Formation of [5.5]cyclopentadienidophanes by macrocyclization of [3-(methylammonio)propyl]cyclopentadienides under Mannich conditions

Article abstract of DOI:10.1016/j.tet.2009.05.014

2-Acyl-1,4-bis(methoxycarbonyl)-3-[3-(methylammonio)propyl]cyclopentadienides 1 and aqueous formaldehyde can undergo a double Mannich reaction leading to the bisbetainic 2,12-diazonia-[5,5](1,3)cyclopentadienidophanes 2. The success of this macrocyclizati

Full text of DOI:10.1016/j.tet.2009.05.014

Tetrahedron 65 (2009) 5733–5738
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Formation of [5.5]cyclopentadienidophanes by macrocyclization of
[3-(methylammonio)propyl]cyclopentadienides under Mannich conditions
,
a
a
b
Gerhard Maas a , Andreas Mu¨ller , Andreas Endres , Ju¨rgen Schatz
*
a Institute for Organic Chemistry I, University of Ulm, Albert-Einstein-Allee 11, D-89081 Ulm, Germany
b Organic Chemistry I, University of Erlangen-Nu¨rnberg, Henkestraße 42, D-91054 Erlangen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Acyl-1,4-bis(methoxycarbonyl)-3-[3-(methylammonio)propyl]cyclopentadienides
1
and aqueous
Received 18 March 2009
Accepted 7 May 2009
Available online 13 May 2009
formaldehyde can undergo a double Mannich reaction leading to the bisbetainic 2,12-diazonia-
[5,5](1,3)cyclopentadienidophanes 2. The success of this macrocyclization reaction seems to depend on
the length of the
u
-ammonioalkyl chain and the individual acyl substituent. In the cases of
u-(methyl-
ammonio)butyl and
u
-(methylammonio)pentyl chains, as well as with -ammoniopropyl derivatives
u
Keywords:
Cyclopentadienides
Cyclophanes
Macrocyclization
Mannich reaction
Aminomethylation
Aminofulvenes
bearing particularly electron-rich 4-methoxybenzoyl or 2-furoyl substituents, a mixture of oligomers is
formed. On the other hand, DCC-assisted cyclocondensation of 1b,d (acyl¼4-methoxybenzoyl and
thiophene-2-carbonyl, respectively) occurs only intramolecularly, leading to the bicyclic 6-amino-
pentafulvenes 4b,d in good yields.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
pentadienidophane, which was not isolated nor characterized spec-
troscopically, however. The dianionic [2.2](2,7)fluorenidophane has
Benzenoid cyclophanes nowadays represent a well-developed
class of aromatic ring systems incorporated in a three-dimensional
molecular architecture, offering many interesting properties in
terms of structural chemistry, reactivity, and applications.1,2 In the
structural motif of the phanes, the benzene ring can and has been
replaced, inter alia, by a large variety of other benzenoid and non-
benzenoid entities, one of them being the anionic cyclopentadienide
ring system. A particular variety of the phane motif is found in the
metallocenophanes.3,4 Most members of this metallocene family
feature a metallocene unit with the two cyclopentadienide rings
connected by a single bridge, and some of the research on these
compounds has aimed at potential applications in homogeneous
catalysis, in particular for stereoselective olefin polymerization.5
also been described.9
In previous communications,10,11 we have reported that (
u-
ammonioalkyl)cyclopentadienides 1 result from the rhodium-cat-
alyzed reaction of dimethyl 3-diazo-1-propene-1,3-dicarboxylate
with semicyclic enaminoketones (Scheme 1). Betaines 1 are loaded
with different functional groups, partly with complementary re-
activity. It could be expected that this functional group pattern
would allow intra- or intermolecular reactions of the betaines to
take place. A twofold reaction of two cyclopentadienide building
blocks, i.e., a cyclodimerization reaction, would pave the way to
[n.n]cyclopentadienidophanes. Eventually, the length of the alkyl
side chain in 1 (3–5 methylene groups) should decide on whether
such reactions would occur intramolecularly or between two
Only
a few multiply bridged metallocenophanes, including
[45](1,2,3,4,5)ferroceno-phane,6 have been synthesized up to now.
Little is known about metal-free cyclopentadienidophanes. It
appears that the first phane of this class was the ansa-compound
[9](1,3)cyclopentadienidophane.7 In 1999, Neuenschwander and co-
workers8 described the first doubly bridged cyclopentadienophane,
namely a [2.2]cyclopentadienophane; it is likely that this phane
resulted from protonation of the corresponding dianionic [2.2]cyclo-
O
E
R
n
E
+
N
CH3
N2
E
H2+N
CH3
cat. Rh2(OAc)4
-N2
n
O
E
R
E = COOMe
1
* Corresponding author. Tel.: þ49 (0)731 5022790; fax: þ49 (0)731 5022803.
E-mail address: gerhard.maas@uni-ulm.de (G. Maas).
Scheme 1. Synthesis of (
u
-ammonioalkyl)cyclopentadienides 1 (n¼1–3).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.014

5734
G. Maas et al. / Tetrahedron 65 (2009) 5733–5738
Table 1
cyclopentadienide molecules. A hint to this issue was obtained
from the inspection of the solid-state structures of two betaines
Products obtained from betaines 1a–h and formaldehyde
1:12 while an (
u
-methylammoniopropyl)-substituted derivative
forms an intramolecular N–H/Oacyl hydrogen bond, an ( -methyl-
ammoniopentyl)-substituted derivative is arranged as co-
1–3
n
R
Yield of 2 (%)
Yield of 3 (%)
u
a
1
1
Ph
52
a
b
C6H4–4-OCH3
45
ordination dimer held together by two such hydrogen bonds.
c
1
20
2. Results and discussion
NO2
d
e
f
g
h
1
1
1
2
3
2-Thienyl
2-Furyl
1-Adamantyl
2-Thienyl
2-Thienyl
80
79
2.1. Reaction of betaines 1 with formaldehyde
45
74
81
The presence of a secondary amine group in betaines 1 sug-
gested its transformation into a methylene iminium function,
which could attack the cyclopentadienide ring intra- or inter-
molecularly. The aminomethylation of a cyclopentadienide ring
under Mannich conditions (formaldehyde/sec-amine13) or by re-
lated methods (e.g., CH2(NMe2)2/H3PO414) is an established method
in metallocene chemistry.
showed ill-defined broad signals, and many signals in the 13C NMR
spectra were broadened by the presence of additional closely
spaced signals. By the same NMR arguments as given above for 2d,
the presence of a CcpCH2N moiety can be assumed and therefore,
these products are tentatively considered as oligomers 3b and 3d.
