Intramolecular [4 + 2] trapping of a hexadehydro-diels-alder (HDDA) benzyne by tethered arenes

Article abstract of DOI:10.1021/ol5037024

We report here the efficient, intramolecular trapping in a Diels-Alder (DA) sense of thermally generated benzynes by one of two pendant arene rings. A more electron-rich ring (p-methoxyphenyl) reacted substantially faster than a simple phenyl ring, which was, in turn, slightly more reactive vs a 4-carbomethoxyphenyl ring. Photoinduced di-π-methane rearrangement of the initial DA adducts gave rise to unusual isomeric polycyclic adducts.

Full text of DOI:10.1021/ol5037024

Letter
pubs.acs.org/OrgLett
Intramolecular [4 + 2] Trapping of a Hexadehydro-Diels−Alder
(HDDA) Benzyne by Tethered Arenes
Vedamayee D. Pogula, Tao Wang, and Thomas R. Hoye*
Department of Chemistry, University of Minnesota, 207 Pleasant Street, SE Minneapolis, Minnesota 55455, United States
S
* Supporting Information
ABSTRACT: We report here the efficient, intramolecular trapping in a Diels−Alder (DA) sense of thermally generated
benzynes by one of two pendant arene rings. A more electron-rich ring (p-methoxyphenyl) reacted substantially faster than a
simple phenyl ring, which was, in turn, slightly more reactive vs a 4-carbomethoxyphenyl ring. Photoinduced di-π-methane
rearrangement of the initial DA adducts gave rise to unusual isomeric polycyclic adducts.
Scheme 1. Reported Bimolecular Diels−Alder Reactions
between o-Benzyne (1) as the Dienophile and Various
Monosubstituted Benzene Derivatives 2 as the Diene Partner
To Give [4 + 2] Adducts 3a−b
enzene (and its substituted derivatives) are generally
unwilling partners in typical Diels−Alder (DA) [4 + 2]
B
cycloaddition reactions. In fact, a solvent such as benzene,
toluene, xylene, or 1,2-dichlorobenzene is often used as an
effectively inert solvent medium for DA reactions between other
pairs of diene/dienophile reactants. The energetic penalty of
dearomatization of the benzenoid ring is typically too costly to
permit it to participate in cycloaddition. o-Benzyne (1) and its
substituted derivatives comprise one of the very few classes of
dienophiles with sufficient reactivity to engage a benzenoid as a
diene. The first example of the reaction of 1,2-dehydrobenzene
(1) with benzene produced benzobarrelene (3a or 3b with X =
H) in ≤12% yield (along with biphenyl and benzo-
cycloctatetraene).1 This accentuates the inherent difficulty in
DA reactions of arenes, even when a highly energetic benzyne is
conscripted as the dienophile.
In 1977 Yoshida, Oda, and co-workers reported2 the relative
reactivity of 1 with several monosubstituted benzenoid
derivatives (i.e., 2) through sets of bimolecular competition
experiments (Scheme 1). The reactivity pattern was that more
electron-rich arenes reacted faster; however, the range of relative
rates varied only from ca. 15 for the fastest (anisole) to 1 for the
slowest (trifluoromethylbenzene). Anisole was also the only
trapping agent that showed a propensity to favor addition across
the C1/C4 positions of the arene ring (to give 3a); the other
derivatives favored formation of the C2/C5 adduct 3b. In all of
these experiments the aromatic trapping agents were used as the
solvent; the sole isolated yield reported (for the anisole case)
were 32% and 8% for 3a (X = OMe) and 3b (X = Me),
respectively.
reactive benzyne intermediates can be trapped in many useful
ways, including by reaction in a [4 + 2] Diels−Alder sense with
an aromatic benzenoid ring in either a bimolecular (e.g., 5 to 6)4
or unimolecular (e.g., 8 to 9)4,5 fashion. To understand in more
detail the influence on reactivity of substituents on the aromatic
ring acting in the role of the diene, we designed a substrate that
would pit two aromatic rings in competition for the benzyne
dienophile. Specifically, we have prepared and studied the
reactivity of a number of substrates of general structure 10,
having two aryl groups that bear substituents of differing
electronic character, yet otherwise were equally well-poised to
engage in intramolecular [4 + 2] trapping of the HDDA-
The cycloisomerization of triynes such as 4 (and 7) to give
benzynes such as 5 (and 8) by a simple thermal process3 has
considerable generality (Scheme 2).4 We have termed this
cyclization a hexadehydro-Diels−Alder (HDDA) reaction. The
Received: December 25, 2014
© XXXX American Chemical Society
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DOI: 10.1021/ol5037024
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HDDA reaction of a triynone similar to that of 10 is ca. 4 h at 85
°C.4 Accordingly, we heated each of 10a−f in an 80−85 °C bath
in a sealed vial containing a solution of the triyne for ca. 48 h in
CDCl3. This solvent has proven repeatedly to be inert toward
HDDA-generated benzynes, underscoring the fact that these
benzynes should not be considered to engage in reaction
processes that are radical in character. Analysis of the 1H NMR
spectra of the reaction mixture itself was used to judge the
product ratios in the cases where competitive reaction pathways
were detected.
