Benzocyclobutadienes: An Unusual Mode of Access Reveals Unusual Modes of Reactivity

Article abstract of DOI:10.1002/anie.201803872

The reaction of an aryne with an alkyne to generate a benzocyclobutadiene (BCB) intermediate is rare. We report here examples of this reaction, revealed by Diels–Alder trapping of the BCB by either pendant or external electron-deficient alkynes. Mechanistic delineation of the reaction course is supported by DFT calculations. A three-component process joining the benzyne first with an electron-rich and then with an electron-poor alkyne was uncovered. Reactions in which the BCB functions in a rarely observed role as a 4π diene component in Diels–Alder reactions are reported. The results also shed new light on aspects of the hexadehydro-Diels–Alder reaction used to generate the benzynes.

Full text of DOI:10.1002/anie.201803872

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Accepted Article
Title: Benzocyclobutadienes: An unusual mode of access reveals
unusual modes of reactivity
Authors: Thomas R. Hoye, xiao xiao, and Brian P Woods
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Benzocyclobutadienes: An unusual mode of access reveals unusual
modes of reactivity
Xiao Xiao, Brian P. Woods, and Thomas R. Hoye*
Abstract: The reaction of an aryne with an alkyne to generate a
benzocyclobutadiene (BCB) intermediate is rare. We report here
examples of this reaction, revealed by Diels-Alder trapping of the
BCB by either pendant or external, electron-deficient alkynes.
Mechanistic delineation of the reaction course is supported by DFT
calculations. A three-component process joining a benzyne, first,
with an electron-rich and, then, an electron-poor alkyne was
uncovered. Reactions in which the BCB functions in a rarely
observed role as a 4 diene component in Diels-Alder reactions are
reported. The results also shed new light on aspects of the
hexadehydro-Diels-Alder reaction used to generate the benzynes.
Therefore, in the absence of a trapping reagent, we presume
that the HDDA-benzyne engages one of the several alkynes in
the substrate, generally in a non-selective fashion to generate a
host of BCB intermediates, resulting in intractable product
mixtures. Thus, we were surprised to observe that heating the
triyne 7 in the absence of any trapping partner gave one major
1
product ( H NMR spectrum of the crude product mixture)—the
dimer 8, which was isolated in 45% yield (Figure 1c). Five alkyne
units in two molecules of 7 had been transformed into a
naphthalene core bearing one tBu-ethynyl substituent. This
purely thermal process raises a number of intriguing mechanistic
questions.
o-Benzyne (1) and its analogs have been widely studied and
used in organic synthesis. The major classic reaction modes of
the distorted triple bond involve nucleophilic addition and [4+2]
or 1,3-dipolar cycloadditions.[1] Another highly reactive
intermediate benzocyclobutadiene (2, BCB) is not nearly as
explored due to its relative inaccessibility.[2] Moreover, reactions
of BCBs, once formed, are often not highly selective and give
rise to an array of products. In principle, BCB can be generated
by reaction of a benzyne with an alkyne via a net [2+2]
a) Benzocyclobutadiene formation via [2+2] of benzyne and alkyne
R2
R2
R2
[
2+2]
R1
(solvent)
R2
R1
1
2
R1
R1
N2
3 (1–29%)
6
examples
CO2
b) Examples of [2+2] of benzyne and ynolate
cycloaddition. However, reports of such transformations are
extremely rare.[3,4] This is surprising because the reaction of a
benzyne with an alkyne is computed to be significantly exergonic
Ar
R
R
4
OLi
(in situ)
OLi
R
benzyne
(x2)
Ar
Ar
O
Ar
HO
cf. 58.5 kcal•mol-1 for 9 to 10, Figure S1 in the SI) and to
Ar
(
F
nBuLi
THF
proceed with a low activation energy.[5] Therefore, the paucity of
reports of alkyne benzyne [2+2] reactions may reflect
5
6
1
(27–69%)
2 examples
+
c) Our initial experiment
O
inefficiency in the subsequent manifold of reactions into which
an initially formed BCB intermediate enters rather than inherent
difficulty in its generation. In the initial discovery, Stiles et al.
O
O
O
MeCN
tBu
(Figure
1a)
rationalized
the
formation
of
dibenzocyclooctatetraenes
3
by dimerization of BCB
tBu
130 °C
intermediates 2.[3] In the only other example of this type of
process to our knowledge, Shindo and Alabugin recently
reported the reaction of various benzynes with electron-rich
tBu
X-ray
7
O
8 (45%)
ynolates 4 to give triptycenes 6, which they proposed to arise via
initial formation of formal [2+2] adducts 5 (Figure 1b).[4]
Figure 1. Only previous examples of benzyne + alkyne net [2+2] cyclization (a,
b) and our first encounter: dimerization of 7 (c).