As an accurate integration of the 1H NMR spectra was not possible,
it cannot be excluded that these oligomers also contain subunits
resulting from an aminomethylation of the anisyl and furyl rings.
Considering the deviation from the expected values for the ele-
mental analyses, it is likely that the number of repeating units in
the oligomers is small, so that the influence of the (unknown) end
groups is no longer negligible. The FAB mass spectra showed, in
addition to peaks for the dimer (n¼2), several very weak peaks in
the measured m/z range up to 2000 Da.
The 2-[3-(methylammonio)propyl]-3-(2-thenoyl)cyclopenta-
dienide 1d was investigated first. From a solution of 1d and an
equimolar quantity of aqueous formaldehyde in THF, a crystalline
yellow precipitate separated within 24 h. The water-soluble prod-
uct was identified as the bisbetainic 2,12-diazonia-[5,5](1,3)cyclo-
pentadienidophane 2d (Scheme 2) by its spectroscopic and
analytical data; a further structural proof was furnished by an X-ray
crystal structure determination (see Section 2.2). A field-desorption
(FD) mass spectrum showed the molecular ion peak at m/z¼750,
accompanied only by a lower-intensity peak of the ‘monomer’
(m/z¼376), which probably resulted from a thermal fragmentation.
The 1H and 13C NMR spectra, recorded in CDCl3 solution, pointed to
a time-averaged symmetrical structure of 2d, showing only the
number of signals expected for the monomeric subunit. The in-
corporation of the formaldehyde-derived methylene group (i.e.,
CcpCH2N) was indicated by the disappearance of the cyclo-
pentadienide CH proton signal and by new signals for the methyl-
ene group at dH¼4.30/5.31 ppm and dC¼54.57 ppm. Further NMR
observations are discussed in Section 2.2.
Mixtures of oligomers were also obtained from the reaction of
formaldehyde with betaines 1g and 1h, which bear
ammonio)butyl and -(methylammonio)pentyl side-chains, re-
u-(methyl-
u
spectively. In these cases, the unfavorable entropy factor is likely to
prevent the formation of [6,6]- and [7,7]cyclopentadienidophanes.
The tentative assignment of the products as oligomers 3g and 3h,
which in contrast to 3b,d are seemingly insoluble in common or-
ganic solvents, is supported by the elemental analyses and a solid-
state 13C NMR spectrum of 3h.
H
Me
N+
R
2.2. Structure of [5.5]cyclopentadienidophane 2d
MeOOC
O
O
MeOOC
COOMe
COOMe
A plot of the solid-state molecular structure of 2d is shown in
Figure 1. One recognizes a cone-shaped molecular framework at
which the positions of the two methoxycarbonyl groups at the
upper rim, as well as those at the lower rim, have an approximate
C2-symmetrical relationship. In contrast, the two thenoyl groups
are arranged differently, with one of the thiophene rings taking the
endo orientation, the other one the exo orientation relative to the
macrocyclic scaffold. Two intramolecular N–H/O hydrogen bonds,
each involving the carbonyl oxygen atom of an ester group, are
present and are likely to stabilize the given conformation in the
aliphatic chains.
N+
MeOOC
n
R
H H
N+
H
H2C=Oaq
THF, r.t.
Me
n = 1
2
Me
n = 1−3
COOMe
MeOOC
n
O
R
x
N+
Me
1
H
COOMe
O
R
3
Scheme 2. Reaction of betaines 1 with formaldehyde; see Table 1 for substituents and
yields.
Betaines 1a,c,f reacted with formaldehyde in the same manner as
1d and were transformed into bisbetaines 2a,c,f (Scheme 2 and Table
1). Obviously, all these bisbetaines result from a twofold Mannich-
type aminomethylation reaction, in which two molecules of 1 are
combined by a regioselective attack of an in situ formed methylene
iminium unit at the cyclopentadienide ring of the second molecule.
The success of the described macrocyclization by a twofold
Mannich reaction of betaines 1 seems to depend on the length of
An inspection of the relevant torsion angles in the structure of
2d reveals that the thenoyl group with the thiophene ring in exo
position is perpendicular to the adjacent cyclopentadienide ring,
whereas the orientation of the thenoyl group with the thiophene
ring in endo position is such that a significant amount of p-conju-
gation is still possible (torsion angle C21–C22–C28–O8¼136.1ꢀ).
Thus, the conformation with the endo position of one thiophene
ring appears to be energetically more favorable, but an arrange-
ment of both thiophene rings pointing to the interior of the macro-
cycle is disfavored for steric reasons. In order to corroborate these
ideas, we performed a conformation analysis for 2d using semi-
empirical calculations (see Experimental for details). Table 2 sum-
marizes the results for the six structures of lowest energy. In all the
the
u-ammonioalkyl chain and the individual acyl substituent
(Table 1). In the cases of 3-(methylammonio)propyl betaines 1b and
1d, bearing particularly electron-rich 4-methoxybenzoyl or 2-
furoyl substituents, solid products were obtained, which are likely
to be mixtures of oligomers. The 1H NMR spectra of these products

G. Maas et al. / Tetrahedron 65 (2009) 5733–5738
5735
Figure 2. Calculated (PM3) structure of 2d in the alternate conformation of the
macrocyclic framework.
