Preparation of stable fulvene and difulvene aldehydes from benzaldehydes and an indene-derived enamine: formation of novel indene-fused benzodiazepines and attempted syntheses of di- and tricarbaporphyrinoid systems

Article abstract of DOI:10.1016/j.tet.2009.10.013

Although carbaporphyrins and related systems have been widely studied, far less work has been carried out on the synthesis of porphyrin analogues with more than one carbocyclic subunit. Fulvene aldehydes are potentially valuable intermediates for studies

Full text of DOI:10.1016/j.tet.2009.10.013

Tetrahedron 65 (2009) 9935–9943
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Preparation of stable fulvene and difulvene aldehydes from benzaldehydes and an
indene-derived enamine: formation of novel indene-fused benzodiazepines and
attempted syntheses of di- and tricarbaporphyrinoid systemsq
*
Randall N. Davis, Timothy D. Lash
Department of Chemistry, Illinois State University, Normal, Illinois 61790-4160, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Although carbaporphyrins and related systems have been widely studied, far less work has been carried
out on the synthesis of porphyrin analogues with more than one carbocyclic subunit. Fulvene aldehydes
are potentially valuable intermediates for studies of this type. A versatile methodology has been developed
where benzaldehydes are reacted with an indene-derived enamine in the presence of dibutylboron triflate
to give fulvene monoaldehydes. This chemistry allows halo, alkyl, methoxy or cyanovinyl units to be in-
troduced and the resulting fulvenes are stable compounds that are easily purified by column chroma-
tography. Isophthalaldehydes afford difulvene dialdehydes that are equally stable and these can be reduced
with CeCl3-NaBH4 to give the related dicarbinols. The difulvene dialdehydes failed to give macrocyclic
products when reacted with o-phenylenediamine in the presence of CeCl3 but instead gave unprecedented
bis-indene-fused benzodiazepines. Fulvene monoaldehydes also reacted under these conditions to give
benzodiazepine products in good yields. These results highlight the potential utility of fulvene aldehydes
for synthetic applications both inside and outside of the area of porphyrin analogue chemistry.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 2 September 2009
Received in revised form 3 October 2009
Accepted 5 October 2009
Available online 8 October 2009
Keywords:
Fulvenes
Carbaporphyrins
Enamines
Indenes
Benzodiazepines
1. Introduction
ketal derivatives of carbaporphyrins have been shown to be
promising agents in the treatment of leishmaniasis.15 Although
Porphyrins (1) have many biological functions, generally in the
form of metalated species such as the hemes and chlorophylls, but
they are in many respects unique natural products that exhibit
strongly nonbenzenoid aromatic properties.1 The porphyrin nu-
cleus shows strong diatropic characteristics in proton NMR spec-
troscopy, where the external meso-protons are deshielded to
approximately þ10 ppm while the internal NH resonances are
shifted upfield to ca., ꢀ4 ppm2. These properties can be attributed
to the presence of [18]annulene substructures (shown in bold),3,4
although a full description of porphyrinoid aromaticity needs to
take into account contributions from all four of the pyrrole sub-
units.5,6 Carbaporphyrins (2) have been synthesized where a pyr-
role unit has been replaced by a cyclopentadienyl moiety, and
these macrocycles show comparable diatropic properties to tetra-
pyrrolic porphyrins.7–9 In addition, carbaporphyrins 2, and the
more commonly studied benzocarbaporphyrins 3, have been
shown to easily form silver(III) and gold(III) derivatives,10–12 and
readily undergo unusual regioselective oxidations.13,14 In addition,
true carbaporphyrins possess a five-membered carbocyclic sub-
unit, many related porphyrin analogues have been synthe-
sized,1,16,17 including tropiporphyrins (4),18 oxybenziporphyrins
(5),19–22 carbachlorins,23 azuliporphyrins (6)24–27 and benzipor-
phyrins (7).19,20,28,29 These systems show a range of aromatic
properties and have demonstrated a wealth of chemical proper-
ties,4,16,17 including the ability to generate organometallic derivates
under mild conditions.10–12,30–32 In addition, N-confused porphy-
rins 8 have the same type of coordination core33–37 and have
attracted considerable interest since they were first discovered
fifteen years ago.38 For these reasons, the synthesis of further
modified porphyrinoid systems has been a focus of our research
group for a number of years.39 Quatyrin (9), a tetracarbaporphyrin,
is of great theoretical interest and although it has not yet been
synthesized, it is considered to be the Holy Grail of porphyrin an-
alogue chemistry.39 The synthesis of 9 represents a considerable
challenge, but porphyrin analogues with an intermediary number
of carbocyclic rings should be more accessible. The first example of
a dicarbaporphyrin (10) was first reported by our group in 1999,39
and two types of doubly N-confused porphyrins were subsequently
reported by Furuta and co-workers.40,41 Dicarbaporphyrin 10 was
easily prepared by reacting 3,4-diethylpyrrole and 1,3-indanedi-
carbaldehyde in the presence of HBr, followed by oxidation with
q
Part 52 in the series ‘Conjugated Macrocycles Related to the Porphyrins’.
* Corresponding author. Tel.: þ1 309 438 8554; fax: þ1 309 438 5538.
E-mail address: tdlash@ilstu.edu (T.D. Lash).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.10.013

9936
R.N. Davis, T.D. Lash / Tetrahedron 65 (2009) 9935–9943
ferric chloride.39 However, although this opp-dicarbaporphyrin
showed a porphyrin-like UV–vis spectrum and gave highly dia-
tropic proton NMR spectra, it was somewhat unstable and this has
limited further investigations.39 Porphyrinoid 11 with mixed azu-
lene and indene subunits was prepared by a ‘3þ1’ methodology but
this also proved to be rather unstable.42,43 The synthesis of por-
phyrins and their analogues generally relies on the ability of pyr-
Recently, we have reported the synthesis of adj-dicarbapor-
phyrinoids 12 and 1345,46 using a MacDonald ‘2þ2’ strategy.47
This methodology requires access to intermediary dialdehydes
with two carbocyclic units linked by a single carbon bridge.
