Overcoming Strain-Induced Rearrangement Reactions: A Mild Dehydrative Aromatization Protocol for Synthesis of Highly Distorted p-Phenylenes

Article abstract of DOI:10.1021/jacs.6b00538

A series of p-terphenyl-based macrocycles, containing highly distorted p-phenylene units, have been synthesized. Biaryl bonds of the nonplanar p-terphenyl nuclei were constructed in the absence of Pd-catalyzed or Ni-mediated cross-coupling reactions, usin

Full text of DOI:10.1021/jacs.6b00538

Subscriber access provided by UNIV OF CALIFORNIA SAN DIEGO LIBRARIES
Article
Overcoming Strain-Induced Rearrangement Reactions: A Mild Dehydrative
Aromatization Protocol for the Synthesis of Highly Distorted para-Phenylenes
Nirmal K. Mitra, Rolande Meudom, Hector H. Corzo, John D. Gorden, and Bradley L. Merner
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b00538 • Publication Date (Web): 11 Feb 2016
Downloaded from http://pubs.acs.org on February 11, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 13
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Overcoming Strain-Induced Rearrangement Reactions: A Mild De-
hydrative Aromatization Protocol for the Synthesis of Highly Dis-
torted para-Phenylenes
Nirmal K. Mitra, Rolande Meudom, Hector H. Corzo, John D. Gorden, and Bradley L. Merner*
Auburn University, Department of Chemistry and Biochemistry, Auburn, AL 36849, United States
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
KEYWORDS: macrocycles, bent paraꢀphenylenes, benzenoid, aromatization, Burgess reagent
ABSTRACT: A series of pꢀterphenylꢀbased macrocycles, containing highly distorted paraꢀphenylene units, have been synthesized.
The biaryl bonds of the nonplanar pꢀterphenyl nuclei were constructed in the absence of Pdꢀcatalyzed or Niꢀmediated crossꢀ
coupling reactions, using 1,4ꢀdiketones as surrogates to strained arene units. A streamlined synthetic protocol for the synthesis of
1,4ꢀdiketo macrocycles has been developed, using only 2.5 mol% of the HoveydaꢀGrubbs secondꢀgeneration catalyst in both meꢀ
tathesis and transfer hydrogenation reactions. Under protic acidꢀmediated dehydrative aromatization conditions, the central and
most strained benzene ring of the pꢀterphenyl systems was susceptible to rearrangement reactions. To overcome this, a dehydrative
aromatization protocol using the Burgess reagent was developed. Under these conditions, no strainꢀinduced rearrangement reacꢀ
tions occur, delivering paraꢀphenylene units with up to 28.4 kcal/mol of SE and deformation angles that sum up to 40°.
INTRODUCTION
The formation of biaryl bonds via transition metalꢀcatalyzed,
or mediated, crossꢀcoupling reactions are venerable transforꢀ
mations in organic synthesis.1 A plethora of conditions, modiꢀ
fications, and optimizations have been reported over the past
30 years,1a and the presence of biaryl systems in natural prodꢀ
ucts,2 important pharmaceuticals,3 axially chiral molecules,4
and designed molecules relevant to materials science5 has inꢀ
stigated a tireless interest in this area of synthetic method deꢀ
velopment.6 Thus, it is surprising to find that such methods
have not enjoyed widespread applicability in the synthesis of
macrocyclic systems that contain areneꢀbridged units as they
have in the synthesis of acyclic (linear) areneꢀarene, or polyꢀ
aryl systems. In fact, biaryl bond formation that results in the
construction of strained macrocyclic compounds has proven to
be a significant challenge for chemical synthesis.7 One of the
main problems posed by the synthesis of macrocyclic areneꢀ
bridged systems is the build up of strain in carbonꢀcarbon (Cꢀ
C) bond forming reactions that furnish the intended targets. In
particular, if the desired crossꢀcoupling reaction requires bendꢀ
ing the arene, or multiple arene, unit(s), lowꢀyielding reactions
result (mode 1, Figure 1a).7 Furthermore, if areneꢀarene bond
formation requires stretching or elongating CꢀC bonds within
an alkyl chain upon macrocycle formation, the corresponding
macrocyclization can be energetically prohibitive (mode 2,
Figure 1a). Recently, arylation reactions that avoid crossꢀ
coupling reaction partners have emerged as powerful tools for
assembling strained macrocyclic systems.8
Figure 1. (a) Strain inducing carbonꢀcarbon bond forming
The synthesis of distorted benzene rings has been
reactions; (b) biaryl bond formation using a macrocyclic 1,4ꢀ
ongoing for over 65 years,9 and the quest to synthesize the
diketone surrogate and a mild dehydrative aromatization reacꢀ
most perturbed cyclic 6π system culminated with kinetically
tion
stabilized [4]paracyclophane derivatives in 2003.10 However,
this field of chemical synthesis has remained quite vigorous
over the past decade. The discovery of natural products conꢀ
bottom–up chemical synthesis of carbon nanotubes (CNTs)12
taining highly strained paraꢀphenylene subunits, particularly
the haouamine alkaloids,11 and the notion that macrocyclic
benzenoid hydrocarbons may serve as templates in the
has kept the level of interest in new synthetic method develꢀ
opment high. It is noteworthy that in both of the aforemenꢀ
tioned examples, the bent paraꢀphenylene units are part of
biaryl macrocyclic systems. The most distorted benzene rings
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 13
to be characterized by Xꢀray crystallography belong to the interesting sizeꢀdependent, diastereoselective Grignard reacꢀ
1
2
3
4
5
6
7
8
paracyclophanes. In the case of Tobe’s [6]paracylophane deꢀ
rivative 113 and Tsuji’s [1.1]paracyclophane 2,14 the highly
distorted piꢀsystems were obtained upon valence isomerization
of Dewar benzene precursors (Figure 2). For a long time,
valence isomerization reactions were viewed as the ultimate
method for synthesizing severely distorted aromatic systems.
