A Crystalline Ready-to-Use Form of Cyclopentadiene

Article abstract of DOI:10.1055/s-0037-1610442

Cyclopentadiene (Cpd) is widely used as a starting material in organic and inorganic chemistry. In neat form, Cpd dimerizes, making it necessary to distill it prior to use to obtain fully reactive material. We have screened three different tetraphenyladamantane octaethers for their ability to act as encapsulating organic crystal (EnOC) hosts for Cpd. To this end, we also synthesized 1,3,5,7-tetrakis(3,5-dimethoxyphenyl)adamantane, a new octaether, dubbed iso -TDA. Only one of the octaethers was found to produce inclusion complexes with Cpd in the crystalline state. The encapsulated diene was stable for one month and showed full reactivity in a series of different synthetic transformations.

Full text of DOI:10.1055/s-0037-1610442

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
©
Georg Thieme Verlag Stuttgart · New York
2018, 29, A–D
letter
A
en
Synlett
F. Krupp et al.
Letter
A Crystalline Ready-to-Use Form of Cyclopentadiene
Felix Krupp
Shiliang He
Wolfgang Frey
Clemens Richert*
Institut für Organische Chemie, Universität Stuttgart,
7
0569 Stuttgart, Germany
lehrstuhl-2@oc.uni-stuttgart.de
Received: 04.04.2018
Accepted after revision: 29.05.2018
Published online: 27.06.2018
dienes, making Cpd unattractive for medicinal chemistry
and other fields that rely heavily on combinatorial tech-
niques.
DOI: 10.1055/s-0037-1610442; Art ID: st-2018-b0209-l
We have recently described a methodology for encapsu-
Abstract Cyclopentadiene (Cpd) is widely used as a starting material
in organic and inorganic chemistry. In neat form, Cpd dimerizes, mak-
ing it necessary to distill it prior to use to obtain fully reactive material.
We have screened three different tetraphenyladamantane octaethers
for their ability to act as encapsulating organic crystal (EnOC) hosts for
Cpd. To this end, we also synthesized 1,3,5,7-tetrakis(3,5-dimethoxy-
phenyl)adamantane, a new octaether, dubbed iso-TDA. Only one of the
octaethers was found to produce inclusion complexes with Cpd in the
crystalline state. The encapsulated diene was stable for one month and
showed full reactivity in a series of different synthetic transformations.
lating reagents in crystalline matrices of tetraarylada-
manantes.3
–5
The tetraphenyladamantane octaethers
1
,3,5,7-tetrakis(2,4-dimethoxyphenyl)adamantane (TDA, 1,
Figure 1) and 1,3,5,7-tetrakis(2,4-diethoxyphenyl)adaman-
tane (TEO, 2) showed efficient capture, storage, and release
3–5
of small molecules. A suppression of problematic proper-
ties of reagents was achieved simply by inclusion in the
OMe
Key words cycloadditions, cyclopentadiene, inclusion complexes, up-
take and release, X-ray crystal structure
OEt
OMe
OMe
MeO
Organic synthesis relies on starting materials of known
structure and quality. For some important starting materi-
als, this requires freshly prepared reagents, either by pro-
ducing them in a chemical conversion, by crystallizing, or
by distilling them. This leads to significant extra effort com-
pared with reactions, for which all starting materials are
OEt
EtO
OEt
MeO
OMe
EtO
OMe
OEt
OEt
MeO
1
stable.
TDA (1)
EtO
TEO (2)
One organic compound that suffers from limited stabili-
ty due to ‘self-reactivity’ is cyclopentadiene (Cpd). It is one
of the most important starting materials for cycloadditions
and is also widely used as ligand in inorganic chemistry. A
recent search in the SciFinder database yielded 29920 en-
tries for cyclopentadiene, which underlines its importance
MeO
OMe
MeO
OMe
2
as a substrate in chemistry.
MeO
MeO
OMe
Usually, Cpd has to be freshly distilled before use, unless
it is kept in carbanionic form or at very low temperature.
This makes it difficult to use Cpd in modern, automated
synthesis without time-consuming manual steps. Combi-
natorial syntheses that require a daily supply of Cpd are
thus costlier than comparable procedures using stable
OMe
iso-TDA (3)
Figure 1 Structures of the tetraaryladamantane octaethers TDA (1),
TEO (2), and iso-TDA (3)
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