Macrocycles 12 and 13 with adjacent carbocyclic rings have
proven to be robust systems with significant diatropic character
and 13 also afforded an unusual palladium(II) organometallic
complex.45,46 As porphyrinoids 10 and 11 with alternating car-
bocyclic and pyrrolic subunits (opp-dicarbaporphyrinoids) are far
less stable than 12 or 13, adj-dicarbaporphyrinoids appear to
provide a much better entry into highly modified carbapor-
phyrinoid systems. In order to fully exploit this area, convenient
routes to structurally suitable dialdehyde precursors need to be
developed.45 In particular, fulvene dialdehydes are potentially
well suited for applications in this area, but few examples of this
type of structure have been described in the literature.45 In this
paper, we have investigated the synthesis of fulvenes derived
from benzaldehydes and attempts have been made to use these
structures in the synthesis of di- and tricarbaporphyrinoids. Al-
though benziporphyrin analogues of this type were not obtained,
a general route to fulvene aldehydes has been developed and
roles to undergo electrophilic substitution at their a
-positions.17,42
The formation of carbon–carbon bonds that link the individual
subunits can be generated by using other electron-rich aromatic
precursors such as azulene42 and resorcinol,44 but this approach
has severe limitations with regard to the synthesis of di-, tri- or
tetracarbaporphyrinoid systems.
1 Porphyrin
W = Y = NH; X = Z = N
W
Z
X
Y
2 Carbaporphyrin
W = Y = NH; X = CH; Z = N
9 Quatyrin
W = Y = CH2; X = Z = CH
these have been used to synthesize
a unique series of
benzodiazepines.48
2. Results and discussion
HN
HN
N
In a recent preliminary communication,45 we reported a syn-
thesis of fulvene aldehydes from an easily accessible indene en-
amine 14.49 Azulene carbaldehyde 15a50 reacted with 14 in the
presence of dibutylboron triflate to give, following hydrolysis with
aqueous sodium acetate, the corresponding fulvene aldehyde 16a in
75% yield (Scheme 1).45 This chemistry clearly has potential appli-
cations outside of the area of porphyrin analogue synthesis.51,52
N
NH
NH
4 (Tropiporphyrin)
3 (Benzocarbaporphyrin)
O
HN
N
N
NH
HN
N
Bu2BOTf
CHO
5 (Oxybenziporphyrin)
6 (Azuliporphyrin)
X
15
CHO
X
N
16
a. X = H
b. X = CHO
NMe2
14
HN
N
Scheme 1.
N
NH
HN
N
However, our interests stemmed from the fulvene moiety 16
representing the northern half of the dicarbaporphyrinoid sys-
tem 12.45 Macrocycle formation necessitates the use of a di-
aldehyde 16b. Attempts to formylate 16a (e.g., Vilsmeier–Haack
reaction) were unsuccessful but the required dialdehyde 16b
could be obtained when azulene dialdehyde 15b was reacted
with 1 equiv of the enamine. This intermediate was then suc-
cessfully taken on for the synthesis of the new porphyrinoid
system 12.45 Surprisingly, 1,3-benzenedicarbaldehydes 17a and
17b reacted with 14 in the presence of Bu2BOTf to give the
difulvenes 18 under these conditions (Scheme 2).45 Difulvenes
18 were the only isolatable products under any of the reaction
conditions investigated and even when only one equivalent of
14 was used, little or no fulvene dialdehyde 19 was observed.
Obviously, better yields of the difulvenes could be obtained
when 2 or more equivalents of 14 were used.45 Difulvenes 18
are stable orange solids and are unique systems in their own
right. Difulvene 18c could also be generated from dimethoxy-
isophthalaldehyde 17c but in this case we were unable to fully
purify the product due to its very poor solubility characteristics.
As monofulvenes could not be formed directly from iso-
phthalaldehydes, stepwise routes to fulvene dialdehydes were
8 (N-Confused Porphyrin)
7 (Benziporphyrin)
Et
Et
Me
HN
Et
HN
NH
Et
N
Et
Et
Me
10 (21-23-Dicarbaporphyrin)
t-Bu
11 (23-Carbaazuliporphyrin)
t-Bu
H
H
N
N
N
N
Me
Me
Me
Me
Et
Et
R
R
13
Diazuliporphyrin
12 (22-Carbaazuliporphyrin)

R.N. Davis, T.D. Lash / Tetrahedron 65 (2009) 9935–9943
9937
X
characterized and the proton NMR spectra showed the bridge
methane proton and the isolated indene CH as two 1H singlets near
7.8 ppm (Fig. 1). As expected, the EIMS showed strong molecular
ions, and the unsubstituted fulvene aldehyde 21c gave [Mþ–CHO]
peak as the major fragment ion.
X
R
R
CHO
X
X
17
OHC
CHO
OHC
19
Dimethoxyfulvenes 21d and 21e were synthesized, in part, as
potential precursors for the preparation of fulvene dialdehydes. As
methoxy units generally aid and direct metalation reactions, it was
anticipated that protected fulvenes could be treated with a suitable
lithiating agent, and then reacted with DMF, to introduce the second
formyl moiety (Scheme 4). Aldehydes 21d and 21e were converted
into the corresponding dimethyl acetals 22 by reacting them with
methanol in the presence of cerium chloride. However, all attempts
to metalate these fulvenes failed. Most of these reactions focused on
the bromo-derivative 22b. However, reactions with n-butyllithium
14
X
R
Bu2BOTf
X
CHO
a. R = X = H
18
b. R = Me; X = OMe
c. R - H; X = OMe
CHO
Scheme 2.
OMe
pursued. In addition, we were interested in investigating the ap-
plication of the indene enamine chemistry as a general route for
fulvene synthesis. With this in mind, the conversion of a series of
benzaldehydes 20 to fulvenes 21 was investigated (Scheme 3). In
the original study,45 a series of Lewis acids were investigated as
catalysts for this reaction but only TiCl3 and Bu2BOTf gave signifi-
MeOH
21d or 21e
MeO
CeCl3
22
CH(OMe)2
X
a. X = H
b. X = Br
OMe
Z
Z
MeO
Li
CHO
CH(OMe)2
14
Y
Y
Bu2BOTf
Scheme 4.
