Nickel-catalyzed synthesis of 9-monoalkylated fluorenes from 9-fluorenone hydrazone and alcohols

Article abstract of DOI:10.1080/00397911.2019.1647438

A practical protocol was disclosed for the nickel-catalyzed C-alkylation of 9-fluorenone hydrazone with alcohols using t-BuOK as the base, and 9-monoalkylated fluorene derivatives were obtained in good yields under the benign conditions.

Full text of DOI:10.1080/00397911.2019.1647438

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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Nickel-catalyzed synthesis of 9-monoalkylated
fluorenes from 9-fluorenone hydrazone and
alcohols
Jiang-Tao Fan, Xin-Heng Fan, Yong-Jie Chen, Cai-Yan Gao & Lian-Ming Yang
To cite this article: Jiang-Tao Fan, Xin-Heng Fan, Yong-Jie Chen, Cai-Yan Gao & Lian-Ming Yang
(2019): Nickel-catalyzed synthesis of 9-monoalkylated fluorenes from 9-fluorenone hydrazone and
alcohols, Synthetic Communications, DOI: 10.1080/00397911.2019.1647438
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https://doi.org/10.1080/00397911.2019.1647438
Nickel-catalyzed synthesis of 9-monoalkylated fluorenes
from 9-fluorenone hydrazone and alcohols
Jiang-Tao Fana,b, Xin-Heng Fana, Yong-Jie Chena,b, Cai-Yan Gaoa, and
Lian-Ming Yanga
aBeijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of Green Printing, Institute
b
of Chemistry, Chinese Academy of Sciences, Beijing, P. R. China; University of Chinese Academy of
Sciences, Beijing, P. R. China
ABSTRACT
ARTICLE HISTORY
Received 19 April 2019
A practical protocol was disclosed for the nickel-catalyzed C-alkyl-
ation of 9-fluorenone hydrazone with alcohols using t-BuOK as the
base, and 9-monoalkylated fluorene derivatives were obtained in
good yields under the benign conditions.
KEYWORDS
Benzylic alcohol; 9-
monoalkylated fluorene;
nickel catalyst;
GRAPHICAL ABSTRACT
Introduction
Fluorene motifs are a very useful class of building blocks for organic materials applicable
in optoelectronics, semiconductors, and solar cells.[1] Accordingly, the construction of flu-
orene derivatives, particularly 9-substituted fluorenes, became a valuable subject in syn-
thetic chemistry, and some useful methods have been developed. Representative examples
include: (i) the classical SN2 reaction of 9-lithofluorene with haloalkanes;[2] (ii) the forma-
tion of alkylidenefluorenes via condensation of fluorene and aldehydes and their subse-
quent hydrogenation;[3] (iii) the palladium-catalyzed cross-coupling reaction of fluorene
with aryl halide;[4] (iv) the direct 9-monoalkylation of fluorene with benzylic alcohols
under the forced conditions;[5] and (v) the aldehyde/ketone-catalyzed alkylation of fluo-
rene with benzylic alcohols.[6] Apparently, all the reactions mentioned above are based on
the fluorene as a nucleophile. In recent years, there has appeared a series of reports on
the novel reactions involving aldehyde/ketone hydrazones as the latent carbanion equiva-
lents.[7–9] On the other hand, it has proven that alcohols, which are greener and safer
than halohydrocarbon-type compounds, can be used as alkylating reagents in the pres-
ence of transition-metal catalysts.[10] Inspired by those studies, we combined 9-fluorenone
CONTACT Lian-Ming Yang
yanglm@iccas.ac.cn; Xin-Heng Fan
xinxin9968@iccas.ac.cn
Beijing National
Laboratory for Molecular Sciences (BNLMS), Key Laboratory of Green Printing, Institute of Chemistry, Chinese Academy
of Sciences, Beijing, 100190, P. R. China
Supplemental data for this article is available online at on the publisher’s website
ß 2019 Taylor & Francis Group, LLC