The hexadehydro-Diels–Alder (HDDA) reaction provides a
reagent-free and fully atom-economical method for producing a
benzyne intermediate from a poly-yne substrate,[6] which can be
immediately trapped by an in situ arynophile.[7] The formation of
benzyne is the rate-limiting step in an HDDA generation/trapping
cascade,[8] which means that the benzyne is present in only a
low steady-state concentration along with a larger amount of the
poly-yne precursor, depending upon the stage of conversion.
Our proposed mechanism for this unexpected transformation
is shown in Figure 2. The consumption of 7 proceeded with a
comparable half-life to that of a similar triyne substrate in a
typical HDDA cycloisomerization.[9] Thus, formation of the HDDA
benzyne 9 derived from triyne 7 presumably began the process.
To form the observed regioisomer of naphthalene 8, benzyne 9
would need to selectively undergo a [2+2] cycloaddition with one
of the three triple bonds in 7 and with a preference for one of two
possible orientations. This would produce the BCB intermediate
[
a]
X. Xiao, B. P. Woods, T. R. Hoye*
Department of Chemistry
University of Minnesota
1
0, which could then be trapped regioselectively in a [4+2]
cycloaddition as the 4 component by the intramolecularly
tethered propiolate dienophile to afford the hemi-Dewar
naphthalene 11. Intermediate 11 would be expected to rapidly
open to 8.[10]
2
07 Pleasant St. SE
Minneapolis, Minnesota 55455 USA
E-mail: hoye@umn.edu
Supporting information for this article is given via a link at the end of
the document.
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Figure 2. Proposed mechanism for dimerization of triyne
alkynylnaphthalene derivative 8.
7 to the
To explore some of the generality of the reaction, we
prepared a series of analogs of ester 7, differing in the
substituents at the termini of the diyne and diynophile (12,
Figure 3). Notably, a cyclopropyl group remains intact (13d),
presumably because the spin of the diradical intermediates is
substantially delocalized, thereby slowing the rate of the
potential ring-opening reaction.[11] Aryl substituents (13i–13o)
are compatible. The presence of a TMS group in the aryl-
substituted triynes led to improved yields and facilitated the
solubility and handling of some of the products. Some of the
products exhibited blue fluorescence upon exposure to a 365
nm light source (see SI for two examples).[12]
DFT calculations were performed to inform the mechanistic
thinking (Figure S1). Conversion of 7 to 9 is seen to be
-1 [9,13]
exergonic by 47.7 kcal•mol .
The reaction of 9 with a second
molecule of 7 to form the BCB intermediate 10 was seen to be a
stepwise net [2+2] cyclization proceeding through a diradical
S17).[
5],[14]
Because an alkyne is a strong radical-stabilizing
the lowest energy transition structure (TS) was
(
[15]
group,
Figure 3. Examples of dimerizations of ester-tethered triynes 12. [a] dr = 1:1.
computed to be that implied by arrows “a” (Figure 2). The
subsequent conversion of 10 to the hemi-Dewar naphthalene 11,
a formal Diels-Alder cycloaddition, was also computed to be
stepwise (cf. arrows “b”).[16] A TS for the concerted process was
located but found to have a 24.8 kcal•mol-1 higher barrier
compared to the diradical pathway. Finally, the fragmentation of
1
[
b] a small amount of a regioisomer (see SI for 13i’) was observed ( H NMR
analysis of the crude product mixture). [c] 140 °C, 48 h. [d] 150 °C, 24 h. TBS
tert-butyldimethylsilyl, TMS = trimethylsilyl, TIPS = triisopropylsilyl.
=
benzocyclobutadiene trapping stage in the homodimerization of
. Similarly, two faster-reacting poly-ynes were also tested with
7
1
1 was computed to afford naphthalene 8 via a low barrier TS
-1
the propiolate derivative 7d (Figure 4b); these gave rise to the
polyaromatic compounds (18, 20). The product fluorenone 18 is
noteworthy because it arises from a naphthyne intermediate,
formed by way of a domino-HDDA, double cycloisomerization[
of a pentayne precursor (see SI). Additionally (Figure 4c), the
propiolate diyne 7e captured the benzyne derived from 14a to
give 21, a product suggesting that the bulky mesityl substituent
had steered the intramolecularly linked propiolate to approach
the BCB in an unusual orientation (see the dashed line) to afford
a net [2+2+2] product along with a minor isomer that derives
from the normal pathway (ca. 5:1, see SI).