X
CHO
X
20
21
a. X = Z = H; Y = Cl b. X = Z = H; Y = OMe c. X = Y = H
d. X = H; Y = Z = OMe e. X = Br; Y = Z = OMe
or tert-butyllithium at varying temperatures (ꢀ78 ꢁC to refluxing
ether), varying solvents (diethyl ether or THF), or in the presence of
additives such as TMEDA, all failed to give any reaction and fol-
lowing work up the original fulvene aldehyde 21e was isolated.
The conditions used to synthesize fulvenes 21 cannot tolerate
the presence of acid sensitive groups such as acetals. Cyanovinyl
groups are sometimes used as acid stable protective groups in
pyrrole chemistry,54 and the possible use of this moiety in gen-
erating fulvene dialdehydes was briefly considered (Scheme 5).
Reaction of 4,6-dimethoxyisophthalaldehyde (17c) with ethyl
cyanoacetate in the presence of piperidine and refluxing ethanol
gave a mixture of 17c, monoprotected cyanovinyl derivative 23
and a doubly protected by-product. The required monoaldehyde
was purified by column chromatography and isolated in 44%
yield. Further reaction with 14 and Bu2BOTf in refluxing C2H4Cl2
gave the related fulvene 24 in 61% yield. However, all attempts to
remove the protective group were unsuccessful. Removal of this
group essentially involves a retro-Knoevenagel reaction and is
commonly accomplished with refluxing aqueous sodium hy-
droxide.54 Fulvene 24 completely decomposed under those con-
ditions but milder hydrolysis methods failed to cleave the
cyanovinyl unit.
Scheme 3.
cant amounts of products, and the latter proved to be far superior.
The reaction of azulene carbaldehyde 15a with 14 proceeded effi-
ciently at room temperature in dichloromethane. However, most of
the benzaldehydes only reacted in refluxing 1,2-dichloroethane.
Electron-withdrawing groups appear to increase the reactivity of
the benzaldehydes, and 4-chlorobenzaldehyde (20a) reacted with
14 in dichloromethane at room temperature to give, following the
hydrolysis step, the fulvene aldehyde 21a in 50% yield. 4-Methoxy-
benzaldehyde and benzaldehyde gave good yields of fulvenes 21b
and 21c, respectively, but only when the reaction was conducted in
refluxing C2H4Cl2 for 16 h. 2,4-Dimethoxybenzaldehyde (20d) and
the related bromobenzaldehyde 20e also reacted with 14 under
these conditions but gave mediocre results. However, good yields of
fulvenes 21d and 21e could be obtained when the reactions were
carried out in the presence of a small amount of anhydrous sodium
sulfate.53 The fulvenes were all stable compounds; 21c was isolated
as an oil but the remaining fulvene aldehydes were isolated as
yellow, orange or red colored solids. Fulvenes 21 were fully
OMe
OMe
CHO
CHO
MeO
MeO
MeO
NC
NCCH2CO2Et
piperidine
CHO
23
C
CH
OHC
EtO2C
17c
Bu2BOTf
14
OMe
8.1 8.0 7.9 7.8
ppm
7.3 7.2
ppm
19c
MeO
NC
CHO
C
CH
24
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5
ppm
EtO2C
Figure 1. 500 MHz proton NMR spectrum of fulvene aldehyde 21b in CDCl3.
Scheme 5.

9938
R.N. Davis, T.D. Lash / Tetrahedron 65 (2009) 9935–9943
Although these studies did not afford fulvene dialdehydes 19,
Reaction of 18a with 26 gave the product as yellow needles and FAB
mass spectrometry gave an [MþH]þ ion at m/z 563. High resolution
MS data gave the formula for the [MþH]þ ion as C40H27N4þ (calcd:
563.2236; found: 563.2233), and therefore the product had the
formula C40H26N4; the product obtained from 18b similarly gave
a molecular formula of C43H32N4O2. These data demonstrated that
two equivalents of 26 had reacted with difulvenes 18 to produce
these products. This was confirmed by the proton NMR spectra for
these products in d6-DMSO (Fig. 2). The product derived from 18a
showed a 2H downfield resonance at 13.0 ppm that was consistent
with two equivalent strongly hydrogen bonded NH units, two 2H
singlets corresponding to two types of isolated methines, and
a series of peaks corresponding to 20 aromatic protons. The proton
NMR spectra showed that an element of symmetry must be present
and this was confirmed by the carbon-13 NMR data. Put together,
these results are consistent with the formation of dibenzodiaze-
pines 28 (Scheme 7).
difulvene dialdehydes 18 were easily obtainable and could con-
ceivably be used to prepare tricarbaporphyrinoid systems. As the
difulvenes are already fully conjugated, the dialdehydes are at too
high an oxidation level for our purposes. Reduction of the di-
aldehydes with sodium borohydride gave complex mixtures of
products, presumably due to competitive conjugate additions, but
the Luche conditions (CeCl3–NaBH4) gave good results and the
corresponding diols 25 could be isolated as stable yellow powders
in 66–92% yield (Scheme 6). However, attempts to react these
dicarbinols with pyrrole or 3,4-diethylpyrrole under acid catalyzed
conditions (e.g., BF3$Et2O in CH2Cl2) gave no isolatable macrocyclic
products.
X
R
X
NaBH4
CH2OH
18a,b
CeCl3
25
CH2OH
X
R
H
N
X
R'
8.8 ppm
8.0 7.8 7.6
ppm
R'
R' = H or Et
HN
R'
13
12
11
10
9
8
ppm
R'
Figure 2. 500 MHz proton NMR spectrum of bis-benzodiazepine 28a derived from
difulvene 18a in d6-DMSO.
Scheme 6.
Although the formation of benzodiazepines had not been an-
ticipated, in retrospect the formation of these heterocyclic adducts
is not surprising. Conjugate addition of o-phenylenediamine onto
the central indene carbon, followed by cyclization and elimination
of water, would give a dihydrobenzodiazepine unit and air oxidation
presumably gives the observed products (Scheme 8). This chemistry
should be equally feasible for monofulvene aldehydes 21. As the
products obtained from difulvenes 18 represent a new class of
benzodiazepines, it was of some interest to see whether further
examples of this type could be generated from 21a–e (Scheme 9).
