One-pot synthesis of benzofluorene fused aromatic hydrocarbons

Article abstract of DOI:10.1016/j.tetlet.2019.151299

A new and efficient synthetic approach for the one-pot construction of benzofluorene fused aromatic hydrocarbons was developed via a transient-directing group strategy. The palladium-catalyzed cascade reaction proceeded via consecutive arylation, cyclization and aromatization steps. Moderate to good yields along with broad functional group tolerance were achieved under mild reaction conditions.

Full text of DOI:10.1016/j.tetlet.2019.151299

Journal Pre-proofs
One-pot synthesis of benzofluorene fused aromatic hydrocarbons
Wendan Dong, Zhun Hu, Ziqi Wang, Bing Sun, Xueqiong Zhang, Fang-Lin
Zhang
PII:
S0040-4039(19)31082-2
DOI:
https://doi.org/10.1016/j.tetlet.2019.151299
TETL 151299
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 August 2019
12 October 2019
16 October 2019
Please cite this article as: Dong, W., Hu, Z., Wang, Z., Sun, B., Zhang, X., Zhang, F-L., One-pot synthesis of
benzofluorene fused aromatic hydrocarbons, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.
2019.151299
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One-pot synthesis of benzofluorene fused
aromatic hydrocarbons
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Wendan Donga, †, Zhun Hub, †, Ziqi Wanga, Bing Suna, Xueqiong Zhanga, , and Fang-Lin Zhanga, 
R1 R1
Pd(OAc)2 10 mol%
AgTFA
Glycine 1.0 eq.
R1 R1
CHO
CH3
+
I
I
R2
TfOH 1.0 eq.
AcOH 100 oC 24 h
R2
R2
R1 = C4H9, C6H13, C8H17, C10H21, C12H25
R2 = CH3, OCH3, F, Cl, Br,
Yield 23-91%