Figure 1. Structure of 2d in the solid state (ORTEP plot, ellipsoids of thermal vibration
shown at the 20% probability level). Selected bond lengths (Å): C1–C2 1.409(8), C2–C3
1.430(8), C3–C4 1.379(8), C4–C5 1.428(8), C5–C1 1.418(8). Hydrogen bonds: N1–H
0.92(7), O6/H 1.79(7), N1/O6 2.684(8) Å, angle N1–H/O6 163(6)ꢀ; N2–H 0.88(5),
O6/H 1.79(5), N2/O1 2.643(7) Å, angle N2–H/O1 164(5)ꢀ. Torsion angles (ꢀ): C2–
C3–C9–O3 ꢁ81.8(9), C21–C22–C28–O8 136.1(7).
signals when the NMR spectra were recorded in more polar sol-
vents (CD3CN, CD3OD, DMSO-d6). The 1H spectra of 2d in acetoni-
trile-d3 solution at 300 K, for example, showed these signal sets in
a 4:1:1 ratio, and in the variable-temperature 200 MHz 1H spectra,
(reversible) peak broadening occurred when the temperature was
raised to 335 K. A methanol-d4 solution of 2d showed three signals
for the COOCH3 protons at 300 K, but only one signal at 358 K,
which split into three signals again on cooling. These observations
suggest a dynamic equilibrium between the species responsible for
the different signal sets. We interpret the three signal sets, ob-
served in a 4:1:1 intensity ratio in CD3CN solution, as belonging to
two species. The major component is likely to have the same time-
averaged C2-symmetrical structure as the species observed in CDCl3
solution, while the two minor signal sets of equal intensity are
thought to arise from a rather stable unsymmetrical conformer of
2d, which interconverts with the major conformer only slowly on
the NMR time scale. As pointed out above, the unsymmetrical
conformers listed in Table 2 are expected to interconvert rather fast
by simple bond rotations. We suggest that the unknown confor-
mational isomer has the unsymmetrical structure shown in Fig-
ure 2. PM3 calculations place this isomer at Erel(ZPE)¼18.0 kJ molꢁ1
with respect to the global minimum structure (Table 1, entry 1). It
can be seen that this conformer has an ‘up, down’ arrangement of
the two cyclopentadienide rings; it is still stabilized by two intra-
molecular N–H/O hydrogen bonds, but in contrast to the structure
shown in Figure 1, two chemically different ester groups participate
in these hydrogen bonds (one adjacent to a thenoyl group, the other
one between the aliphatic bridges). Interconversion between the
cone conformation shown in Figure 1 and the alternate confor-
mation is reminescent of the conformational isomerism so well
known in calixarene chemistry (for energy differences between
several conformations in [4]calixarenes, see lit.15). In the case of
phanes 2, this interconversion requires at least one intramolecular
Table 2
Calculated (PM3) conformations of lowest energy for 2d
Entry
Erel (kJ molꢁ1
a
)
Orientation of thiophene
ring/O]C–C–S conformation
Orientation of COOMe
groups at lower rim
1
0
endo/syn
exo/syn
endo/syn
exo/anti
endo/syn
exo/syn
endo/syn
exo/syn
endo/syn
exo/anti
exo/syn
exo/syn
Antiparallel
Antiparallel
Parallel
2
3.52
6.06
9.08
9.65
10.46
3
4b
5
Parallel
Parallel
6
Antiparallel
a
Corrected for zero-point energy (ZPE).
For entry 4, the carbonyl groups at the lower rim point in the opposite direction
b
compared to entry 3.
conformations, the two five-membered chains connecting the two
cyclopentadiene rings are more or less the same, one of the two
chains showing a significant deviation from the solid-state struc-
ture. The structures listed in Table 2 differ by the conformations at
the substituent bonds Ccp–COOMe (lower rim), Ccp–thenoyl, and
C(]O)–Cthienyl. The results show that in the structure of lowest
energy, the conformations around these bonds are the same as in
the solid-state structure. Interestingly, the anti orientation of the
endo-positioned thiophene ring is higher in energy than the listed
structures (E¼13.9 kJ molꢁ1 for the endo/anti, exo/anti conforma-
tion), although syn/anti disorder is evident in the solid-state
structure. The exo, exo orientation of the two thiophene rings is
clearly less favorable (entry 6) than the structure of lowest energy.
The time-averaged C2-symmetrical structures of 2a–d, postu-
lated from the number of signals in the 1H and 13C NMR spectra in
CDCl3 solution (see Section 2.1), should be achieved easily by
equilibration of the six preferred conformations given in Table 2;
a significant barrier to rotation around the bonds C3–C7, C7–C10,
C5–C18 (and their symmetry-equivalent counterparts in the left-
hand part of the molecule, compare Fig. 1) is not expected. There-
fore, it was surprising to observe the presence of three sets of
MeOOC
MeOOC
H
H
DCC,
N+
toluene, rfx, 3 h
COOMe
Me
COOMe
R
N
Me
4
O
R
1
b: R = 4-anisyl; d: R = 2-thienyl
Scheme 3. Cyclocondensation of betaines 1b,d.

5736
G. Maas et al. / Tetrahedron 65 (2009) 5733–5738
4. Experimental
4.1. General information
NMR spectra: Bruker AMX 500 spectrometer (1H: 500.14 MHz;
13C: 125.77 MHz). TMS was used as the internal standard;
values
d
are reported in part per million (mc¼centered multiplet). When
necessary, 13C signal assignments were derived from C,H COSY,
HSQC and gradient-selected HMBC spectra. A solid-state CP-MAS
13C NMR spectrum was recorded on a Bruker DSX 400 instrument
(100.62 MHz, glycine as external reference). IR spectra: Perkin–
Elmer IR spectrophotometer 883; wavenumbers [cmꢁ1] are given.
Elemental analyses: Perkin Elmer EA 240. Mass spectra: Varian
MAT 711 (FD spectra) and SSQ 7000 (EI spectra). Column chroma-
tography was performed under hydrostatic pressure (silica gel Si
60, Macherey-Nagel, 0.063–0.2 mm) and under medium-pressure
conditions [Merck Lobar columns, Lichroprep Si 60, particle size
Figure 3. Structure of 4d in the solid state (ORTEP plot, ellipsoids of thermal vibration
shown at the 30% probability level). Selected bond lengths (Å): C5–C6 1.395(2), C6–C7
1.423(2), C7–C8 1.369(2), C8–C9 1.449(2), C9–C10 1.414(2), C5–C9 1.428(2), C10–N
1.336(2), N–C1 1.455(2), N–C2 1.467(2); C8–C13 1.463(2), C13–O3 1.205(2), C6–C11
1.451(2), C11–O1 1.210(2). Torsion angle: C5–C9–C10–N ꢁ35.4(2)ꢀ.