Reaction of 26 with fulvenes 21 in the presence of cerium trichloride
in dichloromethane–methanol gave the benzodiazepines 29 in 44–
67% yield. These highly unusual benzodiazepines were isolated as
yellow or orange solids and gave high quality proton NMR data in
d6-DMSO (Fig. 3). Again, the NH resonance was observed at 13 ppm
and two isolated singlets were present near 8 ppm. The EIMS gave
strong molecular ions and the less substituted benzodiazepines
29a–c showed little fragmentation.
Tripyrrolic dialdehydes have been widely used to prepare Schiff
base macrocycles (e.g., texaphyrins) that resemble expanded por-
phyrins and show useful biomedicinal applications and co-
ordination chemistry.55 Texaphyrins are prepared by reacting
tripyrrane dialdehydes with o-phenylenediamine (26) and we
speculated that similar macrocyclic products (27) might be
obtained in reactions with diformyl difulvenes 18 (Scheme 7). Ini-
tial attempts to carry out this type of condensation under acid
catalyzed conditions gave rise to no useful products. However,
when difulvenes 18 were reacted with o-phenylenediamine in the
presence of cerium trichloride heptahydrate, a major new product
was generated. The spectroscopic data for these products were not
consistent with the proposed tricarbatexaphyrin system 27.
X
X
R
R
X
X
CHO
N
H2N
H2N
Ar
Ar
N
CHO
NH
NH2
18
C
O
CeCl3
C
H
O
CeCl3
H
27
26
CeCl3.7H2O
NH2
NH2
X
a. R = X = H
b. R = Me; X = OMe
R
-H2O
X
H
N
N
Ar
Ar
H
N
[O]
H
HN
N
N
N
N
28
Scheme 7.
Scheme 8.

R.N. Davis, T.D. Lash / Tetrahedron 65 (2009) 9935–9943
9939
benzaldehyde, 2,4-dimethoxybenzaldehyde, o-phenylenediamine,
ethyl cyanoacetate, piperidine, cerium trichloride heptahydrate and
sodium borohydride were purchased from Aldrich or Acros, and
were used without further purification. 5-Bromo-2,4-dimethoxy-
benzaldehyde was prepared by a literature procedure.56 Chroma-
tography was performed using grade 3 neutral alumina or 70–230
mesh silica gel. Melting points were determined in open capillary
tubes on a Mel-Temp apparatus and are uncorrected. Proton and
carbon-13 NMR data were obtained on Varian Gemini 300 or
400 MHz FT NMR spectrometers; selected spectra, including those
shown in Figures 1–3, were rerun on a Bruker 500 MHz Avance III
NMR spectrometer. Mass spectral determinations were conducted
at the Mass Spectral Laboratory, School of Chemical Sciences, Uni-
versity of Illinois at Urbana-Champaign, and elemental analyses
were obtained from the School of Chemical Sciences Microanalysis
Laboratory at the University of Illinois.
Z
Z
Y
Y
CHO
H
X
N
X
NH2
NH2
21
N
CeCl3.7H2O
29
a. X = Z = H; Y = Cl b. X = Z = H; Y = OMe c. X = Y = H
d. X = H; Y = Z = OMe e. X = Br; Y = Z = OMe
Scheme 9.
4.2. Synthetic procedures
MeO
HN
N
4.2.1. 1-(4-Chlorophenylmethylene)indene-3-carbaldehyde (21a). A
solution of 4-chlorobenzaldehyde (77 mg, 0.55 mmol) in
dichloromethane (60 mL) was added to a 250 mL round-bottomed
flask, and cooled with an ice bath to 5–8 ꢁC. A 1 M solution of
9.2
9.0
8.8
ppm
8.0
7.8
7.6
7.4
ppm
dibutylboron triflate in dichloromethane (600 mL) was then added,
immediately followed by indene enamine 14 (100 mg, 0.58 mmol).
The ice bath was removed and the solution was allowed to stir
overnight at room temperature. The next day, the reaction was
quenched with 50 mL of a saturated sodium acetate solution. The
organic layer was separated and the aqueous phase was extracted
with dichloromethane (3ꢂ). The combined organic layers were
then washed with a saturated sodium bicarbonate solution and
then with brine. The product was dried over sodium sulfate and the
solvent removed under reduced pressure. The resulting residue was
purified by flash chromatography on silica, eluting with 20% hex-
anes–dichloromethane. Recrystallization from chloroform–hexanes
gave the fulvene aldehyde 21a (73 mg, 0.27 mmol, 50%) as a brown
12
11
10
9
8
7
6
5
ppm
Cl
HN
N
solid, mp 98–100 ꢁC; 1H NMR (300 MHz, CDCl3):
d 7.33–7.38 (2H,
m), 7.47 (2H, d, J¼8.4 Hz), 7.57 (2H, d, J¼8.4 Hz), 7.64 (1H, s), 7.74
(1H, d, J¼6.8 Hz), 7.76 (1H, s), 8.10 (1H, d, J¼7.6 Hz),10.19 (1H, s); 13C
8.7
ppm 8.0 7.9 7.8 7.7 7.6 7.5 7.4
ppm
NMR (75 MHz, CDCl3):
d 119.5, 123.0, 126.8, 128.4, 129.4, 131.7,
134.4, 134.6, 136.1, 137.5, 138.7, 139.3, 143.5, 146.6, 188.8; EIMS
(70 eV): m/z (rel int.) 269 (6.5), 268 (35), 267 (21), 266 (92, Mþ), 265
(8.4), 231 (34), 204 (15), 203 (85), 202 (100), 201 (17); HRMS (EI),
m/z calcd for C17H11ClO: 266.0498. Found: 266.0497. Anal. calcd for
C17H11ClO.0.6H2O: C, 73.57; H, 4.43. Found: C, 73.46; H, 4.60.