Scheme 2. Examples of HDDA-Generated Benzynes Reacting
with Arenes Either (a) Bimolecularly or (b) Unimolecularly
and (c) the Substrates Designed for the Intramolecular
Competition Reactions Reported Here
The diphenyl-containing triyne 10a gave the trapped adduct
11a (Figure 1) in 70% yield following chromatographic
generated benzyne. The ratio of the constitutionally isomeric
products 11 (where X ≠ Y) formed upon heating 10 in an inert
solvent would then provide a direct indication of the impact of
substituents X vs Y on the rate of the intramolecular Diels−Alder
(IMDA) trapping reaction.
The substrates examined in this study were triynes 10a−f.
Their preparation by cross-coupling of the diyne 126 and
bromoalkynes 13 (derived from the known benzhydrol
derivatives 14) is outlined in Scheme 3 [see the Supporting
Information (SI) for details].
The rate-limiting step in the conversion of 10 to 11 (Scheme
2c) is the initial HDDA cycloisomerization reaction; the
subsequent Diels−Alder trapping event by the pendant arene
is relatively rapid. We have reported that the half-life for the
Scheme 3. General Route Used for the Synthesis of HDDA
Triyne Substrates 10
Figure 1. Products from competitive IMDA trapping within benzyne
intermediates 15, derived from 10a−f.
purification.7 Hence, a simple phenyl ring is an efficient and
competent trap for the benzyne intermediate (cf. 5, R =
CH2OCHAr1Ar2). The first substrate we studied with two
different pendant arenes was the mono-p-methoxy benzhydryl
ether 10b. It produced a single isolable IMDA adduct, namely,
11b-maj in 88% yield. We did not definitively detect the
isomeric, phenyl-trapped adduct 11b-min (1H NMR). Thus, the
more electron-rich arene is considerably more reactive (cf.
k
anisole/kbenzene = 8, Scheme 1).
We then studied the monocarbomethoxy monophenyl ether
10c. In this substrate an electron-poor arene is pitted against the
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parent phenyl ring. The major product in this case was the
phenyl-trapped adduct 11c-maj, isolated in 64% yield. The
minor component 11c-min was also isolated following careful
separation by HPLC (product ratio = 3.2:1 by 1H NMR analysis
of the reaction mixture). An interesting behavior was observed
for 11c-min (as well as for the analogous 11d and 11e, which also
contain a bridgehead carbomethoxy group). Several resonances
1
in both the H and 13C NMR spectra were broadened when
recorded at ambient temperature. We attributed this to slow
rotation about the bridgehead to carbonyl carbons in these
hindered esters. These resonances sharpened considerably when
the 1H spectrum was recorded at 100 °C (see SI), consistent with
this hindered rotation hypothesis. Similarly, when the bis-ester-
containing substrate 10d (or the monoester 10e) was heated (in
the dark, see below), only the primary Diels−Alder adduct 11d
(or 11e) was observed.
We also examined, in one instance, the effect of the
substitution pattern. Substrate 10f contains both a para- and
an ortho-methoxyphenyl substituent. When heated in 1,2-
dichloroethane at 85 °C for 2 days, 10f produced both 11f-maj
and the ketone 11f-min8 (8.8:1 ratio from 1H NMR analysis) in
89% and 5% isolated yield (MPLC separation). Oda et al.
reported facile in situ hydrolysis of a primary enol ether product
arising from anisole trapping to its ketone, the process we also
presume that gives rise to 11f-min. They also observed a similar
preference for formation of the bridgehead rather than the
alkenyl methoxylated isomer (cf. Scheme 1).
We examined whether DFT calculations are effective at
rationalizing the observed selectivities. Specifically, we have
computed the transition state (TS) structures for the competing
IMDA trapping reactions of the benzynes derived from 10b, 10c,
and 10f. These lead via TS15 (Figure 2a) to the major and minor
products of 11b, 11c, and 11f. Also given in Figure 2a are the
differences in computed free energy of activation (ΔΔG‡) along
with the associated computed and experimentally observed
product ratios. DFT does a good job of accounting for the
relative energies of the competing TS structures for the trapping
of the benzyne. The geometries of those TSs all indicated a high
degree of asynchroneity in these concerted IMDA reactions
(Figure 2b).
Figure 2. (a) DFT calculation [M06-2X/6-31G(d) with SMD
(chloroform)] of the relative TS energies for the competitive IMDA
reactions proceeding via TS15 to 11-maj vs 11 min. (b) DFT
geometries and relative energies for the TSs accounting for the
preferential formation of 11f-maj as well as the observed anti relative
configuration in 11f-min from 10f.