1
Tetrahedron Letters
journal homepage: www.elsevier.com
One-pot synthesis of benzofluorene fused aromatic hydrocarbons
Wendan Donga,†, Zhun Hub,†, Ziqi Wanga, Bing Suna, Xueqiong Zhanga, , and Fang-Lin Zhanga, 
aSchool of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan 430070, PR China
bWuhan Huabenhui Medical Development Co., Ltd., Wuhan 430075, PR China.
———
ARTICLE INFO
ABSTRACT
 Corresponding author. Tel.: +86-27-87859019; fax: +86-27-87859019; e-mail: zhangxq@whut.edu.cn
 Corresponding author. Tel.: +86-27-87859019; fax: +86-27-87859019; e-mail: fanglinzhang@whut.edu.cn
Article history:
A new and efficient synthetic approach for the one-pot construction of benzofluorene fused
†
Received
aromatic hydrocarbons was developed via a transient-directing group strategy. The palladium-
These authors contributed equally.
Received in revised form
Accepted
Available online
catalyzed cascade reaction proceeded via consecutive arylation, cyclization and aromatization
steps. Moderate to good yields along with broad functional group tolerance were achieved under
mild reaction conditions.
2009 Elsevier Ltd. All rights reserved.
Keywords:
Palladium
Transient directing group
One-pot
Aromatization
Polycyclic aromatic hydrocarbons
Previous work: Synthesis of benzofluorenes via multi-step reactions:
1. Introduction
(A) Mohanakrishnan and co-workers10
:
1) Zn dust, HgCl2
concd. HCl, H2O
r.t., 30 min
Benzofluorenes, an important class of polycyclic aromatic
hydrocarbons (PAHs) with rigid planar biphenyl structures,
constitute the core of a variety of biologically active compounds,1
such as secondary metabolites2 which were isolated from
Streptomyces murayamaensis. Moreover, the stable organic
radical containing benzofluorene structure can be used as ligands
in the fields of organometallic and coordination chemistry3 as
well as organic semiconductors.4 Meanwhile, their unique optical
and electronic properties as well as electron-rich structures5
endow them with extensive applications in organic light-emitting
diodes (OLEDs),6, 8 organic field-effect transistors (OFETs)7 and
organic solar cells.8 Due to their widespread applications,
significant efforts have been devoted to the development of new
and efficient synthetic methods for benzofluorenes.9
Mohanakrishnanet reported the synthesis of benzofluorenes
involving cyclization-reductive-dehydration reactions, where 2-
arylmethylnaphthoic acids underwent triflic acid-mediated
cyclization followed by reductive dehydration to give annulated
anthracenes (Scheme 1A).10 Serevičius reported a new synthetic
route to unsymmetrical 2-phenylanthracene and its derivatives
with bridging carbons, as well as the thermal, optical and
electrical properties of these materials (Scheme 1B).11 Wu
reported an efficient preparation of fluorenes and methylene-
bridged polyarenes from haloarenes (or aryl triflates) and
diarylethynes via a one-pot, two-step procedure. This protocol
1) 20 mol% CF3SO3H
dry CH2Cl2, r.t., 30 min
O
HOOC
HOOC
2) NaBH4/EtOH/THF
r.t., 10 min
2) H2O concd, HCl
toluene, reflux
R
48 h
R
R
R
R
3) HCl/H2O
R
R
R
(B) Serevicius and co-workers11
R
:
phthalic anhydride
AlCl3
R
PPA, 80-150 o
NaBH4, diglyme
C
MeOH
(C) Wu and co-workers12
:
1,2-diphenylethene
PdCl2, DPPE
KOH, t-BuOK
18-crown-6
N2H4, reflux
Br
CsOPiv, DBU
Dioxane, reflux
(D) Our previous work: Pd-catalyzed transient directing group strategy for the synthesis
of PAH precursors13,14:
R1
O
I
R1
CHO
Pd 10 mol%
R1
+
R1
TfOH
R1
R1
CH3
O
I
CHO
CH3
I
+
2
R2
R1
Pd 10 mol%
R
(E) This work: one-pot construction of benzofluorenes by Pd catalysis via a transient-directing
group strategy:
R1 R1
R1 R1
CHO
10 mol%
Pd
CH3
I
I
+
2
R
TfOH
R2
R2
Scheme 1. Previous synthesis methods (A-D) and the present
synthesis method (E).
involved palladium-catalyzed cycloisomerization and subsequent
base-mediated retro-aldol condensation (Scheme 1C).12 However,
all the above known methods typically require multiple steps and
harsh reaction conditions, and generate stoichiometric amounts of
waste. Recently, we reported the palladium-catalyzed ortho-
C(sp3)–H arylation of benzaldehydes with aryl diiodides for the
synthesis of PAHs precursors via a transient directing group.
However, a two-step procedure was required to access the final
target product.13 Subsequently, we reported the one-pot Pd(II)-