In the case of the Dewar benzenes, rupture of the central CꢀC
bond in the bicyclo[2.2.0]hexaꢀ2,5ꢀdiene system brought about
a release of strain energy (SE) upon destruction of the bicyclic
intermediate, and a gain in aromatic stabilization energy
(ASE) upon forming the arene system. Until 2014, no bent
paraꢀphenylene ring with an α angle greater than 15° had been
synthesized using a nonꢀvalence isomerization approach. The
pioneering contributions from the groups of Bertozzi15 Itami,16
Yamago,17 and Jasti18 on the [n]cycloparaphenylenes rejuveꢀ
nated this area of chemical synthesis, in the context of strained
(macrocyclic) benzenoid nanohoops. The 2014 syntheses of
[5]CPP19,20 (3) reꢀwrote the record books for the smallest
[n]CPP homologue. With an average mean plane deviation
angle (α) of 15.6° and a total SE of 119 kcal/mol (ca. 24
kcal/mol per benzene ring), [5]CPP is by far the most strained
of the carbon nanohoops yet to be synthetized. The synthesis
of this impressive nanostructure, and related homologs, has led
to the development of powerful aromatization strategies that
employ reductive (aromatization) protocols and not valence
isomerization reactions (Figure 2).
tion of vinylmagnesium chloride with macrocyclic 1,4ꢀdiones,
a new mild dehydrative aromatization protocol for the syntheꢀ
sis of highly strained paraꢀphenylenes that are part of a polyꢀ
aryl system, the Xꢀray crystal structure of the most distorted
homolog, and the computed SE of this compound
RESULTS AND DISCUSSION
Streamlined Synthesis of Macrocyclic 1,4-diketones. The
synthesis of macrocyclic 1,4ꢀdiketones, that are also
[n.4]metacyclophanes, was unknown when we began our synꢀ
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
thetic
investigations
on
the
1,nꢀdioxa[n](3,3'')pꢀ
terphenylophanes. The firstꢀgeneration approach to these benꢀ
zenoid macrocyclic systems involved a threeꢀstage synthetic
process that commenced with an acyclic dialdehyde (9,
Scheme 1). The conversion of 9 to macrocyclic ketone 15 was
accomplished over four steps, which required purification of
three synthetic intermediates.21 Upon scaling up this process, it
was discovered that hydrogenation of the undesired olefin
diastereomer (12) resulted in the production of a benzylic deꢀ
oxygenation product (ca. 15%) 18. To circumvent this byꢀ
product formation and streamline the fourꢀstep process to furꢀ
nish gramꢀscale quantities of a homologous series of macrocyꢀ
clic 1,4ꢀdiones, we explored alternative hydrogenation protoꢀ
cols. Inspired by the recent report of sequential ringꢀclosing
metathesis (RCM) and transfer hydrogenation reactions by
Peese and coꢀworkers,22 using the HoveydaꢀGrubbs secondꢀ
generation (HꢀG II) catalyst, we designed a synthetic sequence
that would facilitate the synthesis of macrocyclic 1,4ꢀ
diketones from acyclic dialdehydes without purification of any
intermediates. Indeed, treatment of dialdehydes 8ꢀ10 with
vinylmagnesium chloride, followed by a HꢀG IIꢀmediated
macrocyclic RCM reaction at 15 mM concentration in diꢀ
chloromethane afforded 11ꢀ13 as mixtures of alkene diastereꢀ
omers, in which the transꢀconfigured (undesired) olefin was
Scheme 1. Streamlined, scalable synthesis of macrocyclic 1,4ꢀ
diones 11-13
Figure 2. Valence isomerization and reductive aromatization
strategies to highly distorted paraꢀphenyleneꢀcontaining moleꢀ
cules
Recently, our group has reported the application of a
nonꢀcrossꢀcouplingꢀbased approach to an areneꢀbridged macꢀ
rocycle, 1,7ꢀdioxa[7](3,3'')pꢀterphenylophane (26, Scheme 2),
which contains nonplanar benzene and pꢀterphenyl units.21
This strategy relied on the conversion of an unstrained macroꢀ
cyclic 1,4ꢀdiketone to a strained paraꢀphenylene unit. Our
overlapping interests in the synthesis of natural products conꢀ
taining biaryl, nonplanar paraꢀphenylene units and the converꢀ
sion of macrocyclic benzenoid systems into polycyclic aroꢀ
matic hydrocarbonꢀcontaining macrocycles led us to investiꢀ
gate the utility of 1,4ꢀdiketoꢀbridged macrocycles in the synꢀ
thesis of highly distorted arene units that comprise biaryl sysꢀ
tems. In this Article we report the synthesis of three new
members of this class of benzenoid macrocycles, a streamlined
synthetic approach to a series of macrocyclic 1,4ꢀdiones, an
ACS Paragon Plus Environment

Page 3 of 13
