Stereodivergent Photoelectrocyclization Reactions of Bis-aryl Cycloalkenones: Intercepting Photoelectrocyclization Intermediates with Acid

Article abstract of DOI:10.1021/acs.orglett.9b03214

Described here are tandem photoelectrocyclization and [1,5]-hydride shift reactions of heteroaryl-containing bis-aryl cyclohexenone derivatives that give heteroaryl-substituted dihydrophenanthrenes. This Letter demonstrates that electrocyclization intermediates can be trapped with acid when the [1,5]-hydride shift is relatively slow. From a practical perspective, the observation that the acid-mediated reaction gives a divergent stereochemical outcome when compared with the reaction run under neutral conditions makes these transformations powerful.

Full text of DOI:10.1021/acs.orglett.9b03214

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Stereodivergent Photoelectrocyclization Reactions of Bis-aryl
Cycloalkenones: Intercepting Photoelectrocyclization Intermediates
with Acid
Xuchen Zhao, Changqing Song, and Jon D. Rainier*
Department of Chemistry, University of Utah, Salt Lake City, Utah 84112, United States
S
* Supporting Information
ABSTRACT: Described here are tandem photoelectrocycli-
zation and [1,5]-hydride shift reactions of heteroaryl-
containing bis-aryl cyclohexenone derivatives that give
heteroaryl-substituted dihydrophenanthrenes. This Letter
demonstrates that electrocyclization intermediates can be
trapped with acid when the [1,5]-hydride shift is relatively
slow. From a practical perspective, the observation that the
acid-mediated reaction gives a divergent stereochemical outcome when compared with the reaction run under neutral
conditions makes these transformations powerful.
s first reported by Horgan and Morgan in 1973, the
treatment of conjugated biaryl alkenes with UV light leads
coupling reactions (Table 1).14,15 Whereas we were pleased to
isolate quaternary substituted dihydrophenanthrenes when 1
A
to the stereoselective generation of dihydrophenanthrenes.1
Subsequent to their initial report, Horgan and Morgan’s
photoelectrocyclization reaction received considerable atten-
tion from researchers around the globe, and, as a consequence,
a considerable amount of mechanistic insight was uncovered.2
From these studies, it has been established that (a) bond
formation involves a sequential 6π conrotatory electrocycliza-
tion, followed by a thermally allowed [1,5]-hydride shift;3,4 (b)
the substrates do not react under thermal condition;5 and (c)
the reaction generally proceeds through a singlet excited state.6
In contrast with all of the mechanistic information that has
been uncovered, neither the scope of the photoelectrocycliza-
tion reaction of bis-aryl alkenes nor the use of the reaction in
the synthesis of more complex substrates has been studied in
any significant detail.2,5,7 With this in mind and with an interest
in using dihydrophenanthrenes in the synthesis of interesting
targets including natural and non-natural products, we set out
to change this.8−10 As a demonstration of the potential of the
electrocyclization process, we recently described the tandem
photoelectrocyclization and [1,5]-hydride shift of a series of
conjugated biphenyldihydropyridones, giving trans-fused dihy-
drophenanthrenes.11 Outlined here is a follow up on these
studies with an investigation of heteroaromatic substrates as a
means of synthesizing diterpene natural products that have
shown the ability to inhibit virulence.12 Our interest in
heteroaromatic substrates comes from both a curiosity about
the properties of the dihydrophenanthrene products and the
possibility of carrying out chemoselective dearomatization
reactions subsequent to the photoelectrocyclization.13 In light
of these interests, we elected to initially examine conjugated
pyrazines.
Table 1. Phenyl Pyrazine Photoelectrocyclizations
a
b
entry
additive
none
none
none
none
none
none
NEt3
solvent
2:3
conversion (%)
1
2
3
4
5
6
7
8
9
10
CHCl3
CDCl3
C6D6
1:2
1:4
93
50
94
65
85
80
86
50
40
65
c
>20:1
12:1
>20:1
>20:1
>20:1
1:2
CD3OD
CD3CN
d
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
HCl (0.5 equiv)
HCl (2 equiv)
TFA (2 equiv)
1:3
<1:20
a
Ratio was determined by 1H NMR integration of the benzylic
b
signals. Conversions were determined by 1H NMR using 2,4,6-
trimethoxybenzeneas an internal standard. Reaction was stopped
after 15 min. CDCl3 was neutralized prior to its use.
c
d
was exposed to 350 nm light, we were surprised that the
reaction not only gave the expected trans-fused product 2 but
also gave cis diastereomer 3 (entries 1 and 2).