13.0 12.5 12.0 11.5 11.0 10.5 10.0 9.5
9.0
8.5
8.0
ppm
Figure 3. 500 MHz proton NMR spectra of benzodiazepines 29b (upper spectrum) and
29a (lower spectrum) in d6-DMSO.
3. Conclusions
Reaction of benzaldehydes with an indene enamine in the
presence of Bu2BOTf gave a series of stable fulvene aldehydes, while
isophthalaldehydes gave related difulvene dialdehydes. This
methodology is quite general and it is anticipated that fulvene
structures will allow access to new families of porphyrin analogues.
Attempts to convert the initially formed fulvene monoaldehydes
into dialdehydes have so far not been successful but these com-
pounds are quite stable and can be transformed into acetals or
carbinol derivatives. In addition, the methodology allows methoxy-,
halo- or cyanovinyl groups to be introduced. Fulvene aldehydes also
reacted with o-phenylenediamine to give a novel series of benzo-
diazepines. Further investigations into the chemistry of fulvene al-
dehydes will no doubt lead to other useful synthetic applications.
4.2.2. 1-(4-Methoxyphenylmethylene)indene-3-carbaldehyde
(21b). Dibutylboron triflate (1.60 mL of
dichloromethane) was added to a stirred solution of p-anisalde-
hyde (144 L, 161 mg, 1.19 mmol) in dichloroethane (250 mL). The
a 1 M solution in
m
mixture was heated under reflux, and a solution of indene enamine
(300 mg, 1.75 mmol) in 1,2-dichloroethane (250 mL) was added
dropwise over 5–10 min. The mixture was allowed to stir under
reflux overnight. The next day, the reaction was quenched by
adding a saturated sodium bicarbonate solution (150 mL). The or-
ganic layer was separated, and the aqueous solution was extracted
with dichloromethane (3ꢂ). The organic layers were combined,
washed with brine, and dried over sodium sulfate. The solvent was
removed on a rotary evaporator, and the residue purified by flash
chromatography on silica gel eluting with 20% hexanes–dichloro-
methane. Recrystallization from chloroform–hexanes gave fulvene
21b (165 mg, 0.63 mmol, 53%) as amber needles, mp 140–141 ꢁC;
4. Experimental
4.1. General
1H NMR (400 MHz, CDCl3):
d
3.90 (3H, s), 7.02 (2H, d, J¼8.4 Hz),
7.30–7.38 (2H, m), 7.65 (2H, d, J¼8.8 Hz), 7.70–7.76 (1H, m), 7.75
Dibutylboron triflate in dichloromethane (1.0 M), iso-
phthalaldehyde, 4-methoxybenzaldehyde, 4-chlorobenzaldehyde,
(1H, s), 7.79 (1H, s), 8.11 (1H, d, J¼8.4 Hz), 10.19 (1H, s); 13C NMR
(100 MHzCDCl3): d 55.5, 114.8, 119.1, 122.7, 126.4, 127.7, 129.0, 132.6,

9940
R.N. Davis, T.D. Lash / Tetrahedron 65 (2009) 9935–9943
136.3, 136.6, 137.0, 138.0, 139.3, 142.5, 161.5, 188.8; EIMS (70 eV):
m/z (rel int.) 263 (21), 262 (100, Mþ), 261 (8.9), 247 (8.8), 233 (16),
219 (20), 202 (13), 189 (31); HRMS (EI), m/z calcd for C18H14O2:
262.0994. Found: 262.0992. Anal. calcd for C18H14O2: C, 82.42; H,
5.38. Found: C, 82.26; H, 5.38.
After removing the solvent under reduced pressure, the product
was purified by chromatography on grade three basic alumina
eluting initially with 10% dichloromethane–hexanes; the polar-
ity was gradually increased to 20% dichloromethane–hexanes
and the first yellow band was collected. Recrystallization from
dichloromethane–hexanes gave the protected fulvene (102 mg,
0.245 mmol, 91%) as yellow needles, mp 128–130 ꢁC; 1H NMR
4 . 2 . 3 . 1 - ( P h e n y l m e t h y l e n e ) i n d e n e - 3 - c a r b a l d e h y d e
(21c). Benzaldehyde (300
mL, 313 mg, 2.95 mmol), dibutylboron
(500 MHz, CDCl3): d 3.39 (6H, s), 3.92 (3H, s), 3.96 (3H, s), 5.54
triflate (2.95 mL of a 1 M solution in dichloromethane) and indene
enamine (504 mg, 2.95 mmol) were reacted under the conditions
described in Section 4.2.2. The crude product was purified by col-
umn chromatography on silica eluting with 25% hexanes–
dichloromethane and the resulting brown oil was washed re-
peatedly with hexanes to give the fulvene 21c (658 mg, 2.84 mmol,
(1H, br d, J¼1.0 Hz), 6.51 (1H, s), 7.00 (1H, br t, J¼1.0 Hz), 7.21–
7.28 (2H, m), 7.51–7.53 (1H, m), 7.65 (1H, s), 7.69–7.72 (1H, m),
7.80 (1H, s); 13C NMR (100 MHz, d6-DMSO):
d 52.9, 56.2, 56.6,
96.3, 100.4, 102.8, 119.4, 120.1, 120.7, 123.2, 124.6, 125.5, 127.5,
135.2, 137.7, 138.4, 139.9, 143.7, 157.4, 159.0; EIMS (70 eV): m/z
(rel int.) 419 (11), 418 (48), 417 (11), 416 (48, Mþ), 388 (29), 387
(99), 386 (30), 385 (100); HRMS (EI), m/z calcd for C21H21BrO4:
416.0623. Found: 416.0624. Anal. calcd for C21H21BrO4: C, 60.44;
H, 5.07. Found: C, 59.91; H, 4.99.
