Fluorene-Based Multicomponent Reactions

Article abstract of DOI:10.1055/a-1471-9080

Fluorene and fluorenone are privileged structures with extensive utility in both materials science and drug discovery. Here, we describe syntheses of those moieties through isocyanide-based multicomponent reactions (IMCRs) and the incorporation of the products in diverse and complex derivatives that can be further utilized. We performed six different IMCRs, based on the dual functionality of 9-isocyano-9H-fluorene, and we describe 23 unprecedented adducts.

Full text of DOI:10.1055/a-1471-9080

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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 32, A–F
letter
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EuCheMS Organic Division Young Investi-
X. Lei et al.
Letter
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Fluorene-Based Multicomponent Reactions
Xiaofang Leia,b
Maria Thomaidia
Giasemi K. Angelia
Alexander Dömling*b
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Constantinos G. Neochoritis*a
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a Department of Chemistry, University of Crete, Voutes,
70013, Heraklion, Greece
kneochor@uoc.gr
b Department of Pharmacy, Drug Design Group, University
of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The
Netherlands
a.s.s.domling@rug.nl
Dedicated to Professor Ioulia Stephanidou-Stephanatou for
her contributions to heterocyclic chemistry
Published as part of the Special Section EuCheMS Organic
Division Young Investigator Workshop
Corresponding Authors
Received: 03.03.2021
Accepted after revision: 31.03.2021
Published online: 31.03.2021
DOI: 10.1055/a-1471-9080; Art ID: st-2021-b0083-l
Abstract Fluorene and fluorenone are privileged structures with ex-
tensive utility in both materials science and drug discovery. Here, we
describe syntheses of those moieties through isocyanide-based multi-
component reactions (IMCRs) and the incorporation of the products in
diverse and complex derivatives that can be further utilized. We per-
formed six different IMCRs, based on the dual functionality of 9-isocya-
no-9H-fluorene, and we describe 23 unprecedented adducts.
Key words fluorene, fluorenone, multicomponent reactions, Ugi re-
action, isocyanofluorene, spiro compounds
Assistant Professor Constantinos G. Neochoritis received his PhD in Or-
ganic Chemistry under the guidance of Professors J. Stephanidou
Stephanatou and C. Tsoleridis in the Department of Chemistry at Aris-
totle University of Thessaloniki, Greece in 2011. Being fascinated by the
applied multicomponent reaction (MCR) chemistry, he joined the re-
search group of Prof. Alexander Dömling in the Drug Design Group at
the University of Groningen for his postdoctoral studies, whereas in
2014 he cofounded the biotech company TelesisPharma. In 2019, he
was appointed as assistant professor in the chemistry department of
University of Crete, Greece. His research interests include bioactive het-
erocycles, multicomponent reactions, novel materials and high
throughput synthesis. He has published more than 50 peer-reviewed
papers and book contributions.
Fluorene derivatives have traditionally been at the epi-
center of many research studies in various fields from opto-
electronics1 and solar cells2 to synthetic3 and medicinal
chemistry.4 The unique electronic properties of fluorenes
make it highly interesting to study their charge-transfer
complexes as electron-deficient candidates with semicon-
ducting and photoconducting properties and as electron-
transport materials (Figure 1A).1,2,5 Fluoren-9-one, in partic-
ular, is considered to be a privileged structure, as it is rela-
tively planar with high thermal stability and good electron-
transport properties. Many of its derivatives exhibit both
aggregation-induced emission and bathochromic solid-
state fluorescence.6
shows antimyocardial ischemia activity (Figure 1Α).9 More-
over, fluorene derivatives have been reported as effective
inhibitors, for example of cyclophorin A,4 fibril formation of
human transthyretin,10 or glycoside hydrolases (Figure
1Β).11,12 Finally, fluorene derivatives have been utilized in
synthetic organic chemistry in the archetypical protective
group Fmoc.13 For these reasons, multiple synthetic ways to
access fluorene derivatives, including one-pot strategies
and catalysts, have been reported.14–22
In addition, the fluorene structural motif is present in
many natural products and bioactive compounds.7 For ex-
ample, dendroflorin (from Dendrobium densiflorum) is a
natural product with high antioxidant activity,8 and caulo-
phine (from the radix of Caulophyllum robustum Maxim.)