Journal of the American Chemical Society
the major product. After evaporation of the solvent, the resiꢀ lents of TsOH at 80 °C resulted in clean isomerization to 28
1
2
3
4
5
6
7
8
due was dissolved in 1:9 methanol/dichloromethane and the
addition of 3.0ꢀ5.0 equivalents of NaBH4 resulted in smooth
transfer hydrogenation of the olefin in less than three hours,
without any benzylic deoxygenation. It is noteworthy that
only 2.5 mol% of the HꢀG II catalyst was used in both the
metathesis and transfer hydrogenation reactions, all of which
was added at the RCM stage. Furthermore, the use of a 1:9 vs
a 1:19 methanol/dichloromethane solvent mixture, as originalꢀ
ly reported by Peese and coꢀworkers,22 provided much shorter
reaction times in the transfer hydrogenation step. Finally, diꢀ
rect exposure of the crude 1,4ꢀdiol mixtures to the Dessꢀ
Martin reagent, in the presence of NaHCO3, furnished pure
macrocyclic 1,4ꢀdiketones 14ꢀ16 in up to 66% yield. Running
this fourꢀstep reaction protocol on a gramꢀscale provided acꢀ
cess to 500ꢀ650 milligram quantities of the desired diketone
while using less than 500 mL of solvent and 50 g of silica gel
for a single chromatographic separation. Furthermore, the
desired products can be obtained in less than 7 hours starting
from acyclic dialdehydes 8ꢀ10. So far, we have not been able
to find a faster and more efficient protocol for the synthesis of
macrocyclic 1,4ꢀdiketones.
(Xꢀray, Scheme 2), presumably through a strain relief driven
protonation of the bridgehead carbon followed by migration of
the terminal arene unit.24 It has been speculated that a similar
“backbone” rearrangements occur when CPPs are subjected to
protic or Lewis acidꢀmediated reaction conditions, however, to
the best of our knowledge, no supporting structural evidence
has been reported to corroborate such a rearrangement.25
Scheme 2.
Conversion of 1,4ꢀdiones 14ꢀ16 to pꢀ
9
terphenylophanes 25ꢀ27
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
( )X
vinylMgCl,
THF
O
O
O
O
60 °C, 1 h
O O
19: x = 1; 63%
20: x = 2; 51%
21: x = 3; 47%
x = 1; >20:1 d.r.
x = 2; 5.5:1 d.r.
x = 3; 2.3:1 d.r.
( )X
O
14-16
syn-isomer
bent arene precursors:
( )X
( )X
O
Grubbs II (2.5 mol%),
CH2Cl2, 40 °C, 2 h
O
O
O
22: x = 1; 86%
23: x = 2; 77%
24: x = 3; 59%
Protic Acid-Mediated Dehydrative Aromatization: Strain-
Induced Rearrangements of Severely Distorted Biaryl para-
phenylenes. The conversion of the 1,4ꢀdiketoꢀbridging group
into a strained 1,4ꢀarene bridge (bent paraꢀphenylene) was
previously accomplished by employing a threeꢀstep reaction
protocol. The first of which involved a Grignard reaction with
vinylmagnesium chloride. The diastereoselectivity of this
reaction was critical to the formation of the desired arene preꢀ
cursor, as only the synꢀallylic diol (20) was converted to the
bridged cyclohexꢀ2ꢀeneꢀ1,4ꢀdiol system (23).21 After completꢀ
ing the synthesis of a homologous series of macrocyclic 1,4ꢀ
diketones, it was discovered that the diastereoselectivity of
this Grignard reaction is dependent on the size of the macroꢀ
cyclic system employed. Larger macrocyclic rings (18 and 17ꢀ
membered) gave lower diastereoselectivities (21, x = 3, 2.3:1
d.r.; 20, x = 2, 5.5:1 d.r., Scheme 2), while smaller macrocyꢀ
clic rings (16 and 15ꢀmembered) gave much higher diastereꢀ
oselectivities (19, x = 1, >20:1 d.r., Scheme 2, and 30, x = 0
>20:1 d.r., Scheme 3a). To the best of our knowledge, no studꢀ
ies have been carried out to explore the origin of diastereoseꢀ
lectivity in related macrocyclic systems. We are currently
conducting an extensive investigation of this reaction in our
laboratory.
HO
O
OH
HO
OH
22-24
19-21
( )X
TsOH H2O (5.0-7.0 equiv),
PhMe, 50-60 °C, 1-15 h
O
25: x = 1;
26: x = 2;
27: x = 3;
n
n
n
= 6; 42%
= 7; 82%
= 8; 74%
25-27
TsOH H2O
PhMe, 70-80 °C
4-12 h
x = 1; n = 6
55-67%
( )X
O
O
28: rearranged
-terphenylophane (MTPP)
X-ray crystal structure of [6]MTPP
m
To investigate this strainꢀinduced rearrangement reꢀ
of (3,3")pꢀterphenylophanes to (3,3")mꢀ
action
terphenylophanes, we synthesized a smaller macrocyclic homꢀ
olog 31. The synthesis of 31 proceeds along the same pathꢀ
way previously described for 22ꢀ24. It is worth mentioning
that the yield of the 4ꢀstep 1,4ꢀdiketone synthesis is lower than
the three previously described homologues (14ꢀ16) at 22%.
