Synthesis of substituted fluorenes by cascade allenylation, electrocyclization and intramolecular friedel-crafts reaction of 1,3-diene-substituted propargylic alcohols

Article abstract of DOI:10.1055/s-0032-1318104

A concise, one-step synthesis of substituted fluorenes through TiCl ₄-promoted cascade allenylation, electrocyclization and intramolecular Friedel-Crafts reaction of 1,3-diene-substituted propargylic alcohols has been developed. An interesting substituent-dependent regioselectivity was observed.

Full text of DOI:10.1055/s-0032-1318104

LETTER
▌383
lSetyternthesis of Substituted Fluorenes by Cascade Allenylation, Electrocyclization
and Intramolecular Friedel–Crafts Reaction of 1,3-Diene-Substituted
Propargylic Alcohols
Synthesis of Substituted Fluorenes
Xiangsheng Xu,* Tao Li, Xiaoqing Li,* Jiangbin Shao
College of Chemical Engineering and Materials Science, Zhejiang University of Technology, Hangzhou 310014, P. R. of China
Fax +86(571)88320799; E-mail: future@zjut.edu.cn; E-mail: xqli@zjut.edu.cn
Received: 15.11.2012; Accepted after revision: 31.12.2012
dium catalyst but also phosphorus ligands and base for
Abstract: A concise, one-step synthesis of substituted fluorenes
both the reaction and the preparation of the starting mate-
through TiCl4-promoted cascade allenylation, electrocyclization
rials.4a,5d Thus, the development of a new strategy for the
and intramolecular Friedel–Crafts reaction of 1,3-diene-substituted
direct synthesis of substituted fluorenes from readily
available starting materials represents a valuable but chal-
lenging target.
propargylic alcohols has been developed. An interesting
substituent-dependent regioselectivity was observed.
Key words: allenylation,
electrocyclization,
intramolecular
reactions, Friedel–Crafts, 1,3-dienes, fluorenes
Recently, it was reported that propargyl dienes can under-
go propargyl–allenyl isomerizations and electrocycliza-
tions that allow access to polysubstituted benzenes
(Scheme 1, eq 1).6 In addition, Zhou’s group has devel-
oped an efficient method for the direct synthesis of di-
Fluorene and its derivatives are being extensively used as
ligands in organometallic chemistry becaue of their high
donor ability and varied coordination modes.1 In addition,
fluorene derivatives are important structural moieties
found in various functional materials2 and biologically ac-
tive molecules.3 Although many viable methods for con-
struction of fluorenes have been developed, including the
coupling of two fragments4 and direct cyclization of a
multifunctional substrates,5 the approaches usually suffer
from the use of expensive transition-metal catalysts or
multistep preparation of the starting materials. Moreover,
some C–H bond activation protocols need not only palla-
hydro-
and
tetrahydroisoquinolines
based
on
allenylation/intramolecular Friedel–Crafts (IFC) reaction
of benzylamino-substituted propargylic alcohols (Scheme
1, eq 2).7 In this context, we became interested in the pos-
sibility of combining these two reactions in one step when
suitable substrates were used. On the basis of this idea, a
cascade allenylation/electrocyclization/IFC reaction of
1,3-diene-substituted propargylic alcohols was designed
(Scheme 1, eq 3). Herein, we report the construction of
R2
R2
R2
R3
R3
R3
R4
DBU
ref. 6
(1)
X
electrocyclization
R1
R1
X
X
R1
R4
R4
R5
R5
R5
X
X
X
X
IFC reaction
FeCl3
ref. 7
(2)
HO
R1
R2
R2
R2
R1
R1
R1
R2
R1
OH
R2
R2
R2
R2
electrocyclization
IFC reaction
this work
R1
(3)
R1
R1
Scheme 1 Design of a cascade reaction based on previous works
SYNLETT 2013, 24, 0383–0388
Advanced online publication: 21.01.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1318104; Art ID: ST-2012-W0980-L
© Georg Thieme Verlag Stuttgart · New York