B
Synlett
F. Krupp et al.
Letter
crystalline lattices of these readily crystallizing host com-
pounds. The term ‘encapsulating organic crystals’ (EnOCs)
6
was coined to describe this phenomenon. Our initial work
was focused on solvents and reagents, leaving open a wide
field of possible applications of EnOCs.
We wished to extend our studies to organic starting ma-
terials, and we wished to better understand the structural
basis of the encapsulation of guest molecules in crystalline
matrices of tetraaryladamantanes. For this, we screened
three compounds as potential crystalline hosts: TEO, TDA,
and a new compound dubbed ‘iso-TDA’ (3), whose synthe-
sis is disclosed in this communication. Both TEO and iso-
TDA crystallize readily from Cpd, but only TDA encapsulates
it during the process. This allowed us to report a new meth-
odology for the ‘formulation’ of cyclopentadiene in a crys-
talline matrix. The formulation contains overstoichiometric
amounts of Cpd and gives full reactivity of the guest in syn-
thetic transformations but is stable for up to 30 days. This is
7
–11
shown for different cycloaddition reactions,
including a
12
target molecule from medicinal chemistry, for which
combinatorial syntheses are an attractive way to prepare
derivatives with new properties.
Scheme 1 Synthesis of iso-TDA (3). To the left of the target molecule, a
portion of its X-ray crystal structure is shown (crystals obtained by ther-
mal crystallization from acetone). Note that this structure lacks encap-
sulated guest molecules.
As mentioned above, we selected known tetraarylada-
mantanes TDA (1) and TEO (2) and the new octaether
1,3,5,7-tetrakis(3,5-dimethoxyphenyl)adamantane (3) as
hosts. Since 3 is an isomer of 1; it was called ‘iso-TDA’. It was
prepared to test the limits of EnOC formation. Earlier work
had shown that the ability of 1 to form inclusion complexes
with a broad range of guest molecules is lost when methoxy
With 3 in hand, crystallization experiments were per-
formed with solvents known to form inclusion complexes
with TDA or TEO.3 This included crystallization from p-xy-
lene, acetone, and pyridine, as well as from cyclopentadi-
ene. Neither of these solvents was found in crystals of 3. In-
stead, iso-TDA crystallized in the tightly packing monoclinic
crystal system shown in the lower part of Scheme 1. Fur-
ther details of the structure can be found in the Supporting
Information. We concluded from this that the regioisomeric
structure of TDA is important for its ability to produce
EnOCs, and subsequent efforts focused on finding a stabiliz-
ing ‘formulation’ for Cpd with the established EnOC-form-
ing octaethers 1 and 2.
–5
3
groups are replaced by ethyl groups. In the case of 3, the
alkoxy groups were kept, but their positions were changed.
Introducing the four aryl rings of 3 via electrophilic aro-
matic substitution meta to two methoxy groups of a diether
starting material appeared all but impossible. So, benzene
derivatives with ortho/para-directing groups seemed un-
likely starting materials, and their counterparts with two
meta-directing groups were considered too unreactive to
achieve fourfold substitution of the adamantane. (The
fourth aryl substituent is usually slow to be introduced.)
Although halogens normally direct into the ortho and para
positions due to their +M effect, a protocol from Reichert
and Mathias was known to produce tetraphenyl adaman-
With these two tetraaryladamantane octaethers, crys-
tallization from freshly distilled cyclopentadiene again pro-
duced crystals. But, the crystal structure of TEO did not
contain solvent inclusions, even though this compound is
known to accommodate overstoichiometric amounts of
13
tanes with unusual substitution patterns. Starting from
,3,5,7-tetrabromoadamantane, the synthesis of 1,3,5,7-
tetrakis(1,3-dibromophenyl)adamantane was achieved,
1
5
larger aromatic ring systems, such as xylenes. Only TDA
13
using 1,3-dibromobenzene and AlCl3.
Results from
showed the desired encapsulation of Cpd, which was found
in the X-ray crystal structure at an overstoichiometric ratio
attempts to obtain the desired regioisomer in pure form on
the level of the halogenides were not encouraging, so copper-
of 4:5 (TDA:Cpd). A portion of the crystal structure and an
14
1
catalyzed nucleophilic substitution was performed with
the crude, and the desired 1,3,5,7-tetrakis(3,5-dimethoxy-
phenyl)adamantane (3) was then obtained in 15% overall
yield (Scheme 1).
H NMR spectrum of a sample dissolved in CDCl are shown
3
in Figure 2.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

