Synthesis of Fluorescent 4-Azapyrenes by Palladium(II)-Catalyzed Dual C?H Bond Activation and Annulation

Article abstract of DOI:10.1002/adsc.202001404

Unique dual-emissive and deep-blue/green fluorescent multi-substituted 4-azapyrenes with bathochromic shift emission, quantum yields up to 0.60 and long excited-state lifetime were synthesized successfully by annulative π-extension reactions. This synthesis constitutes a palladium-catalyzed dehydrogenative annulation of N-acyl-2-aminobiaryls with in situ 1,3-diynes as a key step, giving substituted phenanthrenes via a rollover C?H bond activation, followed by Bischler-Napieralski cyclization. Further π-extension by superacid-mediated cyclization produced a blue fluorescent naphtho 4-azapyrene. (Figure presented.).

Full text of DOI:10.1002/adsc.202001404

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DOI: 10.1002/adsc.202001404
Synthesis of Fluorescent 4-Azapyrenes by Palladium(II)-Catalyzed
Dual CÀ H Bond Activation and Annulation
Huan-Chang Hsiao,a, b Pratheepkumar Annamalai,a, b Jayachandran Jayakumar,a, b
Shang-You Sun,a, b and Shih-Ching Chuanga, b,*
a
Department of Applied Chemistry, National Chiao Tung University, Hsinchu 30010, Taiwan
E-mail: jscchuang@faculty.nctu.edu.tw; jscchuang@nycu.edu.tw
Department of Applied Chemistry, National Yang Ming Chiao Tung University, Hsinchu 30010, Taiwan
b
Manuscript received: November 20, 2020; Revised manuscript received: January 27, 2021;
Version of record online: Februar 4, 2021
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202001404
Abstract: Unique dual-emissive and deep-blue/green fluorescent multi-substituted 4-azapyrenes with bath-
ochromic shift emission, quantum yields up to 0.60 and long excited-state lifetime were synthesized
successfully by annulative π-extension reactions. This synthesis constitutes a palladium-catalyzed dehydrogen-
ative annulation of N-acyl-2-aminobiaryls with in situ 1,3-diynes as a key step, giving substituted
phenanthrenes via a rollover CÀ H bond activation, followed by Bischler-Napieralski cyclization. Further π-
extension by superacid-mediated cyclization produced a blue fluorescent naphtho 4-azapyrene.
Keywords: palladium catalysis; phenanthrene; fluorescence; 4-azapyrene; CÀ H activation
Introduction
threnes have been critical synthetic building blocks for
synthesizing complex molecules and natural products,
Heteroaromatic hydrocarbons have received substantial and the developed synthetic approaches towards
attention in the fields of physical organic chemistry,[1] phenanthrenes have relied on photochemical synthesis,
natural product chemistry,[2] molecular biology,[3] and Pd-catalyzed coupling of aryl halides,[12] and Pd-
material science[4] due to their atypical physical proper- catalyzed decarboxylative coupling of 2-phenylbenzoic
ties exhibited through heteroatom doping. Specifically, acids with alkynes (Scheme 1a).[13] The N-(9,10-
dual-emissive fluorescent organic molecules are bene-
ficial for organic light-emitting diode materials and
bioimaging applications,[5] making them noteworthy
synthetic targets for transition-metal catalysis.[6] In the
conventional approaches, prefunctionalized substrates
such as organohalides, pseudohalides, and moisture-
sensitive organometallic compounds are employed as
reagents for various annulation reactions.[7] Transition-
metal-catalyzed and directing group-assisted multiple
CÀ H bond activation is a recent, promising synthetic
methodology that facilitates the synthesis of annulated
π-conjugated molecules using simple and available
precursors.[8] Azapyrenes and their isomeric analogues
containing mono- and di-cations have exhibited inter-
esting pharmacological properties as well as antiviral,
antibacterial, and anticancer activity.[9] However, pre-
vious syntheses of 1-aza, 2-aza and 4-azapyrenes have
relied on conventional multistep organic synthesis,[10]
wherein the parent azapyrenes typically exhibit
fluorescence below 400 nm.[11] Additionally, phenan-
Scheme 1. Annulation reactions by using CÀ H bond activation
for synthesis of a) phenanthrenes b) bisheterocycles c) sub-
stituted phenanthrenes and 4-azapyrenes.