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X. Lei et al.
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ably formed. Intramolecular attack by the nucleophilic
amine on the isocyanide carbon of 3 is the driving force to-
ward cyclization to give fluoreno-2-imidazolines 2 (Scheme
1; red arrows).33
Orru three-component reaction
O
R1
N
R2
R3
NC
N
Na2SO4
R1NH2
+
+
R3
R2
CH2Cl2, 18 h
2, 20–91%
1
R1
N
R2
R1
H
N
R3
H
N
R3
R2
R2
R3
R1
H
O
R5
N
N
N
4
3
NC-functionality
vs
α−H functionality
this work
O
R3
R1
R4
HN
H
R2
N
R2
N
R1
O
N
R3
R3
N
R2
O
O
NH
O
NH
O
R1
O
Figure 1 A. Fluorene-based derivatives in applied materials and natural
products; B. Fluorene-based molecules in drug discovery: Left: inhibitor
of transthyretin [Protein Data Bank identifier (PDB ID): 5E4A]; Right: -
L-fucosidase inhibitor (PDB ID: 2XII).
HN
R4
Ugi "classical" 4-component (U-4CR)
and Ugi 3-component (U-3CR)
Multicomponent reactions (MCRs) are powerful tools
for one-step assembly, functionalization, and transforma-
tion of molecules. They can accelerate the exploration of
chemical space and improve the sustainability of the chem-
ical enterprise.23 A very important and diverse class of
MCRs are the isocyanide-based MCRs (IMCRs),24 in which a
versatile isocyanide moiety is added to the final prod-
uct.25,26
R1
HN
N
N
N
FG
O
R2
N
R2
N
functionalization via
IMCRs
Ugi tetrazole 4-component
(UT-4CR)
spirooxazoles
The incorporation of fluorene derivatives by MCRs to
give adducts with many points of diversification is of high
importance, but is quite underexplored and limited in
scope.27–32 Structural diversity and complexity in such li-
braries are critical to the elucidation of structure–activity
relationships that drive the development of new products
and technologies. Orru and co-workers,33 in their pioneer-
ing work, took advantage of the -acidic nature of 9-isocya-
no-1H-fluorene (1; pKa = 12.3 in DMSO), which becomes ar-
omatic after deprotonation,34–36 and were able to synthe-
size the druglike spiro-2-imidazolines 2 through a three-
component reaction, now known as the Orru reaction (Or-
ru-3CR; Scheme 1).33,37–39 Due to the acidic nature of the
isocyanide, in which the isocyano functionality competes
with -Η acidity, the Mannich-type intermediate 3 is prob-
R2
N
O
N
R3
O
X
N
NH
R3
O
O
R2
O
NH
NH
Gröbcke–Biename–Blackburn
(GBB-3CR)
Ugi-Joullié 3-component
Passerini 3-component
(P-3CR)
Scheme 1 -H versus NC functionality of the isocyanofluorene 1 yield-
ing the Orru-3CR, and our proposed IMCR-based use of fluorenes, in-
cluding the synthesis of spirooxazoles
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In this work, we elaborate the fluorene moiety by its in-
corporation into various isocyanide-based MCRs. Our study
was based primarily on 9-isocyano-1H-fluorene (1) as a
versatile building block, and focused on the isocyano func-
tion (Scheme 1; blue arrows, intermediate 4); in parallel,
we investigated the formation of the 2-imidazolines under
the appropriate conditions. For example, it has been report-
ed that in an Ugi reaction setup, reducing the nucleophilici-
ty of the nitrogen of the amine component might shift the
reaction toward the classical pathway for bisamides
(Scheme 1, intermediate 4).31,33 Taking this into account, we
examined a series of IMCRs including the classical Ugi reac-
tion and some of its main variants: the Ugi-tetrazole four-
component reaction (U-4CR),40 the Ugi three-component
reaction (U-3CR),41 the Ugi–Joullié reaction,42 and the Ugi–
Smiles four-component reaction,43–45 along with the Groeb-
ke–Blackburn–Bienaymé (GBB-3CR)46–48 and Passerini
three-component (P-3CR) reactions.49 Moreover, we were
able to combine functions of the acidity and the isocyano
moiety of 9-isocyano-9H-fluorene to permit access to
spirooxazolidine derivatives.
whereas the solution of isocyanide 1 in dichloromethane
fluoresced light-green on excitation at 254 nm (Scheme
2C).