It turns out that the transformation to 3 was dependent on
the solvent employed in the reaction. In contrast with the
We began our efforts with conjugated phenylpyrazine
cyclohexenone 1 that comes from sequential Suzuki−Miyaura
Received: September 10, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03214
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
result with CHCl3, trans-2 was the nearly exclusive product
when the reaction was run in deuterated benzene, methanol, or
acetonitrile (entries 3−5). With an interest in utilizing related
derivatives as precursors to interesting alkaloids,16 we set out
to determine whether we could find conditions to selectively
generate 3. As far as the result with CHCl3 was concerned, we
reasoned that the presence of HCl in the CHCl3 might be
responsible for its generation. Consistent with this hypothesis
were experiments showing that the use of neutralized CHCl3
led to the isolation of 2 as the sole product (entries 6 and 7).
In contrast, the addition of larger quantities of HCl proved
detrimental. That is, the addition of exogenous HCl to the
photoelectrocyclization reaction led to both a slower reaction
and relatively less cis product when compared with running the
reaction in CHCl3 or CDCl3 that had not been neutralized
(compare entries 1, 2, 8, and 9). After considerable
experimentation, we ultimately found that the use of a weaker
acid, namely TFA, nearly exclusively gave 3 (entry 10). In
addition to optimizing conditions for its formation, we were
curious about whether 3 came from the isomerization of 2
during the reaction. When 2 was exposed to TFA, no
equilibration occurred in either the presence or the absence
of light.
consistent with a subsequent six-electron conrotatory electro-
cyclization providing intermediate 8. Apparently, the [1,5]-
hydride shift from 8 is relatively slow, enabling other events
like protonation to intervene. Under acidic conditions,
stereoselective protonation, as depicted, provides 3. In the
absence of acid, the normal suprafacial [1,5]-hydride shift leads
to 2.
There are several unique features of the 1 to 2 or 3
transformations. To the best of our knowledge, 2 represents
the first photoelectrocyclization precursor of the bis-aryl vinyl
class of substrates whose photoelectrocyclization intermediate
can be manipulated nonoxidatively. As was previously
mentioned, this manipulation leads to a completely divergent
stereochemical outcome that makes these transformations not
only mechanistically interesting but also synthetically powerful.
In an effort to ascertain whether other heteroaromatics
might be susceptible to the generation of cis products when
exposed to acid, we examined the impact of TFA on the
photoelectrocyclization of other nitrogen heterocycles. It was
interesting that both the position and the number of nitrogen
atoms were important in the protonation reaction (Table 2).
Table 2. Heteroaromatic Photoelectrocyclizations
Having established conditions to generate either 2 or 3, we
next set out to determine the source of the benzylic proton in
both products. To do this, we examined the photoelectrocyc-
lization of penta-deuterated cyclization precursor 4 (Scheme
1). Subjecting 4 to 350 nm light in the presence of TFA
Scheme 1. Labeled Pyrazine Photoelectrocyclizations
resulted in cis-dihydrophenanthrene 6 with no label at the
benzylic position. In contrast, when 4 was exposed to 350 nm
light in CH3CN in the absence of acid, we isolated 5, having
>95% deuterium incorporation at the benzylic position. These
results confirm that protonation rather than a [1,5]-hydride
shift of the photoelectrocyclization intermediate leads to the
cis-dihydrophenanthrene.
On the basis of the information presented above, we propose
the mechanism outlined in Scheme 2. We believe that both 2
and 3 result from the excitation of 1 and the generation of the
corresponding excited state 7. Because the use of triplet
sensitizers and quenchers has not been informative to date, we
do not currently know whether the reaction involves a singlet
or a triplet excited state. Our labeling experiments are
a
b
A: CHCl3, TFA (1 equiv). B: CH3CN. Reaction was run on a 1
mmol scale.
