Formation and isomerization of polycyclic 1,5-enynes Dedicated to Harry H. Wasserman

Article abstract of DOI:10.1016/j.tetlet.2015.01.145

A 1,5-enyne with the alkyne flanked by a cyclopropane and a cyclobutane, formed by intramolecular [2+2] photocycloaddition of a pyridone with an enyne, undergoes gold catalyzed ring closure to give a cyclopentene, without isomerization of either small rin

Full text of DOI:10.1016/j.tetlet.2015.01.145

Tetrahedron Letters 56 (2015) 3567–3570
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Tetrahedron Letters
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q
Formation and isomerization of polycyclic 1,5-enynes
Paul B. Finn , Svitlana Kulyk a,b, Scott McN. Sieburth a,
a
⇑
a
Department of Chemistry, Temple University, 1901 N. 13th Street, Philadelphia, PA 19122, USA
Department of Chemistry, University of California at Berkeley, Berkeley, CA 94720, USA
b
a r t i c l e i n f o
a b s t r a c t
Article history:
A 1,5-enyne with the alkyne flanked by a cyclopropane and a cyclobutane, formed by intramolecular
Received 17 December 2014
Revised 12 January 2015
Accepted 17 January 2015
Available online 31 January 2015
[
2+2] photocycloaddition of a pyridone with an enyne, undergoes gold catalyzed ring closure to give a
cyclopentene, without isomerization of either small ring. The ring closure can also be effected by thiol
radical conditions. The chemistry of the resulting tetracycle with its five stereogenic centers, has been
studied.
Ó 2015 Elsevier Ltd. All rights reserved.
Dedicated to Harry H. Wasserman
Keywords:
Pyridone
Photochemistry
Gold catalysis
Enyne
Thiol radical
Assembly of polycyclic molecules with useful complexity from
2
simple reagents is a gold standard in organic synthesis. During
our investigations of 2-pyridone photochemistry we have studied
its cycloaddition with 1,3-enynes and discovered two different
pathways based on the presentation of the enyne.3 When the
enyne is attached through the alkyne (1), only [4+4] cyclization
results and the highly strained allene product 2 is, in most cases,
unstable and undergoes further reaction. In contrast, when the
enyne is linked to the pyridone through the alkene (3), only
,4
[
2+2] products are observed (see Scheme 1). The stereochemically
rich cyclobutane 4 presented opportunities to study the reactivity
of this strained and densely functionalized structure, particularly
its cis-1,5-enyne. We report herein our investigation of the forma-
tion and reactivity of 4 and related structures.
Scheme 1. Tether-dependent pyridone–enyne photocycloaddition.4
The formation of [2+2] adduct 4 is notable for several reasons.
In addition to creating two adjacent quaternary carbons, the
cycloaddition occurs with retention of the alkene stereochemistry,
whereas [2+2] cycloaddition of enones with alkenes is typically
photocycloaddition of 3 would be consistent with the retention
of (E) alkene geometry observed for this reaction as well as for
the corresponding (Z) alkene 5, Scheme 2.
In four additional examples, with hydrogen, trimethylsilyl and
cyclopropyl (7a–d) terminating the alkyne, with and without bro-
mine at C-5 of the pyridone, a clean [2+2] cycloaddition is
observed, yielding the [2+2] adducts 8a–d as single isomers,
Scheme 3. These reactions were typically run in NMR spectrometer
tubes (3.5 mm diameter) using a 400 W medium-pressure mercury
lamp in a water-cooled jacket and a PyrexÒ filter, standardized as
5
accompanied by scrambling of the alkene stereochemistry. Enone
photochemistry is largely triplet-derived and bond formation in
enone [2+2] cycloadditions are often stepwise and reversible, lead-
ing to the stereochemical isomerization. In contrast, pyridone pho-
tochemistry is mostly singlet-derived.6 A singlet process for the
q
See Ref. 1.
⇑
Corresponding author. Tel.: +1 215 204 7916; fax: +1 215 204 1532.
E-mail address: scott.sieburth@temple.edu (S.McN. Sieburth).
0
6 6
.025 M solutions of 3 or 7 in C D or toluene. As noted in Scheme 3
http://dx.doi.org/10.1016/j.tetlet.2015.01.145
040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
0

