β-Silyl-Assisted Tandem Diels-Alder/Nazarov Reaction of 1-Aryl-3-(trimethylsilyl) Ynones

Article abstract of DOI:10.1021/acs.orglett.7b00911

A one-pot tandem Diels-Alder/Nazarov reaction of 1-aryl-3-(trimethylsilyl) ynones has been achieved to generate carbo- and heterocyclic fused ring systems in good to excellent yields. The β-silyl effect is instrumental in accessing this otherwise challenging cascade annulation reaction. The tandem reaction proceeds in the presence of BCl₃ to generate three new carbon-carbon bonds, a quaternary carbon, and two stereogenic centers with excellent diastereocontrol. A variety of substituted arenes, and even heteroaromatics, are tolerated to provide tricyclic products that are of interest as advanced intermediates toward biologically relevant compounds.

Full text of DOI:10.1021/acs.orglett.7b00911

Letter
pubs.acs.org/OrgLett
β‑Silyl-Assisted Tandem Diels−Alder/Nazarov Reaction of 1‑Aryl-3-
(trimethylsilyl) Ynones
Rachael A. Carmichael, Punyanuch Sophanpanichkul, and Wesley A. Chalifoux*
Department of Chemistry, University of NevadaReno, 1664 North Virginia Street, Reno, Nevada 89557, United States
S
* Supporting Information
ABSTRACT: A one-pot tandem Diels−Alder/Nazarov re-
action of 1-aryl-3-(trimethylsilyl) ynones has been achieved to
generate carbo- and heterocyclic fused ring systems in good to
excellent yields. The β-silyl effect is instrumental in accessing
this otherwise challenging cascade annulation reaction. The
tandem reaction proceeds in the presence of BCl3 to generate
three new carbon−carbon bonds, a quaternary carbon, and
two stereogenic centers with excellent diastereocontrol. A variety of substituted arenes, and even heteroaromatics, are tolerated to
provide tricyclic products that are of interest as advanced intermediates toward biologically relevant compounds.
he design of efficacious synthetic methodology is integral
to pharmaceutical development as well as expanding the
T
frontiers of synthetic organic chemistry.1 Terpenoids and
related structures have a rich history for piquing the interest of
synthetic groups, primarily due to the interesting biological
activities inherent in many of these compounds.2 Fused five-
and six-membered polycyclic ring systems comprise the basic
structure for a large number of important biologically active
molecules.3 New and efficient methods for the rapid
construction of polycyclic substructures are highly sought
after as a means to achieve more economical syntheses of
naturally occurring or derivatized compounds of interest.4 One
can achieve this through the use of multicomponent and/or
tandem reaction processes, and in the case of polycyclic
compound synthesis this would likely involve an annulation
step. The Nazarov cyclization is a synthetically valuable reaction
toward cyclopentenones, and while a general catalytic
asymmetric strategy has not yet been developed,5 significant
advancements have been made in regard to the Nazarov
reaction.6 There has been considerable interest in an aryl
Nazarov cyclization as this bond formation is viewed by some
as an essential step in the syntheses of several biologically
important naturally occurring compounds.7 However, the
formation of the five-membered rings through a Nazarov
cyclization involving aryl substrates is a synthetically challeng-
ing feat, requiring either dication intermediates via superacids8
or highly activated substrates.9 The Frontier group has
conducted impressive studies on an Ir(III)-catalyzed Nazarov
cyclization of polarized aryl vinyl ketone substrates (Figure
1a).10 Photolysis has been successfully used by Smith and
Agosta with aryl vinyl ketones to form a new five-membered
ring embedded within a [6−5−6] polycyclic framework.11 The
Gao group has expanded the substrate scope of the photo-
Nazarov reaction to a variety of substituted arenes and
heteroaromatics (Figure 1b).12 In many cases, the aryl vinyl
ketone substrate for the Nazarov reaction must be synthesized
with a heavy bias toward reactivity; otherwise, the Nazarov
Figure 1. (a) Nazarov cyclizations of polarized aryl vinyl ketones
through an iridium catalyst.10 (b) Photo-Nazarov cyclization of
diversified aryl vinyl ketones.12
cyclization is unlikely to be the favored pathway. A more
general method that can tolerate a variety of aryl vinyl ketone
substrates, and additionally can be coupled with a multi-
component and/or tandem reaction event starting from
relatively simple substrates, would be highly attractive for
arriving at these useful synthetic scaffolds.