The reactivities of substituted pyrazine 9 and quinoxaline 10
were essentially identical to the behavior of 1. That is, both
gave exclusively trans-fused products when subjected to light in
the absence of acid while resulting in cis product when TFA
was added to the reaction mixture (entries 1−4). In contrast
with these results, the photoelectrocyclization of conjugated
pyridine 11 gave exclusively trans product 15 regardless of
whether acid was present (entry 5). It was interesting that the
regioisomeric pyridine 12 gave the cis product 16 as the major
component of a 1.6:1 mixture when subjected to TFA and light
Scheme 2. Proposed Mechanism
B
DOI: 10.1021/acs.orglett.9b03214
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
and exclusively gave trans-16 in the absence of acid.17 As with
the pyrazines, we believe that the rate of the [1,5]-hydride shift
is dictating the product formation here; substrates like
biphenylpyridones or pyridine 11 undergo a relatively fast
hydride shift and appear to not be susceptible to protonation,
at least under the TFA conditions. Our results also suggest that
having a nitrogen atom proximal to the benzylic carbon
undergoing protonation was important for the generation of
the cis product. We are currently examining other hetero-
aromatic substrates with the goal of gaining a better
understanding of this phenomenon.
Finally, in an effort to determine whether acid could be used
to intercept photoelectrocyclization intermediates with other
“challenged” substrates, we examined the effect of acid on the
photoelectrocyclization of cyclobutenone 17. As illustrated in
Scheme 3, when 17 was exposed to light in the absence of acid
tions leads to the efficient synthesis of heteroaromatic-
containing dihydrophenanthrenes. Over the course of these
studies, we have demonstrated that substitution can have a
dramatic impact on the stereoselectivity of the reaction and
that those electrocyclization intermediates that do not undergo
a ready [1,5]-hydride shift can be intercepted through
protonation.
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.9b03214.
Experimental protocols and spectral data for all
compounds (PDF)
Accession Codes
Scheme 3. Attempted Cyclobutenone
Photoelectrocyclizations
CCDC 1952750−1952752 contain the supplementary crys-
tallographic 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
and the presence of methanol it did not undergo the
photoelectrocyclization, [1,5]-hydride shift sequence but
instead decomposed to ring-opened ester 18.18 We propose
that the reason for the lack of photoelectrocyclization products
from the reaction of 17 was a consequence of the [1,5]-hydride
shift from 19 being energetically unfavorable as a result of it
leading to the generation of trans-fused cyclobutanone 20.
If our hypothesis about the reactivity of 17 was correct, then
we imagined that we might be able to isolate the photo-
electrocyclization product by capturing 19 with a proton. To
our delight, when 17 was exposed to 350 nm light and a
mixture of 5 equiv of TFA and 0.05 equiv of TFAA, we isolated
cis-fused dihydrophenathrene 21 in 37% yield after reducing
the relatively unstable cyclobutanone electrocyclization prod-
uct immediately after its generation (Scheme 4).19 This
experiment shows that the protonation of the photoelectrocyc-
lization intermediate may be a general phenomenon, especially
for substrates whose [1,5]-hydride shift is relatively slow.
In summary, we have demonstrated that a combination of
Suzuki−Miyaura coupling and photoelectrocyclization reac-
■
Corresponding Author
*E-mail: rainier@chem.utah.edu.
ORCID
Jon D. Rainier: 0000-0003-4386-2463
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the financial support from the National
Science Foundation (CHE 1465113) and the National
Institutes of Health (GM132531-01). We also thank Dr.
Peter Flynn (University of Utah), Dr. Hsiaonung Chen
(University of Utah), and Dr. Ryan Vanderlinden (University
of Utah) for help with NMR, mass spectrometry, and X-ray
structure acquisition, respectively.
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D
DOI: 10.1021/acs.orglett.9b03214
Org. Lett. XXXX, XXX, XXX−XXX