2
catalyzed C(sp3)–H arylation of benzaldehydes via a transient
directing group strategy and further accessed anthracene and
tetraphenylene via cyclization and aromatization.14 Nevertheless,
the above one-pot approach is restricted to the functionalization
of aryl monoiodides, which limits its further application (Scheme
1D). Herein, we report a new and efficient strategy for the
synthesis of benzofluorenes with a fused ring structure via a one-
step cascade reaction sequence (Scheme 1E).
temperature for this reaction was determined as 100 °C (Table 1,
entries 16-18).
With the optimized procedure in hand, the reaction of a broad
scope of benzaldehydes with various diiodobenzenes was probed
(Table 2). When o-methylbenzaldehyde is substituted with
electron-donating groups, the yields were significantly reduced
(3af, 3ah). To our delight, a series of halogenated products were
all transformed into the corresponding products in moderate to
good yields (3aa, 3ac-3ae and 3ag). Moreover, the heterocyclic
aldehyde 3ai also reacted well to provide the expected product in
moderate yield (3ai). To improve the substrate solubility in
organic solvents, a series of straight chain alkyl groups were
introduced at the C9-position of the iodofluorenes. The length of
the alkyl chain on 2,7-diiodoindole did not exert an obvious
effect on the yields (3an, 3ao). The X-ray crystal structure of
compound 3ag is shown in Figure 1.15
2. Results and Discussion
To explore the feasibility of this strategy, 9,9-dibutyl-2,7-
diiodo-9H-fluorene (1a) and 2-fluoro-6-methylbenzaldehyde (2a)
were used as model reactants to explore the optimal reaction
conditions (Table 1). After extensive screening, we found that the
reaction conditions must include the followings: 10 mol%
Pd(OAc)2, 1.0 equiv. glycine and TfOH in AcOH with 3.0 equiv.
AgTFA. This reaction was sensitive to the amount of glycine and
AgTFA (Table 1, entries 1-6). The best result was obtained in the
presence of 1.0 equiv. glycine and 3.0 equiv. AgTFA (Table 1,
entry 2). As an essential additive, TfOH was a key factor leading
to the intramolecular aromatization to afford the arylation
product. The optimized amount of TfOH was found to be 1.0
equiv., showing superior yield than the cases of a higher or less
amount of TfOH (Table 1, entries 7-8). Systematic screening of
the solvents revealed that the reaction proceeded only when
Table 2. Substrate scope investigation.
R1
R1
Pd(OAc)2 (10 mol%)
AgTFA
Glycine 1.0 eq.
R1
CHO
Het
R1
I
I
R
+
R2
TfOH 1.0 eq.
R2
AcOH 100 oC 24 h
1
2
3
C4H9 C4H9
C4H9 C4H9
R
a
a
R
Table 1. Optimization of the reaction conditions.a
R
R
3aa
3ac
R=F,
80%
R=F,
72%
a
3ad
R=Br,
47%a
3ab
R=H.
70%
C4H9 C4H9
O
Pd(OAc)2 (10 mol%)
Glycine
C4H9
C4H9
C4H9 C4H9
C4H9 C4H9
F
H3C
AgTFA
CH3
I
I
+
R
Additive
Solvent T oC 24 h
R
F
F
a
1a
2a
3ae
R=F,
R=CH3,
3ag
45%
3aa
a
a
3ah
65%
R
3af
47%
a
Entry Glycine AgTFA
(equiv.) (equiv.)
Additive
(equiv.)
Solvent
Yield
3aa
R=Cl,
83%
R
C4H9 C4H9
1
0.5
1.0
1.5
2.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
3.0
3.0
3.0
3.0
1.5
4.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
TfOH 1.0
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
TFA
33%
Br
2
TfOH 1.0
TfOH 1.0
TfOH 1.0
TfOH 1.0
TfOH 1.0
TfOH 1.5
TfOH 0.5
-
80%
81%
82%
65%
81%
79%
31%
trace
N.R.
N.R.
N.R.
N.R.
N.R.
N.R.
81%
67%
trace
S
S
Br
a
a
3aj
45%
R=C6H13
,
,
a
3ai
51%
3ak
R=C8H17
R
35%
3
R
C8H17
C8H17
4
R
R
5
6
a
a
, 3an
3al
R=C10H21
26%
R=Cl,
R=F,
42%
a
7
3am
R=C12H25, 3ao 23%a
60%
C8H17
C8H17
C8H17
C8H17
C8H17
C8H17
8
R
R
9
F
b
10
11
12
13
14
15
16b
17c
18
-
3bd
R=CH3,
55%
b
b
3ba
R=H,
R=CH3,
3bc
71%
b
3be
R=F,
58%
b
3bh
70%
3bb
53%
b
TfOH 1.0
TfOH 1.0
TfOH 1.0
TFA 1.0
TFA 5.0
TfOH 1.0
TfOH 1.0
TfOH 1.0
DCE
b
3bf
R=Cl,
R=Br,
60%
R=F,
C8H17
77%
b
3bg
57%
DCM
THF
C8H17
R
R
R1
AcOH
AcOH
AcOH
AcOH
AcOH
R2
F
b
3bl
R=C4H9,
R=C6H13
R=C8H17
90%
1
2
3bi 53%b
3bj
R =H, R =CH3,
b
3bm
3bn
,
,
91%
1
2
b
R =CH3, R =CH3,
61%
b
b
74%
1
2
3bk
R =Br, R =CH3,
,74%
b
3bo
3bp
R=C10H21
R=C12H25
,
,
68%
b
74%
a Reagents and conditions: 1 (0.2 mmol, 1.0 equiv.), 2 (0.5 mmol,
2.5 equiv.), Pd(OAc)2 (10 mol %), AgTFA (3.0 equiv.), glycine
(1.0 equiv.), TfOH (1.0 equiv.), AcOH (1.0 mL), 100 °C, 24 h.
Isolated yields.
a
Reagents and conditions: 1a (0.1 mmol, 1.0 equiv.), 2a (0.25
mmol, 2.5 equiv.), Pd(OAc)2 (10 mol%), solvent (1.0 mL), 100
°C, 24 h. Isolated yields.
b 120 °C.
b 2 (0.3 mmol, 1.5 equiv.), AgTFA (1.5 equiv.).
c 80 °C.
AcOH was used (Table 1, entries 9-13). No reaction occurred
with either 1.0 equiv. or 5.0 equiv. of TFA (Table 1, entries 14-
15). Meanwhile, a minimum temperature was required for this
reaction. When the temperature was lower than 50 °C, only trace
amounts of products were observed. Additionally, there was no
significant improvement at 120 °C. Therefore, the optimum
Figure 1. X-ray structure of 3ag.

