Phenalenannulations: Three-Point Double Annulation Reactions that Convert Benzenes into Pyrenes

Article abstract of DOI:10.1002/anie.202006087

3-Point annulations, or phenalenannulations, transform a benzene ring directly into a substituted pyrene by “wrapping” two new cycles around the perimeter of the central ring at three consecutive carbon atoms. This efficient, modular, and general method for π-extension opens access to non-symmetric pyrenes and their expanded analogues. Potentially, this approach can convert any aromatic ring bearing a -CH₂Br or a -CHO group into a pyrene moiety. Depending upon the workup choices, the process can be directed towards either tin- or iodo-substituted product formation, giving complementary choices for further various cross-coupling reactions. The two-directional bis-double annulation adds two new polyaromatic extensions with a total of six new aromatic rings at a central core.

Full text of DOI:10.1002/anie.202006087

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Accepted Article
Title: “Phenalenannulations: Three-Point Double Annulation Reactions
that Convert Benzenes into Pyrenes”
Authors: Rahul Kisan Kawade, Chaowei Hu, Nikolas R. Dos Santos,
Noelle Watson, Xinsong Lin, Kenneth Hanson, and Igor
Alabugin
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“Phenalenannulations: Three-Point Double Annulation Reactions
that Convert Benzenes into Pyrenes”
Rahul Kisan Kawade, Chaowei Hu, Nikolas R. Dos Santos, Noelle Watson, Xinsong Lin, Kenneth
Hanson and Igor V. Alabugin*[a]
[a]
Dr. R. K. Kawade, C. Hu, N. R. D. Santos, N. Watson, Dr. X. Lin, Dr. K. Hanson, Dr. I. V. Alabugin
Department of Chemistry and Biochemistry, Florida State University,
Tallahassee, FL 32306-4390 (USA)
E-mail: alabugin@chem.fsu.edu
Supporting information for this article is given via a link at the end of the document
Abstract: “3-Point annulations”, or ‘‘phenalenannulations” transform
a benzene ring directly into a substituted pyrene by “wrapping” two
new cycles around the perimeter of the central ring at three
consecutive carbon atoms. This efficient, modular, and general
method for extension opens access to non- symmetric pyrenes and
their expanded analogues. Potentially, this approach can convert any
aromatic ring bearing a -CH2Br or a –CHO group into a pyrene moiety.
Depending upon the workup choices, the process can be directed
towards either tin- or iodo-substituted product formation, giving
complementary choices for further various cross-coupling reactions.
The two-directional bis-double annulation adds two new polyaromatic
extensions with a total of six new aromatic rings at a central core.
generation of aryl and vinyl radicals via two compatible pathways
(Scheme 1b). Each of these intermediates are sufficiently reactive
Annulation reactions expand molecular frameworks by using
an existing ring as a scaffold for attaching a new cycle.[1] The
usual cyclization approach (i.e., a single annulation) creates one
new connection and attaches one new cycle onto the existing one.
Such synthetic methods are well-documented and very useful.[1,2]
As a part of our continuing efforts to develop conceptually new
annulations, we were interested in designing a cascade that
creates two new cycles at three consecutive atoms at the
perimeter of an existing cycle (Scheme 1b). We refer to such
double cyclizations as “3-point annulations” to distinguish them
from the usual “2-point annulations” that add only one ring to the
molecular core.[2] The potential utility of 3-point annulations is in
enabling controlled and faster growth of extended polyaromatic
systems. In order to accomplish this goal, we envisioned a
modular design described in Scheme 1. In the first step, one of
the three atoms involved in the formation of two new cycles serves
as the anchoring point (the “red circle” in Scheme 1) for attaching
the partner reactant. After the attachment, the partner reactant is
activated to initiate a cascade where the two new cycles form at
the remaining atoms (“blue circles” in Scheme 1) of the “three-
point” reaction locus. These two atoms do not need to be pre-
functionalized as long as the transient reactant functionalities
formed at the “partner reactant” are sufficiently reactive to pierce
the aromatic armor.
Scheme 1. Comparison of 2-point (a) and 3-point (b) annulations
to attack an existing aromatic system, annealing a new ring to the
latter. When two such radicals are generated, two new cycles are
formed. Because the radicals are formed sequentially, the 1st
cycle-forming reaction creates the necessary geometric
environment for the formation of the 2nd new cycle. More
specifically, the aryl radical cyclization creates a bay region which
serves as a target in the next cyclization of the vinyl radical formed
from an alkyne.
The simplest version of such cascade would convert a
benzene ring into a respective phenalene but, considering the
relative instability of phenalenes,[3] we added an aromatic ring in
the reacting partner, so the benzene ring is converted into a
pyrene.