C
Synlett
F. Krupp et al.
Letter
O
O
O
O
5
4
6
6
5
TDA
7
7
MeO2C
CO2Me
CO2Me
CO2Me
8
9
NC
NC
CN
CN
CN
CN
CN
CN
1
0
7
7
7
7
Figure 2 Encapsulating cyclopentadiene in an EnOC with 1 as host.
a) Microscopic image of a crystalline sample, obtained by heating TDA
1
1
(100 mg) and cyclopentadiene (3 mL) to 55 °C and subsequent cooling
O
O
O
to 22 °C. b) Details of the X-ray crystal structure of the inclusion com-
O
O
O
plex 7 showing two TDA molecules in gray and the Cpd guest molecules
1
in green. Hydrogen atoms were omitted for clarity. c) H NMR spectrum
12
(
300 MHz) of a sample of the EnOC dissolved in CDCl , showing its
3
composition, with signals of the host and the guest.
S
13
S
S
Dimer formation via cycloaddition can readily be
S
S
1
detected by NMR spectroscopy. When a series of H NMR
14
S
spectra was measured over time, less than 15% conversion
of the inclusion complex to any products was detected
during more than one month of monitoring at room tem-
perature (Figure S3, Supporting Information), whereas a
control sample of neat Cpd reacted with a half-life time of
approx. 48 h (at room temperature), as expected, based on
the literature for samples kept at or slightly above room
O
15
O
+
H3N
I
I
O
Br
16
17
O
N
H
O
Br
15
temperature.
18
The encapsulated cyclopentadiene, abbreviated [Cpd]TDA
Scheme 2 Reactions performed with TDA-encapsulated or freshly
distilled cyclopentadiene. The reaction conditions are listed in Table 1.
Representative protocols are given below.17
(
7), proved reactive when samples of the EnOC were used
for synthetic transformations. The stabilizing ‘formulation’
released the diene when the crystals were dissolved in
common organic solvents, and the reactions expected of
freshly distilled Cpd ensued. This was shown for a series of
different dienophiles as reaction partners (Scheme 2).
First, the yield of a control conversion of free Cpd (4)
and benzoquinone (5) to give 6 was determined, followed
by the reaction with the encapsulated version 7. In either
case, a yield of 78 ± 4% was obtained. When either form of
Cpd was allowed to stand at room temperature for 14 d, the
yield of a subsequent reaction with 5 remained unchanged
for 7, whereas unencapsulated Cpd lost almost all of its re-
activity toward the dienophile (yield 2%; Table 1). Other re-
actions with 7 produced products such as 6, 9, 11, and 13
(Scheme 2) in yields that were near-identical to those found
in the literature.7
–10
Besides the four different Diels–Alder reactions named
above, 7 was also found to perform well in a hetero-Diels–
Alder reaction with di-2-thienyl thioketone (14), producing
15 in 67% yield, accompanied by a recovery of 98% of TDA
during purification (Table 1, entry 8). To confirm the poten-
tial of the encapsulation methodology for combinatorial
protocols, the synthesis of a target molecule typical for me-
dicinal chemistry, was performed next. For this, we chose
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