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diphenylphenanthren-4-yl)acetamide was reported to
be a byproduct (<6%) in the reaction of N-acyl 2-
aminobiphenyl with diphenylacetylene under Pd-catal-
ysis through dual CÀ H bond activation.[14] Further-
more, 1,3-diynes have been prepared from the Glaser-
Hay reaction and are widely applied for preparing
diverse arenes and heteroarenes.[15] Glorius et al. first
reported a rhodium-catalyzed regioselective annulation
of benzamides with 1,3-diynes through CÀ H bond
activation for the synthesis of diverse polysubstituted
bisheterocycles (Scheme 1b).[16]
Table 1. Condition Optimization studies for the synthesis of
substituted phenanthrenes.[a]
Entry Oxidants
(equiv.)
Solvent
(mL)
Additives
(equiv.)
Yield
[%][d]
1
Cu(OAc)2 (1) DMF (2)
NaOAc (1)
NaOAc (1)
NaOAc (1)
NaOAc (1)
LiOAc (1)
KOAc (1)
29
9
2[b] Cu(OAc)2 (1) DMF (2)
To uncover the photophysical properties of sub-
stituted 4-azapyrenes, we explored the feasible syn-
thesis of 4-azapyrenes through the annulation of 2-
aminobiaryls 1 with alkynes 2 to phenanthrenes
followed by Bischler-Napieralski cyclization.[17] This
approach demands an efficient rollover CÀ H bond
activation,[18] which was previously considered imprac-
tical with the use of 2-aminobiaryls as substrates due
3[c]
4
5
6
7
Cu(OAc)2 (1) DMF (2)
CuCl(1) DMF (2)
Cu(OAc)2 (1) DMF (2)
Cu(OAc)2 (1) DMF (2)
28
22
35
17
12
38
Cu(OAc)2 (1) DMSO (2) LiOAc (1)
8
Cu(OAc)2
(1.5)
DMF (2)
LiOAc (1)
9
Cu(OAc)2 (2) DMF (2)
LiOAc (1)
45
51
57
45
63
to the inherently strong Pd(II)À N bonding in the 10[e] Cu(OAc)2 (2) DMF (4) LiOAc (1)
11[f] Cu(OAc)2 (2) DMF (4)
12[f] Cu(OAc)2 (2) DMF (4)
13[f] Cu(OAc)2 (2) DMF (4)
14[f] Cu(OAc)2 (2) DMF (4)
LiOAc (1)
AcOH (10)
PivOH (10)
palladacycle (Scheme 1c). After extensive analysis,
however, the 1,3-diynes generated in situ from readily
available terminal alkynes were recognized as a
suitable coupling partner for a comprehensive study on
π-extended annulation-producing phenanthrenes in a
reliable, straightforward catalytic system. The prod-
ucts, phenanthrenes 3, were treated with POCl3 that
underwent Bischler-Napieralski reaction to provide
substituted dual emissive and deep-blue/green fluores-
cent 4-azapyrenes 4 through an intramolecular electro-
philic aromatic substitution reaction. Further π-exten-
sion of 4-azapyrenes by superacid-mediated
cyclization produced a blue fluorescent naphtho 4-
azapyrene 5. These multi-substituted 4-azapyrenes
exhibited bathochromic shift and dual fluorescent
emission beyond 400 nm.
Propionic acid 86
(10)
15[f] Cu(OAc)2 (2) DMF (4)
16[f] Cu(OAc)2 (2) DMF (4)
n-Butyric acid 56
(10)
i-Butyric acid
(10)
–
58
3
17
Cu(OAc)2 (1) DMF (2)
[a] All reactions were performed with 1a (0.1 mmol), 2a
(0.2 mmol), 10 mol% of Pd(OAc)2 and oxidants in the listed
°
solvent under O2 (1 atm) at 120 C for 24 h unless otherwise
noted.
[b]
°
80 C.
[c]
°
100 C.
[d] Yields were determined by 1H NMR spectroscopy using
dimethyl maleate as an internal standard.
[e] 4 equiv. of 2a.
Results and Discussion
[f] 6 equiv. of 2a.
We first embarked on the successful rollover CÀ H
bond activation methodology for the preparation of
phenanthrenes. The initial attempt with N-acyl 2- as the polar aprotic solvent DMSO was not effective
aminobiphenyl (1a, 0.1 mmol), phenylacetylene (2a, for product formation (entry 7).