We attribute this lower yielding process to the reduced solubilꢀ
ity of the macrocyclic RCM product, as well as the propensity
for the precursor diene to form a higher molecular weight meꢀ
tathesis byꢀproduct at 15 mM concentration.26 Nonetheless,
synthetically useful quantities of 30 can be prepared in short
order. The Grignard reaction of 30 with vinylmagnesium
chloride demonstrated the same macrocyclic trend as deꢀ
scribed above (14ꢀ16 to 19ꢀ21, >20:1, d.r., 15ꢀmembered 1,4ꢀ
diketone) and a RCM reaction of the afforded diene gave the
cyclohexꢀ2ꢀeneꢀ1,4ꢀdiol precursor 31 in 65% overall yield.
Treatment of 31 with TsOH in toluene at 60 °C gave, what
was believed to be, a partial elimination product, which perꢀ
sisted in solution at this temperature. Increasing the temperaꢀ
Fortunately, the synꢀdiastereomer is the major prodꢀ
uct of the vinylmagnesium chloride addition, and the insepaꢀ
rable (minor) antiꢀdiastereomer could be easily removed after
a RCM reaction.23 Treatment of 19ꢀ21 with the Grubbs seꢀ
condꢀgeneration catalyst completed the conversion of the 1,4ꢀ
dione unit into a sixꢀmembered ring, and the precursor macroꢀ
cycle for a dehydrative aromatization reaction. In the case of
24 (n = 8) and 23 (n = 7), conversion to the bent pꢀterphenyl
systems was high yielding and straightforward using TsOH
(Scheme 2). For the next smallest macrocycle in the series, 22
(n = 6), clean isolation of the highly distorted pꢀterphenyl sysꢀ
tem proved to be more challenging and slightly lower yielding
at 42%. Controlling the temperature of this reaction is critical
to avoid the formation of unwanted byꢀproducts, and the reacꢀ
tion must not be heated above 60 °C, as the isomeric and less
strained (3,3")mꢀterphenylophane derivative is formed. Heatꢀ
ing a toluene solution of 25 in the presence of 5.0ꢀ7.0 equivaꢀ
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 13
ture to 70 °C furnished only the rearranged 1,5ꢀ
dioxa[5](3,3")mꢀterphenylophane product after hours
ble 1, entry 7) gave a 16% yield of the desired pꢀ
1
2
3
4
5
6
7
8
3
terphenylophane 34 (8% from 31, Scheme 3b). Shifting our
focus to nonꢀacidic dehydration conditions, we attempted the
synthesis of 34 by employing the Burgess reagent. Remarkaꢀ
bly, 34 was isolated in 58% yield upon heating a toluene soluꢀ
tion of 31 at 80 °C in the presence of the Burgess reagent,29
without the formation of the rearranged isomer 32! In comꢀ
parison, heating toluene solutions of the cyclohexꢀ2ꢀeneꢀ1,4ꢀ
diol (arene) precursors 22ꢀ24 at 80 °C in the presence of TsOH
for 30 minutes saw rearrangements occur at the n = 7 homolog
stage (Table 1, entry 11). Indeed, subjecting all of the remainꢀ
ing cyclohexeꢀ2ꢀeneꢀ1,4ꢀdiol precursors (20ꢀ22, n = 8ꢀ6, reꢀ
spectively) to identical reaction conditions, with the Burgess
reagent, furnished the desired pꢀterphenylꢀcontaining macroꢀ
cycles in comparable yields (Table 1, entries 8, 9, 10, and 12).
To the best of our knowledge, this represents the first applicaꢀ
tion of the Burgess reagent in the synthesis of a nonplanar
benzenoid system.
(Scheme 3a and Table 1, entry 3). Thinꢀlayer chromatography
analysis of the reaction mixture revealed that an initially
formed product (34, Rf = 0.43) was quantitatively converted
into a slightly slower moving byꢀproduct (32, Rf = 0.41). This
analysis is identical, albeit more rapid, to that observed for the
conversion of 25 to 28 (Scheme 2), indicating that the desired
1,5ꢀdioxa[5](3,3")pꢀterphenylophane (34) is formed during the
course of the acidꢀmediated dehydrative aromatization reacꢀ
tion. In order to demonstrate the utility of cyclohexꢀ2ꢀeneꢀ1,4ꢀ
diol units as precursors to bent paraꢀphenylenes, we sought an
alternative dehydration strategy.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. (a) Synthesis of rearranged mꢀterphenylophane 32
under protic acid conditions; (b) Synthesis of [5]PTPP (34) under
nonꢀprotic acid conditions
Table 1. Optimized conditions for the conversion of macrocyclic
cyclohexꢀ2ꢀeneꢀ1,4ꢀdiols 22ꢀ24, and 31 to pꢀterphenylophanes 25ꢀ
27, and 34, respectively
X-Ray Crystal Structure and Strain Energy of a Highly Dis-
torted para-Phenylene Ring. Recrystallization of 34 from
dichloromethane and hexanes produced a single crystal suitaꢀ
ble for Xꢀray analysis, revealing the highly distorted pꢀ
terphenyl nucleus and paraꢀphenylene ring of the macrocycle.