3
8. Beaupré, S.; Boudreault, P. L. T.; Leclerc, M. Adv. Mater.
2010, 22, 6.
9. (a) Itoh, M.; Hirano, K.; Satoh, T.; Shibata, Y.; Tanaka, K.; Miura,
M. J. Org. Chem. 2013, 78, 1365. (b) Bucher, J.; Wurm, T.;
Taschinski, S.; Sachs, E.; Ascough, D.; Rudolph, M.; Rominger,
F.; Hashm. A. S. K. Adv. Synth. Catal. 2017, 359, 225. (c)
Rodrìguez, D.; Domingo Quintás, D.; Garcìa, A.; Saá, C.;
Domìnguez, D. Tetrahedron Lett. 2004. 45. 4711.
10. Rafiq, S. M.; Sivasakthikumaran, R.; Karunakaran, J.;
Mohanakrishnan, A. K. Eur. J. Org. Chem. 2015, 23, 5099.
11. Serevicius, T.; Adomėnas, P.; Adomėnienė, O.; Rimkus,R.;
Jankauskas, V.; GruodisM, A.; Kazlauskas,K.; Juršėnas, S. Dyes
and Pigments 2013. 98. 304.
12. Lee, C. W.; Liu, E. C.; Wu, Y. T. J. Org. Chem. 2015, 80, 10446.
13. Tang, M.; Yu, Q. Q.; Wang, Z. Q.; Zhang, C.; Sun, B.; Yi, Y.;
Zhang, F. L. Org. Lett. 2018, 20, 7620.
14. Wang, Z. Q.; Dong, W. D.; Sun, B.; Yu Q. Q.; Zhang, F. L.
Tetrahedron 2019, 75, 4031.
15. CCDC 1942414 (3ag) contains the supplementary crystallographic
data for this paper. These data are provided free of charge by The
Cambridge Crystallographic Data Centre.
The above success led us to continue to explore the reaction of
2-iodo-9H-fluorene and o-methylbenzaldehyde. Surprisingly,
when the amount of AgTFA was decreased to 1.5 equiv., the
reaction of benzaldehydes with 9,9-dialkyl-2-iodofluorene
proceeded successfully, giving 3ba-3bp in 53-90% yield. The
substrate scope of the benzaldehydes was then verified and good
to excellent yields were generally achieved, whether substituted
by electron-donating (3bb, 3bd, 3bi, 3bj) or electron-
withdrawing groups (3bc, 3be-3bh). We then studied the effect
of the alkyl chain length on the reaction of 2-iodoindole with 2-
methyl-6-fluorobenzaldehyde (2a). The solubility of the product
was improved with the increase of the alkyl carbon chain length
(3bl-3bp). In contrast, the yield decreased with shorter alkyl
carbon chains (3bl-3bp).
Supplementary data
Supplementary data associated with this article can be found
in the online version containing experimental procedures and
characterization data for all new compounds.
3. Conclusion
In summary, benzofluorenes were easily constructed in one-
pot from o-methylbenzaldehyde and 9H-fluorene via palladium-
catalyzed C(sp3)‒H arylation and subsequent acid-mediated
dehydration condensation. Moderate to excellent yields were
obtained under mild conditions, proving the wide practicality and
functional group compatibility.
Acknowledgments
We thank the National Natural Science Foundation of China
(grant no. 21703162) and Natural Science Foundation of Hubei
Province (grant no. 2018CFB505) for financial support.
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4
Highlights

An efficient method for one-pot
synthesis of benzofluorenes was
developed.


Glycine was used as the optimal
transient directing group.
Mild reaction conditions and wide
substrate range were also highlighted.