40–63
m
m, two columns (240ꢂ10 mm and 310ꢂ25 mm) con-
nected; gradient pump Merck-Hitachi L6200].
4.2. Materials
Betaines 1a,b,d,e,g,h10 and 1c,f11 were prepared as described
previously.
N–H/O hydrogen bond to be broken temporarily, and this should
be facilitated in rather polar solvents such as acetonitrile, methanol,
and dimethyl sulfoxide.
4.3. Synthesis of bisbetaines 2
2.3. Cyclocondensation of betaines 1b,d
4.3.1. 3,12-Dimethyl-9,18,19,20-tetrakis(methoxycarbonyl)-8,17-
dibenzoyl-3,12-diazoniatricyclo[14.2.1.17,10]-eicosa-1(18),7,9,16-
tetraene-19,20-diylide (2a)
It was expected that the sec-amine group in betaines 1 under
appropriate conditions would react with one of the carbonyl
functional groups. By analogy with the formation of cyclo-
pentadienidophanes 2, a cyclodimerization reaction could lead to
macrocyclic bis-lactams (reaction with an ester group) or bis-en-
amines (reaction involving the keto function). However, when be-
taines 1b,d were treated with dicyclohexylcarbodiimide, only an
intramolecular cyclocondensation involving the keto function took
place, and the bicyclic 6-aminopentafulvenes 4b,d were obtained in
80–85% yield (Scheme 3).
The constitution of 4d was confirmed by a crystal structure
determination (Fig. 3). The bond lengths in the aminofulvene
moiety, the deviation from coplanarity at the formal double bond
C9–C10, and the presence of a trigonal-planar coordinated nitrogen
atom (sum of valence angles¼360.0ꢀ) all indicate the strong con-
tribution of an iminio-cyclopentadienide resonance structure. This
is typical for 6-aminofulvenes; see for example, the structure of
methyl 6-dimethylamino-6-ethylfulvene-2-carboxylate.16
To a suspension of betaine 1a (231 mg, 0.65 mmol) in THF (1 mL)
was added aqueous formaldehyde (35%, 0.057 mL, 0.72 mmol), and
the resulting solution was stirred at rt for 24 h. After concentration
of the solution to half of the volume, the precipitated yellow
product was isolated by centrifugation and washed with a small
volume of cold THF, then dried at 20 ꢀC/0.008 mbar. Yield: 128 mg
(52%); mp 161 ꢀC. IR (KBr):
1648 (vs),1625 (vs), 1596 (s), 1469 (vs), 1265 (s), 1233 (vs),1215 (vs),
1104 (s) cmꢁ1 1H NMR (CDCl3):
n
¼3250–2400 (several bands, br, m),
.
d
¼1.59 and 2.20 (br mc, 2ꢂ1H,
NCH2CH2), 2.76 and 3.16 (mc, 2ꢂ1H, NCH2CH2), 2.87 (d, J¼5.1 Hz,
3H, NCH3), 2.93 (mc, 2H, CcpCH2CH2), 2.97 (s, 3H, OCH3), 3.83 (s, 3H,
OCH3), 4.43 (d, 2J¼12.0 Hz, 1H, CcpCH2N), 5.28 (dd, 2J¼12.1 Hz,
3J¼9.0 Hz, 1H, CcpCH2N), 7.36 (mc, 3H, HPh), 7.55 (d, J¼7.1 Hz, 2H,
HPh), 9.34 (br, 1H, NþH). 13C NMR (DMSO-d6):
d¼22.93 (CcpCH2CH2),
24.97 (NCH2CH2), 39.92 (NCH3), 49.58 (OCH3), 49.77 (OCH3), 50.52
(NCH2CH2), 53.19 (NCH2Ccp), 112.00, 112.97, 120.47, 127.54, 128.42,
129.26, 130.81, 141.87, 166.11 and 167.99 (COOCH3), 196.10 (C]O).
Anal. Calcd for C42H46N2O10ꢂ1H2O (738.83þ18.02): C 66.65, H 6.39,
N 3.70. Found: C 66.87, H 6.27, N 3.50.
3. Conclusion
We have presented here a novel access to the barely known
[n.n]cyclopentadienidophanes. 2-Acyl-1,4-bis(methoxycarbonyl)-
3-[3-(methylammonio)propyl]cyclopentadienides, easily prepared
from semicyclic enaminoketones and a 3-diazopropene-1,3-dicar-
boxylate by a carbenoid reaction, and formaldehyde can undergo
a bimolecular macrocyclization through a twofold Mannich re-
action to yield [5.5](1,3)cyclopentadienidophanes. The success of
4.3.2. Betaine 2c (R¼20-nitrobiphenylyl)
To a suspension of betaine 1c (103 mg, 0.21 mmol) in THF (1 mL)
was added aqueous formaldehyde (35%, 0.019 mL, 0.24 mmol) and
a few drops of water to obtain a clear solution. After stirring the
solution for 7 days, the solvent was evaporated and the residue was
dissolved in ethyl acetate/methanol at 50 ꢀC. After several days in
a refrigerator (ꢁ18 ꢀC), a yellow powder precipitated (22 mg, 20%);
mp 209 ꢀC (dec). The product decomposed partially on standing in
this transformation seems to depend on the length of the
u-
(methylammonio)alkyl side chain. With ( -methylammonio)butyl
u
CDCl3 solution and in hot solvents. IR (KBr):
2400 (little structured series of weak bands), 1678 (vs), 1619 (vs),
1532 (m), 1468 (vs), 1442 (s), 1267 (vs), 1238 (vs), 1221 (vs), 1105
n
¼3434 (br, m), 3050–
and -pentyl side-chains, a controlled macrocyclization does not
take place and mixtures of oligomers are formed instead. On the
other hand, a simple intramolecular cyclocondensation rather than
(s) cmꢁ1. 1H NMR (CDCl3):
d
¼1.51 and 1.95 (br mc, 2ꢂ1H, NCH2CH2),
a
macrocyclization occurs, when the same (3-methyl-
2.93 (d, J¼4.8 Hz, 3H, NCH3), 2.98 and 3.16 (mc, 2ꢂ1H, NCH2CH2),
3.11 (mc, 2H, CcpCH2CH2), 3.18 (s, 3H, OCH3), 3.66 (s, 3H, OCH3), 4.29
(d. 2J¼12.4 Hz, 1H, CcpCHN), 5.02 (dd, 2J¼12.4 Hz, 3J¼8.7 Hz, 1H,
CcpCHN), 7.28–7.90 (m, 4H, Haryl), 8.93 (br, 1H, NþH). 13C NMR
ammoniopropyl)cyclopentadienides are treated with DCC: the re-
action of the sec-amine group with the adjacent acyl function yields
bicyclic 6-aminopentafulvenes.