Scheme 2. Two practical designs for the 3-point double annulation
Based on our expertise in using radical chemistry of alkynes
for benzannulation,[4] we designed a cascade on the sequential
A suitable “anchoring functionality” for this design is a Z-
double bond. This choice makes a Z-selective Wittig reaction a
1
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logical approach to the preparation of the cyclization precursors
from a variety of aromatic aldehydes or benzyl bromides as the
readily available starting materials. The use of ortho iodo-
substituted aryl halides in one of starting material serves two
purposes; 1) to control stereochemistry of the Wittig reaction,[5]
and 2) provide a weak C-I bond that can be used to generate the
required aryl radical.[6]
the first cyclization. After 16 hours, the formation of phenanthrene
2a is complete (from 1H NMR of the reaction mixture). In the 2nd
step, a solution of Bu3SnH (3.0 equiv.) and AIBN (2.0 equiv.) in
toluene was added to the reaction mixture over 12h using a
syringe pump at 110 °C. This sequence affords the desired
pyrene 3a in 71% yield. Interestingly, the reaction performed
directly at 110 °C gives a complex mixture, possibly due to the
poor selectivity of Sn-radical attack at the alkyne vs. Ar-I.
For the two reactive functionalities that perform the
cyclizations (i.e., the Ar-I and the alkyne), there are two choices –
a) to place them at different rings (Scheme 2, design A) or to put
them on the same ring (Scheme 2, design B). In the first version,
the two partners before the anchoring step are di-substituted
arenes. The second version pairs a mono-substituted arene with
a tri-substituted arene. The possibility of several designs adds
synthetic flexibility to this approach.
The key challenge in this cascade is to ensure the correct
timing for selective activation (i.e., aryl iodide vs. alkyne). We
report herein that the initial activation of an Ar-I bond with the
delayed activation of the alkyne is achieved by the use of
Bu3SnH/azobisisobutyronitrile (AIBN) in toluene with a two-
temperature procedure and the “double-duty” use of AIBN as both
the initiator and the oxidant.[7]
Scheme 4. Chemoselectivity of the initial Sn-radical attack
With the optimized reaction conditions, we have tested the
scope of the transformation by varying the R1 and R2 substituents
(Table 2). The choice of the work-up (either protonolysis or iodo-
destannylation) delivers different products in one-pot processes.
Table 1. Scope of 3-point double annulations (Design A)
Scheme 3. Mechanistic challenges and possibilities for the one-pot and two-pot
3-point annulations
As shown earlier,[8] addition of Bu3Sn radical to diaryl alkynes
is reversible. Hence the new C-Sn bond is a “dynamic covalent
bond”[9] and its formation becomes permanent only when a
productive subsequent step is available, i.e. when the first cycle
is formed from an radical produced via the irreversible Ar-I
activation. In this scenario, the timing of the two steps is perfectly
controlled.
An intrinsic challenge of such cascades is in ensuring the
radical chain propagation. The initially formed cyclization product
is a highly delocalized radical that is reluctant to participate in the
chain propagation. Instead, it may aromatize by an H-atom
transfer to either Sn- or AIBN-radicals and stopping the radical
chain in the process. We found that the use of >0.5 equiv. of AIBN
solves this problem.
The starting materials 1a-1k are readily prepared from the 3-
halo aldehydes via Sonogashira cross-coupling followed by a
Wittig reaction (See SI). Fortuitously, the C=C bond-forming Wittig
process for o-substituted aryl aldehydes proceeded with the
requisite Z-selectivity.[5] The initial optimization (see SI) found that
a suitable procedure involves sequential steps with a stepwise
increase in temperature. First, the precursor 1a (1.0 equiv.) is
heated with Bu3SnH (1.3 equiv.), and AIBN (0.3 equiv.) in
anhydrous toluene at 90 °C. This step activates the Ar-I bond for
a. i) Bu3SnH (1.3 equiv.), AIBN (0.3 equiv.), 90 oC; ii) Bu3SnH (3.0 equiv.), AIBN
(2.0 equiv.), toluene, 110 oC iii) for X= H: CF3CO2H (TFA), dichloromethane
(DCM), for X= I: I2, DCM; b isolated yields are reported from precursor 1
The radical annulation is compatible with both electron donating
and accepting groups R1 at the alkyne termini as illustrated by the
high yields of the target products 4a-4e. The reaction tolerates a
heterocyclic thiophene core as well. However, an alkyl-substituted
2
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alkyne undergoes unproductive alkyne reduction to give 6j.
