Boronate Ester Bullvalenes

Article abstract of DOI:10.1021/jacs.9b12930

Boronate ester bullvalenes are now accessible in two to four operationally simple steps. This unlocks late-stage diversification through Suzuki cross-coupling reactions to give mono-, di-, and trisubstituted bullvalenes. Moreover, a linchpin strategy enab

Full text of DOI:10.1021/jacs.9b12930

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Communication
Boronate Ester Bullvalenes
Harshal D Patel, Thanh-Huyen Tran, Christopher J. Sumby, Lukáš F. Pašteka, and Thomas Fallon
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b12930 • Publication Date (Web): 10 Feb 2020
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Journal of the American Chemical Society
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Boronate Ester Bullvalenes
a
a
a
b
a*
Harshal D. Patel, Thanh-Huyen Tran, Christopher J. Sumby, Lukáš F. Pašteka, and Thomas Fallon
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[
a] Department of Chemistry, The University of Adelaide, Adelaide, SA 5005, Australia
b] Department of Physical and Theoretical Chemistry and Laboratory for Advanced Materials, Faculty of Natural Sciences,
[
Comenius University, Ilkovičova 6, Bratislava, Slovakia.
*Corresponding author: thomas.fallon@adelaide.edu.au
Supporting Information Placeholder
ABSTRACT: Boronate ester bullvalenes are now
accessible in two to four operationally simple steps. This
unlocks late-stage diversification through Suzuki cross-
coupling reactions to give mono-, di-, and tri-substituted
bullvalenes. Moreover, a linchpin strategy enables
preprogrammed installation of two different substituents.
Analysis of solution phase isomer distributions and single
crystal X-ray structures reveals that isomer preference in
the crystal lattice is due to general shape selectivity.
In the 1960s the fluxional caged hydrocarbons were
1
discovered and intently studied. The canonical examples
2
3
4
are bullvalene, semibullvalene, and the barbaryl cation.
Bullvalene is extraordinary as the only stable organic
structure with the property of total degeneracy. Each of
the ten positions in the molecule exchange with every
other, and there are no permanent carbon-carbon bonds.
For
substituted
bullvalenes,
substituents
will
spontaneously explore all possible relative arrangements
and exist as a dynamic ensemble of isomers (Figure 1a).
For such an intriguing molecular scaffold, the synthetic
methods available to prepare and modify derivatives are
5
surprisingly limited. Schröder first prepared the parent
hydrocarbon in 1963 through a serendipitous two-step
6
sequence from cyclooctatetraene (COT). While this
method was scalable, it had no versatility and further
substitution was only achieved through low-yielding
bromination/elimination sequences (Figure 1b).7
Recently, Echavarren reported the preparation of
mono- and di-substituted bullvalenes using a modular
This revival of interest in shape-shifting molecules is
accompanied by a recognition of their potential in the
context of dynamic covalent chemistry and molecular
gold-catalysed oxidative cyclisation as the key step
8
(
Figure 1c). In a series of reports, Bode demonstrated the
synthesis of highly complex tetra-substituted bullvalenes.
10
devices. The foremost demonstration of these concepts
9
(
Figure 1d). However, this approach required relatively
is Bode’s use of a tetrasubstituted bullvalene as a dynamic
molecular sensor array for polyols. However, further
long synthetic sequences.
11
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Page 2 of 7
advances in this field demand more efficient synthetic
methods.
condensation with N-methyliminodiacetic acid to give the
corresponding ester 11.
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We recently reported a two-step approach to mono- and
di-substituted bullvalenes through [6+2] cycloaddition of
COT to alkynes followed by di-π-methane rearrangement
With this range of boronate ester BDTs in hand we
were delighted to find that the photochemical di-π-
methane rearrangement proceeded smoothly to give the
corresponding bullvalenes in good to excellent yields.
The use of inexpensive and operationally simple 365 nm
LED lamps together with 9H-thioxanthen-9-one as a
triplet sensitizer renders this transformation particularly
1
2
(
Figure 1e). While this represents the shortest synthetic
strategy to date, the substrate scope with respect to both
reaction steps was admittedly limited. We recognised the
overarching need for synthetic building blocks and
methodology that would allow for the modular late-stage
incorporation of desired substituents through versatile
and reliable chemistries. Boronate ester functionalised
bullvalenes became irresistible targets.
1
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rapid and convenient.