G. Maas et al. / Tetrahedron 65 (2009) 5733–5738
5737
(CDCl3):
d
¼22.64 (CcpCH2CH2), 23.52 (NCH2CH2), 39.69 (NCH3),
a small excess of aqueous formaldehyde (35%), and the mixture was
stirred at rt for 1–3 days. The precipitate was isolated by centrifu-
gation and washed with cold THF, then dried at 20 ꢀC/0.01 mbar.
Products 3b,e,g,h were insoluble in water, and 3g,h were also in-
soluble in common organic solvents.
49.53 (OCH3), 50.05 (OCH3), 50.32 (NCH2CH2), 51.44 (NCH2Ccp),
111.36, 115.34, 121.26, 124.22, 127.40, 127.52, 128.40, 128.48, 128.90,
131.80, 132.32, 132.39, 136.05, 149.02, 166.31 and 167.08 (COOCH3),
196.81 (C]O). Anal. Calcd for C54H52N4O14ꢂ3H2O (981.02þ54.06):
C 62.66, H 5.65, N 5.41. Found: C 62.14, H 5.45, N 5.12.
4.4.1. Oligomer 3b (n¼1, R¼4-anisyl)
4.3.3. Bisbetaine 2d (R¼2-thienyl)
Reaction time: 3 days. A beige powder was isolated in 45% yield;
To a suspension of betaine 1d (200 mg, 0.55 mmol) in THF
(1 mL) was added aqueous formaldehyde (35%, 0.045 mL,
0.57 mmol), and the resulting solution was stirred at rt for 24 h. The
precipitated yellow product was isolated by centrifugation and
washed with a small volume of cold THF, then dried at 20 ꢀC/
mp 138–144 ꢀC (dec). IR (KBr):
n
¼3439 (br, m), 2948 (s), 1728 (s),
1678 (vs), 1599 (vs), 1458 (vs), 1303 (s), 1251 (vs), 1166 (vs), 1108 (s),
1027 (s) cmꢁ1 13C NMR (CDCl3; many of the following signals, in
particular those in the aliphatic region, appear as the most intense
ones in a group of peaks with very close chemical shifts):
.
d¼22.8
0.008 mbar. Yield: 169 mg (80%); mp 186 ꢀC (dec). IR (KBr):
(br m), 2945 (s), w2870–2400 (little structured series of weak
bands), 1679 (vs), 1610 (vs), 1459 (br, vs), 1414 (vs), 1274 (vs), 1211
(br, vs), 1101 (vs), 1040 (s), 1016 (s) cmꢁ1. 1H NMR (CDCl3, 303 K):
n
¼3486
(CcpCH2CH2), 24.3 (CH2), 30.6 (NCH3), 39.5 (NCH2), 50.3 (OCH3),
50.5 (OCH3), 55.3 (CcpCH2N), 113.0, 113.2, 113.6, 120.7, 128.8, 130.6,
134.6, 161.7, 162.1, 167.2. Anal. Calcd for (C22H25NO6)n (nꢂ399.44): C
66.15, H 6.31, N 3.51. Found C 60.46, H 6.11, N 3.35.
d
¼1.62 and 2.14 (br mc, 2ꢂ1H, NCH2CH2), 2.81 (d, J¼4.9 Hz, 3H,
NCH3), 2.92 (mc, 2H, NCH2CH2), 3.16 (mc, 2H, CcpCH2CH2), 3.22 (s,
3H, OCH3), 3.82 (s, 3H, OCH3), 4.30 and 5.31 (broad unstructured
signal and t, 2ꢂ1H, CcpCH2N), 6.98 (dd, 3J¼3.8 and 4.7 Hz, 1H, 4-
Hthienyl), 7.10 (br, 1H, 3-Hthienyl), 7.45 (d, 3J¼4.7 Hz), 9.34 (br, 1H,
NþH). 1H NMR (CD3CN, 300 K): three sets of signals with the in-
tensity ratio 4:1:1 are observed, which coincide in the case of the
4.4.2. Oligomer 3f (n¼1, R¼2-furyl)
The reaction was carried out with 163 mg (0.47 mmol) of beta-
ine 1f. After a reaction time of 3 days, a white precipitate (24 mg),
which was practically insoluble in organic solvents, was filtered off
and discarded. The filtered solution was concentrated to dryness,
and the solid residue was triturated with THF (1 mL) for 30 min.