The central arene unit in the pꢀterphenyl system has an α angle
of 15.7°, which is comparable to the α angle found in the bent
paraꢀphenylene units of [5]CPP – cf. 15.6° – and is greater
than that found in the natural product haouamine A.30 It is,
however, less than that of the mean plane deviation found in
compounds 1 and 2 (Figure 1). The β angles found in 34 have
an average value of 24.6°, with the largest deviation coming in
at 26.8°. This is identical to the largest β angle measured in a
bent paraꢀphenylene unit – Tsuji’s [1.1]paracyclophane derivꢀ
ative 2.14 The 1,3ꢀpropanoxy bridge of 34 severely bends the
pꢀterphenyl system from an ideal planar geometry, but also
twists and bows the terminal arene units. In fact, the biaryl
bonds in 34 are canted forward at an average angle of 9.8°
(C11–C22–C23 and C14–C25–C24). The overall SE of 34 has
A Mild Dehydrative Aromatization Protocol. Several different
reaction conditions that employ milder acidic reagents were
screened to facilitate the synthesis of 25 and 34 from 22 and
31, respectively. Application of NaHSO4 in the presence of oꢀ
chloranil, which has been used by Itami and coꢀworkers to
aromatize cyclohexaneꢀ1,4ꢀdiol units of [n]CPP macrocyclic
precursors,27 gave a low yield of 25 with the formation of the
rearranged isomer 28 (entry 4, Table 1). Using a modification
of Yamago and coꢀworkers tin(II) chloride dihydrateꢀmediated
aromatization reaction, which was used successfully to syntheꢀ
size [5]CPP (3),20 gave only the partial dehydration product
33. Furthermore, application of the recently reported
SnCl2/HCl ate complex (H2SnCl4),28 did not afford the aromaꢀ
tized product. However, treating 33 with Tf2O in pyridine (Taꢀ
ACS Paragon Plus Environment

Page 5 of 13
Journal of the American Chemical Society
Detailed experimental procedures, characterization data, and all
been computed at the DFT B3LYP level of theory using the 6ꢀ
1H and 13C NMR spectra for all new compounds. This material is
available free of charge via the Internet at htpp://pubs.acs.org
1
2
3
4
5
6
7
8
31G(d) basis set, and is estimated to be 46.8 kcal/mol. The SE
of the pꢀterphenyl system comprises 40.2 kcal/mol of the total
SE found in 34, the majority of which is localized on the cenꢀ
tral arene unit. At 28.4 kcal/mol, the SE of the paraꢀphenylene
ring is approximately 4.6 kcal/mol greater than that of the
average SE/paraꢀphenylene unit in [5]CPP – the most strained
CPP homolog to be prepared by chemical synthesis. The SE
of [4]CPP, which has yet to be synthesized, is predicted to be
144 kcal/mol,31 giving an average SE/paraꢀphenylene of 36
kcal/mol. Currently, we are pursuing the synthesis of a smaller
homolog of 34 as well as a macrocyclic precursor of [4]CPP.
Both of these targets will provide the ultimate tests of our
AUTHOR INFORMATION
Corresponding Author
* Corresponding Author: blm0022@auburn.edu
ACKNOWLEDGMENT
9
The authors are grateful to Auburn University and the Department
of Chemistry and Biochemistry for financial support of this work.
RM would like to thank the Auburn University Cellular and Moꢀ
lecular Biosciences (AUꢀCMB) program and NSF EPSCoR,
(NSFꢀEPSꢀ1158862, Grant G00006750) for a graduate fellowꢀ
ship.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Burgess
reage
ABBREVIATIONS
CNT, carbon nanotube; CPP, cycloparaphenylene; PTPP, (3,3")pꢀ
terphenylophane; MTPP, (3,3")mꢀterphenylophane; SE, strain
energy; DFT, density functional theory; RCM, ringꢀclosing meꢀ
tathesis; TLC, thin layer chromatography; TsOH, pꢀtoluene sulꢀ
fonic acid;
REFERENCES
(1) (a) JohanssonꢀSeechurn, C. C. C.; Kitching, M. O. Colacot, T. J.;
Snieckus, V. Angew. Chem. Int. Ed. 2012, 51, 5062ꢀ5085; b) Wu, X.
F.; Anbarasan, P.; Neumann, H.; Beller, M. Angew. Chem. Int. Ed.
2010, 49, 9047ꢀ9050.
(2) Bringmann, G.; Gulder, T.; Gulder, T. A. M.; Breuning, M. Chem.
Rev. 2011, 111, 563ꢀ639; b) Kozlowski, M. C.; Morgan, B. J.; Linton,
E. C. Chem. Soc. Rev. 2009, 38, 3193ꢀ3207.
(3) Applications of Transition Metal Catalysis in Drug Discovery and
Development, Crawley, M. L.; Trost, B. M. 2012, John Wiley and
Sons, Hoboken, pp. 25ꢀ96.