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J.-T. FAN ET AL.
Table 1. Screening of conditions for the Ni-catalyzed reaction of 9-fluorenone hydrazone and 4-
methoxybenzyl alcohola.
Entry
[Ni(II)] (mol%)
None
NiBr2 (5)
Ligand(mol%)
None
Base
t-BuOK
Solvent
Dioxane
Yieldb(%)
1
2
3
4
5
6
7
8
29
48
67
67
80
60
69
69
68
16
21
Trace
Trace
34
54
73
25
DPPPc (5)
DPPP (5)
DPPP (5)
DPPP (5)
PPh3 (10)
DPPEe (5)
DPPFf (5)
Phenag (5)
DPPP (5)
DPPP (5)
DPPP (5)
DPPP (5)
DPPP (5)
DPPP (5)
DPPP (3)
DPPP (5)
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuONa
KOH
K3PO4
K2CO3
t-BuOK
t-BuOK
t-BuOK
t-BuOK
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
THF
Ni(acac)2 (5)
NiCl2(PPh3)2 (5)
Cat.-1d (5)
Cat.-1 (5)
Cat.-1 (5)
Cat.-1 (5)
Cat.-1 (5)
Cat.-1 (5)
Cat.-1 (5)
Cat.-1 (5)
Cat.-1 (5)
Cat.-1 (5)
Cat.-1 (5)
Cat.-1 (3)
Cat.-1 (5)
9
10
11
12
13
14
15
16
17h
Toluene
Dioxane
Dioxane
aReaction conditions: 9-fluorenone hydrazone (0.5 mmol), 4-methoxybenzyl alcohol (1.5 mmol), base (0.75 mmol), solvent
(4 mL), in N2, 110oC, 9 h.
bNMR yields: determined by 1H NMR analysis using 1,3,5-trimethoxybenzene as an internal standard.
cDPPP: 1,3-bis(diphenyphosphino)propane.
dCat.-1: Ni(PPh3)2(1-naphthyl)Cl.
eDPPE: 1,2-bis(diphenylphosphino)ethane.
fDPPF: 1,1’-bis(diphenylphosphino)ferrocene.
gPhena: 1,10-phenanthroline.
h100ꢀC.
hydrazone as the latent carbanion with alcohols as alkylating reagents to develop a new
route to 9-monoalkylated fluorenes. Herein, we wish to report our outcome.
Results and discussion
Initially, 9-fluorenone hydrazone and 4-methoxybenzyl alcohol were chosen as model
substrates for screening reaction conditions, and the results are summarized in Table 1.
We first performed the reaction only in the presence of the base;[5] as a result, the
desired product was produced in a low yield (entry 1). The reaction with no catalyst
and its mechanism were documented in a very earlier publication.[5a] The role of nickel
catalysts was demonstrated in the further investigation (entries 2–5), among which
Ni(PPh3)2(1-naphthyl)Cl (Cat.-1) was found to be the most effective (entry 5) with the
yield of 80%. As for this reaction investigated, the major byproduct was 9-fluorenone
that should be from the decomposition of the starting 9-fluorenone hydrazone. Several
commonly used ligands were surveyed, suggesting that PPh3, DPPE, DPPF, and 1,10-
phenanthroline were all inferior to DPPP (entry 5 vs. entries 6–9). The nature of the
base was extremely important for this reaction since t-BuOK was far superior to t-
BuONa, KOH, K3PO4 or K2CO3 (entry 5 vs. entries 10–13). Different from those reac-
tions reported recently,[7,9] the addition of CsF did not improve the reaction yield at all.
For the solvents used, dioxane appeared to be the solvent of choice compared with

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Table 2. Ni-catalyzed synthesis of 9-monoalkylated fluorenes by the reaction of 9-fluorenone hydra-
zone and alcoholsa.
Isolated yield
Entry
1
Alcohol
Product
(%)
73
2a
3a
3b
3c
3d
3e
3f
2
3
4
5
6
7
8
64
62
62
47
66
71
71
2b
2c
2d
2e
2f
2g
3g
3h
2h
(continued)

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J.-T. FAN ET AL.
9
55
2i
2j
3i
4j
40
25
10
3k
3l
11
12
13
52
64
78
2k
2l
3m
2m
2n
2o
3n
3o
3p
14b
15b
55
60
16b
17b
51
52
2p
2q
3q
3r
(continued)