The classic U-4CR reaction is one of the most versatile
transformations in organic chemistry. It gives access to
huge libraries due to its four points of diversification, and it
also serves as an excellent hub for a plethora of secondary
transformations.51,52 We employed both the isocyanide 1
and the fluorene-based aldehyde and amine to obtain the
corresponding bisamides 5a–c in yields of 34-89%, respec-
tively. Notably, in the case of 5c, three molecules of fluorene
were incorporated into one adduct, demonstrating a favor-
able architectural aspect of this reaction (Figure 2). Inter-
estingly, when we switched to aliphatic aldehydes such as
Cl
Cl
CHO
N
N
OHC
Cl
HN
O
HN
O
HN
O
N
We synthesized 9-isocyano-9H-fluorene (1) from 9H-
fluoren-9-one by our recently described Leuckart–Wallach
procedure50 toward the corresponding formamide 1a
(Scheme 2A). The standard procedure33 starts with the
formylation of 9H-fluorene-9-amine, which is commercial-
ly available as its hydrochloride salt (CAS 5978-75-6) but is
substantially more expensive than 9H-fluoren-9-one (CAS
486-25-9). Dehydration of formamide 1a under the typical
conditions afforded the required solid odorless starting ma-
terial 1 on a gram scale in 92% yield. Notably, a solution of
formamide 1a in dichloromethane showed a characteristic
bright-blue fluorescence on excitation at 366 nm (Scheme 2B),
OHC
5a, 71%
5b, 89%
5c, 34%
F
N
N
O
N
N
N
N
N
N
O
O
O
HO
O
HO
N
O
N
NH
NH
NH
NH
7a, 84%
6b, 75%
7b, 43%
6a, 64%
O
O
O
O
O
O
O
O
O
N
N
N
N
N
N
N
HN
HN
NH
N
N
N
N
N
7e, 79%
7d, 83%
7c, 86%
O
Cl
O
O
O
O
N
O
NH
N
NH
NH
Cl
Scheme 2 (A) Access to the isocyanide 1 through the Leuckart–Wallach
reaction of 9H-fluoren-9-one. (B) Fluorescence of 9H-fluoren-9-one
(green color; right-hand vial) and formamide 1a (blue color, left-hand
vial) on excitation at 366 nm, both as a solid and as a solution in CH2Cl2.
(C) Fluorescence of 9-isocyanofluorene on excitation by visible light
(left) and at 254 nm (right) both as a solid and as a solution in CH2Cl2.
9a, 31%
9b, 24%
8, 21%
Figure 2 Syntheses of U-4CR (5a–c), U-3CR (6a and 6b), UT-4CR (7a–e),
GBB-3CR (8), and P-3CR (9a and 9b) adducts by utilizing fluorene moi-
eties as isocyanide, aldehyde, and amine components
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X. Lei et al.
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5-chloropentanal, and thereby increased the nucleophilici-
ty of the nitrogen of the amine, the corresponding 2-imid-
azoline 2a was obtained (Figure 3).
In the last twenty years, the Groebke–Blackburn–
Bienaymé reaction (GBB-3CR) has emerged as one of the
most important MCRs.55–57 The resulting imidazo[1,2-
a]heterocycles with diverse substitution patterns are a
prime class of heterocycles present in many commercially
available drugs and drugs in late-stage clinical trials.58 We
have performed a GBB reaction with 4-chloropyridin-2-
amine, yielding the adduct 8 (Figure 2). Interestingly, when
we employed 4-methoxypyridin-2-amine, the imidazoline
2c was obtained, highlighting the aforementioned mecha-
nistic assumptions (Figure 3). Notably, an Ugi–Smiles reac-
tion that we attempted as an additional Ugi variant afforded
the imidazolines 2d and 2e as the sole products. In support
of this, we solved the crystal structure of compound 2e,
proving the different pathway taken by the reaction (Figure
3).59
The Passerini reaction (P-3CR) belongs to the classic rep-
ertoire of MCR chemistry, as it provides easy access to -
acyloxy carboxamides. We attached a fluorene moiety to a
Passerini scaffold to give compounds 9a and 9b (Figure 2).