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In this communication we report the efficient synthesis
of a family of mono- di- and tri-substituted boronate ester
bullvalenes 1-4 (Figure 1f) and demonstrate their general
utility in Suzuki cross-coupling reactions. The
disubstituted bullvalene 3 incorporates a pinacol boronate
ester (Bpin) as well as an N-methyliminodiacetic acid
boronate ester (BMIDA) group. This linchpin enables
selective double Suzuki cross-coupling reactions. The
unparalleled versatility of this toolbox opens the way to
explore shape-shifting chemical behaviour in a wide
range of settings.
Suzuki cross-couplings gave access to a series of aryl
substituted bullvalenes, many of which are highly
crystalline. This allows for a comparative analysis of
isomer preference in solution and the solid state. Solution
phase population distributions were characterised through
low-temperature NMR experiments and compared with
the results of density functional theory (DFT)
calculations. The isomer population distributions follow
generally predictable lines. Single crystal X-ray analyses
reveal several examples whereby a minor solution phase
isomer is preferred in the crystal through what appears to
With this collection of boronate ester bullvalenes in
be “shape-selective” crystallisation phenomena
-
hand we set out to demonstrate their ease of use in Suzuki
whereby resolution of a dynamic ensemble of isomers to
a single isomer crystal is governed predominantly by
dispersion forces and effective packing, rather than
specific non-covalent interactions.
20
cross-coupling reactions.
Mono-Bpin-bullvalene 1
couples with a range of aryl bromides to give the
corresponding bullvalenes 13a-g in good to excellent
yields under simple and traditional catalytic conditions
(Scheme 2a). Bis-Bpin-bullvalene 2 couples with bromo
arenes to give diarylbullvalenes 14a-g under identical
reaction conditions (Scheme 2b).
The key to our synthetic strategy is the cobalt-catalysed
1
3
[
6+2] cycloaddition of alkynes with COT. This catalytic
system has emerged in the past two decades as a powerful
1
4
and versatile tool. Among the pioneering contributions
of Hilt are several examples of [4+2] cycloaddition
MIDA boronate esters have emerged as excellent
boronic acid masking group leading to effective linchpin
1
5
reactions involving alkynyl boronate esters. This
encouraging precedent suggested that mono-Bpin-
21
cross-coupling strategies. In the case of Bpin-BMIDA
-
bullvalene 3, the reactivity of the Bpin and BMIDA groups
can be cleanly differentiated with exclusive mono-
coupling with p-bromobenzotrifluoride to give 15 in
excellent yield (Scheme 3a). This was followed by a
second coupling with a small range of aryl bromides to
give differentially substituted diarybullvalenes 16a-c
(Scheme 3b). This strategy opens up a wide range of
possibilities for the targeted synthesis of fluxional
molecules.
1
6
acetylene 6 and bis-Bpin-acetylene 7 might be good
reaction partners in [6+2] cycloadditions with
cyclooctatetraene. Happily, this turned out to be true
providing
access
to
the
corresponding
bicyclo[4.2.2]deca-2,4,7,9-tetraenes (BDT) 9 and 10 in
good yield and on gram scale (Scheme 1). COT-Bpin 8,
prepared in two steps, undergoes [6+2] cycloaddition
with 7 to give reliable access to the tri-Bpin-BDT 12,
1
7
albeit in low yield. Bis-Bpin-BDT 10 was modified by
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coupling conditions,
Scheme 2. Suzuki cross-coupling of bullvalenes 1 and 2a
but
cleanly
furnished
1
2
3
4
5
6
7
8
9
Ar
Ar
triphenylbullvalene 17 in 71% yield (Scheme 3c).
Triphenylbullvalene was previously prepared by
Schröder and known to display intriguing dynamic
behaviour. In solution the major populated isomer is
isomer B. However, recrystallisation gives exclusively
the C symmetric isomer A, as confirmed by single crystal
X-ray analysis. Isomer A is also kinetically metastable
with an experimentally determined room-temperature
Bpin
a) Ar Br
2
other
isomers
22
1
isomer A
isomer B
exp. A/B: 72:28
calc. A/B: 93:6
X-ray: isomer A
3
CF3
NO2
22
solution half-life of 1h. The origin of this kinetic feature
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was explored in a recent study by our laboratory and
traced to high barriers in the first and second generation
isomerisation from isomer A. DFT analysis and kinetic
modelling of triphenylbullvalene predict an isomer A
half-life of 4.5 min (see SI for full details).