Our research endeavors are directed toward method
development for rapidly accessing biologically interesting
polycyclic frameworks, via multicomponent and tandem
reaction sequences, that starts from alkyne-containing sub-
strates.13 The use of high-energy alkyne- and polyyne-
containing substrates provides the thermodynamic driving
force for arriving at complex polycyclic products by way of
multicomponent/tandem reaction sequences. We recently
reported a novel one-pot method for the formation of [6−5−
6] tricyclic products resulting from a multicomponent double
Diels−Alder/Nazarov tandem reaction of cross-conjugated
diynones.13a,b We were curious as to whether aryl-substituted
ynones would also undergo a tandem Diels−Alder/Nazarov
reaction. This would arrive at a [6−5−6]-tricyclic scaffold
containing an aryl moiety, a structural characteristic present in
the taiwaniaquinol family of biologically active natural
Received: March 27, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00911
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Organic Letters
Letter
products.3a,14 Ynone starting materials such as 1 were of
particular interest to us as they readily undergo Diels−Alder
cycloadditions with 2 to form a skipped diene intermediate 3.
We noted that compound 3 contains the necessary
functionality to participate in a Nazarov cyclization (shown in
red) (Scheme 1a, R = H) and wondered if we could effect this
Table 1. Substrate Scope of Ynone 5 for the Tandem Diels−
Alder/Nazarov Reaction
Scheme 1. Tandem Diels−Alder/Nazarov Reaction
transformation to give 4. We have previously screened Lewis
acids that promote the alkyne Diels−Alder cycloaddition along
with subsequent reactions and have found aluminum and boron
Lewis acids to be most suitable.13 We observed that the Diels−
Alder product 3 formed rapidly with both aluminum and BCl3.
However, we did not observe any formation of the desired
product 4 and more forcing conditions resulted in decom-
position of 3. In a previous study, we observed that silyl-
substituted diynones demonstrated increased reactivity in both
the Diels−Alder and Nazarov reaction.13a,b Since silyl
substitution can have a strong stabilizing effect on the oxyallyl
cation intermediate via the β-silyl effect,15 we wondered
whether silyl group incorporation onto the terminus of the
ynone would sufficiently stabilize the reaction intermediates,
enabling the Nazarov reaction to proceed under more mild
conditions. Indeed, silyl-substituted ynone 5a underwent the
tandem Diels−Alder/Nazarov reaction rapidly to generate the
desired product 6a in good yield (56%) and excellent
diastereoselectivity (>20:1, based on GC−MS analysis),
presumably via the oxyallyl cation intermediate 7 (Scheme
1b). The syn relationship between the methine hydrogen and
the TMS group was confirmed by 2D NOESY NMR
spectroscopic analysis. Although desilylation is typical in
other Nazarov reactions resulting in excellent regiocontrol of
the resulting double bond,13a,b,15 rearomatization via loss of a
proton is preferred in this case, leaving the TMS group intact. A
stoichiometric amount of Lewis acid was necessary for full
conversion of the starting material, a requirement that has often
been reported for Nazarov cyclizations.5,13a,b
Having established the proof of concept, we began looking at
the scope of this reaction (Table 1). We first looked at electron-
rich aryls, and although the o-methoxy-substituted ynone 5b
rapidly formed the Diels−Alder adduct, it was not surprising
that this intermediate was demethylated7a to provide
compound 8 in 75% yield with no formation of the Nazarov
product (entry 2). We opted for a slightly bulkier ethyl group
(5c, entry 3) in an attempt to minimize dealkylation, but this
pathway was still faster than the Nazarov step, resulting only in
the formation of 8. Interestingly, EtAlCl2 proved ineffective to
promote the Nazarov cyclization for both 5b and 5c. The use of
AlBr3 also effected the demethylation side reaction of 5b to
provide only compound 8. However, using AlBr3 with 5c, we
did obtain desired product 6c, albeit in poor yield (entry 3).
The p-methoxy-substituted ynone 5d successfully underwent
the Diels−Alder/Nazarov reaction to generate 6d in modest
a
b
c
Isolated yield. Isolated yield of compound 8. Yield of 6c using
AlBr3. Note: A significant amount of product 8 was also detected at the
end of the reaction.
yield (entry 4). It is not surprising that electron-donating
groups (EDG) in the ortho and para positions (5b−d) perform
poorly as they are less reactive dienophiles for the Diels−Alder
cycloaddition and they inductively deactivate the aryl carbon
B
DOI: 10.1021/acs.orglett.7b00911
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Organic Letters
Letter
undergoing the rate-determining Nazarov cyclization. We were
pleased that bromine-substituted ynones 5e and 5f both reacted
to give compounds 6e and 6f in 51% and 63% yield,
respectively, as these products will be suitable for subsequent
transition-metal-catalyzed coupling reactions (entries 5 and 6).