(9.2 kcal•mol ). Notably, the overall transformation that converts
the five CC bonds in two molecules of 7 to the naphthalene 8 is
-
1
computed to be 199 kcal•mol (!) exergonic.
17]
To bring additional light to bear on our hypothesized
mechanism, hetero-dimerization experiments were carried out.
The HDDA precursors 14a–d and triynes 7a–d (Figure 4a) have
the indicated mismatched half-lives for their rates of
cycloisomerization. We presumed that, when heated together at
8
0 °C, triyne 7 would remain essentially intact, while tetrayne 14
would cyclize to the benzyne 15. In the event, 15 was trapped by
to give 16a–d in a process paralleling the
7
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[
2
a] t1/2 = ca. 3 h @ 80 °C. [b] t1/2 = ca. 3 h @ 130 °C [c] Each of products 16c,
0, and 21 was accompanied by a minor regioisomer (see SI). [d] Yields are
for chromatographically purified compounds.
Figure 5. Three-component reactions: benzyne + electron-rich alkyne + BCB
“
dienophile”. Five equivalents of each (relative to the HDDA substrate) were
Figure 4. Hetero-dimer formation between a fast-reacting HDDA substrate
used in each experiment. DMAD = Dimethyl acetylenedicarboxylate.
(e.g., 14) and propiolate 7 and its analogs. Ms = methanesulfonyl.
2
4 gave 25b–d. Each of these reactions could have produced 8
We next hypothesized that an initial stepwise [2+2] reaction
constitutionally isomeric, 3-component adducts, but the only
such product observed (direct LC-MS analysis of the reaction
mixture) was that having the skeleton common to 25b–d.
between a benzyne and a simple alkyne (but one bearing a
radical stabilizing group) would also form a BCB intermediate,
which might then be trapped preferentially by a second,
electron-deficient alkyne. This was first demonstrated (Figure
a) in a three-component reaction involving the HDDA-precursor
2, the (relatively) electron-rich 2,4-hexadiyne (23a), and
electron-poor dimethyl acetylenedicarboxylate (24). The
naphthalene derivative 25a (38%) was produced; its structure
was assigned on the basis of nOe and HMBC analyses (see SI).
This reaction most likely proceeds through three reactive
intermediates: the benzyne 26, the BCB 27, and the hemi-Dewar
naphthalene 28. Similarly, we surmised that simple arylethynes
We then showed it is not essential to use an alkyne as the
electron-deficient BCB trapping agent for this transformation. For
example, reactions of 22 with 23a/23b in the presence, now, of
maleimide 29 as the third component led to dihydronaphthalene
products 25e/25f (Figure 5c). To demonstrate that these
reactions are not unique to only the benzyne 26, the ester-linked
triyne HDDA substrate 7d was also examined. When heated in
the presence of DMAD (24) and 2,4-hexadiyne (23a), this gave
25g (Figure 5d), the direct analog of product 25a. Interestingly,
when this reaction was performed in the absence of 24, a three
component product was still observed—namely, 25h. This 2:1
5
2
2
3b–d might also serve as effective initial alkyne traps for the
benzyne (Figure 5b). Indeed, heating 22 with one of 23b–d and
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adduct has incorporated two equivalents of 2,4-hexadiyne (23a)
and the benzyne from 7d. The regioselectivity of this process
supports the view that net [4+2] trapping of the BCB is a highly
asynchronous event with considerable diradical character—the
non-participating, second alkyne in 23a is a powerful radical
stabilizing group.[15]
trapping—namely, as a 4 component in DA reactions—was
also uncovered. This results in the production of alkynyl
naphthalene derivatives under purely thermal conditions. DFT
calculations support a stepwise formation of the BCB and guided
us in the design of several multicomponent reactions. These
results provide new mechanistic insights about thermal alkyne
chemistry.
Acknowledgements
This work was supported by the U.S. Dept. of Health and
Human Services [National Institute of General Medical Sciences
(R01 GM65597 then R35 GM127097)] and the National Science
Foundation (CHE-1665389). Computational work was made
possible by the University of Minnesota Supercomputing
Institute (MSI). Some of the NMR data were obtained with an
instrument funded by the NIH Shared Instrumentation Grant
program (S10OD011952). We thank Victor G. Young, Jr.
(University of Minnesota) for the X-ray diffraction analysis.
Conflict of interest
The authors declare no conflict of interest.
[
a] a small amount of a (symmetrical) regioisomer (see SI) was also observed.