384
X. Xu et al.
LETTER
O
O
KOH, EtOH–H2O
r.t.
R1
+
Ph
Ph
Ph
O
R1
OH
n-BuLi
R2
R2
THF, –78 °C
R1
–78 °C
1
Scheme 2 Substrate synthesis
substituted fluorene frameworks by Lewis acid promoted 0.5 and 2 molar equivalents of TiCl4 (entries 15 and 16).
one-pot cascade allenylation, electrocyclization and IFC Neither elevating the reaction temperature nor lengthen-
reaction of 1,3-diene-substituted propargylic alcohols.
ing the reaction time improved the yield. Some insepara-
ble and unidentified byproducts were also formed in the
process, as indicated by TLC. The structure of 2a was
confirmed by single-crystal X-ray diffraction (Figure 1).10
Firstly, 1,3-diene-substituted propargylic alcohols 1 were
easily synthesized in good yield by the aldol reaction of
cinnamaldehyde with ketones8 followed by treatment with
lithium acetylides (Scheme 2).9 We observed that the re-
sulting propargylic alcohols 1 were unstable in the pres-
ence of silica gel. Therefore, crude products 1 were
purified by column chromatography on neutral alumina
and used immediately upon isolation.
Table 1 Optimization of Reaction Conditions for 2aa
Ph
Ph
Ph
OH
conditions
Ph
We initiated our study by testing 1a in the presence of var-
ious Lewis acid catalysts and solvents to establish the op-
timum reaction conditions; Table 1 summarizes the major
results. No desired product was formed when the reaction
was conducted in toluene using FeCl3, Yb(OTf)3,
Cu(OTf)2 or ZnCl2 as catalyst (entries 1–4). Brønsted ac-
ids such as TfOH, PTS or HCl were also not efficient cat-
alysts for this transformation (entries 5–7). To our delight,
when AlCl3 and TiCl4 were used as catalysts, the desired
fluorene 2a could be isolated in 20 and 38% yield, respec-
tively (entries 8 and 9). The yield increased to 59% when
PhCl was used as solvent (entry 10), while the use of other
solvents such as dioxane, THF, MeCN or o-dichloro-
benzene did not work for the reaction (entries 11–14). The
yield decreased when the reactions were performed using
Ph
1a
2a
Entry
Catalyst
FeCl3
Solvent
Yield (%)b
1
2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
PhCl
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
20
Yb(OTf)3
Cu(OTf)2
ZnCl2
TfOH
PTS
3
4
5
6
7
HCl
8
AlCl3
TiCl4
9
38
10
11
12
13
14
15
16
TiCl4
59
TiCl4
dioxane
THF
n.d.
n.d.
n.d.
n.d.
15
TiCl4
TiCl4
MeCN
o-DCB
PhCl
TiCl4
c
TiCl4
d
TiCl4
PhCl
34
a Reaction conditions: 1a (0.5 mmol), solvent (2 mL), Lewis acid (0.5
mmol), r.t., 8 h (n.d. = not detected);
TfOH = trifluoromethanesulfonic acid; PTS = p-toluenesulfonic acid
monohydrate; o-DCB = 1,2-dichlorobenzene.
b Isolated yield.
c 0.25 mmol.
Figure 1 ORTEP diagram of the single-crystal X-ray structure of 2a
Synlett 2013, 24, 383–388
d 1.0 mmol.
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Substituted Fluorenes
385
To define the generality of the one-step protocol, a selec- fluorenes in moderate yield. Similarly, analogous cycliza-
tion of 1,3-diene substituted propargylic alcohols 1b–h tion with starting alcohols containing either an alkyl or
was investigated using TiCl4 as a catalyst in chloroben- styryl functional group at the R1 position can also afford
zene;11 Table 2 summarizes the results. Reactions of the expected fluorenes (entries 6 and 7). However, no de-
propargylic alcohols bearing either an electron-withdraw- sired product 2h was obtained under the optimal condi-
ing (Cl; entry 2) or electron-donating group (Me, OMe, tions when 2-thienyl-substituted propargylic alcohol 1h
Pr; entry 3–5) on the alkyne carbon can afford the desired was used as the substrate (entry 8).
Table 2 Synthesis of Substituted Fluorenes 2a
Entry
Substrate
Product
Yield (%)b
Ph
Ph
Ph
Ph
OH
1
59
Ph
Ph
1a
2a
4-ClC6H4
C6H4-4-Cl
C6H4-4-OMe
C6H4-4-Me
C6H4-4-Pr
OH
Ph
2
3
4
5
6
30
45
42
32
41
Ph
1b
2b
4-MeOC6H4
Ph
OH
Ph
Ph
1c
2c
4-MeC6H4
Ph
Ph
OH
Ph
Ph
1d
2d
4-PrC6H4
OH
Ph
Ph
1e
2e
Ph
Ph
Ph
OH
OH
Ph
1f
2f
Ph
Ph
Ph
7
8
29
Ph
1g
2g
Ph
S
OH
Ph
Ph
S
0
1h
2h
a Reaction conditions: 1 (0.5 mmol), PhCl (2 mL), TiCl4 (0.5 mmol), r.t., 8 h.
b Isolated yield.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 383–388