Scheme 3. Suzuki cross-coupling of bullvalenes 3 and 4a
23
1
3a, 81%
13b, 92%
13c, 94%
13d, 91%
exp. A/B: 80:20
exp. A/B: 72:28
calc. A/B: 72:26
exp. A/B: 78:22
calc. A/B: 89:11
X-ray: isomer A
exp. A/B: 79:21
calc. A/B: 93:7
X-ray: isomer A
calc. A/B: 87:13b
X-ray: isomer A
OMe
N
N
CF3
CF3
CF3
S
a)
Bpin
Br
b) Ar Br
13e, 81%
13f, 97%
13g, 76%
BMIDA
Ar
BMIDA
exp. A/B: 79:21
calc. A/B: 87:13
X-ray: isomer A
exp. A/B: 84:16
calc. A/B: 95:5
X-ray: isomer A
exp. A/B: 72:28
calc. A/B: 89:11
1: X-ray: isomer A
3
15, 97%
16a-c
CF3
CF3
CF3
Ar
Ar
Ar
Bpin
b) Ar Br
Bpin
12 other
isomers
Ar
S
N
Ar
Ar
2
isomer A
isomer B
isomer C
N
exp. A/B/C: 18:74:8
calc. A/B/C: 87:11:0
X-ray: isomer A
16a, 61%
16b, 76%
16c, 97%
exp. A/(B,B’)/C: 59:41:0
calc. A/(B,B’)/C: 96:4:0
exp. A/(B,B’)/C: 64:36:0
calc. A/(B,B’)/C: 97:3:0
exp. A/(B,B’)/C: 48:44:8
calc. A/(B,B’)/C: 89:10:0
X-ray: isomer B
X-ray: isomer A
CF3
NO2
R1
R1
R2
R1
R1
2
6 other
isomers
R2
R2
R2
isomer C
isomer A
isomer B
isomer B’
CF3
NO2
14a, 73%
14b, 46%c
14c, 89%
14d, 76%
exp. A/B/C: 51:39:10
calc. A/B/C: 94:6:0 calc.: 43:26:3
X-ray: isomer A
exp.: -
exp.: 52:40:8
calc.: 95:4:0
X-ray: isomer B X-ray: isomer A
exp.: -
calc.: 95:5:0
Bpin
Ph
c) PhBr
1%
OMe
7
Bpin
Bpin
Ph
Ph
N
N
4
17
S
exp. A/B/C: 0:40:60
calc. A/B/C: 51:35:3
exp. A/B/C: 25:48:27
calc. A/B/C: 23:74:2
S
N
1
7: X-ray: isomer A
R
R
R
RT solution t1/2 = 1h
OMe
N
R
R
14e, 42%
14f, 88%
14g, 65%
R
R
39 other
isomers
exp.: 60:40:0
calc.: 94:5:0
exp.: 66:29:5
calc.: 97:3:0
exp.: 37:53:10 2: X-ray: isomer A
calc.: 87:12:1
X-ray: isomer A
isomer A
isomer B
R
isomer C R
a
Reagents and conditions: (a) p-bromobenzotrifluoride (1.1 eq),
a
Reagents and conditions: (a) Ar-Br (1.1 eq), Pd(PPh ) (5 mol%),
o
3
4
Pd(PPh3)4 (5 mol%), Ag CO (1.5 eq), THF, 60 C. (b) Ar-Br (1.1
2 3
NaOH(aq), THF, 60 °C. (b) Ar-Br (2.2 eq), Pd(PPh3)4 (5 mol%),
NaOH(aq), THF, 60 °C. Single-point DFT calculations performed
at B3LYP-D3BJ/Def2-TZVPPD/CPCM solvent (chloroform) in
Orca.
bromotoluene.
eq), Pd(PPh3)4 (5 mol%), NaOH(aq), THF, 60 °C. (c) Ph-Br (3.3
eq), Pd(PPh3)4 (10 mol%), NaOH(aq), THF, 80 °C. Single-point
DFT calculations performed at B3LYP-D3BJ/Def2-TZVPPD/CPCM
solvent (chloroform) in Orca.