D
Synlett
F. Krupp et al.
Letter
Table 1 Results of Reactions with TDA-Encapsulated (7) or Unencap-
sulated Cyclopentadiene (4)
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610442.
S
u
p
p
ortioIgnfmr oaitn
S
u
p
p
o
nrtogI
i
f
rm oaitn
Entry Reactants Conditions
Target
Compound
Yield (%) Recovered
TDA (%)b
1
2
3
4
5
6
7
8
4+5
7+5
CHCl
CHCl
CHCl
CHCl
CHCl
3
3
3
3
3
, 2 h
, 2 h
, 2 h
, 2 h
, 4 h
6
6
82
74
2
–
References and Notes
90
–
(
1) Grachev, A. A.; Klochkov, A. O.; Shiryaev, V. I. Russ. J. Appl. Chem.
2012, 85, 629.
(2) Accessed at https://scifinder.cas.org/scifinder/view/scifinder/
4a+5
6
7a+5
6
74
85
88
73
67
89
90
90
89
95
98
96
scifinderExplore.jsf; search performed on 29.03.2018.
7+8
9
(3) Schwenger, A.; Frey, W.; Richert, C. Chem. Eur. J. 2015, 21, 8781.
7+10
7+12
7+14
THF, 1 h
CHCl , 2 h
THF, 26 h
11
13
15
(4) Schwenger, A.; Frey, W.; Richert, C. Angew. Chem. Int. Ed. 2016,
5, 13706.
5) Richert, C.; Alexandre, P.-E.; Schwenger, A.; Frey, W. Chem. Eur. J.
017, 23, 9018.
5
3
(
2
9
7+16+17 CHCl
3
, MeCN, 5 h 18
(6) Richert, C.; Krupp, F. Synlett 2017, 28, 1763.
(7) Mal, D.; Ray, S. Eur. J. Org. Chem. 2008, 3014.
(8) To, K. K. W.; Wang, X.; Yu, C. W.; Ho, Y-P.; Au-Yeung, S. C. F.
Bioorg. Med. Chem. 2004, 12, 4565.
a
two weeks after distillation/crystallization.
TDA recovered during purification.
b
(9) Bartlett, P. D.; Wu, C. J. Org. Chem. 1984, 49, 1880.
(
(
(
10) Michieletto, I.; Fabris, F.; De Lucchi, O. Tetrahedron: Asymmetry
the route to iodinated tetrahydroquinolines of Arterburn et
al. (Scheme 2). Compound 18 had been prepared by those
12
2000, 11, 2835.
11) Mlostoń, G.; Grzelak, P.; Linden, A.; Heimgartner, H. Chem. Het-
erocycl. Compd. 2017, 53, 518.
12) Ramesh, C.; Nayak, T. K.; Burai, R.; Dennis, M. K.; Hathaway, H.
J.; Sklar, L. A.; Prossnitz, E. R.; Arterburn, J. B. J. Med. Chem. 2010,
53, 1004.
authors for its activity toward G protein coupled estrogen
12
receptors GPR30. It is accessible via a three-component
12
Povarov cyclization that involves cyclopentadiene. Using
Cpd]TDA, the synthesis of 18 was achieved with a yield sim-
ilar to that reported for the conversion with freshly distilled
[
(13) Reichert, V. R.; Mathias, L. J. Macromolecules 1994, 27, 7015.
12
(14) Jing, L.; Ma, H.; Fan, P.; Jia, Z. Chem. Nat. Compd. 2017, 53, 248.
Cpd (Table 1, entry 9).
(
(
(
15) Krupka, J. Pet. Coal 2010, 52, 290.
16) Moffett, R. B. Org. Synth., Coll. Vol. IV 1963, 32, 41.
17) Compound 6
In conclusion, we have synthesized a new tetraarylada-
mantane (3) that helps to better define the structural pa-
rameters required for EnOC formation, and we have devel-
oped a ‘formulation’ for Cpd that allows for daily use of this
compound for extended periods of time, without prior dis-
Samples of [Cpd]TDA (7, 20 mg, corresponding to 0.027 mmol
Cpd) and p-benzochinone (5, 3.2 mg, 0.029 mmol) were dis-
solved in CHCl (0.1 mL). The solution was stirred for 2 h at
3
16
22 °C. After removing the solvent under reduced pressure, the
resulting crude product was purified by column chromatogra-
phy (silica, CH Cl /PE 7:1, v/v, R = 0.27). The title compound
tillation or cooling to –80 °C. Encapsulated Cpd (7) is read-
ily prepared and keeps the diene in a form that does not un-
dergo dimerization upon storage, resulting in a shelf-life of
several weeks. The formulation can release reactive mono-
meric Cpd upon dissolving in organic reaction media. The
2
2
f
was isolated as a yellowish solid (3.5 mg, 0.020 mmol, 74%) and
8 mg, 0.026 mmol TDA (90%) was recovered by eluting with
1
the above mentioned solvent mixture.
[
Cpd]TDA may pave the way for the routine use of cyclopen-
Compound 18
tadiene in automated synthesis, both in organic and in inor-
ganic chemistry. Our results also expand the scope of the
EnOC methodology to substrates rather than reagents of
synthetic transformations. We are actively pursuing the en-
capsulation of other self-reactive or labile substrates.
A sample of 6-bromopiperonal (16, 4.27 mg, 0.019 mmol),
p-iodoaniline (17, 4.04 mg, 0.019 mmol) and encapsulated
cyclopentadiene (7, 75 mg, corresponding to 0.095 mmol Cpd)
were dissolved in CHCl3 (0.2 mL). Then, Sc(OTf)3 (0.91 mg,
0.0018 mmol) was dissolved in dry MeCN (0.04 mL). This solu-
tion was slowly added to the reaction mixture. The mixture was
stirred for 5 h at 22 °C. After removing the solvent in vacuo, the
resulting crude was purified via column chromatography (silica,
PE/CH Cl 1:4, v/v, R = 0.8). Compound 18 was isolated as an
Funding Information
2
2
f
off-white solid (8.4 mg, 0.0175 mmol, 89%) and 72 mg, 0.11
mmol TDA (96%) was recovered by eluting with the above-men-
tioned solvent mixture. The analytical data were in accordance
This work was supported by DFG grant RI 1063/15-1 and the Univer-
sity of Stuttgart.
D
e
ustch
e
F
orsch
u
n
gsg
e
m
en
i
schatf
R( I
1
0
6
3
1/5-1)
7,12
with the literature.
Acknowledgment
The authors thank Alexander Schwenger for discussions and Helmut
Griesser for a review of the manuscript.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D