After filtration, a beige-brownish powder remained (83 mg, 45%
N(CH2)3 protons;
d (signals of the three sets are separated by
a slash, the major signal is given first)¼1.40 and 2.05 (br mc, 2ꢂ1H,
NCH2CH2), 2.77 and 3.12 (br mc, 2ꢂ1H, CcpCH2CH2), 2.81–2.88 (mc,
2H, NCH2CH2), 2.81/2.85/2.88 (3ꢂd, J¼5.2, 5.2, 5.5 Hz, 3H, NHCH3),
3.17/3.02/3.16 (3ꢂs, 3H, OCH3), 3.76/3.78/3.81 (3ꢂs, 3H, OCH3), 4.02
(dd, J¼12.8 and 2.4 Hz) and 5.18 (dd, J¼12.8 and 9.1 Hz)/4.14 (d) and
5.02 (dd)/4.29 (d) and 4.95 (dd) (CcpCH2N), 7.02/6.94/6.98 (3ꢂdd,
1H, 4-Hthienyl), 7.05–7.10 (br m, 1H, 3-Hthienyl), 7.56/7.53/7.55 (3ꢂd,
yield); mp 164–166 ꢀC (dec). IR (KBr):
n
¼3448 (br, m), 2946 (s),
w2850–2400 (little structured series of weak bands), 1676 (vs),
1619 (vs), 1563 (s), 1469 (vs), 1395 (s), 1267 (vs), 1221 (vs), 1161 (s),
1119 (vs), 1015 (s) cmꢁ1
.
1H NMR (CDCl3):
d
¼1.88 and 2.25 (br m,
2ꢂ1H, NCH2CH2), 2.7–3.2 (several br m, 7H, NCH3 NCH2CH2,
CcpCH2CH2), 3.3 (m, OCH3), 3.7 (m, OCH3), 4.7–5.0 (CcpCH2N), 6.4/
6.7/7.5 (each: br m, 3ꢂHfuryl), 9.15 (br s, NþH). 13C NMR (CDCl3;
many of the following signals, in particular those in the aliphatic
region, appear as the most intense ones in a group of peaks with
1H, 5-Hthienyl), 9.00/9.2 (br, NH). 13C NMR (CDCl3):
d
¼22.93
(CH2CH2Ccp), 24.99 (NCH2CH2), 39.57 (NCH3), 49.99 (OCH3), 50.68
(OCH3), 51.29 (NCH2CH2), 54.57 (NCH2Ccp), 112.41 and 113.29 (both
C–COOCH3), 120.91 (O]C–Cthienyl), 127.18 (Ccp), 127.64 (4-Cthienyl),
128.58 (Ccp),131.53 (3-Cthienyl),132.09 (5-Cthienyl),150.04 (C-2thienyl),
167.31 and 169.66 (both COOCH3), 187.6 (C]O). MS (FD, 8 kV):
m/z¼750 (100) [Mþ], 376 (18). Anal. Calcd for C38H42N2O10S2ꢂ1H2O
(750.89þ18.02): C 59.36, H 5.77, N 3.64. Found: C 59.3, H 5.9, N 3.7.
very close chemical shifts):
d
¼22.1 (CcpCH2CH2), 27.7 (CH2), 40.1
(NCH3), 50.0 (NCH2), 50.3 (OCH3), 50.8 (OCH3), 55.3 (CcpCH2N),111.6
(C-4furyl), 115.4, 116.9, 119.9 (C-3furyl), 121.1, 124.9, 144.4, 145.1 (C-
5furyl), 155.7 (C-2furyl), 170.0 (COOCH3), 190.0 (C]O). Anal. Calcd for
(C19H21NO6)n (nꢂ359.38): C 63.50, H 5.89, N 3.90. Found: C 55.39, H
5.73, N 3.45.
4.3.4. Betaine 2f (R¼1-adamantyl)
4.4.3. Oligomer 3g (n¼2, R¼2-thienyl)
To a suspension of betaine 1f (165 mg, 0.39 mmol) in THF (1 mL)
was added aqueous formaldehyde (35%, 0.04 mL, 0.51 mmol), and the
resulting solution was stirred for 24 h. The colorless precipitate was
isolated by centrifugation and washed with a small volume of cold
THF, then dried at 20 ꢀC/0.008 mbar. Yield: 138 mg (79%); mp 197 ꢀC.
Yellow powder. Yield: 74%; mp 195–197 ꢀC (dec). IR (KBr):
n
¼3460 (m, very broad), 3050–2400 (little structured series of
weak bands), 1675 (vs), 1633 (vs), 1513 (w), 1466 (vs), 1420 (m),
1398 (m),1370 (w),1346 (w),1306 (w),1277 (m),1247 (s), 1229 (vs),
1188 (m), 1142 (w), 1102 (vs), 1060 (w), 1044 (w) cmꢁ1. Anal. Calcd
for (C20H23NO5S)n (nꢂ389.47): C 61.68, H 5.95, N 3.59. Found: C
61.7, H 6.2, N 3.5.
IR (KBr):
(vs),1409 (s),1355 (s),1313 (s),1267 (vs),1191 (vs),1160 (vs),1104 (vs),
1087 (vs) cmꢁ1.1H NMR (CDCl3):
n¼w3500–3400 (very br m), 2903 (s), 1657 (vs, br), 1454
d¼1.61 (mc, 6H, Hadam.),1.81 (mc, 6H,
Hadam.),1.94 (mc, 3H, Hadam.), 2.07 and 2.28(mc, 2ꢂ1H, NCH2CH2), 2.91
(t, J¼11.6 Hz, 2H, NCH2CH2), 3.03 (d, J¼3.0 Hz, 3H, NCH3), 3.38 (t,
J¼12.5 Hz, 2H, CcpCH2CH2), 3.48 (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 4.22
and 5.04 (br mc, 2ꢂ1H, CcpCH2N), 9.31 (br, 1H, NþH). 13C NMR CDCl3,
4.4.4. Oligomer 3h (n¼3, R¼2-thienyl)
Yellow powder. Yield: 81%; decomposition at ꢃ250 ꢀC. IR (KBr):
n
¼3460 (m, very broad), 3050–2400 (little structured series of
weak bands), 1674 (s), 1633 (s), 1601 (s), 1468 (vs), 1277 (m), 1248
125.77 MHz):
d
¼22.64 (CcpCH2CH2), 23.52 (NCH2CH2), 39.69 (NCH3),
(s), 1229 (vs), 1187 (m), 1101 (s) cmꢁ1. Solid-state 13C NMR (CP-
49.53 (OCH3), 50.05 (OCH3), 50.32 (NCH2CH2), 51.44 (NCH2Ccp),
111.36, 115.34, 121.26, 124.22, 127.40, 127.52, 128.40, 128.48, 128.90,
131.80, 132.32, 132.39, 136.05, 149.02, 166.31 and 167.08 (COOCH3),
196.81 (C]O). Anal. Calcd for C50H66N2O10ꢂ2H2O (855.08þ36.04): C
67.39, H 7.92, N 3.14. Found: C 66.93, H 7.65, N 3.30.