b
c
See ref 26. 2-iodotoluene used in place of 2-
The solution phase isomer population distributions of
most of the bullvalenes prepared herein was
experimentally determined using low temperature NMR
Tri-Bpin-bullvalene
bromobenzene under somewhat more forcing Suzuki
4 underwent coupling with
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Journal of the American Chemical Society
measurements.24 Population distributions follow
Page 4 of 7
Similarly, most disubstituted bullvalenes crystallise in
their major solution phase isomer. However, for bis-Bpin-
bullvalene 2, aryl disubstituted variants 14c, 14g, 16a,
and the trisubstituted 17, the inherent thermodynamic
preference is overturned, and crystallisation gives a minor
solution isomer. To guard against the possibility that
single crystal structures might not reflect the bulk solid
phase isomer preference, we recorded powder X-ray
diffraction (PXRD) data for compounds 2, 14c, 14d, 16a,
and 16c. Experimental data closely matches patterns
simulated from the single crystal structures (see SI for full
details).
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predictable patterns. Substituents generally prefer the
olefinic positions, with a slight preference for the
positions adjacent to the apical bridgehead. A DFT survey
of relative stabilities was conducted employing our
previously reported methods.12 The experimental and
computational ratios are expressed as A:B, A:B:C, or
A:(B,B’):C patterns (Schemes 2-4). The results are in
excellent agreement with experiment for monosubstituted
bullvalenes. For di- and tri-substituted bullvalenes
agreement with experiment is qualitative, but calculations
tend to somewhat overestimate the stability of isomer A.
This is likely an artefact of the intramolecular dispersion
interaction between the substituents.
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(a)
Diarylbullvalenes exist as dynamic ensembles of 15
isomers (homogeneous substituents) or 30 isomers
(
heterogeneous substituents), respectively. However,
most of their time is spent within the A:B:C set of
favoured isomers. Network analysis of
diphenylbullvalene 14a exemplifies this character (Figure
). The network graph represents nodes as isomers and
14a: isomer A
14d: isomer A
14g: isomer A
2
edges as transitions structures; all colour coded according
to calculated relative energy. The A:B:C set of isomers
are closely interconnected through a low energy
isomerisation path and will be in rapid equilibrium at
ambient temperature.
14c: isomer B
16a: isomer B
16c: isomer A
(b)
60.1 kJ.mol-1
Ph
61.4 kJ.mol-1
55.7 kJ.mol-1 Ph
E
Ph
Ph
Ph
Ph
Ph
8.3 kJ.mol-1
1
Ph
6.3 kJ.mol-1
isomer B
9.9 kJ.mol-1
isomer C
0
kJ.mol-1
isomer A
16c: isomer A
16a: isomer B
Figure 3. (a) Single crystal X-ray structures of diarylbullvalenes.
b) Hirshfeld surface analysis. Single crystal X-ray structures of
4
6
TS
91
49
(
ent-B
diarybullvalenes (grey – C, white – H, blue – N, red – O, and
yellow – F). Hirshfield surface analysis for 16c and 16a with
selected contacts highlighted. Regions of close contact
significantly closer than the sum of their respective van der Waals
radii are shown in red.
0
GS
kJ.mol
-1
.
Figure 2. Network analysis of diphenylbullvalene 14a. Single-
point DFT calculations performed at B3LYP-D3BJ/Def2-
TZVPPD/CPCM solvent (chloroform) in Orca.
Diarylbullvalenes 16a and 16c provide an intriguing
comparison. They are structurally very similar, differing
only in the exchange of a phenyl group with a pyrimidine
group, and would be expected to adopt nearly identical
shapes. 16c follows the solution preference and
recrystallises into the V-shaped isomer A in which the
pyrimidine group of one molecule intercalates within the
cleft of an adjacent molecule. The two molecules
involved in this solid state dimer appear to be stabilised
McGonigal recently reported
a
study on the
crystallisation behaviour of substituted barbaralanes –
shape-shifting hydrocarbons that exist as bistable
2
5
dynamic ensembles. Detailed analysis using a range of
experimental and computational techniques led to the
conclusion that crystallisation into a minor barbaralane
solution phase isomer is due to general shape-selectivity
rather than specific non-covalent interactions. Similar
phenomena seem to play out herein for aryl substituted
bullvalenes.
by weak C-H···π (D
stacking interactions (D
= 2.62 Å) and offset π-
H-π(centroid)
2
7
= 4.00 Å). The
π(centroid)-π(centroid)
Single-crystal X-ray structures were obtained for
bullvalenes 1, 2, 13c, 13d, 13e, 13f, 14a, 14c, 14d, 14g,
16a, 16c, 17, and 18 (selection shown in Figure 3a). For
the monosubstituted bullvalenes, all compounds except
latter is reasonable as pyrimidine has a reasonably large
dipole moment and in the A-type crystal, these dipoles are
in an antiparallel orientation adding an additional
electrostatic stabilization to the π-stacking. In contrast,
2
6
18 crystallise as the major solution phase isomer A.