Having an electron-withdrawing group (EWG) in the ortho-
position (5g) resulted in significant decomposition with only
26% yield of 6g being isolated (entry 7). However, the
electron-poor para-substituted ynone 5h successfully gave 6h in
very good yield (entry 8). Fluorinated compounds have
considerable importance in biologically active molecules, and
as such, we were pleased to observe that substrate 5i underwent
the tandem Diels−Alder/Nazarov reaction quickly to form 6i in
excellent yield (entry 9). The naphthyl-substituted ynone 5j
was also tolerated and rapidly generated 6j in 57% yield (entry
10).
Scheme 2. Tandem Diels−Alder/Nazarov Reaction of
Heteroaryl-Substituted Ynones
determined to be desilyated products 11a−c. While 11a was
isolated in 7% yield (relative stereochemistry not determined)
and 11c was only detected in a trace amount, we were unable to
isolate 11b due to its decomposition upon attempted isolation.
A plausible explanation for the formation of desilylated product
11 is that, due to the less aromatic character of these heteroaryl
systems, the rate of desilylation in the oxyallyl cation
intermediate 12 becomes competitive with the rate of
deprotonation/rearomatization, as seen in analogous sys-
tems.15d A subsequent [1,5]-hydride shift in 13 to re-establish
aromaticity followed by protonation of 14 during workup
would provide product 11. Nonetheless, we were pleased that
the heteroaryl-substituted ynones reacted to generate an
interesting class of [5−5−6] heterotricyclic ring systems.
In conclusion, we have demonstrated a tandem Diels−Alder/
Nazarov reaction of 3-(trimethylsilyl)-1-aryl and 3-(trimethyl-
silyl)-1-heteroaryl ynones to yield biologically important
polycyclic scaffolds in a one-pot reaction. Additionally, we
have shown that our method can be applied to a variety of
substituted ynones, allowing for extensive modification of the
core structure. The one-pot tandem Diels−Alder/Nazarov
reaction is highly regio- and diastereoselective, providing
concise and efficient access to broad structural diversity while
also imparting useful functional handles (arene, alkene, TMS,
and ketone) for further chemical elaboration.
We also decided to look at meta-substituted aryl ynones in
order to gain insight into the regioselectivity of the Nazarov
step with regard to these substrates (Table 2). Once again,
Table 2. Regioselectivity of Meta-Substituted Aryl Ynones
a
b
entry
R
product
yield (%)
6/6′
1
2
3
4
5
MeO (5k)
MeO (5k)
CF3 (5l)
6k
6k
6l
trace
c
72
15:1
45:1
10:1
3:1
d
47
CH3 (5m)
6m
6n
41
d
Cl (5n)
44
a
b
Isolated yield. Regioisomeric ratio of crude products determined by
GC−MS analysis. Stereochemistry of minor regioisomers was assigned
c
d
by analogy. Using AlBr3. Isolated yield as an inseparable mixture of
regioisomers (6/6′).
demethylation occurred over the course of the reaction for
substrate 5k when using BCl3, resulting in only trace amounts
of 6k (entry 1). However, using AlBr3 resulted in the formation
of desired product 6k in excellent yield with excellent
regioselectivity (entry 2). Both the trifluoromethyl- and
methyl-substituted ynones, 5l and 5m, reacted to generate
the Nazarov products 6l and 6m, in modest yields 47%, and
41%, respectively (entries 3 and 4). Chloro-substituted ynone
5n provided product 6n in modest yield as an inseparable 3:1
mixture of regioisomers (entry 5). This decrease in
regioselectivity can possibly be attributed to a steric effect as
cyclization at C-2 of the aryl would be relatively easier in 5n on
account of the smaller chlorine substituent at C-3. Our
observations suggest that having an EDG para to the carbon
that is making the C−C bond during the rate-determining
Nazarov cyclization (and meta to the carbonyl) increases the
rate of the reaction and the yield.
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.7b00911.
Experimental procedures and compound characterization
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wchalifoux@unr.edu.
ORCID
We were interested to see whether heteroaryl-substituted
ynones would also participate in the tandem Diels−Alder/
Nazarov reaction (Scheme 2). Thiophene-substituted ynone 9a
rapidly underwent the tandem reaction to give 10a in 66%
yield.16 The furan-substituted ynone 9b also worked to provide
10b in good yield.17 We were very excited that the N-
methylpyrrole derivative 9c was also successful in this reaction
to provide 10c in good yield. It should be noted that we
observed an unexpected minor side product in these reactions,
Wesley A. Chalifoux: 0000-0002-6849-6829
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
W.A.C. acknowledges the National Science Foundation for
supporting this work through a CAREER Award (CHE-
1555218). This material is based upon work supported by the
C
DOI: 10.1021/acs.orglett.7b00911
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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National Aeronautics and Space Administration under Grant
No. NNX10AN23H issued through the Nevada Space Grant
Program (R.A.C.). We thank Casey Philbin (University of
Nevada, Reno) for assisting with mass spectra data collection.
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