We used acetic acid as the acid component, together with
substituted aromatic aldehydes containing electron-donat-
ing or electron-withdrawing groups.
Figure 3 Synthesis of imidazolines 2a–e by an Orru-3CR, and the X-ray
structure of compound 2e (CCDC 2065539)
The Ugi three-component reaction (U-3CR) is a variant
of the Ugi reaction in which water plays the role of nucleo-
phile. Often, the resulting -aminoacylamides which are
present in many bioactive compounds and commercially
available drugs, lead to improved pharmacokinetic/phar-
macodynamic properties, including oral bioavailability and
water solubility, due to the incorporation of a basic amine.53
We therefore investigated the U-3CR that gave the -ami-
noacylamides 6a and 6b (Figure 2). We employed second-
ary amines in an aqueous solution of formaldehyde with no
catalysts, additives, or other solvents to access caine-type
adducts. It was observed that an additional molecule of
formaldehyde was added as a hydroxymethylene moiety in
a Mannich-type addition. This was attributed to the acidic
proton of the fluorene moiety and to the aqueous reaction
conditions.
The Ugi–Joullié reaction42 is an extremely versatile cy-
clic variant of the Ugi reaction that yields conformationally
constrained peptidomimetics and antibacterial depsipep-
tides.60 It utilizes a preformed C=N bond in a three-compo-
nent setup, and it has been widely used in various second-
ary transformations after an initial multicomponent reac-
tion.61 Hence, we synthesized the spiroindolenine 10,
which is attractive due to its 3D character,62 through a
Fischer indole synthesis, and we performed its Ugi–Joullié
reaction with 9-isocyano-9H-fluorene (1). The reaction
proceeded smoothly, yielding the adducts 11a and 11b
(Scheme 3).
NC
O
N
The Ugi-tetrazole variant (UT-4CR) is one of the most
well-known and well-studied variants of the Ugi reaction. It
gives easy access to tetrazole derivatives, which are very
important bioisosteres of carboxylic acid and cis-amide
moieties. Moreover, they have enhanced metabolic stability
and other beneficial physicochemical properties.54 We used
a variety of aryl amines, aldehydes, and ketones, which all
yielded the desired fluorene–tetrazole compounds 7a–e in
good to excellent yields (Figure 2). Compounds 7a and 7b
bear additional functional groups that can allow various
subsequent modifications (e.g., SNAr reactions and depro-
tection of the acetal group). Interestingly, when we em-
ployed 3-phenylpropanal in combination with 3,4,5-trime-
thoxybenzylamine, the corresponding imidazoline 2b was
formed (Figure 3).
R3
N
O
NH
MeOH
rt
+
10
O
OH
R3
11a,b
Cl
N
N
O
O
O
NH
O
NH
11a, 89%
11b, 77%
Scheme 3 Synthesis of Ugi–Joullié adducts 11a and 11b by using 9-
isocyano-9H-fluorene (1)
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In recent years, there has been great interest in increas-
ing the number of 3D-shaped alicyclic building blocks in
drug discovery (‘escape from Flatland’), and spiro com-
pounds are of high importance.63,64 For this reason, we were
interested in combining the -acidity of isocyanide 1 with
its isocyano functionality; we therefore subjected it to reac-
tion with an aldehyde in a similar fashion to the van Leusen
oxazole synthesis using tosylmethyl isocyanide (TosMIC).65
To our delight, the reaction proceeded under mild condi-
tions to give the required spirooxazolidines 12a–c in good
to excellent yields after treatment with K2CO3 at room tem-
perature (Scheme 4). Furthermore, we solved the crystal
structure of compound 12c (Scheme 4).59
In conclusion, we have synthesized 23 new derivatives
based on ten different scaffolds by functionalizing a fluo-
rene building block through an MCR-based array of reac-
tions.66,67 We have demonstrated the potential of MCR
chemistry by utilizing this privileged scaffold of proven in-
terest in materials science and drug discovery. We envision
that our strategy will add to the arsenal of synthetic meth-
ods for materials containing fluorene moieties.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/a-1471-9080.
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Conflict of Interest
The authors declare no conflict of interest.