1
6a (as well as 14c) crystallise into the more elongated
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Journal of the American Chemical Society
isomer B, contrary to the solution preference. In this case
1
2
3
4
5
6
7
8
9
the broad cleft of one molecule encompasses the
bullvalene core structure of an adjacent molecule.
Curiously, no dominating intermolecular interactions
appear to account for the stability of this crystal form
despite its deviation from the preferred solution isomer; a
bullvalene C-H···F contact (DH-F = 2.48 Å) appears to be
the most significant contact.
Disubstituted bullvalenes 2, 14a, 14d, and 14g all
crystallise in the V-shaped isomer A, for which only 14a
1
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(phenyl substituents) and 14g (pyrimidine) adopt the
intercalated dimer arrangement seen for 16c. Presumably
isomer A in 2 and 14d are prevented from close approach
due to steric bulk and lack of an acidic CH for a weak C-
H···π contact, respectively. Diphenylbullvalene 14a
exhibits polymorphism between our single crystal
2
8
structure, and that previously recorded by Echavarren.
Both structures are in the V-shaped isomer A, yet differ
in the relative orientation of one of the phenyl groups.
Consequently, our structure of 14a adopts the intercalated
dimer arrangement whereas Echavarren’s does not.
Returning to the synthetic implications of this study, we
wished to demonstrate the general utility of building
blocks 1-4 beyond the scope of Suzuki cross-coupling
reactions. Mono-Bpin-bullvalene 1 was subjected to a
selection of transformations (Scheme 4). Chan-Lam
The intriguing crystallisation behaviour of substituted
bullvalenes prompted us to holistically explore the
packing arrangements computationally. For all di- and tri-
substituted bullvalene crystal structures, the Hirshfeld
3
1
cross-coupling with imidazole furnishes bullvalene 18.
Simple oxidation with hydrogen peroxide smoothly gives
2
9,30
surfaces
were calculated. This analysis highlights
3
2
bullvalone 19. Rhodium-catalysed 1,2- and 1,4-addition
regions where intermolecular distances are significantly
closer than the sum of their respective van der Waals
radii. The results are illustrated for compounds 16c and
16a (Figure 3b). Aside from the interactions noted above,
only weak intermolecular interactions govern the
packing. This conclusion is supported by DFT modelling
(CE-B3LYP**) of the intermolecular interaction energies
for clusters of bullvalenes 2, 14a, 14c, 14d, 14g, 16a, 16c,
reactions to benzaldehyde and cyclohexenone gives
3
3
bullvalenes 20 and 21, respectively. Despite their
attachment to a constantly metamorphosing core
structure, the reactivity of the pinacol boronate ester
appears to be robust and reliable.
In summary, this work provides the first practical and
general synthetic platform to prepare mono-, di-, and tri-
substituted bullvalenes. Our boronate ester bullvalenes 1-
4 are easy to make and have predictable reactivities. Bpin-
3
0
and 17. In all cases, the total interaction lattice energy is
dominated by the dispersion energy contribution (see SI
for full details). Spontaneous resolution of these
ensembles in the crystal lattice appears to be governed by
general shape-selectivity, which can override the inherent
thermodynamic preferences observed in solution.
BMIDA-bullvalene 3 is an effective linchpin enabling the
logical synthesis of differentially disubstituted
bullvalenes. We hope that these methods will spur further
research and applications based on this most enigmatic
hydrocarbon.
ASSOCIATED CONTENT
Supporting Information. The Supporting Information is
available free of charge on the ACS Publications website.
Experimental procedures and supporting figures with
additional data (PDF).