96%); 1H NMR (300 MHz, CDCl3):
d 7.35–7.41 (2H, m), 7.45–7.56 (3H,
m), 7.62–7.67 (2H, m), 7.68 (1H, s), 7.74 (1H, d, J¼8.7 Hz), 7.81 (1H,
s), 8.12 (1H, d, J¼8.4 Hz), 10.16 (1H, s); 13C NMR (75 MHz, CDCl3):
d
119.4, 122.7, 126.6, 128.1, 129.0, 129.7, 130.6, 136.08, 136.13, 137.3,
137.6,138.7,139.4,143.0,188.8; EIMS (70 eV): m/z (rel int.) 234 (2.5),
233 (20), 230 (100, Mþ), 231 (20), 204 (21), 203 (78), 202 (63);
HRMS (EI), m/z calcd for C17H12O: 232.0888. Found: 232.0885.
4.2.7. 1-(5-(2-Cyano-2-ethoxycarbonylvinyl)-2,4-dimethoxyphenyl-
methylene)indene-3-carbaldehyde
(24). 2,4-Dimethoxybenzene
dialdehyde 17c (199 mg, 1.02 mmol), two drops of piperidine, and
absolute ethanol (10 mL) were added to a round-bottomed flask
equipped for reflux. Ethyl cyanoacetate (0.091 g) was added
dropwise through an addition funnel and was further rinsed in
with an additional 10 mL of ethanol. The reaction mixture was
allowed to stir under reflux for 3 h. The diprotected by-product
was removed by suction filtration, and the filtrate was evaporated
under reduced pressure. The residue was purified by column
chromatography on silica, eluting initially with 60% dichloro-
methane–hexanes and then gradually increasing the polarity to
100% dichloromethane. Recrystallization from chloroform–hex-
anes gave 23 (130 mg, 0.45 mmol, 44%) as a yellow powder, mp
4.2.4. 1-(2,4-Dimethoxyphenylmethylene)indene-3-carbaldehyde
(21d). 2,4-Dimethoxybenzaldehyde (286 mg, 1.17 mmol), indene
enamine (415 mg, 2.43 mmol) and a 1 M solution of dibutylboron
triflate in dichloromethane (2.40 mL) were reacted under the
previous conditions in the presence of sodium sulfate (0.50 g). Puri-
fication by flash chromatography on silica, eluting with 10% hexanes–
dichloromethane, and recrystallization from chloroform–hexanes
gave the fulvene 21d (223 mg, 0.76 mmol, 44%) asan orange solid, mp
1
127–128 ꢁC; H NMR (400 MHz, CDCl3):
d 3.89 (3H, s), 3.92 (3H, s),
6.52 (1H, d, J¼2.4 Hz), 6.63 (1H, dd, J¼11.2 Hz, J¼2.4 Hz), 7.30–7.40
(2H, m), 7.60 (1H, d, J¼8.8 Hz), 7.69 (1H, s), 7.78–7.84 (1H, m), 8.11
(1H, d, J¼8.8 Hz), 8.13 (1H, s), 10.17 (1H, s); 13C NMR (100 MHz,
166–169 ꢁC; 1H NMR (300 MHz, CDCl3):
4.01 (3H, s), 4.03 (3H, s), 4.36 (2H, q, J¼7.2 Hz), 6.46 (1H, s), 8.56
(1H, s), 8.78 (1H, s), 10.26 (1H, s); 13C NMR (75 MHz, CDCl3):
14.2,
56.1, 56.3, 62.4, 94.5, 101.9, 114.3, 115.6, 119.1, 131.8, 147.9, 162.9,
165.1, 166.6, 186.9. Dibutylboron triflate (800 L of a 1 M solution
d
1.38 (3H, t, J¼7.2 Hz),
CDCl3):
d
55.6, 55.7, 98.6, 105.9, 118.7, 119.3, 122.5, 126.2, 127.4, 132.3,
d
133.2, 136.3, 137.1, 138.1, 140.0, 141.9, 160.3, 163.3, 188.8; HRMS (EI), m/
z calcd for C19H16O3: 292.1100. Found: 292.1102. Anal. calcd for
C19H16O3: C, 78.06; H, 5.58. Found: C, 77.76; H, 5.31.
m
in dichloromethane) was added to a solution of 23 (100 mg,
0.35 mmol) in dichloroethane (75 mL). The mixture was heated
under reflux, and indene enamine (102 mg, 0.60 mmol) in 75 mL
of dichloroethane was then added dropwise over a 5–10 min pe-
riod. Once all the indene enamine was added the reaction was
allowed to stir at reflux overnight. The next day the reaction was
quenched with 65 mL of a saturated sodium acetate solution. The
product was extracted, and the aqueous layer was washed with
dichloromethane (3ꢂ). The organic layers were combined and
washed with a saturated aqueous sodium bicarbonate solution
and then with brine. The product was dried over sodium sulfate
and the solvent removed under reduced pressure. The residue was
purified via flash chromatography on silica and eluting with 10%
hexanes–dichloromethane. Recrystallization from chloroform–
hexanes gave the fulvene (88 mg, 0.21 mmol, 61%) as an orange
4.2.5. 1-(5-Bromo-2,4-dimethoxyphenylmethylene)indene-3-carbal-
dehyde (21e). 5-Bromo-2,4-dimethoxybenzaldehyde (286 mg,
1.17 mmol), dibutylboron triflate (2.4 mL of a 1 M solution in
dichloromethane) and indene enamine (400 mg, 2.34 mmol) were
reacted under the same conditions as described in Section4.2.4 in
the presence of sodium sulfate (0.50 g). The crude product was
purified by flash chromatography on silica eluting with 10% hex-
anes–dichloromethane. Recrystallization from acetone and hex-
anes afforded the fulvene (216 mg, 0.58 mmol, 50%) as a red
crystalline solid, mp 208–210 ꢁC; 1H NMR (400 MHz, CDCl3):
d 3.96
(3H, s), 4.00 (3H, s), 6.54 (1H, s), 7.30–7.36 (2H, m), 7.64 (1H, s), 7.76
(1H, d, J¼8.0 Hz), 7.81 (1H, s), 8.01 (1H, s), 8.11 (1H, d, J¼8.0 Hz),
10.21 (1H, s); 13C NMR (100 MHz, CDCl3):
d 56.1, 56.5, 96.3, 103.2,
119.4, 122.7, 126.4, 127.7, 130.2, 135.4, 137.2, 137.8, 139.28, 139.35,
139.39, 142.5, 158.6, 159.5, 189.0; HRMS (EI), m/z calcd for
C19H15BrO3: 370.0205. Found: 370.0208. Anal. calcd for C19H15BrO3:
C, 61.47; H, 4.07. Found: C, 61.40; H, 4.09.