Figure 6. A four-atom tether thwarts the HDDA reaction by allowing for faster
formation of the CB 32.
Keywords: benzocyclobutadiene • cyclization • benzyne • Diels–
Alder • alkyne cascades
[
1]
a) R. W. Hoffmann, Dehydrobenzene and Cycloalkynes; Organic
Finally, we have observed that the high, strain relief-driven
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formation.[18] In particular, when heated in the presence of
DMAD (24), the tetrayne 30 (Figure 6) gave the adducts 33a and
Chemistry; a Series of Monographs 11; Academic Press, New York, 1967; b)
J.-A. Garcia-López, M. F. Greaney, Chem. Soc. Rev. 2016, 45, 6766, and refs
3-16 therein to previous reviews.
[
2]
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a) M. P. Cava, M. J. Mitchell, Cyclobutadiene and Related Compounds;
3
3b as the only tractable products. These most likely arise from
a [4+2] reaction between the fused cyclobutadiene (CB) 32 and
4. It is surprising that the tetrayne 30, which contains a four-
[
2
[
atom tether between its internal alkynes, gives a CB to the
exclusion of a benzyne.[19] This is the first time we have gained
insight to why there is a nearly absolute requirement that HDDA
substrates contain a three-atom tether linking the diyne and
diynophile moities—a four-atom linker is more capable of
accommodating formation of a fused cyclobutadiene (cf. 32) and
the diradical (cf. 31) does so (black arrow) in preference to
cyclizing at the distal terminus of the propargylic radical (gray
arrow), even though the resulting benzyne is computed to be
[5]
[6]
K. J. Cahill, A. Ajaz, R. P. Johnson, Aust. J. Chem. 2010, 63, 1007.
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[
7]
a) T. R. Hoye, B. Baire, D. W. Niu, P. H. Willoughby, B. P. Woods,
Nature 2012, 490, 208; b) B. Baire, D. Niu, P. H. Willoughby, B. P. Woods, T.
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Diamond, T. B. Marder, Org. Chem. Front. 2017, 4, 891.
(
see SI) 30.5 kcal•mol-1 more stable than the isomeric CB 32.
Additionally, trapping of 32 with N-phenylmaleimide (34) was
explored. Initially, a mixture of multiple stereoisomeric products,
composing what we surmised to be 2:1 adducts from DA
reaction of the maleimide with 35, was observed. This
complication was avoided when the reaction was performed in
the presence of manganese dioxide, an oxidant that effectively
intercepted diene 35 by its conversion to the phthalimide 36.[20]
[
8]
a) B. P. Woods, B. Baire, T. R. Hoye, Org. Lett. 2014, 16, 4578; b) P. H.
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[
9]
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978, 111, 2563.
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D. J. Marell, L. R. Furan, B. P. Woods, X. Y. Lei, A. J. Bendelsmith, C. J.
[
In conclusion, we have described a series of polyalkyne
1
cascade
processes
via
benzocyclobutadiene
(BCB)
[
intermediates. These demonstrate the feasibility of generating
BCBs from certain (thermally generated) benzynes and
appropriate alkyne trapping partners. A rare mode of BCB
[
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[
13] a) A. Ajaz, A. Z. Bradley, R. C. Burrell, W. H. H. Li, K. J. Daoust, L. B.
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[
[
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075-y.
18] Related substrates that might have produced a fused CB have been
[
0
[
shown to proceed, instead, through a propargylic ene reaction, a process not
feasible for 30: a) S. Saaby, I. R. Baxendale, S. V. Ley, Org. Biomol. Chem.
2
005, 3, 3365; b) J. M. Robinson, T. Sakai, K. Okano, T. Kitawaki, R. L.
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2
006, 71, 8417.
19] As a control, 30 was heated in the presence of excess furan, an
excellent benzyne trap, and no evidence for benzyne formation was seen.
20] E. J. Corey, S. E. Lazerwith, J. Am. Chem. Soc. 1998, 120, 12777.
[
[
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COMMUNICATION
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Benzocyclobutadiene (BCB) has
been accessed via a [2+2]
X. Xiao, B. P. Woods, T.
R. Hoye*
cycloaddition of a benzyne and an
alkyne. The BCB generated by this
method exhibited rare reactivity—
namely, as a 4 component in a
Diels–Alder reaction to furnish highly
substituted polyaromatic compounds
as the product. DFT calculations
revealed many mechanistic details of
this cascade process.
Page No. – Page No.
Benzocyclobutadienes:
An unusual mode of
access reveals unusual
modes of reactivity
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