AUTHOR INFORMATION
Corresponding Author
Thomas Fallon, thomas.fallon@adelaide.edu.au
Funding Sources
We gratefully acknowledge the New Zealand Royal Society
(Marsden Fund No. 15-MAU-154). Calculations were
performed using the supercomputing infrastructure of the
Computing Center of the Slovak Academy of Sciences
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acquired in project ITMS 26230120002 and 26210120002
supported by the Research & Development Operational
Programme funded by the ERDF. LFP is grateful for the
support from the Slovak Research and Development Agency
(grant No. APVV-15-0105) and the Scientific Grant Agency
of the Slovak Republic (grant No. 1/0777/19). CJS
acknowledges the Australian Research Council for
equipment provided under grant LE0989336.
(12) Yahiaoui, O.; Pašteka, L. F.; Judeel, B.; Fallon, T. Synthesis
and analysis of substituted bullvalenes. Angew. Chem. Int. Ed. 2018,
7, 2570–2574.
13) (a) Achard, M.; Mosrin, M.; Tenaglia, A.; Buono, G. Cobalt(I)-
catalyzed [6+2] cycloadditions of cyclooctatetra(tri)ene with alkynes.
J. Org. Chem. 2006, 71, 2907–2910. (b) D’yakonov, V. A.; Kadikova,
G. N.; Dzhemileva, L. U.; Gazizullina, G. F.; Ramazanov, I. R.;
Dzhemilev, U. M. J. Cobalt-catalyzed [6 + 2] cycloaddition of alkynes
with 1,3,5,7-cyclooctatetraene as a key element in the direct
construction of substituted bicyclo[4.3.1]decanes. Org. Chem. 2017,
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4
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5
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REFERENCES
(14) For reviews, see: (a) Hess, W.; Treutwein, J.; Hilt, G. Synthesis
008, 2008, 3537–3562. (b) Gandeepan, P.; Cheng, C.-H. Cobalt
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(1) (a) H. Hopf, Classics in Hydrocarbon Chemistry, Wiley‐VCH,
Weinheim, 2000. (b) G. A. Olah, Á. Molnár, Hydrocarbon Chemistry,
catalysis involving π components in organic synthesis. Acc. Chem. Res.
015, 48, 1194–1206. (c) Röse, P.; Hilt, G. Cobalt-catalysed bond
formation reactions; part 2. Synthesis 2016, 48, 463–492.
15) The catalytic system used in Hilt’s [4+2] cycloadditions of
alkynyl boronate esters is analogous to the catalytic system reported in
6+2] cycloadditions. For selected works by Hilt see: (a) Hilt, G.;
2
2
nd Edition, Wiley‐VCH, Weinheim, 2003.
2) von E. Doering, W.; Roth, W. R. A rapidly reversible degenerate
cope rearrangement: Bicyclo[5.1.0]octa-2,5-diene. Tetrahedron 1963,
(
(
1
9, 715–737.
[
(3) Zimmerman, H. E.; Grunewald, G. L. The chemistry of
barrelene. III. A unique photoisomerization to semibullvalene. J. Am.
Chem. Soc. 1966, 88, 183–184.
Smolko, K. I. Alkynylboronic esters as efficient dienophiles in cobalt-
catalyzed diels–alder reactions. Angew. Chemie Int. Ed. 2003, 42,
2
795–2797. (b) Hilt, G.; Lüers, S.; Smolko, K. I. A two-step reaction
sequence for the syntheses of tetrahydronaphthalenes. Org. Lett. 2005,
, 251–253. (c) Auvinet, A.-L.; Harrity, J. P. A.; Hilt, G. J. Ambient-
(4) (a) Barborak, J. C.; Daub, J.; Follweiler, D. M.; Schleyer, P. von
R. Degenerate rearrangements of the 9-barbaralyl cation. J. Am. Chem.
Soc. 1969, 91, 7760–7761. (b) Ahlberg, P.; Harris, D. L.; Winstein, S.
Direct observation of the totally degenerate 9-barbaralyl cation and the
bicyclo[4.3.0]nonatrienyl cation, a 1,4-bishomotropylium ion. J. Am.
Chem. Soc. 1970, 92, 4454–4456.
7
temperature cobalt-catalyzed cycloaddition strategies to aromatic
boronic esters. Org. Chem. 2010, 75, 3893–3896.
(16) Mono-Bpin-acetylene 6 and bis-Bpin-acetylene 7 are both
commercially available. See the SI for details on their preparation.