(4) For a recent review article on this subject, see: Cherney, A. H.;
Kadunce, N. T.; Reisman, S. E. Chem. Rev. 2015, 115, 9587ꢀ9652.
(5) Xu, S.; Kim, E. H. Wei, A.; Negishi, E.ꢀi. Sci. technol. Adv. Maꢀ
ter. 2014, 15, 44201ꢀ44223.
(6) MetalꢀCatalyzed CrossꢀCoupling Reactions, 2nd Edition, A. de
Meijere, F. Diderich, 2008, WileyꢀVCH, Weinheim.
(7) Gulder, T.; Baran, P. S. Nat. Prod. Rep. 2012, 29, 899−834.
(8) For recent examples see: Mysliwiec, D.; Kondratowicz, M.; Lis,
T.; Chmielewski, P.J.; Stępien, M. J. Am. Chem. Soc. 2015, 137,
1643ꢀ1649, as well as ref. 19 and 20
(9) Brown, C. J.; Farthing, A. C. Nature 1949, 164, 915ꢀ916
(10) Tsuji, T.; Okuyama, M.; Ohkita, M.; Kawai, H.; Suzuki, T. J.
Am. Chem. Soc. 2003, 125, 951ꢀ961.
(11) Garrido, L.; Zubia, E.; Ortega, M. J.; Salva, J. J. J. Org. Chem.
2003, 68, 293ꢀ299.
(12) For an extensive review on the subject, see: (b) Lewis, S. E.
Chem. Soc. Rev. 2015, 44, 2221−2304.
(13) Tobe, Y.; Kakiuchi, K.; Odaira, Y.; Hosaki, T.; Kai, Y.; Kasai,
N. J. Am. Chem. Soc. 1983, 105, 1376−1377.
(14) Kawai, H.; Suzuki, T.; Ohkita, M.; Tsuji, T. Angew. Chem. Int.
Ed. 1998, 37, 817ꢀ819.
(15) Jasti, R.; Bhattacharjee, J.; Neaton, J. B.; Bertozzi, C. R. J. Am.
Chem. Soc. 2008, 130, 17646−17647.
(16) Takaba, H.; Omachi, H.; Yamamoto, Y.; Bouffard, J.; Itami, K.
Angew. Chem. Int. Ed. 2009, 48, 6112ꢀ6116.
(17) Yamago, S.; Watanabe, Y.; Iwamoto, T. Angew. Chem. Int. Ed.
2010, 49, 757ꢀ759.
(18) Sisto, T. J.; Golder, M. R.; Hirst, E. R.; Jasti, R. J. Am. Chem.
Soc. 2011, 133, 15800ꢀ15802.
(19) Evans, P. J.; Darzi, E. R.; Jasti, R. Nat. Chem. 2014, 6, 404−408.
(20) Kayahara, E.; Patel, V. K.; Yamago S. J. Am. Chem. Soc. 2014,
136, 2284ꢀ2287.
ntꢀmediated aromatization protocol of macrocyclic cyclohexꢀ
2ꢀeneꢀ1,4ꢀdiols.
Figure 3. Xꢀray crystal structure of 1,5ꢀdioxa[5](3,3")pꢀ
terphenylophane (34)
CONCLUSION
In summary, a streamlined synthetic approach that involves
the conversion of acyclic dialdehydes to macrocyclic 1,4ꢀ
diketones has been developed. This fourꢀreaction process can
be conducted on a gramꢀscale, completed in just 7 hours, and
requires a single chromatographic separation to afford pure
1,4ꢀdiketones. The addition of vinylmagnesium chloride to
these macrocyclic 1,4ꢀdiketones, gave higher diastereoselecꢀ
tivities when smaller macrocyclic systems were employed (15
to 18ꢀmembered rings). The origin of this (macrocyclic) sizeꢀ
dependent diastereoselectivity, as well as its synthetic utility,
is currently under investigation in our laboratory. Finally, a
nonꢀprotic acidꢀmediated dehydrative aromatization reaction
of areneꢀbridged cyclohexꢀ2ꢀeneꢀ1,4ꢀdiol precursors has been
demonstrated to be a mild and powerful tool for the synthesis
of highly distorted paraꢀphenylene units that are part of polyꢀ
aryl systems, or benzenoid macrocycles. In the case of the
smallest homolog synthesized, over 37 kcal/mol of SE is genꢀ
erated upon elimination of two molecules of water (31 to 34,
Scheme 3b). The application of this reaction to a smaller homꢀ
olog of 34, the synthesis of small, functionalized CPPs, and
biaryl natural products containing bent benzene rings are unꢀ
derway in our laboratory. The results of these studies will be
reported in due course.
ASSOCIATED CONTENT
Supporting Information
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 13
(21) Mitra, N. K.; Meudom, R.; Gorden, J. D.; Merner, B. L. Org.
Lett. 2015, 17, 2700ꢀ2703.
(29) Atkins, G. M. Jr.; Burgess, E. M. J. Am. Chem. Soc. 1968, 90,
4744ꢀ4745.