Funding Information
The research project was supported by the Hellenic Foundation for
Research and Innovation (H.F.R.I.) under the ‘2nd Call for H.F.R.I. Re-
search Projects to support Post-Doctoral Researchers’ (Project Num-
ber: 0911). X.L. acknowledges support from the China Scholarship
Council. This project has received funding (to A.D.) from the European
Lead Factory (IMI) under Grant Agreement 115489, the Qatar Nation-
al Research Foundation (NPRP6-065-3-012), the European Union’s
Horizon 2020 research and innovation program under the Marie
Sklodowska-Curie [ITN ‘Accelerated Early stage drug dIScovery’, Grant
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Scheme 4 Synthesis of the spirooxazolidines 12a–c, and the X-ray structure of 12c (CCDC 2065540)
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(66) Ugi-Tetrazole Four-Component (UT-4CR) Synthesis of 7a–e
and 2b; General Procedure
The appropriate aniline (1.0 mmol), isocyanide (1.0 mmol), and
trimethylsilyl azide (1.0 mmol) were added to a stirred solution
of the appropriate aldehyde (1.0 mmol) in MeOH (1.0 mL) at rt,
and the mixture was stirred vigorously for 1–2 h. Half the
solvent was removed under reduced pressure and, if a solid
residue appeared, it was collected by filtration and washed with
Et2O. Alternatively, the solvent was removed under reduced
pressure, and the residue was purified by column chromatogra-
phy [silica gel, PE–EtOAc (1:1)].
N-{1-[1-(9H-Fluoren-9-yl)-1H-tetrazol-5-yl]cyclohexyl}-
3,4,5-trimethoxyaniline (7c)
1
Gray solid; yield: 427 mg (86%); mp 216–218 °C. H NMR (500
MHz, DMSO-d6):  = 7.94 (d, J = 7.6 Hz, 2 H), 7.44 (t, J = 7.6 Hz, 2
H), 7.26 (s, 1 H), 7.12 (s, 2 H), 6.39 (s, 2 H), 5.72 (s, 2 H), 3.59 (s, 3
H), 3.47 (s, 6 H), 2.87 (s, 1 H), 2.61–2.58 (m, 2 H), 2.352–2.348
(m, 2 H), 1.80–1.69 (m, 5 H), 1.47–1.44 (m, 1 H). 13C NMR (126
MHz, DMSO-d6):  = 160.3, 153.6, 141.6, 141.5, 140.0, 129.7,
129.5, 128.0, 124.1, 120.8, 91.6, 61.9, 60.5, 55.5, 53.5, 45.5, 24.8,
20.9. MS (ESI): m/z [M + Na]+ calcd for C29H31N5NaO3: 520.23;
found: 520.07.
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(67) Oxazoles 12a–c; General Procedure
K2CO3 (1.5 mmol) was added to a stirred solution of the appro-
priate aldehyde (1.0 mmol) and 9-isocyano-9H-fluorene (1; 1.0
mmol) in MeOH (3.0 mL) at rt, and the mixture was stirred vig-
orously for 1–5 h. The solvent was then removed under reduced
pressure and the residue was collected by filtration and washed
with Et2O. Alternatively, the solvent was removed under
reduced pressure and the residue was purified by column chro-
matography [silica gel, PE–EtOAc (4:1)].
5′-(2-Phenylethyl)spiro[fluorene-9,4′-[1,3]oxazole] (12c)
White solid; yield: 276 mg (85%); mp 161–163 °C. 1H NMR (500
MHz, DMSO-d6):  = 7.89–7.83 (m, 2 H), 7.69 (s, 1 H), 7.43–7.27
(m, 6 H), 7.10–7.05 (m, 3 H), 6.76 (d, J = 6.9 Hz, 2 H), 4.68–4.65
(m, 1 H), 2.30–2.25 (m, 1 H), 2.13–2.07 (m, 1 H), 1.89–1.88 (m, 1
H), 1.32–1.28 (m, 1 H). 13C NMR (126 MHz, DMSO-d6):  = 158.2,
148.1, 143.5, 140.6, 140.0, 139.9, 129.0, 128.9, 128.23, 128.18,
128.0, 127.4, 126.0, 125.9, 124.5, 120.5, 120.2, 85.1, 80.6, 32.9,
31.5. MS (ESI): m/z [M + Na]+ calcd for C23H19NNaO: 348.14;
found: 348.10.
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