MAS):
d
¼22–34 (several signals), 40.7, 41.7, 50.5, 52.8, 53.5
(broadened by additional signals), 113.1, 116.6, 121.7, 126.9, 128.0,
129.0, 132.3, 134.2, 150.4, 166.6, 170.9, 187.6. Anal. Calcd for
(C21H25NO5S)n (nꢂ403.49): C 62.51, H 6.24, N 3.47. Found: C 62.4, H
6.5, N 3.6.
4.4. Reaction of betaines 1b,e,g,h with formaldehyde;
general procedure
4.5. Dimethyl 2-methyl-1-(4-methoxyphenyl)-2,3,4,5-
tetrahydrocyclopenta[c]azepine-6,8-dicarboxylate (4b)
To a suspension of the appropriate betaine 1 (0.27–0.64 mmol)
A
magnetically stirred mixture of betaine 1b (213 mg,
in THF (1 mL) was added an equimolar amount (0.021–0.05 mL) or
0.55 mmol), dicyclohexylcarbodiimide (114 mg, 0.55 mmol), and

5738
G. Maas et al. / Tetrahedron 65 (2009) 5733–5738
toluene (10 mL) was heated at reflux for 3 h. After cooling, the sol-
vent was evaporated in vacuo, and 4b was separated from also
formed dicyclohexylurea by column chromatography (elution with
methanol). The product was dissolved in ethyl acetate and pre-
cipitated as a yellow powder by addition of ether (162 mg, 80%
all 5769 data gave final R indices of R1¼0.2220, wR2¼0.1721 (0.0790
and 0.1411 for 1910 reflection data with (I>2 (I)). Residual electron
s
density between 0.54 and ꢁ0.39 e Åꢁ3. The positions of the N–H
hydrogen atoms were refined freely. All other hydrogen atoms were
treated as riding on their bond neighbors. The thiophene ring
containg atom S2 appears to be disordered over two positions
(rotation by 180 ꢀC about the C28–C29 bond). Efforts to include this
disorder in the refinement resulted in unreasonable geometries,
probably due to the low occupancy factor of the second ring
position.
yield); mp 205 ꢀC. IR (KBr):
n
¼1700 (sh),1679 (vs), 1603 (s), 1540 (s),
1508 (m), 1478 (s), 1437 (vs), 1407 (m),1320 (m),1305 (m), 1253 (vs),
1220 (s), 1206 (vs), 1186 (s), 1144 (s), 1057 (s) cmꢁ1. 1H NMR (CDCl3):
d
¼2.54 (quin, 2H, NCH2CH2), 3.23 (t and s, 5H, NCH2CH2CH2 and
COOCH3), 3.41 (s, 2H, NCH3), 3.78 (s, 3H, COOCH3), 3.80 (t, 2H, NCH2),
3.85 (s, 3H, aryl-OCH3), 6.90/7.30 (AA0BB0 system, 4H, Haryl), 7.38 (s,
1H, CHcp). 13C NMR (CDCl3, 125.77 MHz):
d¼23.00 (NCH2CH2CH2),
4.7.2. Data for 4d
35.04 (NCH2CH2), 40.87 (NCH3), 50.45 (2ꢂCOOCH3), 55.43 (aryl-
OCH3), 56.74 (NCH2), 113.46 (CHaryl), 116.71 (CH2C]C), 119.44 and
120.02 (2ꢂC–COOCH3), 127.98 (Caryl), 129.16 (CHcp), 133.30 (CHaryl),
143.06 (NC]C), 162.28 (Caryl–OCH3), 165.52 (C]O), 166.66 (C]O),
172.81 (NC]). MS (EI, 70 eV): m/z (%)¼369 (100) [M]þ, 354 (19), 338
(24), 310 (31), 148 (31).
Crystal data: C18H19NO4S, M¼345.4, orthorhombic, space group
Pbca, a¼12.906(1), b¼9.921(1), c¼26.645(4) Å,
a
¼
b
¼
g
¼90ꢀ,
V¼3411.4(7) Å3, Z¼8, Dc¼1.345 g cmꢁ3
,
m
¼0.211 mmꢁ1. Data col-
lection: crystal size 0.57ꢂ0.23ꢂ0.15 mm, 19,916 reflections in the
range
q
¼2.70–28.02ꢀ, 4023 unique reflections (Rint¼0.0445).
Structure refinement: refinement of 261 parameters using all data
gave final R indices of R1¼0.0597, wR2¼0.1070 (0.0405 and 0.0992
4.6. Dimethyl 2-methyl-1-(2-thienyl)-2,3,4,5-tetrahydro-
for 2902 reflection data with (I>2s(I)). Residual electron density
cyclopenta[c]azepine-6,8-dicarboxylate (4d)
between 0.21 and ꢁ0.19 e Åꢁ3. Hydrogen atoms were treated as
riding on their bond neighbors. The thiophene ring is disordered
over two positions (rotation by 180 ꢀC about the C10–C15 bond).
This disorder was included in the refinement procedure, yielding
occupancy factors of 0.74 and 0.26.
Prepared from 1d (200 mg, 0.55 mmol) as described for 4b
(Section 4.5). The product obtained after column chromatography
was dissolved in ethyl acetate and exposed to diffusion of ether
vapor to furnish red needles (167 mg, 85% yield); mp 162 ꢀC. IR
(KBr):
(m), 1250 (s), 1215 (s), 1141 (m), 1094 (m), 1058 (s) cmꢁ1. 1H NMR
(CDCl3):
n
¼1677 (br, vs), 1520 (m), 1476 (m), 1439 (s), 1408 (m), 1390
4.8. Computational conformation analysis of 2d
d
¼2.53 (quin, 2H, NCH2CH2), 3.21 (broadened t, J¼7.4 Hz,
The calculations were performed using the semiemperical PM3
method as implemented in the SPARTAN 06 program package.19
Starting with the atom position coordinates from the solid-state
structure of 2d, 256 conformations were generated automatically
and optimized. The 12 structures with lowest energy were char-
acterized as minimum-potential structures by frequency calcula-
tions. In Table 2, the six structures with lowest energy (ZPE
corrected) are listed.