386
X. Xu et al.
LETTER
CF3
Ph
Ph
R = CF3
+
24%
F3C
2i/2i' = 71:29
Ph
R
OH
2i'
2i
Ph
1i R = CF3
1j R = Me
1k R = OMe
Ph
R = Me or OMe
R
2j R = Me 39%
2k R = OMe 21%
Scheme 3 Effect of substituents on reaction regioselectivity
Interestingly, it was found that the electronic properties of On the basis of the above experimental results, a proposed
the substituents on the aryl ring of the R1 have a signifi- mechanism for the present cascade reaction is proposed
cant effect on the regioselectivity of the reaction. When (Scheme 4). In the presence of a Lewis acid, propargylic
the R1 group in the 1,3-diene-substituted propargylic alco- alcohols 1 were converted into E,E-cation intermediate I,
hols was an aryl group bearing the electron-withdrawing which was isomerized to E,Z-cation intermediate III via
trifluoromethyl group (1i) in the para position, the reac- intermediate II. Then, intermediate III was converted into
tion give both 1,9-disubstituted fluorene 2i and 1,7,9-tri- diene-allenylic cation intermediate IV through a Meyer–
substituted fluorene 2i′ as regioisomers in 24% yield; the Schuster rearrangement,7,12 which could undergo electro-
regioisomer ratio was 71:29 based on GC-MS, NMR and cyclization to form vinyl cation intermediate V.4b Isomer-
MS/MS analyses (see the Supporting Information). On the ization of vinyl cation intermediate V to benzyl cations VI
other hand, when the R group was an aryl group bearing and subsequent IFC reaction gives fluorenes through two
electron-donating groups such as Me (1j) and OMe (1k) different routes based on the structures of the R1 group in
in the para position, only 1,7,9-trisubstituted fluorene de- propargylic alcohols 2. When the R1 group was an alkyl or
rivatives 2j and 2k were isolated as single isomer in 39 styryl functional group, the IFC reaction could afford flu-
and 21% yields, respectively (Scheme 3). The X-ray crys- orenes 2b–g (route A). On the other hand, when R1 was an
tallographic study of 2k unambiguously confirmed the re- aryl group bearing electron-donating groups, the substrate
gioselectivity (Figure 2).10
showed higher activity towards the IFC reaction than un-
substituted benzene ring and formed fluorenes 2k–l (route
B). Finally, when the R1 was phenyl or an aryl group bear-
ing electron-withdrawing groups, both routes were possi-
ble and provided 2a and regioisomers of 2i/2i′. Because
aryl groups bearing electron-withdrawing groups showed
lower activity towards the IFC reaction than unsubstituted
benzene ring, 2i was formed as the major isomer. Notably,
the formation of 2a–g and 2i through the allenyl-
ation/IFC/electrocyclization sequence (route C) also can-
not be ruled out.
In summary, a concise and versatile cascade allenylation,
electrocyclization and IFC reaction of 1,3-diene-substitut-
ed propargylic alcohols has been established. This trans-
formation provides a facile and direct strategy for the
construction of substituted fluorenes from easily accessi-
ble starting materials. We also found that the regioselec-
tivity of the cascade reaction was dependent on the
substituent group on the propargylic alcohol. Further stud-
ies regarding the mechanistic details, scope of this process
and application of the substituted fluorenes are in prog-
ress.
Figure 2 ORTEP diagram of the single-crystal X-ray structure of 2k
Synlett 2013, 24, 383–388
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Substituted Fluorenes
387
R1
R1
Ar
Ar
OH
LA
Ar
Ph
R1
Ar
Ph
R1
I
1
II
III
R1
R1
route C
Ar
Ar
R1
Ar
R1
R1
Ar
R1
Ar
Ar
route A
2a–g,i
IV
VI
V
R2
Ar
R2
R1 =
route B
R2
Ar
2a,i',k,l
VI
Scheme 4 Plausible mechanism for the formation of fluorenes 2
(4) (a) Dong, C. G.; Hu, Q. S. Angew. Chem. Int. Ed. 2006, 45,
2289. (b) Wang, X. C.; Yan, R. L.; Zhong, M. J.; Liang, Y.
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Kim, H. J.; Chang, J. S. Org. Lett. 2009, 11, 4588.
Acknowledgment
We thank the National Natural Science Foundation of China
(21102130) and the Key Innovation Team of Science & Technology
in Zhejiang Province (2010R50018) for financial support. We also
thank Prof. Zuguang Li for helpful assistance in obtaining MS/MS
data and Prof. Yunkui Liu and Prof. Xiaoliang Xu for helpful
discussion.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
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References and Notes
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Wolford, L. T.; Hooper, C. L.; Fan, D.; Jursic, B. S. J. Med.
Chem. 2003, 46, 4552. (b) Banala, A. K.; Levy, B. A.;
Khatri, S. S.; Furman, C. A.; Roof, R. A.; Mishra, Y.;
Griffin, S. A.; Sibley, D. R.; Luedtke, R. R.; Newman, A. H.
J. Med. Chem. 2011, 54, 3581. (c) Hicks, L. D.; Hyatt, J. L.;
Stoddard, S.; Tsurkan, L.; Edwards, C. C.; Wadkins, R. M.;
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Hou, T.-P. Chem. Biol. Drug Des. 2011, 78, 94.
(9) General procedure for the preparation of propargylic
alcohols 1: To a solution of phenylacetylene (0.56 g, 5.5
mmol) in anhydrous THF (15 mL) was added n-BuLi (1.6 M
in hexane, 3.44 mL, 5.5 mmol) dropwise at –78 °C, and the
reaction mixture was stirred for 0.5 h at that temperature,
followed by the addition of a solution of 1,5-diphenylpenta-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 383–388