(17) The use of alkynyl boronate esters, in particular bis-Bpin-
acetylene 7, under these cobalt-catalysed reaction conditions was
initially capricious and required extensive optimisation. We found that
stringent purification and drying of all of the reaction components is
necessary in order to suppress proto-deborylation of the substrate (see
(5) For a recent review, see: Ferrer, S.; Echavarren, A. M. Synthesis
of bullvalenes: Classical approaches and recent developments.
Synthesis 2019, 51, 1037–1048.
(6) (a) Schröder, G. Preparation and properties of
tricyclo[3,3,2,04,6]deca-2,7,9-triene (bullvalene). Angew. Chem. Int.
Ed. Engl. 1963, 2, 481–482. (b) Schröder, G. Synthese und
eigenschaften von tricyclo[3.3.2.04.6]deca‐2.7.9‐trien (bullvalen).
Angew. Chem. 1963, 75, 722–722. (c) Schröder, G. Synthese und
I
SI for full details). Proto-deborylation of bis-Bpin-acetylene 7 in a Co
catalysed [2+2+2] cycloaddition has been reported, see: Iannazzo, L.;
Vollhardt, K. P. C.; Malacria, M.; Aubert, C.; Gandon, V.
4
.6
2.3)
eigenschaften von tricyclo[3.3.2.0 ]decatrien-(2.7.9) (bullvalen).
I
I
Alkynylboronates and ‐boramides in Co ‐ and Rh ‐catalyzed [2+2+2]
cycloadditions: Construction of oligoaryls through selective suzuki
couplings. Eur. J. Org. Chem. 2011, 2011, 3283–3292.
Chem. Ber. 1964, 97, 3140–3149.
(7) (a) Schröder, G.; Merenyi, R.; Oth, J. F. M. Moleküle mit
schneller und reversibler valenzisomerisierung.II: Synthese und
eigenschaften von brombullvalen und tert-butyl-bullvalyläther.
Tetrahedron Lett. 1964, 5, 773–777. (b) Oth, J. F. M.; Merényi, R.;
Engel, G.; Schröder, G. Synthese und nmr-spektroskopisches verhalten
zweier disubstituierter bullvalene. Tetrahedron Lett. 1966, 7, 3377–
(18) This reaction was selective for mono-condensation.
(19) Williams, J. D.; Nakano, M.; Gérardy, R.; Rincón, J. A.; de
Frutos, Ó.; Mateos, C.; Monbaliu, J.-C. M.; Kappe, C. O. Finding the
perfect match: A combined computational and experimental study
toward efficient and scalable photosensitized [2 + 2] cycloadditions in
flow. Org. Process Res. Dev. 2019, 23, 78–87.
3
382.
8) Ferrer, S.; Echavarren, A. M. Synthesis of barbaralones and
bullvalenes made easy by gold catalysis. Angew. Chem. Int. Ed. 2016,
5, 11178–11182.
9) (a) Lippert, A. R.; Keleshian, V. L.; Bode, J. W. Dynamic
(
(
20) Stille couplings of triflate substituted bullvalene have been
reported by Echavarren, see ref 8.
21) Gillis, E. P.; Burke, M. D. Iterative cross-coupling with MIDA
5
(
(
boronates: Towards a general platform for small molecule synthesis.
Aldrichimica Acta 2009, 42, 17–27.
supramolecular complexation by shapeshifting organic molecules.
Org. Biomol. Chem. 2009, 7, 1529–1532. (b) Lippert, A. R. Naganawa,
A. Keleshian, V. L. Bode, J. W. Synthesis of phototrappable shape-
shifting molecules for adaptive guest binding. J. Am. Chem. Soc. 2010,
(
22) Rebsamen, K.; Röttele, H.; Schröder, G. Mono-, di-, tri-, tetra-
penta-und hexaphenylbullvalene. Chem. Ber. 1993, 126, 1429–1433.
23) Yahiaoui, O.; Pašteka, L. F.; Blake, C. J.; Newton, C. G.;
,
(
1
32, 15790–15799. (c) He, M.; Bode, J. W. Racemization as a
Fallon, T. Network analysis of substituted bullvalenes. Org. Lett. 2019,
21, 9574–9578.
stereochemical measure of dynamics and robustness in shape-shifting
organic molecules. PNAS. 2011, 108, 14752–14756. (d) Larson, K. K.;
He, M.; Teichert, J. F.; Naganawa, A.; Bode, J. W. Chemical sensing
with shapeshifting organic molecules. Chem. Sci. 2012, 3, 1825–1828.
o
(24) Low temperature NMR measurements were made at -60 C. In
some cases, population analysis was precluded due to poor solubility
(
3, 14d), or severe signal overlap and/or restricted single bond rotation
effects (14b, 15, 21).