2H, NCH2CH2CH2), 3.33 (s, 3H, OCH3), 3.55 (s, 3H, NCH3), 3.74 (t,
J¼5.9 Hz, 2H), 3.78 (s, 3H, OCH3), 7.14 (dd, J¼5.0 and 3.8 Hz, 1H, 4-
4
Hthienyl), 7.35 (dd, 3J¼3.8 Hz, j Jj¼1.2 Hz, 1H, 3-Hthienyl), 7.39 (s, 1H,
4
CHcp), 7.68 (dd, 3J¼5.0 Hz, j Jj¼1.3 Hz, 1H, 5-Hthienyl). 13C NMR
(CDCl3):
d
¼22.94 (NCH2CH2CH2), 35.14 (NCH2CH2), 40.87 (NCH3),
50.48 and 50.53 (2ꢂOCH3), 56.83 (NCH2), 117.28 and 119.93 (2ꢂC–
COOCH3), 120.20 (CH2C]), 127.58 C-4thienyl), 129.53 (C-3thienyl),
137.61 (C-2thienyl), 143.42 (NC]C), 163.95 (NC]), 165.52, 166.66
(2ꢂC]O). MS (EI, 70 eV): m/z (%)¼347 (7), 345 (100) [M]þ, 336 (16),
314 (20) [MꢁCH3O]þ, 286 (37). Anal. Calcd for C18H19NO4S (345.42):
C 62.59, H 5.54, N 4.06. Found: C 62.18, H 5.73, N 4.50.
References and notes
1. (a) Vo¨gtle, F. Cyclophan-Chemie; B.G. Teubner: Stuttgart, 1990; (b) Diederich, F.
Cyclophanes; Royal Society of Chemistry: Cambridge, 1991.
2. Hopf, H. Classics in Hydrocarbon Chemistry; Wiley-VCH: Weinheim, 2000; pp
317–378.
3. Long, N. J. Metallocenes; Blackwell Science: Oxford, 1998; pp 178–212.
4. Shapiro, P. J. Coord. Chem. Rev. 2002, 231, 67–81.
5. (a) Prashar, S.; Antinolo, A.; Otero, A. Coord. Chem. Rev. 2006, 250, 133–154; (b)
Wang, B. Coord. Chem. Rev. 2006, 250, 242–258.
6. Hisatome, M.; Watanabe, J.; Yamakawa, K.; Iitaka, Y. J. Am. Chem. Soc. 1986, 108,
1333–1334.
4.7. Crystal structure determination for compounds
2d and 4d
Data collection was performed at ambient temperature with an
image-plate diffraction system (IPDS, Stoe) using monochromated
Mo K
a
radiation (
l¼0.71073 Å). The structures were solved with
direct methods and refined with a full-matrix least-squares pro-
cedure using F2 values. Software for structure solution and re-
finement: SHELX-97;17 molecule plots: ORTEP-3.18 CCDC-717015
(2d) and 717016 (4d) 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.a-
c.uk/data_request/cif.
7. Bradamante, S.; Marchesini, A.; Pagani, G. Tetrahedron Lett. 1971, 48, 4621–4622.
8. Fischer, M.; Bo¨nzli, P.; Stofer, B.; Neuenschwander, M. Helv. Chim. Acta 1999, 82,
1509–1519.
9. Haenel, M. W. Tetrahedron Lett. 1977, 18, 1273–1276.
10. Maas, G.; Mu¨ller, A. Org. Lett. 1999, 1, 219–222.
11. Mu¨ller, A.; Endres, A.; Maas, G. Acta Chim. Slov., in press.
12. Mu¨ller, A.; Maas, G. Z. Naturforsch. 2000, 55b, 541–545.
13. Lindsay, J. K.; Hauser, C. R. J. Org. Chem. 1957, 22, 355–358.
14. (a) Nesmeyanov, A. N.; Perevalova, E. G.; Shilovtseva, L. S. Izv. Akad. Nauk SSSR,
Ser. Khim 1962, 1767–1772; (b) Elias, A. J.; Kumar, M. S.; Gupta, R. P.; Behera, N.
Synth. React. Inorg. Metal-Org. Chem. 2007, 37, 729–733.
4.7.1. Data for 2d
15. Schatz, J. Collect. Czech. Chem. Commun. 2004, 69, 1169–1193.
16. Ficini, J.; Revial, G.; Jeannin, S. Tetrahedron Lett. 1981, 22, 2367–2370.
17. Sheldrick, G. M. SHELX-97-Program for the Solution and Refinement of Crystal
Structures from Diffraction Data; University of Go¨ttingen: Go¨ttingen, 1997.
18. Farrugia, L. J. ORTEP-3 for Windows; University of Glasgow: Glasgow, 1998.
19. Deppmeier, B. J.; Driessen, A. J.; Hehre, T. S.; Hehre, W. J.; Johnson, J. A.;
Klunzinger, P. E.; Leonard, J. M.; Pham, I. N.; Pietro, W. J.; Yu, J. Spartan ’06 (build
129); Wavefunction: Irvine, CA, Jun 8 2007.
Crystal data: C38H42N2O10S2, M¼750.9, monoclinic, space group
P21/n, a¼12.254(2), b¼19.970(2), c¼15.607(3) Å,
b
¼104.61(2)ꢀ;
V¼3695.7(10) Å3, Z¼4, Dc¼1.349 g cmꢁ3
,
m
¼0.21 cmꢁ1. Data col-
lection: crystal size 0.35ꢂ0.32ꢂ0.22 mm, 19,211 reflections in the
range
q
¼1.69–24.14ꢀ, 5769 unique reflections (Rint¼0.2045).
Structure refinement results: refinement of 475 parameters using