Variation of the substituents at the central ring is tolerated as
products 4g-4i were formed in good yields. Iodinated products,
such as 4-iodopyrenes 5b-5c and 5i-5k, can be formed using the
one-pot iodo-destannylation (Table 1, Bottom). The molecular
structure of the 5b is further confirmed by X-ray crystallography.
10a-10e in the one-pot 48-64% yields. Interestingly, isolation of
naphtho[1,2-a]pyrene 10c opens a new route to iodo-substituted
fused 4-helicenes, which are otherwise difficult to synthesize.[11]
The molecular structure of compound 10d was further confirmed
by X-ray analysis.The reaction is also suitable for synthesis of a
photophysically interesting non-symmetric peropyrene 10e.
Importantly, the Ar-I moiety in the product can serve as a chemical
handle for further functionalization via variety of cross-coupling
reactions.
Preparation of the trifunctionalized component in design B is
more labor-intensive as it requires three substituents at the
adjacent positions (e.g., aldehyde, iodide and alkyne).
Nevertheless, its synthesis was readily accomplished via classic
aromatic chemistry (see SI). Importantly, once this cascade
partner is made, it can be coupled with a broad selection of
Encouraged by these results, we have tested precursors 9 in
the sequence of radical and Brønsted acid benzannulations
shown in Table 3 (condition B). This alternative protocol provides
the intermediate alkynes 11a-11f in excellent yields (see SI).
aromatic counterparts. As
a
variety of monosubstituted
polyaromatics are available, this design lends itself for the
preparation of larger PAHs from extended polyaromatic cores.
Table 3. Two-step radical and Brønsted acid phenalenannulations (Design B)
Gratifyingly, the type B cascades are also viable (Table 2).
Again, the 2nd cyclization is considerably slower than both the first
cyclization and a topologically similar cyclization of alkynyl
substituted biphenyls.[7] This difference in rates is useful, since it
allows to interrupt the cascade. For example, if the Sn-substituted
product is desired, the one-pot addition of Bu3SnH/AIBN and
temperature/time increase are used. On the other hand, if there is
no need to introduce an additional substituent, the 2nd cyclization
can be accomplished in the presence of Lewis or Brønsted acids
as shown most recently by Chalifoux and co-workers (Table 3).[10]
Table 2. Scope of 3-point double annulations (Design B)
a) 7 (1.0 equiv.), KOtBu (1.4 equiv.), THF; b) Initial concentration [9] = 0.02 M;
Bu3SnH (2.6 equiv.), AIBN (0.6 equiv.), toluene, 90oC; c) TfOH, DCM; d overall
isolated yields from 9 to 12
These alkynes are potential benzannulation precursors that can
be functionalized using various electrophilic and radical reagents
at the bay-region.[2] Further efforts are underway along these
directions. In particular, the trifluomethanesulfonic acid catalyzed
reaction (TfOH, 0.01M in DCM) of intermediate alkynes 11a-11f
produces fully cyclized products 12a-12f in good yields as shown
in Table 3. This process can be expanded to give benzo[a]pyrene
12b, naphtho[1,2-a]pyrene 12c and isomeric naphtho[3,4-
a]pyrene 12d and to prepare non-symmetric peropyrenes 12e
and 12f.
As a single three-point annulation on benzene ring creates a
pyrene, the two such annulations on the single aryl core would
a) KOtBu (1.4 equiv.), tetrahydrofuran (THF); b) i) [9a] 0.02 M, Bu3SnH (1.3
equiv.), AIBN (0.3 equiv.), toluene, 90oC, ii) Bu3SnH (3.0 equiv.), AIBN (2.0
equiv.), 110oC iii) I2 (5.0 equiv.), DCM; isolated yields are reported from 9 to 10
anneal it to two phenalenes.
In other words, a bis-
phenalenannulation would convert benzene into a peropyrene or,
even more interestingly, directly transform naphthalenes into
The Wittig reaction between the anchoring unit 7 and a variety of
phosphonium salts 8 assembles a range of precursors 9a-9e.
Their three-point double annulation produces Sn-substituted
products which are converted into iodo-substituted polyromatics
isomeric pyrano[a]pyrenes. Design
B facilitates such bis-
annulations by taking advantage of the suitable naphthalene-
based precursors 13 and 16 (Scheme 5). The double Wittig
3
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Scheme 5. Left: Bis-phenalenannulations on the naphthalene cores; reagents and condition: a) KOtBu (2.5 equiv.), THF; b) Bu3SnH (7.5 equiv.), AIBN (1.5 equiv.),
toluene, 90 oC; c) TfOH (1.0 equiv.), DCM, d) NaH (3.0 equiv.), THF; isolated yields are reported; right: X-ray crystal structure and solid state packing of 15
reaction of the 1,5- and 1,8- bis-phosphonium salts with the
anchoring unit 7 gives respective starting precursor 13 and 16 in
4:1 and 3:1 ratio for Z,Z:E,Z isomers of the respective olefins (see
SI). The isomers are separated by silica column chromatography
and Z,Z isomers are used for radical cyclization. The two-step
optimized reaction conditions B give isomeric pyranopyrenes 15
and 18 as shown in Scheme 5.
