Pyridone photoelectrocyclizations to pyridophenanthrenes

Article abstract of DOI:10.1016/j.tet.2017.06.062

This article describes the synthesis of pyridophenanthrenes from the stereoselective electrocyclization and [1,5]-hydride shift sequences of biphenyl pyridones. The regioselectivity of the reaction of meta-substituted biphenyl substrates depended on the electronic environment of the substituents. That is, substrates having electron-withdrawing substituents underwent a regioselective sequence while electron-donating substituents gave mixtures of products.

Full text of DOI:10.1016/j.tet.2017.06.062

Tetrahedron xxx (2017) 1e4
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Pyridone photoelectrocyclizations to pyridophenanthrenes
Xuchen Zhao, Jon D. Rainier*
Department of Chemistry, University of Utah, Salt Lake City, UT, 84112, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
This article describes the synthesis of pyridophenanthrenes from the stereoselective electrocyclization
and [1,5]-hydride shift sequences of biphenyl pyridones. The regioselectivity of the reaction of meta-
substituted biphenyl substrates depended on the electronic environment of the substituents. That is,
Received 24 March 2017
Received in revised form
21 June 2017
Accepted 27 June 2017
Available online xxx
substrates having electron-withdrawing substituents underwent
electron-donating substituents gave mixtures of products.
a regioselective sequence while
© 2017 Elsevier Ltd. All rights reserved.
Keywords:
Electrocyclization
Pyridone
Photochemistry
Dihydrophenanthrene
As part of our program targeting the synthesis of quaternary
substituted carbolines, we recently described the use of a four-step
Suzuki coupling, oxidative cyclization, free-radical coupling
sequence that converts bromodihydropyridone 1 into quaternary
substituted carbolines like 6 (Scheme 1).1
In addition to its use in the sequence outlined above, we became
interested in employing 1 to synthesize phenanthrene analogs, i.e.
8, from vinyl biphenyl electrocyclization/[1,5]-hydride shift se-
quences from the corresponding dihydropyridones 7 (Scheme 2).
We envisioned numerous applications for phenanthrene analogs
including their use as precursors to structurally and biologically
interesting targets like ergoline and ergoline analogs and their use
as ligands/reagents/catalysts for organic synthesis.2e4
While dihydropyridones had not been used previously in vinyl
biphenyl electrocyclization reactions, a wealth of information on
related transformations exists.5 In particular, Lewis and Zuo
examined the photoinduced electrocyclization of vinyl biphenyl
derivatives to give dihydrophenanthrene 10 from a tandem elec-
trocyclization, [1,5]-hydride shift sequence.6,7 Interestingly, Lewis
and co-workers subsequently calculated an essentially barrierless
transition for the reaction after excitation (see Scheme 3).8
In addition to determining whether dihydropyridones would
participate in reactions related to Lewis' we planned to examine the
effect of substituents on the regio- and stereoselectivity of the re-
action. In this regard, the precedent for regioselective
electrocyclization reactions is mixed. Schultz and co-workers re-
ported that the photocyclization of meta-methoxy aryloxyenone
11a was regioselective giving benzofuran 12a as the only isolated
product (Scheme 4).9 In contrast to this result, meta-methyl enone
11b and meta-methylester enone 11c gave 3:1 and 2:1 mixtures of
12b and 12c and 13b and 13c, respectively. Schultz applied this
reaction to the synthesis of the morphine skeleton.10
The effect of substitution on the electrocyclization of stilbene
derivatives has also been examined. The studies that are most
relevant to ours came from Mallory and Mallory where they re-
ported that essentially 1:1 mixtures of phenanthrene isomers 15
and 16 were formed from the photocyclization/oxidation sequence
of meta-CF3, Cl, and CH3 substituted stilbenes 14 (Scheme 5).11
Also worthy of mention are studies from Lewis and co-workers
that demonstrated that amino pyridine 17 undergoes a regiose-
lective tandem electrocyclization, [1,7]-hydride shift sequence that
gives a mixture of 18 and 19 (Scheme 6).12 Lewis reported that the
amount of 18 was greatest when the reaction was run in the
absence of oxygen and attributed this phenomenon to a reversible
6p electrocyclization reaction. That is, under anaerobic conditions
the intermediate leading to 18 undergoes a relatively rapid [1,7]-
hydride shift and aromatization while the intermediate leading to
19 preferentially reverts back to starting material. When the reac-
tion was run in the presence of oxygen the equilibration was sup-
pressed by the rapid oxidation of the regioisomeric
electrocyclization products.
With the aforementioned studies in mind, we set out to examine
the cyclization chemistry of dihydropyridones.
A series of
* Corresponding author.
E-mail address: rainier@chem.utah.edu (J.D. Rainier).
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X. Zhao, J.D. Rainier / Tetrahedron xxx (2017) 1e4
Scheme 1. Suzuki Coupling-Oxidative Cyclization Sequence to Carbolines.
Scheme 2. Proposed Electrocyclization Sequence to Dihydrophenanthrenes.