3
568
P. B. Finn et al. / Tetrahedron Letters 56 (2015) 3567–3570
Scheme 2. Stereochemistry of the alkene is preserved in pyridone [2+2]
photocycloadditions.
Scheme 5. Gold-catalyzed cyclization of 1,5-enynes.9,10
Scheme 3. Pyridone–enyne [2+2] photocycloadditions.
Scheme 6. Gold-catalyzed cyclization of 1,5-enynes.
for the reaction of 7b, increasing the size of the reaction tube from
to reform starting 9e followed by rapid re-photocycloaddition, or
reversible cleavage of the cyclobutane bond that is both propar-
gylic and allylic. Photocleavage reactions have been described for
3
.5 mm to 15 mm diameter led to a near tripling of the time
required for completion of the reaction (TLC) and a drop in the iso-
lated yield by 8%. Use of a flow apparatus led to a much improved
8
7
related structures.
process. Using 3.2 mm diameter PTFE tubing allowed the reaction
With cyclobutane products 8 in hand, we turned to investiga-
tions of the reactivity of this 1,5-enyne. Nonconjugated enynes
can cyclize when treated with a variety of reagents such as gold
and radicals. For substrates 4 and 8, the cyclobutane adjacent to
the alkyne could participate in these reactions, based on precedent
volume to be dramatically increased and the reaction time sub-
stantially decreased. Moreover, under these conditions the yield
of product 8b increased by 9%.7
One exception to the stereochemical fidelity found for sub-
strates 7 was substrate 7e, that gave a diastereomeric mixture of
products 8e and 9e, Scheme 3. The loss of stereocontrol for sub-
strate 7e is a consequence of the conjugated phenyl group. It
should be noted that isomerization of the alkene in 7e is not
observed during the photoreaction, suggesting that if the photore-
action of 7e involves triplet intermediates the photocycloaddition
with the pyridone is faster than isomerization, and that the
resulting 8e may isomerize to 9e in a subsequent photochemical
transformation. Indeed, subjecting a purified sample of 9e to iden-
tical photochemical conditions resulted in a mixture of 8e and 9e,
in a ratio that changed over time, Scheme 4. After 6 h the 2:1 mix-
ture observed for the initial cycloaddition was achieved. This is
consistent with either photo-cleavage of the product cyclobutane
9
of substrate 10, for example, Scheme 5. For substrates 8b and 8d
in particular, with the alkyne flanked by both cyclobutane and
cyclopropane, the potential for new reaction pathways through
participation of these strained rings was obvious. Alternatively,
the electron-rich ene-amide group nearby might intercept the
coordinated alkyne and its reaction intermediates, much like other
1
0
nucleophiles can, for example, 15.
1
In the event, treatment of 8b with a mixture of Au in wet ace-
tonitrile gave tetracycle 14 in high yields, Scheme 6, with no
change in the strained rings. This reaction presumably starts with
coordination of the gold with the alkyne, with the resulting inter-
mediate 15 possibly electronically biased by the cyclopropane.
Fensterbank and Malacria found that platinum-catalyzed reactions
of non-conjugated enynes were compatible with terminal cyclo-
1
1
propane substitution similar to 8b. Trapping of this electrophile
by the electron-rich enamide then yields iminium 16 that is inter-
cepted by water, yielding 14. The structure of 14 was confirmed by
X-ray crystallography (see Supporting information).
Scheme 4. Equilibration of the phenylalkyne product.

P. B. Finn et al. / Tetrahedron Letters 56 (2015) 3567–3570
3569
Scheme 9. Thiol radical cyclization.
Scheme 7. Only cis enynes cyclize.
Not surprisingly, cyclization is possible only when the ene and
yne are cis to each other. Subjecting the mixture of 8e and 9e to
the gold catalyzed cyclization conditions led to quantitative recov-
ery of the trans enyne 9e and formation of cyclization product 17 in
good yields (see Scheme 7).
Without the cyclopropane of 8b terminating the alkyne, sub-
strate 4, lower yields for the gold-catalyzed cyclization were
observed, Scheme 8. Treatment of 4 under the standard conditions
gave 18 in 23% yield. With a terminal alkyne and a bromine on the
enamide (8c), gold catalysis gave cyclization but with a twist: the
bromine was lost and the hemiaminal functionality was replaced
with a carbonyl, imide 19. It is likely that 19 results from initial
trapping of the iminium by water, viz., 15, followed by dehydro-
halogenation. The latter presumably is an E2-like process, with sol-
volysis of the allylic bromide initiating the dehydrohalogenation.
While the gold-catalyzed cyclization was promoted by substitu-
tion of the alkyne by phenyl and cyclopropane, attempts to elicit
cyclization of trimethylsilyl substrate 8a led only to recovered
starting material. Low reactivity for platinum-catalyzed reactions
Scheme 10. Elaboration of the aminal.
pathway, the resulting hemi-aminal can be readily elaborated.
Overall, the 2–4 step sequence creates a tetracyclic product with
up to six stereogenic centers from an achiral starting material with
single aromatic ring. Further studies are in progress.
1
1
of an alkyne terminated by a trimethylsilyl group has been noted.
Nevertheless, treatment of 8a with thiophenol in the presence of
AIBN led to clean cyclization and formation of product 21,
1
2
Scheme 9.
Acknowledgment
Several reactions of the tetracyclic aminal 14 have been
explored, Scheme 10. Reduction of the aminal hydroxyl was readily
accomplished by treatment with sodium cyanoborohydride under
acidic conditions to give 21.13 Alternatively, the alcohol was
replaced by methoxy by dissolving in acidic methanol. This meth-
oxy group was efficiently replaced with an allyl group with a com-
Support from the National Science Foundation (1152159) is
gratefully acknowledged.
Supplementary data
1
4,15
bination of borontrifluoride and allyl silane, yielding 23.
In all
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.01.
cases, the nucleophiles were found to add only from the convex
face of the system.
1
45.
Photochemical reactions of enynes with 2-pyridones can take
the form of [4+4] cycloaddition or [2+2] cycloadditions, depending
on the presentation of the enyne, readily controlled by performing
the reactions intramolecularly.4 The [2+2] pathway is notable for
the retention of alkene geometry, suggesting a singlet photo-
chemical pathway. Moreover, this intramolecular cycloaddition
creates two quaternary carbons. When the alkyne in the cycloaddi-
tion product is cis to the alkene of the enamide derived from the
pyridone, cyclization to give a cyclopentene can be effected using
gold(I) catalysis or by thiol radical addition. For the former
References and notes
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