solid, mp 204–206 ꢁC; 1H NMR (300 MHz, CDCl3):
d 1.41 (3H, t,
J¼6.9 Hz), 3.98 (3H, s), 4.00 (3H, s), 4.38 (2H, q, J¼6.9 Hz), 6.45 (1H,
s), 7.26–7.38 (2H, m), 7.63 (1H, d, J¼8.1 Hz), 7.94 (1H, s), 8.05 (1H,
s), 8.09 (1H, d, J¼8.4 Hz), 8.52 (1H, s), 8.64 (1H, s), 10.16 (1H, s); 13C
NMR (75 MHz, CDCl3):
d 14.2, 56.2, 62.4, 94.6, 100.7, 114.6, 116.6,
4.2.6. 1-(5-Bromo-2,4-dimethoxyphenylmethylene)-3-dimethoxy-
methylindene (22b). Fulvene 21e (100 mg, 0.27 mmol), trimethyl
orthoformate (2.5 mL), and dichloroethane (30 mL) were added
to a round-bottomed flask equipped with a drying tube. Cerium
trichloride heptahydrate (265 mg) and methanol (80 mL) were
added, and the contents of the flask were allowed to stir at room
temperature overnight. The reaction was quenched with a satu-
rated sodium bicarbonate solution (40 mL), and the mixture
extracted with dichloromethane and dried over sodium sulfate.
118.9, 119.4, 122.9, 126.2, 126.5, 127.8, 128.7, 131.0, 132.0, 137.8,
140.3, 143.0, 148.4, 162.7, 163.0, 164.2, 190.0; EIMS (70 eV): m/z (rel
int.) 417 (9.6), 416 (28), 415 (100, Mþ), 387 (15); HRMS (EI), m/z
calcd for C25H21NO5: 415.1420. Found: 415.1417. Anal. calcd for
C25H21NO5: C, 72.28; H, 5.09; N, 3.37. Found: C, 71.96; H, 4.99; N,
3.26.
4.2.8. Difulvene dicarbinol 25b. Dialdehyde 18b45 (92 mg,
0.20 mmol) and cerium trichloride heptahydrate (86 mg) were

R.N. Davis, T.D. Lash / Tetrahedron 65 (2009) 9935–9943
9941
placed in a round-bottomed flask equipped with a drying tube, and
dichloromethane (20 mL), absolute ethanol (10 mL), and methanol
(25 mL) were added to dissolve the reagents. Sodium borohydride
(19 mg) was then added and the contents of the flask were allowed
to stir at room temperature for 35 min. The reaction was quenched
with water (25 mL) and the product precipitated out as a yellow
solid. The precipitate was collected via suction filtration and
washed with two 5 mL portions of hexanes. The product was
recrystallized from chloroform to give the dicarbinol (61 mg,
0.13 mmol, 66%) as yellow needles, mp 233 ꢁC, dec; 1H NMR
hexanes, and recrystallization from chloroform–hexanes, gave the
bis-diazepine product (77 mg, 0.14 mmol, 55%) as a yellow solid,
mp 214 ꢁC, dec; 1H NMR (500 MHz, d6-DMSO):
d 7.21–7.25 (2H, m),
7.26–7.30 (2H, m), 7.39–7.43 (2H, m), 7.44–7.48 (2H, m), 7.56 (2H, d,
J¼7.7 Hz), 7.77 (2H, d, J¼7.7 Hz), 7.79 (1H, t, J¼7.7 Hz), 7.97 (2H, dd,
J¼1.4, 7.7 Hz), 8.03 (2H, d, J¼7.3 Hz), 8.04 (2H, s), 8.07 (2H, s), 8.16
(1H, br t), 8.64 (2H, d, J¼7.4 Hz), 13.02 (2H, s); 13C NMR (125 MHz,
d6-DMSO):
d 111.3, 119.6, 119.9, 122.0, 123.3, 123.6, 124.8, 126.3,
127.9, 130.0, 130.7, 131.0, 132.9, 134.4, 135.5, 137.4, 138.1, 139.0, 139.1,
144.3, 148.2; HRMS (FAB), m/z calcd for C40H26N4þH: 563.2236.
Found: 563.2233. Anal. calcd for C40H26N4.CHCl3: C, 72.20; H, 3.99;
N, 8.21. Found: C, 72.32; H, 4.25; N, 7.99.
(500 MHz, d6-DMSO):
d 2.25 (3H, s), 3.76 (6H, s), 4.61 (4H, d,
J¼5.6 Hz), 5.16 (2H, t, J¼5.6 Hz), 6.85 (2H, br t, J¼1.8 Hz), 7.24–7.30
(4H, m), 7.34–7.38 (2H, m), 7.62 (1H, s), 7.66 (2H, s), 7.85–7.88 (2H,
m); 13C NMR (75 MHz, d6-DMSO):
d
9.1, 57.7, 61.0, 119.19, 119.25,
4.2.12. 12-(4-Chlorophenylmethylene)benzo[b]indeno[1,2-f]-1,4-dia-
zepine (29a). A mixture of fulvene aldehyde 21a (102 mg,
0.38 mmol), cerium trichloride heptahydrate (141 mg) and o-phe-
nylenediamine (39 mg, 0.36 mmol) in dichloromethane (20 mL)
and methanol (60 mL) was stirred under reflux overnight. The
mixture was washed with water, the aqueous layer was back
extracted with dichloromethane and the combined organic solu-
tions dried over sodium sulfate. After removing the solvent on
a rotary evaporator, the residue was purified by column chroma-
tography on grade three basic alumina eluting with 60% dichloro-
methane–hexanes. Recrystallization from chloroform–hexanes
gave the diazepine (59 mg, 0.17 mmol, 44%) as yellow needles, mp
120.2, 122.1, 124.7, 125.2, 125.8, 127.1, 130.8, 137.6, 138.6, 140.3, 149.1,
158.5; EIMS (70 eV): m/z (rel int.) 466 (9.5), 465 (33), 464 (100, Mþ),
446 (44), 415 (13); HRMS (EI), m/z calcd for C31H28O4: 464.1988.