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5
29
2
18 b
2r
3s
4t
19 c
55
2s
3u
aReaction conditions: 9-fluorenone hydrazone (0.5 mmol), benzylic alcohols (1.5 mmol), Cat.-1 (5 mol%), DPPP (5 mol%),
t-BuOK (0.75 mmol), 1,4-dioxane (4 mL), in N2.
b24 h.
c2-bromo-9-fluorenone hydrazine (0.5 mmol).
other solvents such as THF (entry 14) and toluene (entry 15). Reducing the loading of
the catalyst adversely affected the reaction (entry 16), and lowering the reaction tem-
perature caused a drastic drop in yields (entry 17). Finally, our standard conditions
were set up as entry 5 in Table 1.
With optimized reaction conditions in hand, we then investigated the scope and limi-
tations of the reaction, and the results were summarized in Table 2. As shown in
Table 2, benzylic alcohols, whether electron-neutral (entries 1, 3a and 6, 3f), -rich
(entries 2–4, 3b–3d), or -poor (entries 7–9, 3g–3i), delivered the corresponding 9-
monoalkylated fluorenes in good yields; but o-methoxybenzyl alcohol gave only a lower
yield (entry 5, 3e), indicating that the reaction was sensitive to the steric effect. It
should be noted that halogen atoms in the substrates were well tolerated in the reaction
system (entries 7–9, 3g–3i). Such halogen-containing products as in the cases of entries
8 and 9 (3h and 3i) would be very useful in organic synthesis since they can be further
transformed. Exceptionally, the reaction of p-iodobenzyl alcohol (entry 10, 4j and 3k)
gave a 25% yield of 9-benzylfluorene and 40% yield of 9-benzylidenefluorene, rather
than the expected molecule 9-(4-iodobenzyl)fluorene. The reason might be that primary
deiodination of p-iodobenzyl alcohol proceeds with a single electron transfer (SET)
mechanism, leading to the deiodination of iodobenzyl alcohol.[5c,11] This result may be
of interest from the synthetic and mechanistic points of view. It seems to be that fused
aromatic (entries 11, 3l and 12, 3m) and heteroaryl (entry 13, 3n) carbinols were also
suitable substrates for this reaction. To our pleasure, primary aliphatic alcohols and the
sterically demanding secondary alcohol afforded the desired products with good yields
over a prolonged reaction time (entries 14–17, 3o–3r). Secondary benzylic alcohol, 1-
phenyl ethanol, gave only 31% isolated yield with a ratio of 95% of the desired product
1
to 5% of 9-(1-phenylethylidene)-9H-fluorene (determined by H NMR) (entry 18, 3s
and 4t). In part of nucleophilic partners, 2-bromo-9-fluorenone hydrazone was utilized,
giving the corresponding product in 55% yield (entry 19, 3u). The reaction of 1,2-

6
J.-T. FAN ET AL.
Scheme 1. A proposed catalytic cycle.
propanediol only gave fluorene and 9,9’-bifluorenyl as the products. Additionally, two
control experiments were carried out by the use of aldehyde and tertiary alcohol as the
starting reactants, which produce no desired products, but 1-(9H-fluoren-9-ylidene)-2-
(4-methoxybenzylidene)hydrazone and 9,90-bifluorenylidene, respectively.
[8b,12]
By combining the relevant literature
with our experimental results, we proposed
a plausible mechanistic path for this reaction (Scheme 1). As shown in Scheme 1, a
Ni(0) complex B is formed via the coordination of the Ni(II) precursor with alcohol
and the subsequent b-hydride elimination. Insertion of the complex B into the C–O
bond of an alcohol (an oxidative addition process) provides the intermediate C, which
further undergoes an alcohol exchange to produce the corresponding water and nickel
complex D. Then, the complex D underwent transmetalation with carbon-nucleophile E
derived from deprotonation of hydrazone 1 to form intermediate F. Reductive elimin-
ation gave the diimide G and regenerated Ni (0) catalyst. Finally, the desired product 3
was formed by the wolf-kishner reaction, and the byproduct 4 might be obtained by a
base-assisted b-elimination of G.
Conclusions
In summary, we have developed a practical new approach to the synthesis of 9-monoal-
kylfluorenes from 9-fluorenone hydrazones and alcohols, which would constitute a

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7
valuable part of fluorene chemistry. Further work to expand the scope of substrates and
elucidate the mechanistic details is currently underway in our lab.
Experimental
General procedure for Ni-catalyzed reaction of 9-fluorenone hydrazone and benzylic
alcohols: An oven-dried 25-mL flask was charged with t-BuOK (0.75 mmol),
Ni(PPh3)2(1-naphthyl)Cl (0.025 mmol) and DPPP (0.025 mmol). Then the 9-fluorenone
hydrazone (0.5 mmol) and the benzyl alcohol (1.5 mmol) (if solid) were added. The flask
was evacuated and backfilled with nitrogen, with the operation being repeated twice.
Dried 1,4-dioxane (4 mL) and the benzyl alcohol (1.5 mmol) (if liquid) were added via
syringe at this time. The reaction mixture was performed on WATTECS WP-TEC-1020
parallel reactor of 110 ꢀC for 9 h and then allowed to cool to room temperature; it was
then filtered through a silica-gel pad that was washed with ethyl acetate. The combined
organic phases were evaporated under reduced pressure and the residue purified by sil-
ica-gel column chromatography to give the desired products.
Full experimental details, and 1H and 13C NMR spectra can be seen in
Supplementary Material.
Funding
The authors thank National Natural Science Foundation of China (Project Nos. 21503234 and
21572235) for financial support of this work.
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