We were also successful in using DFT to account for the sense
of diastereoselectivity (i.e., anti) observed in the formation of
11f-min8 (cf. Figure 1). The TS TS15f-min-anti was favored by
1.8 kcal·mol−1 over the alternative TS15f-min-syn (Figure 2b),
presumably reflecting the greater steric congestion in the latter,
which possesses cis-(and endo)oriented methoxy and aryl
groups.
We observed that some of the IMDA products containing
bridgehead substituents on their benzobicyclo[2.2.2]octatriene
units underwent facile photoinduced rearrangement reactions
(Figure 3.). Either ambient laboratory light or exposure of a
chloroform solution to a 75 W incandescent light source was
sufficient to induce these changes in these typically yellow
fluorenone compounds. Specifically, the primary HDDA-IMDA
products 11c-min, 11d, and 11e gave rise via di-π-methane
rearrangement9 to the cyclopropane-containing products 16c,
16d, and 16e, respectively. Irradiation of 11f in CDCl3 produced
Figure 3. Di-π-methane rearrangement products from light-induced
transformations of the primary HDDA-IMDA products 11c-min, 11d,
11e, and 11f-maj.
Interestingly, products of trapping by a parent phenyl ring, i.e.
11a and 11c-maj, did not show evidence of the di-π-methane
rearrangement, likely reflecting the greater steric strain in those
dibenzobarrelenes having a non-hydrogen bridgehead substitu-
ent.
Finally, a pendant naphthalene substituent was shown to
efficiently capture the HDDA benzyne. Triyne 18 gave the
Diels−Alder adduct 19 in high yield following chromatographic
1
a structure whose H NMR spectrum was consistent with the
cyclopropane 16f, which, upon chromatographic purification on
silica gel, cleanly gave rise to the ketone 17f. The structure
assignments for 16c and 17f were confirmed by single crystal X-
ray analysis. The hydrogen locations in the renderings in Figure 3
are idealized, and some have been omitted for clarity.
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1
purification (Figure 4). The in situ H NMR spectrum of this
reaction mixture is indicative of the cleanliness of this
transformation.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: hoye@umn.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This investigation was supported by a grant awarded by the U.S.
Department of Health and Human Services (National Institute
of General Medical Sciences, GM-65597). Portions of this work
were performed with hardware and software resources available
through the University of Minnesota Supercomputing Institute
(MSI). T.W. acknowledges the support of a Wayland E. Noland
Fellowship and a University of Minnesota Graduate School
Doctoral Dissertation Fellowship. We thank Victor G. Young, Jr.
of the University of Minnesota for assistance with the X-ray
diffraction analysis.
REFERENCES
■
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Figure 4. 1H NMR spectrum of the product mixture produced directly
upon heating 18 in CDCl3 at 85 °C.
(6) Suffert, J.; Abraham, E.; Raeppel, S.; Bruckner, R. Liebigs Ann. 1996,
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447−456.
(7) We typically observed some amount of competitive cleavage of the
benzhydryl ether to its corresponding ketone (or benzylic ether to
aldehyde in the case of 10e). For 10a benzophenone itself was observed.
Although this byproduct formation reduced the overall yield of IMDA
products isolated from these experiments, it did not compromise our
ability to assess the relative propensity of two different arenes to
participate in the Diels−Alder trapping reactions. The IMDA products
do not further fragment to give these benzophenone derivatives.
(8) The relative configuration of the two stereocenters in 11f-min was
assigned on the basis of NOE experiments (see Supporting
Information).
In conclusion, we have studied intramolecular Diels−Alder
reactions between various pendent aromatic groups to trap
thermally generated benzynes. The arene functions as the 4π
dienic component, and the HDDA benzyne, as the 2π
dienophile. More electron-rich arenes are more reactive dienes,
consistent with the view of the benzyne as an electrophilic
partner. DFT calculations were effective in accounting for the
observed product ratios for three substrates containing two
different and competing arenes. The transition state structures
for these reactions show a substantial degree of asynchroneity
(Figure 2b). Adducts containing a bridgehead carbomethoxy
substituent show hindered rotation about the ester carbonyl to
the barrelene bridgehead C−C bond. Some of the initial Diels−
Alder adductsyellow, dibenzobarrelene, fluorenone-contain-
ing derivativesunderwent smooth di-π-methane rearrange-
ment when exposed to ambient light. Finally, a pendant
naphthalene substituent is a particularly effective diene.
Collectively these results provide guidance about what types of
substituents can be selected to enhance bimolecular Diels−Alder
trapping of arynes by structurally more complex arenes, a topic
that is under further study here.
(9) Liu, R. S. H.; Krespan, C. G. J. Org. Chem. 1969, 34, 1271−1278.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, characterization data, copies of 1H and
13C NMR spectra for all isolated compounds, ORTEP
renderings, and DFT computational methods. This material is
available free of charge via the Internet at http://pubs.acs.org.
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