388
X. Xu et al.
LETTER
chlorobenzene (1 mL) was added dropwise a solution of
2,4-dien-1-one (1.17 g, 5 mmol) in THF (10 mL) dropwise.
The mixture was allowed to warm to r.t. and stirred for 4 h.
The mixture was quenched by addition of sat. NH4Cl and the
aqueous layer was extracted with CH2Cl2 (3 × 20 mL). The
combined organic layers were washed with brine, dried
(Mg2SO4), filtered and concentrated in vacuo. The crude
product was purified by neutral Al2O3 column
chromatography (PE–EtOAc) to give 1a as a yellow oil
(1.38 g, 82%). 1H NMR (CDCl3, 500 MHz): δ = 2.65 (s,
1 H), 6.05–6.10 (m, 1 H), 6.61–6.67 (m, 1 H), 6.77–6.81 (m,
2 H), 7.25–7.39 (m, 11 H), 7.52–7.54 (m, 2 H), 7.71 (s, 1 H),
7.73 (d, J = 1.5 Hz, 1 H); 13C NMR (CDCl3, 125 MHz): δ =
143.5, 137.1, 136.7, 134.2, 131.8, 129.7, 128.7, 128.6,
128.5, 128.4, 128.0, 127.8, 127.7, 126.5, 125.8, 122.4, 90.0,
87.4, 73.2; Anal. Calcd for C25H20O: C, 89.25; H, 5.99.
Found: C, 89.21; H, 5.95
TiCl4 (94.8 mg, 0.50 mmol) in chlorobenzene (1 mL) at
0 °C. The mixture was stirred at r.t. for 8 h, then the reaction
mixture was quenched with sat. NaHCO3 and the aqueous
layer was extracted with CH2Cl2 (3 × 10 mL). The combined
organic extracts were dried over anhydrous Mg2SO4,
filtered, and concentrated in vacuo. The crude product was
purified by thin-layer chromatography on silica gel to afford
the desired product 2. 1,9-Diphenyl-9H-fluorene (2a; 93.8
mg, 59%); white solid; mp 131–132 °C; 1H NMR (CDCl3,
500 MHz): δ = 5.24 (s, 1 H), 6.58–6.60 (m, 2 H), 6.89–6.94
(m, 3 H), 7.11–7.12 (m, 2 H), 7.18–7.20 (m, 6 H), 7.35–7.37
(m, 1 H), 7.47 (t, J = 7.5 Hz, 1 H), 7.83 (d, J = 7.5 Hz, 2 H);
13C NMR (CDCl3, 125 MHz): δ = 148.8, 145.8, 141.9, 140.8,
140.7, 140.6, 140.5, 128.6, 128.4, 128.1, 127.9, 127.8,
127.5, 127.2, 126.8, 125.9, 125.2, 119.9, 118.8, 54.0; HRMS
(EI): m/z calcd for C25H18: 318.1409; found: 318.1374
(12) (a) Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971,
71, 429. (b) Wang, S.; Zhu, Y.; Wang, Y.; Lu, P. Org. Lett.
2009, 11, 2615. (c) Zhu, Y.; Yin, G.; Hong, D.; Lu, P.;
Wang, Y. Org. Lett. 2011, 13, 1024.
(10) CCDC 868935 and 868936 contain the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge
Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
(11) General procedure for the preparation of fluorenes 2: To
a stirred solution of propargylic alcohol (0.50 mmol) in
Synlett 2013, 24, 383–388
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