25) Bismillah, A. N.; Sturala, J.; Chapin, B. M.; Yufit, D. S.;
(e) He, M.; Bode, J. W. E pluribus unum: isolation, structure
determination, network analysis and DFT studies of a single metastable
structure from a shapeshifting mixture of 852 bullvalene structural
isomers. Org. Biomol. Chem. 2013, 11, 1306–1317.
(10) For recent reviews, see: (a) Rowan, S. J.; Cantrill, S. J.; Cousins,
G. R. L.; Sanders, J. K. M.; Stoddart, J. F. Dynamic covalent chemistry.
Angew. Chem. Int. Ed. 2002, 41, 898–952. (b) Corbett, P. T.; Leclaire,
J.; Vial, L.; West, K. R.; Wietor, J.-L.; Sanders, J. K. M.; Otto, S.
Dynamic combinatorial chemistry. Chem. Rev. 2006, 106, 3652–3711.
(c) Jin, Y.; Yu, C.; Denman, R. J.; Zhang, W. Recent advances in
dynamic covalent chemistry. Chem. Soc. Rev. 2013, 42, 6634–6654.
(
Hodgkinson, P.; McGonigal, P. R. Shape-selective crystallisation of
fluxional carbon cages. Chem. Sci. 2018, 9, 8631–8636.
(
26) Echavarren reported the single X-ray crystal structure of 13a
CCDC 1487024), see ref 8.
27) Martinez, C. R.; Iverson, B. L. Rethinking the term “pi-
stacking”. Chem. Sci. 2012, 3, 2191–2201.
28) For Echavarren’s crystal structure of 14a (CCDC 1487025), see
ref 8.
(
(
(
(29) (a) Spackman, M.A.; McKinnon, J.J. Fingerprinting
(11) Teichert, J. F.; Mazunin, D.; Bode, J. W. Chemical sensing of
intermolecular interactions in molecular crystals. CrystEngComm
polyols with shapeshifting boronic acids as a self-contained sensor
array. J. Am. Chem. Soc. 2013, 135, 11314–11321.
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Page 7 of 7
Journal of the American Chemical Society
2
002, 4, 378–392. (b) Spackman M. A.; Jayatilaka, D. Hirshfeld
surface analysis. CrystEngComm 2009, 11, 19.
30) All calculations were performed using the CrystalExplorer
software package, version 17.5. http://crystalexplorer.scb.uwa.edu.au
last accessed 22/11/2019)
31) Vantourout, J. C.; Miras, H. N.; Isidro-Llobet, A.; Sproules, S.;
Klumpp, G.; Rubin, R. M.; Saunders, M. A rational synthesis of
bullvalene barbaralone and derivatives; bullvalone. Tetrahedron 1967,
23, 3943–3963.
1
2
3
4
5
6
7
8
9
(
(33) (a) Zhang, C.; Yun, J. Rh-catalyzed addition of β-carbonyl
pinacol alkylboronates to aldehydes: Asymmetric synthesis of γ-
butyrolactones. Org. Lett. 2013, 15, 3416–3419. (b) Simmons, E. M.;
Mudryk, B.; Lee, A. G.; Qiu, Y.; Razler, T. M.; Hsiao, Y. Development
of a kilogram-scale process for the enantioselective synthesis of 3-
isopropenyl-cyclohexan-1-one via Rh/DTBM-SEGPHOS-catalyzed
asymmetric hayashi addition enabled by 1,3-diol additives. Org.
Process Res. Dev. 2017, 21, 1659–1667.
(
(
Watson, A. J. B. Spectroscopic studies of the chan–lam amination: A
mechanism-inspired solution to boronic ester reactivity. J. Am. Chem.
Soc. 2017, 139, 4769–4779.
(32) This 3-step procedure constitutes the shortest synthesis of
bullvalone to date. For the original work on bullvalone, see: W. von E.
Doering, W.; Ferrier, B. M.; Fossel, E. T.; Hartenstein, J. H.; Jones, M.;
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2
2
2
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3
3
3
3
3
3
3
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4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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1
2
3
4
5
6
7
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