relayed
with an organocatalytic hydrogenation), which necessarily
limits the scope of the available products to 2-substituted
materials (Scheme 1, eq 2, substituent R2). The Povarov
reaction relies upon the protic or Lewis acid mediated
condensation of an aniline and an aldehyde followed by
capture of the resultant aza-diene with an alkene (Scheme 1, eq
3); thus, the Povarov reaction is often limited to electron-rich
anilines and alkene components. There are successful
asymmetric variants of each of these strategies that further
impinge upon the scope of the available substrates (e.g., by
requiring structural features such as Lewis basic groups that
facilitate catalyst binding).3,4,7−9
We report here a practical synthesis of the tetrahydroquino-
line scaffold as part of our broader research program
investigating the special reactivity of N,N-dialkylaniline N-
oxides (Scheme 1, eq 4).10 The aniline N-oxides undergo O-
acylation events with a host of electrophiles, and we have
developed chemistry by which the weak N−O bond is excised
in a Polonovski-type reaction to give an iminium ion.11
Following that event, the imine is captured by an electron-rich
alkene, and the resultant cation is then attacked by the pendant
aniline. Thus, the reaction constitutes the stepwise formal [4 +
2] cycloaddition (aza-Diels−Alder reaction) of the Povarov
reaction. In the case of aniline N-oxides, O-acylation requires
an electrophile that will not undergo the N → C group transfer
we have previously described;10,11 elimination can be achieved
efficiently under the action of a Lewis acid to give a stable
iminium ion (Scheme 2). The elimination pathway is favored
over group transfer by employing di-tert-butyl dicarbonate
(Boc2O) as the acylating agent (which does not undergo N →
C group transfer at a significant rate, Scheme 2b, 2 → 3b),
followed by treatment with tin(IV) chloride as a Lewis acid.
The Lewis acid assisted elimination reaction to generate
medicinal compounds, ligands, catalyst frameworks, and a
myriad of other natural and synthetic materials.1 Convenient
access to this special structure is impactful in a variety of fields
and disciplines, and a number of approaches to the
tetrahydroquinoline structure have been described.2
Modern strategies toward the synthesis of highly substituted
tetrahydroquinolines include the hydrogenation of quinolines,3
tandem hydroamination−hydrogenation of alkynyl anilines,4
and the classical Povarov reaction5 which combines an aniline,
an aldehyde, and some alkene component in a formal inverse-
electron-demand aza-Diels−Alder6 reaction (Scheme 1, eqs 1−
3). Each of these approaches is limited by the nature of the
reactions and the reagents required. For example, hydro-
genation of quinolines can be achieved under the action of
various transition metals7 or organocatalysts;8 however, the
reaction conditions are often quite harsh, and the preparation
of quinoline starting materials can be laborious (Scheme 1, eq
Scheme 1. Representative Synthetic Approaches to
Tetrahydroquinolines
Received: July 23, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02318
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. (a) Mechanism of the Tandem Polonovski−
Povarov Reactions with Aniline N-Oxides. (b) Group-
Transfer Reactions Avoided by Use of Boc2O
Scheme 3. Tandem Polonovski−Povarov Reactions Joining
a
Aniline N-Oxides with Ethyl Vinyl Ether
a
Yields of isolated products; reactions were performed on a 1 mmol
scale.
We then employed cyclic vinyl ethers in the Polonovski−
Povarov reaction sequence and found these to be similarly
reactive. By subjecting 2,3-dihydrofuran and 3,4-dihydro-2H-
pyran to the same reaction conditions (Scheme 4), we
obtained the polycyclic scaffolds 8 and 9 in 42−74% yields.
The ring junctions of the furanoquinoline and pyranoquinoline
Scheme 4. Tandem Polonovski−Povarov Reactions Joining
iminium ions proceeds cleanly on a variety of substituted N,N-
dimethylaniline N-oxides (Scheme 2a, 2 → 3a). We have
successfully captured this electrophile with a variety of
electron-rich vinyl ethers, thus restoring the electron-rich
anilines (3a → 4). The resultant cations are sufficiently stable
to undergo intramolecular attack by the aniline (4 → 5) to give
a variety of polycyclic scaffolds.
a
Aniline N-Oxides with Cyclic Vinyl Ethers
After the intramolecular attack by the aromatic ring, loss of a
proton restores aromaticity (5 → 6). We extensively screened
Lewis acidic reaction conditions (BF3·OEt2, BCl3, FeCl3,
ZnBr2, CuBr, CuI, InCl3, TiCl4, SnCl4, and LiClO4) and
temperature profiles to support the cationic cyclization
sequence and determined that tin(IV) chloride (0.25 equiv)
in cold dichloromethane routinely afforded clean cyclized
materials. As part of our study, we found these N-oxides to be
far easier to handle and manipulate as complexes with m-
chlorobenzoic acid. Following oxidation of the anilines with m-
CPBA,10 the N-oxides cocrystallize with the acid byproduct to
give robust crystalline solids that are bench stable and
nonhygroscopic (see the Supporting Information, SI). More-
over, the m-chlorobenzoic acid does not interfere with the
capture of iminium ions by exogenous nucleophiles, provided
that excess activating agent is employed. For example, upon
treatment of 4-acetoxy-N,N-dimethylaniline N-oxide (1a) with
di-tert-butyl dicarbonate (Boc2O) and 4-(N,N-dimethyl-
amino)pyridine (DMAP) at 0 °C, followed by cooling to
−94 °C and addition of tin(IV) chloride and ethyl vinyl ether,
the cationic cascade reaction afforded the substituted
tetrahydroquinoline 7a in 78% yield (Scheme 3).12 The
reaction is tolerant of both electron-rich and electron-poor
substituents on the aromatic ring, giving 4-ethoxy-N-methyl-
tetrahydroquinolines in 42−78% yields in 5−6 h at low
temperature.
a
Yields of isolated products; reactions were performed on a 1 mmol
scale.