6p electrocyclization and a subsequent thermally allowed supra-
facial [1,5]-hydrogen shift from the cyclohexadiene intermediate
(See Scheme 8). Substituted variants of 24 also underwent photo-
chemical electrocyclization. The cyclization of ortho-methoxy
biphenyl dihydropyridone 25 (entry 2) gave dihydrophenanthrene
36 in 88% yield.
In contrast to Mallory's precedent, when meta-substituted
biphenyldihydropyridones were subjected to 350 nm UV light the
regioselectivity of the cyclization was dependent on the electronic
nature of the substituents. When meta-electron-withdrawing
substituents (R’ ¼ C(O)CH3, CF3, NO2) were present, 1H NMR of
the crude reaction mixture showed dihydrophenanthrene A to be
the only product after photocyclization (entries 3e5). In contrast,
the presence of electron-donating substituents (R’ ¼ OCH3, F, Cl,
CH3) led to a nearly equal mixture of dihydrophenathrenes A and B
(entries 6e9). The exception to this was dimethyl amino substrate
33 (entry 10) which gave a 20:1 ratio of A:B in 95% yield. Because
the corresponding isopropyl substrate 34 gave a 4:3 ratio of A and B
(entry 10) we do not believe that the selectivity of 33 was a
consequence of steric interactions during the reaction.
Although more extensive studies are needed, the facial selec-
tivity in the electrocyclization reaction can be influenced by sub-
stituents on the pyridone amine. When phenethyl and naphthethyl
amide biphenyl substrates 46 and 47 were subjected to photo-
chemical conditions we isolated dihydrophenanthrenes 48 and 49
as 3.3:1 and 6:1 mixtures of diastereomers, respectively (see
Scheme 7).
Scheme 3. Lewis and Zuo's Generation of Dihydrophenanthrenes.
substituted cyclization precursors that differed in their substitution
pattern on the aromatic ring distal to the dihydropyridone were
obtained from a sequential Suzuki-Miyaura coupling sequence as is
outlined in Table 1.13 We initially investigated the electrocyclization
reaction of unsubstituted substrate 24 (entry 1) that came from the
coupling of bromoarene 22 with boronic acid 23 (R, R” ¼ H). Based
on work from other laboratories it was not surprising that our at-
tempts to carry out the thermal electrocyclization of 24 were un-
successful. In contrast, piperidonephenanthrene 35 was isolated in
90% yield when 24 was subjected to 350 nm UV light. Shorter
wavelength light (300 nm) gave lower yields presumably as a result
of significant decomposition of starting material and/or product. As
has been proposed for related reactions, we believe that the con-
version to 35 is the result of a photochemically allowed conrotatory
Scheme 4. Schultz and co-workers aryloxyenone photocyclization.
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X. Zhao, J.D. Rainier / Tetrahedron xxx (2017) 1e4
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Scheme 5. Mallory and Mallory's Stilbene Electrocyclization Reactions.
Scheme 6. Lewis and Co-Workers Regioselective Stilbene Cyclizations.
Table 1
Synthesis and Photoelectrocyclization of Dihydropyridones.
for the meta-substituted substrates we proposed two possibilities
for the selective cyclization reactions: (a) a reversible electro-
cyclization for 53 and a relatively rapid [1,5]-hydride shift for 52
(R’ ¼ electron-withdrawing group) or14; (b) a shorter excited state
lifetime for 51 when compared to 50 (R’ ¼ electron-withdrawing
group). To be accurate this argument requires that when R0 is an
electron-donating groups that 52 and 53 were generated in nearly
equal amounts and that they underwent [1,5]-hydride shifts at
equivalent rates. It also requires that when R0 is an electron-
donating groups that both 50 and 51 undergo photoinduced elec-
trocyclization. These suppositions were testable; if correct the
substrates having electron-withdrawing substituents should react
Scheme 7. Chiral Amide Cyclizations.
The presumed mechanism for dihydrophenanthrene formation
is shown in Scheme 8. In an attempt to explain the reactivity trends
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X. Zhao, J.D. Rainier / Tetrahedron xxx (2017) 1e4
biphenyl dihydropyridones are effective precursors to substituted
dihydrophenanthrenes. Our investigations have shown a regiose-
lective electrocyclization with biphenyl precursors having an
electron-withdrawing substituent at the meta-position but a
mixture of regioisomers with electron-donating groups. We will
continue to study this reaction and to utilize the products in
complex molecule synthesis.
Acknowledgement
We are grateful to the National Science Foundation for their
support of this work (CHE 1465113). The authors would also like to
thank Professor Joel Harris for helpful discussions and the use of his
Xe lamp and monochromator for quantum yield studies. The sup-
port staff at the University of Utah was helpful to us in carrying out
this work; in particular we would like to thank Dr. Peter Flynn
(NMR) and Dr. Jim Muller (mass spectrometry).
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2017.06.062.
References
Scheme 8. Proposed Electrocyclization Mechanism.
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This manuscript has demonstrated that readily available
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