The molecular structure of compound 15 is confirmed by
single crystal X-ray analysis. To the best of our knowledge, this
particular fusion of the two pyrene units sharing a bond has been
so far unknown. The pyreno[1,2-a]pyrene core of 18 within a
configurationally locked helicene backbone was reported very
recently by Chalifoux and co-workers.[12] Because compound 18
possess unsubstituted cove region, the interconversion of the two
stereoisomers is fast at room temperature.
Pyrenes are among the most popular chromophores with a
number of interesting properties useful for a broad range of
applications.[17] The photophysical characterization of selected
compounds reveal several interesting structural effects on
absorption and emission (see SI for additional details).[18] For
example, isomeric pyrano[a]pyrene 15 and 18, with C2h and C2v
symmetry, respectively, exhibit contrasting photophysical
properties (Figure 1). The S0-S1 transition of 18 is ~4-times
weaker than for 15. The disparity in allowedness of this transition
is further exemplified by the ~10-times longer excited state
lifetime and >20-fold slower radiative rate for 18 compared to 15.
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
0.0
Emission
Absorption
Emission
Absorption
Functionalization of iodo-substituted pyrene and peropyrene
products (Scheme 6) expands the relatively scarce current
synthetic approaches to such substituted polyaromatics.[13] Suzuki
cross coupling of pyrene 5i with 4-cyanophenylboronic acid yields
pyrene 19 in 68% while treatment on 4-iodo-peropyrene 10e with
CuCN delivers CN-substituted peropyrene 20. Structures of these
products are confirmed by X-ray crystallography.[14] In both cases,
the pendant phenyl rings are nearly orthogonal to the central
arene core. The contrasting conformations of the two methoxy
groups in 19 highlight the “stereoelectronic chameleon”[15]
behaviour of -OMe groups.[16]
300
400
500
600
700
300
400
500
600
Wavelength (nm)
Wavelength (nm)
Figure 1. Normalized absorption and emission spectra for the pyranopyrenes
15 (left) and 18 (right)
In summary, we have developed a modular, and general
method for extension that opens access to non-symmetric
pyrenes and their expanded analogues. This cascade is made
possible by selective Ar-I bond activation in the presence of an
alkyne. Potentially, this approach can convert any aromatic ring
bearing a -CH2Br or a –CHO group into a pyrene moiety. The
process can be directed towards either tin- or iodo-substituted
products, giving complementary choices for further various cross-
coupling reactions. The two-directional bis-double annulation
adds two new polyaromatic extensions with six new aromatic
rings at the central core.
Acknowledgements
Financial support of this work by the National Science Foundation
is gratefully acknowledged (CHE1800329 to I.A., DMR-1752782
to K. H.). We thank Dr. R. J. Clark and Dr. X. Lin for X-ray
crystallographic analysis. This work made use of the Rigaku
Scheme 6. Transformations of Iodinated pyrene 5i and peropyrene 10e
4
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[12] R. Bam, W. Yang, G. Longhi, S. Abbate, A. Lucotti, M. Tommasini, R.
Franzini, C. Villani, V. J. Catalano, M. M. Olmstead, W. A. Chalifoux, Org.
Lett. 2019, 21, 8652-8656.
Synergy-S single-crystal X-ray diffractometer which was acquired
through the NSF MRI program (CHE-1828362).
[13] V. M. Nichols,M.T.Rodriguez, G. B. Piland, F. Tham, V. N. Nesterov, W. J.
Youngblood,C.J.Bardeen, J. Phys. Chem. C 2013, 117,16802-16810.
[14] CCDC 1998110 (5b), 1998108 (10d), 1998107 (12a), 1987234 (15),
1987233 (19), 1998109 (20) contain the supplementary crystallographic
data. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre.
Keywords: annulation • alkyne • radical • arenes • pyrenes
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5
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Entry for the Table of Contents
From benzene to pyrene: A new modular design for the phenalenannulation is developed, which can potentially crowns phenalene unit
on any aryl core bearing -CH2Br group. The three point radical annulation can be directed towards either tin- or iodo-substituted products,
giving complementary choices for further various cross-coupling reactions. The two-directional bis-double annulation adds two new
polyaromatic extensions with six new aromatic rings at the central core.
6
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