1
2
3
4
5
6
7
8
(22) Connolly, T.; Wang, Z.; Walker, M. A.; McDonald, I. M.; Peese,
K. M. Org. Lett. 2014, 16, 4444ꢀ4447.
(23) The diastereomeric mixture obtained from this reaction is insepaꢀ
rable by chromatography, however, only the synꢀdiastereomer underꢀ
goes a RCM reaction and this product can be easily separated from
the uncyclized antiꢀdiatereomer.
(30) α = 13.7° and 13.9°. For the Xꢀray crystal structure of the natural
product, see: ref. 10.
(31) Iwamoto, T.; Watanabe, Y.; Sakamoto, Y.; Suzuki, T.; Yamago,
S. J. Am. Chem. Soc. 2011, 133, 8354ꢀ8361.
(24) See Supporting Information for a proposed mechanism.
(25) Golling, F. E.; Quernheim, M.; Wagner, M.; Nishiuchi, T.; Mülꢀ
len, K. Angew. Chem. Int. Ed. 2014, 53, 1525ꢀ1528.
1
9
(26) A slower moving byꢀproduct was isolated from this reaction. H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NMR and HRMS data indicate that this material is a dimer of the
desired product.
(27) Omachi, H.; Segawa, Y.; Itami, K. Acc. Chem. Res. 2012, 45,
1378ꢀ1389.
(28) Patel, V. K.; Kayahara, E.; Yamago, S. Chem. Eur. J. 2015, 21,
5742ꢀ5749.
ACS Paragon Plus Environment

Page 7 of 13
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 13
1
2
a. limitations of C-C bond forming reactions: inducing strain
3
4
5
introduction of strain:
BENT para-phenylene
(MODE 1)
3
2' 3'
3''
C-C bond formation (biaryl)
non-ideal
bond angles
1
1'
4' 1''
6
7
5
5''
6' 5'
X
X
8
X
X
9
X = directing group
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
C-C
bond formation (alkyl bridge)
(8-atom bridge or shorter)
introduction of strain:
C-C bond elongation (alkyl bridge)
(MODE 2)
b. this work: strained para-phenylenes via a mild dehydration reaction
NO
cross-coupling
3 steps:
a. Grignard
O
( )X
O
O
O
b. ring-closing
metathesis
x = 0, 1, 2, and 3
n = 5, 6, 7, and 8
O
O
HO
OH
bent arene
precursor
( )X
Rapid streamlined
protocol from
simple dialdehydes
O
Et3N
S
N
O
c. MILD
dehydrative
aromatization
O
( )X
O
O
STRAINED
1,4-arene-bridged
macrocycles
OMe
Burgess
reagent
-2 H2O
Figure 1. (a) Strain inducing carbon-carbon bond forming reactions; (b) biaryl bond formation using a macrocyclic 1,4-
diketone surrogate and a mild dehydrative aromatization reaction
valence isomerization
reductive aromatization
R
Ar
Ar
Ar
R
R
Ar
R
RO
OR
R = alkyl bridge
R = Me, H; Ar = 1,4-arene bridge
para-phenylene
bend angles
Me3Si
SiMe3
β
C
R
R
d
a
b
α
c
Me3Si
SiMe3
e
f
HO2C
1: Tobe's
[6]paracyclophane [1.1]paracyclophane
α = mean plane
deviation of a & d
R = CONMe2
2: Tsuji's
3: Jasti and Yamago
[5]CPP
β = benzylic
3
2
Csp2-Csp
(
)
sp
α = 20.7o
β = 18.8o
α = 24.9o
β = 24.9o
α = 15.6o
β = NR
deviation
Figure 2. Valence isomerization and reductive aromatization strategies to highly distorted para-phenylene-containing
molecules
ACS Paragon Plus Environment

Page 9 of 13
Journal of the American Chemical Society
1
2
3
4
5
6
Scheme 1. Streamlined, scalable synthesis of macrocyclic 1,4-diones 11-13
7
8
9
H
O
O
H
K2CO3,
DMF,
60-70 °C,
12-18 h
1. vinylMgCl, THF,
0 to 23 °C, 1 h
H
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
HO
Br
4
O
8: x = 1; 87%
9: x = 2; 73%
10: x = 3; 82%
2. H-G II (2.5 mol %),
CH2Cl2, 40 °C, 1 h
( )X
( )X
O
8-10
Br
5: x=1
6: x=2
7: x=3
undesired olefin geometry
macrocyclic RCM
3. NaBH4, MeOH/CH2Cl2
(1:9), 23 °C, 3 h
4. DMP, NaHCO3,
OH
O
CH2Cl2, 23 °C, 30 min.
OH
O
4 synthetic operations
3 C-C bonds
1 column/isolation
7 hours start to finish
O
O
( )X
O
( )X
O
14: x = 1; 51%
15: x = 2; 66%
16: x = 3; 48%
11: x = 1
12: x = 2
13: x = 3
up to 66% overall yield
GRAM-SCALE
Gram-scale hydrogenation: Benzylic deoxygenation
OH OH
OH
H2, Pd/C,
MeOH,
23 °C, 2 h
OH
OH
O
O
O
70-80%
hydrogenation
10-15%
O
O
O
deoxygenation
12
17
18
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 13
1
2
3
Scheme 2. Conversion of 1,4-diones 14-16 to p-terphenylophanes 25-27
O
4
( )X
5
6
vinylMgCl,
THF
O
O
O
7
8
9
O
60 °C, 1 h
O O
19: x = 1; 63%
20: x = 2; 51%
21: x = 3; 47%
x = 1; >20:1 d.r.
x = 2; 5.5:1 d.r.
x = 3; 2.3:1 d.r.