0.6 mmol), Pd(OAc)2 (0.01 mmol), NaOAc (1 equiv.),
When the amount of Cu(OAc)2 was increased from
and Cu(OAc)2 (2 equiv.) under O2 atmosphere in N,N- 1 to 1.5 and 2.0 equivalents, product formation
°
dimethyl formamide (DMF) at 120 C for 24 h increased to 38% and 45%, respectively (entries 8–9).
produced substituted phenanthrene 3a in 29% yield Therefore, we confirmed that the combination of
(Table 1, entry 1). The product was systematically Cu(OAc)2/O2 and DMF played a crucial role, likely for
1
analyzed by using H and 13C NMR spectroscopy and in situ oxidative coupling of phenylacetylenes. By
further proved by single-crystal X-ray diffraction further increasing to 4.0 and 6.0 equivalents of phenyl-
(XRD) technique (see the Supporting Information). acetylene using LiOAc as an additive and diluting the
Furthermore, lowering the reaction temperature to solution, the reaction yields were increased to 51% and
°
°
80 C and 100 C produced 9% and 28% of 3a 57% respectively (entries 10–11). After reaching an
respectively (entries 2–3), and changing the oxidant to optimal yield of 57% using basic additives, we turned
CuCl (1.0 equiv.) was found ineffective (entry 4). to screen acid additives for breaking the Pd(II)À N
Next, LiOAc was found as relatively more promising bond in the inert palladacycle intermediate, thereby
additives than KOAc (entries 5–6), and solvents such enhancing the rollover cyclometalation for concerted
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metalation deprotonation (CMD) pathway.[19] Among provided similar yields: the down ring R2 containing
the tested additives, propionic acid was found to be 4’-OMe or 4’-Me and the upper ring R1 with 4-methyl
promising and produced an 86% yield, compared with group had similar electronic effects and produced up to
other acid additives such as acetic acid, pivalic acid, 71% yields (3j–3l). Substrates with EDGs on both R1
isobutyric acid, and butyric acid (Entries 12–16). A and R2 rings were also well-tolerated, leading to
control experiment without acid or base as additives favourable conversion and yielded 84% of 3m.
gave only 3% of 3a. Based on the aforementioned Furthermore, the electronic interplays between strong
systematic screening and various reaction parameters, EWGs as well as the combination of both donating and
two different catalytic conditions were summarized: withdrawing moieties showed slightly negative effects,
entry 11 was optimal for basic condition, and entry 14 resulting in [4+2] annulated products 3n–3p with
was optimal under acidic conditions.
moderate yields (45%–62%). Although less efficient,
Scheme 2 summarizes the substrate scope for the the substrate with strong EWGs on both rings also
developed [4+2] annulation strategy. A variety of resulted in the formation of 3q in 44% yield. Notably,
arylacetylenes with electron-donating groups (EDGs) the annulation was relatively more efficient when the
or electron-withdrawing groups (EWGs) smoothly down ring was equipped with an EDG that increased
underwent the cyclization reaction with N-acyl 2- the rate of the first CÀ H bond activation.
aminobiphenyl 1, rendering a series of substituted
We further extended the applicability of the
phenanthrenes in moderate to good yields. Initial methodology to other aliphatic alkynes. However, the
screening of EDGs present on the arylacetylenes, such most favourable condition (Table 1, entry 14) was not
t
n
as Me, Bu, OCH3, and Bu, with 1a proceeded in suitable for aliphatic alkynes. We adapted the optimal
moderate to good conversion, producing desired condition under basic conditions (entry 11). All the
products with 61%–92% yields (Scheme 2, 3a–3e); acyclic and cyclic alkyl alkynes successfully rendered
this was attributed to electronic effects exerted from the formation of corresponding products with complete
EDGs on arylacetylenes. EWGs on arylacetylenes also selectivity and in synthetically useful yields
showed a positive effect on the cyclization reaction (Scheme 3). The observed moderate yields for 3r–3y
and produced corresponding products in good yields were caused by the incomplete conversion of the
(80%–82%, 3f–3g). In addition, reactions with 3- starting materials. The corresponding yields with these
ethynyl thiophene also produced the desired product aliphatic terminal alkynes are relatively lower under
3h with a moderate 58% yield. Furthermore, this study the acid condition, likely due to less efficient homo-
investigated the steric effect by using N-acyl 2- coupling of these alkynes. Interestingly, the reaction of
naphthyl aniline as a substrate-rendering the desired 1a with 2-methylbut-3-yn-2-ol (2i) rendered an oxi-
annulation and showed amide rotamers with a moder- dized product lactone 3r in 41% yield, as confirmed
ate yield of 57% (3i). The interplay of the electronic by single-crystal XRD, while its mechanistic pathway
effect (R1 and R2 =EDGs) on both the aryl rings of formation remained unclear. Cyclic aliphatic al-
kynes, such as cyclopropyl (2j), cyclopentyl (2k), and
cyclohexyl (2l), also resulted in oxidative [4+2]
annulation to produce moderate yields of 40–47% (3s–
Scheme 2. Substrate scope study.a)
Scheme 3. The substrate scope of aliphatic alkynes.a)
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3u). Acyclic aliphatic alkynes, such as n-pentyl (2m), yield of product 3a using 1,3-diyne as the substrate
n-hexyl (2n), n-octyl (2o), and n-decyl (2p), also indicated that the desired reaction may proceed at a
produced moderate yields of (3v–3y). The overall lower concentration of 1,3-diyne during the reaction
yields of aliphatic alkynes for this [4+2] annulation course, and may form a chelating complex that
were moderate, presumably due to their less efficient disabled the progress of reaction at higher concen-
in situ 1,3-diyne formation.