B
DOI: 10.1021/acs.orglett.8b02318
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
products are formed exclusively as the cis-fused products as
determined by 1H NMR analysis, and we later confirmed these
structural assignments by X-ray crystallography (8a, 8e, 9a, and
9b, see SI).
Scheme 6. Reactions with Allylic Silanes as Nucleophiles
Moreover, benzofurans are also sufficiently nucleophilic to
participate in the cationic cyclization sequence, giving rise to
tetracyclic products 10 in 41−87% yields (Scheme 5) and
Scheme 5. Tandem Polonovski−Povarov Reactions Joining
a
Aniline N-Oxides with Benzofuran.
a
Yields of isolated products; reactions were performed on a 0.6 mmol
scale.
stepwise ring closure events, and we are further investigating
the lifetime of the secondary cation intermediates under these
reaction conditions.
We are working to further explore similar reactions with
other allylic silanes and will report these and other new
cycloaddition reactions in due course. Importantly, if the
secondary cation intermediate is too stable, the reaction does
not proceed beyond the initial capture of the iminium ion. For
example, a silyl ketene acetal can capture the iminium ion in a
Mannich-type16 reaction (Scheme 7a) directly analogous to
our previous work in the synthesis of indolines (Scheme 7b).11
a
Yields of isolated products; reactions were performed on a 1 mmol
scale.
Scheme 7. Mannich-Type Reactivity with Aniline N-Oxides
offering the opportunity to generate materials with two
distinctly substituted aromatic residues (e.g., 10g and 10h).
The regiochemistry of attack utilizing benzofuran nucleophiles
is inverted relative to their dihydrofuran equivalents, as was
expected.13 The products form exclusively as the cis-fused ring
junction, and these assignments were also confirmed crystallo-
graphically (10a−c and 10e, see the SI).
In an effort to further expand the structural motifs accessible
via the cationic cyclization sequence, we are exploring other
less electron-rich nucleophiles, and we have identified allylic
silanes14 as viable reaction participants (Scheme 6).15 The
allylic silanes can engage the N-aryliminium ions, giving
stabilized secondary carbocation intermediates, which undergo
rapid ring closure. The allylic silanes offer the opportunity to
generate diversely functionalized products 11, which were
formed in 31−92% yields under reaction conditions identical
to those previously identified. Interestingly, the stereochemical
outcome of these reactions with respect to the ring fusion
appears to correlate with the olefin geometry of the starting
materials, though our work with allylic silanes is ongoing. For
example, when we employed E-aryl allylic silanes in the
reaction sequence, we obtained the tetrahydroquinoline
products 11c and 11d in 92% and 90% yields, respectively,
as the trans-substituted products. We view these reactions as
We have described a practical and convenient synthetic
protocol for the rapid assembly of various tetrahydroquinoline
scaffolds via Lewis acid assisted tandem Polonovski−Povarov
cyclizations. The products are obtained in up to 92% yield in
5−6 h at low temperature, and these reactions represent a
novel use of the special reactivity of N,N-dimethylaniline N-
oxides. Owing to the abundance of commercially available
C
DOI: 10.1021/acs.orglett.8b02318
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02318.
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synthesis, see: (j) Reddy, B. V. S.; Grewal, H. Tetrahedron Lett. 2011,
52, 761. (k) Huo, C.; Chen, F.; Quan, Z.; Dong, J.; Wang, Y.
Detailed experimental procedures, spectral data, and X-
ray crystallographic data (PDF)
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the supplementary crystallographic 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.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wchain@udel.edu.
ORCID
Timothy S. Bush: 0000-0002-3735-7156
William J. Chain: 0000-0003-0312-6250
Author Contributions
All experimental procedures were executed by T.B. X-ray
crystallographic data was collected by G.Y.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge Mr. Chad E. Hatch (University of
Delaware) for insightful conversations regarding this work and
for manuscript preparation assistance. The University of
Delaware (UD), the American Chemical Society Petroleum
Research Fund (ACS PRF 54452-ND1), and the National
Science Foundation (NSF CHE-1664954) are gratefully
acknowledged for financial support. Spectral data were
acquired at UD on instruments obtained with the assistance
of NSF and NIH funding (NSF CHE0421224, CHE0840401,
CHE1229234, CHE1048367; NIH S10 OD016267-01, S10
RR026962-01, P20GM104316, P30GM110758).
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DOI: 10.1021/acs.orglett.8b02318
Org. Lett. XXXX, XXX, XXX−XXX