( )X
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
14-16
syn-isomer
bent arene precursors:
( )X
( )X
Grubbs II (2.5 mol%),
CH2Cl2, 40 °C, 2 h
O
O
O
O
22: x = 1; 86%
23: x = 2; 77%
24: x = 3; 59%
HO
O
OH
HO
OH
22-24
19-21
( )X
TsOH H2O (5.0-7.0 equiv),
PhMe, 50-60 °C, 1-15 h
O
25: x = 1; n = 6; 42%
26: x = 2; n = 7; 82%
27: x = 3; n = 8; 74%
25-27
TsOH H2O
PhMe, 70-80 °C
4-12 h
x = 1; n = 6
55-67%
( )X
O
O
28: rearranged
m-terphenylophane (MTPP)
X-ray crystal structure of [6]MTPP
ACS Paragon Plus Environment

Page 11 of 13
Journal of the American Chemical Society
1
2
3
4
Scheme 3. (a) Synthesis of rearranged m-terphenylophane 32 under protic acid conditions; (b) Synthesis of [5]PTPP (34) under
non-protic acid conditions
5
6
a. TsOH-mediated rearrangement: Synthesis of [5]MTPP
7
8
9
1. VinylMgCl, THF,
0 to 23 °C, 30 min.
2. H-G II (2.5 mol%),
CH2Cl2, 40 °C, 2 h
Br
O
O
Br
H
H
K2CO3,
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3. NaBH4, MeOH/
CH2Cl2, 23 °C, 1 h
4. DMP, NaHCO3,
CH2Cl2, 23 °C, 1 h
TBAI, DMF,
70 °C
76%
O
O
O
O
30
29
4
22% (4 steps)
1. VinylMgCl,
CH2Cl2, 40 °C,
30 min, >20:1 d.r.
TsOH,
PhMe,
4 h
O
O
O
O
60-70 °C
2. Grubbs II, 40 °C
CH2Cl2, 2 h
40%
HO
OH
32
31
65% (2 steps)
b. Synthesis of 1,5-dioxa[5](3,3")p-terphenylophane ([5]PTPP)
[5]PTPP:
α = 15.7°
β = 24.6°
O
O
O
O
Burgess
reagent
SEPP = 28.4
[5]CPP:
α = 15.6°
β = NA
PhMe, 80 °C,
15 min.
58%
HO
OH
31
SE = 9.5 kcal/mol
34
SE = 46.8 kcal/mol
SEPP = 23.8
Tf2O, pyr.,
CH2Cl2
23 °C, 1 h
16%
SnCl2 2H2O,
THF/PhMe
partial elimination
O
S
N
Et3N
O
O
O
80 °C, 12 h
49%
O
OMe
Burgess
reagent
HO
33
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 12 of 13
1
2
3
4
5
Table 1. Optimized conditions for the conversion of macrocyclic cyclohex-2-ene-1,4-diols 22-24, and 31 to p-terphenylophanes
25-27, and 34, respectively
6
7
8
( )X
O
O
O
O
O
O
( )X
( )X
dehydrative
conditions
9
acid, solvent,
temp., time
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
HO
OH
desired
p-terphenylophane
(PTPP)
rearranged
m-terpheylophane
(MTPP)
31: x = 1; 22: x = 2
23: x = 3; 24: x = 4
entry x (n)
reagent
solvent
temp (°C) time (h) PTPP (%) MTPP (%)
1
2 (6)
2 (6)
1 (5)
2 (6)
60
80
10
4
42
trace
0
0
55
40
trace
0
TsOH
TsOH
PhMe
PhMe
2
3
TsOH
PhMe
70
3
4
NaHSO4
130
80
24
12
72
0.5
36
0
DMSO/xylenes
5a
6b
7c
1 (5) SnCl2 2H2O THF/PhMe
1 (5)
1 (5)
H2SnCl4
Tf2O
THF
23
0
0
CH2Cl2/pyr.
23
16
0
8
1 (5)
2 (6)
3 (7)
3 (7)
4 (8)
4 (8)
Burgess
Burgess
Burgess
TsOH
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
80
80
80
80
80
80
0.2
0.2
0.2
0.2
0.2
0.2
58
56
68
38
60
62
0
0
9
10
11
12
13
0
19
0
Burgess
TsOH
0
a. Only the monodehydration product 33 (Scheme 3a) was formed; b. H2SnCl4 was
prepared by mixing SnCl2 2H2O and HCl; c. This entry refers to the reaction of 33.
Figure 3. X-ray crystal structure of 1,5-dioxa[5](3,3")p-terphenylophane (34)
ACS Paragon Plus Environment

Page 13 of 13
Journal of the American Chemical Society
1
2
3
4
5
Graphical TOC
6
7
8
9
Dehydrative aromatization
Highly strained arenes
No rearranged products
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ar
Ar
Ar
Ar
OH
HO
BENT
para-phenylene
precursor
No cross-coupling
for biaryl C-C bond formation
ACS Paragon Plus Environment