tration of 2a’.[20] A kinetic isotope effect study revealed
In the control experiments, we first verified that a kH/kD value of 3.01 for the formation of 3a/3a–d4 in
1,3-diynes were formed as an intermediate using a 10-min reaction, indicating a primary kinetic isotopic
arylacetylenes in the standard reaction condition with effect and that CÀ H bond activation might be the rate-
and without palladium acetate, producing 87% and limiting step (Scheme 4d). An asymmetric diynoate
89% of 1,3-diynes, respectively (Scheme 4a-b). It was 2q’ underwent insertion and annulation to form 3z in
a modified Glaser-Hay reaction for the current catalytic 52% yield selectively (Scheme 4e).
system.[11] Furthermore, the reaction carried out by
A tentative yet plausible mechanism involving the
using 1a and the prepared 1,3-diyne 2a’ in the formation of in situ 1,3-diyne from modified Glaser-
standard condition yielded 46% of 3a, accompanied Hay coupling and rollover CÀ H activation/annulation
with 40% of unreacted 1a (Scheme 4c). The decreased is presented in Scheme 5. Initially, the ortho CÀ H bond
was activated on the 2-aryl moiety to yield intermedi-
ate Ia after coordination of substrate 1 with palladium
(II). Coordination and selective migratory insertion of
in situ 1,3-diyne 2’ with intermediate Ia produced an
eight-membered palladacycle Ib. The acid additives
may play a crucial role in the dissociation of the
Pd(II)À N bond that led to intermediate Ic. Further-
more, alkenyl-palladium rollover metalation directed
C3À H activation to a seven-membered palladacycle Ie
through a CMD pathway. The rollover took place
likely due to the steric repulsion imparted by NHAc
and alkenyl-palladium moiety after dissociation of the
Pd(II)À N bond. Subsequently, reductive elimination
gave phenanthrenes 3 exclusively and Pd(0). The
catalytic cycle was furnished by oxidation of Pd(0) to
Pd(II) with Cu(II). With basic additives LiOAc, the
Pd(II)À N bond of Ib may be dissociated and displaced
by acetate. We did not observe formation of multiaryl-
substituted naphthalenes as side-products in the present
work.[14] This is likely due to the possible coordination
of Cu(OAc)2 to the diynes that imparts sterics,
preventing further annulation to form multiaryl-sub-
Scheme 4. Control experiments.
stituted naphthalenes.
Furthermore, selected phenanthrenes 3 were trans-
formed to 4-azapyrenes 4a–4f in moderate to good
yields via Bischler-Napieralski electrophilic annulation
by using POCl3 (Scheme 6). The chemical yield for the
formation of fluoro-substituted 4-azapyrene 4f was
moderate, likely due to its electron-deficient electronic
effect. Except for 4c, these substituted 4-aza-pyrenes
were relatively stable at ambient temperature and
showed deep-blue or green fluorescence.
Phenanthrene 3a and 4-azapyrene 4a were treated
with triflic acid that formed annulated compound 5a’
and 6 in 61% and 78% yields, respectively. The
distinguished chemical reactivity of these two distinct
moieties toward protonation by the superacid was
attributed to their different electronic properties posed
by the amide moiety on phenanthrene. The sp-
hybridized carbon distal to the phenanthrene was
Scheme 5. Proposed catalytic cycle.
relatively more electron-rich due to the resonance
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Scheme 6. Synthesis of 4-azapyrenes.a)
Figure 1. Solid state structures of 3a, 3r, 3z, 4a, 5a’, and 6
drawn at 30% probability.
effect exerted by amide group, and that closer to the 4-
azapyrene was more electron-rich. Therefore, their
protonations occurred at different sp carbon that C3À C4À C13À C26 in 3z are 18.5(3) and À 15.2(3),
resulted in different sizable ring annulation respectively. However, phenanthrene in 3r is less
(Scheme 7). Notably, compound 5b’ could not be distorted due to an extended lactone moiety that locks
formed under Bischler-Napieralski condition; instead, its planar structure, evidenced by a small dihedral
compound 5 was obtained where the exo-cyclic C=C angle C3À C4À C5À C17 of À 3.2(5). This distortion is
bond was cleaved to form a ketone, which is likely due also displayed in the structure of 5a’. Finally, the
to the reaction of alkenyl moiety with nitrilium ion azapyrene moiety in 4a and 6 are nearly planar with
followed by hydrolysis (See Scheme S1 for a proposed torsional angles less than 0.5 degree.
mechanism).
The substituted 4-azapyrenes, featuring methyl,
The solid state crystal structures of molecules 3a, phenyl and alkynyl substitutions at 5, 9, and 10
3r, 3z, 4a, 5a’, and 6 are shown in Figure 1, positions, showed promising photophysical properties
supporting the molecular structure of prepared com- and exhibited typical absorption bands from 355 to
pounds unambiguously.[21] Their single crystals suitable 394 nm (Figure 2). In the case of 4b and 4c, one
for X-ray diffraction analysis were grown by thermal additional visible band related to charge transfer was
evaporation from their hexane and dichloromethane observed spanning from 400 to 475 nm, likely attrib-
(1:1) solution at room temperature. A notable dis- uted to the nature of the substituents. The fluorescence
tortion of the phenanthrene moiety from planarity studies exhibited a strong dual-emission in the visible
occurs due to the steric imparted by NHAc, phenyl- region at 375–500 nm (Table S7). According to the
ethynyl, and phenyl groups. The dihedral angle for Franck-Condon principle, the anomalous dual-emission
C10À C9À C13À C30
in
3a
and
that
for behaviour of 4-azapyrene chromophore involves non-
radiative vibrational relaxation and emission in two
distinct excited electronic states.[22] In comparison with
UV-vis studies, the nature of the substituent played a
crucial role in the emission wavelength (λem), varying
from purple-blue to blue colour emission. Furthermore,
4b showed a larger Stokes shift (54 nm), suggesting
high polarizability in the π-conjugated systems with
respect to other compounds (4a–4f), likely imparted
by EDGs on the alkynyl moiety. The obtained
azapyrene quantum yields ΦF (0.29–0.60) in CHCl3
depended on the nature and position of the substituent.
Except for 4c and 4f having fluoro substituents, 4-
Scheme 7. TfOH-mediated annulations of 3a and 4a.
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acetate followed by filtration through a thin pad of Celite. The
filtrate was concentrated under vacuum and purified by silica
gel column chromatography (hexanes/EtOAc) to afford N-(9-
phenyl-10-(phenylethynyl)-9,10-dihydrophenanthren-4-yl)
acetamide 3.
General Procedure for the Synthesis of
4-Azapyrenes 4
Compound 3 (0.05 mmol), POCl3 (3 equiv.), a stir bar and
freshly distilled DCE (6 mL) were added to a dried reaction
tube under nitrogen. Then the tube was closed with a screw cap
°
and then placed in an oil bath at 110 C with vigorous stirring
for 12 h. Upon completion of the reaction, the reaction mixture
was quenched with ice and then worked up with saturated
sodium bicarbonate solution, and extracted with ethyl acetate.
The organic layer was concentrated under vacuum and purified
by silica gel column chromatography (hexanes/EtOAc/MeOH)
to afford 4.
Figure 2. The UV-vis absorption (dotted line) and emission
(solid line) spectra of compounds 4a–4f and 6 in chloroform at
298 K.
Acknowledgements
azapyrenes 4a–b and 4d–4e exhibited ΦF greater than
0.42 and relatively longer fluorescence lifetime (10.7–
18.1 ns). Notably, the π extended naphtho 4-azapyrene
6 exhibited deep-blue emission at 410 nm with narrow
full width half maximum of 52 nm and a fluorescence
lifetime of 7.0 ns.
We thank the Ministry of Science and Technology of Taiwan
(MOST108-2113-M009-020-MY3) for support of this research.
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Conclusion
To conclude, a novel methodology constituting a
palladium-catalyzed dehydrogenative annulation of N-
acyl-2-aminobiaryls with in situ 1,3-diynes to phenan-
threnes, via a rollover CÀ H bond activation, followed
by Bischler-Napieralski cyclization is demonstrated
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