Found: 464.1985. Anal. calcd for C31H28O4$1/4H2O: C, 79.38; H, 6.12.
Found: C, 79.46; H, 6.04.
4.2.9. Difulvene dicarbinol 47a. Difulvene dialdehyde 18a45 (79 mg,
0.20 mmol) was reacted with cerium trichloride heptahydrate
(98 mg) and sodium borohydride (20 mg) under the foregoing con-
ditions. After quenching the reaction, the product was extracted with
dichloromethane and dried over sodium sulfate. The solvent was
removed under reduced pressure and the residue recrystallized from
chloroform to give the dicarbinol (73 mg, 0.19 mmol, 92%) as yellow
235–238 ꢁC; 1H NMR (500 MHz, d6-DMSO):
d 7.21–7.24 (1H, m),
7.26–7.30 (1H, m), 7.34–7.38 (1H, m), 7.40–7.44 (1H, m), 7.57 (1H, d,
J¼7.8 Hz), 7.61–7.64 (2H, m), 7.76 (1H, d, J¼7.9 Hz), 7.83–7.86 (2H,
m), 7.88 (1H, s), 7.95 (1H, d, J¼7.5 Hz), 7.98 (1H, s), 8.58 (1H, d,
needles, mp 183–184 ꢁC; 1H NMR (400 MHz, CDCl3):
4.86 (4H, br s), 7.16 (2H, s), 7.20–7.35 (7H, m), 7.48–7.56 (4H, m),
7.73–7.78 (2H, m), 8.01 (1H, s); 1H NMR (500 MHz, d6-DMSO):
4.62
d 2.33 (2H, br s),
d
J¼7.4 Hz), 12.99 (1H, s); 13C NMR (75 MHz, d6-DMSO):
d 110.8, 119.1,
(4H, d, J¼5.5 Hz), 5.18 (2H, t, J¼5.5 Hz), 7.00 (2H, br t, J¼1.8 Hz), 7.23–
7.29 (4H, m), 7.34–7.38 (2H, m), 7.60 (1H, t, J¼7.7 Hz), 7.67–7.70 (4H,
m), 7.84–7.87 (2H, m), 7.92 (1H, br t, J¼1.5 Hz); 13C NMR (75 MHz, d6-
119.4, 121.5, 122.8, 123.1, 124.1, 125.7, 127.4, 128.8, 129.4, 131.7, 133.5,
134.0, 135.1, 137.7, 138.4, 138.6, 143.9, 147.7; EIMS (70 eV): m/z (rel
int.) 358 (2.7), 357 (9.7), 356 (40), 355 (41), 354 (100, Mþ), 353 (41),
320 (4.8), 319 (20), 318 (14), 317 (15), 316 (5.1), 238 (8.1), 236 (23);
HRMS (EI), m/z calcd for C23H15N2Cl: 354.0924. Found: 354.0926.
Anal. calcd for C23H15ClN2$1/2CHCl3: C, 68.09; H, 3.77; N, 6.76.
Found: C, 68.35; H, 3.85; N, 6.76.
DMSO): d 57.7,119.2,119.3,120.1,125.2,126.8,127.1,129.1,129.1,129.4,
131.0, 137.0, 137.9, 138.7, 140.1, 149.5; EIMS (70 eV): m/z (rel int.) 391
(31), 390 (100, Mþ), 372 (28); HRMS (EI), m/z calcd for C28H22O2:
390.1620. Found: 390.1624. Anal. calcd for C28H22O2.1/5H2O: C, 85.34;
H, 5.73. Found: C, 85.31; H, 5.51.
4.2.13. 12-(4-Methoxyphenylmethylene)benzo[b]indeno[1,2-f]-1,4-
diazepine (29b). Fulvene 21b (102 mg, 0.39 mmol), cerium tri-
chloride heptahydrate (153 mg), and o-phenylenediamine (48 mg,
0.44 mmol) were reacted under the previously described condi-
tions. The product was purified by column chromatography on
grade three basic alumina eluting with 60% dichloromethane–
hexanes, and recrystallized from chloroform–hexanes to give the
diazepine (71 mg, 0.20 mmol, 52%) as yellow needles, mp 244–
4.2.10. Bis-1,4-benzodiazepine 28b. Difulvene 18b45 (48 mg,
0.10 mmol), cerium trichloride heptahydrate (75 mg), and o-phenyl-
enediamine (23 mg, 0.21 mmol) in dichloromethane (20 mL) and
methanol (55 mL) were stirred under reflux overnight. The mix-
ture was washed with water, and the aqueous layer back extracted
with dichloromethane. The combined organic solutions were dried
over sodium sulfate and evaporated under reduced pressure. The
residue was purified by column chromatography on grade three
basic alumina, eluting initially with 60% dichloromethane–hexanes
and then 75% dichloromethane–hexanes. Recrystallization from
chloroform–hexanes gave the bis-diazepine product (37 mg,
0.058 mmol, 58%) as an orange solid, mp 197 ꢁC, dec; 1H NMR
245 ꢁC; 1H NMR (500 MHz, d6-DMSO):
d 3.86 (3H, s), 7.13 (2H, d,
J¼8.7 Hz), 7.20–7.24 (1H, m), 7.25–7.29 (1H, m), 7.31–7.35 (1H, m),
7.36–7.40 (1H, m), 7.56 (1H, d, J¼7.8 Hz), 7.75 (1H, d, J¼7.8 Hz),
7.82–7.86 (3H, m), 7.93 (1H, d, J¼7.3 Hz), 8.06 (1H, s), 8.58 (1H, d,
J¼7.5 Hz), 12.96 (1H, s); 13C NMR (75 MHz, d6-DMSO):
d 55.2, 110.7,
(500 MHz, d6-DMSO):
d
2.34 (3H, s), 3.82 (6H, s), 7.11–7.17 (4H, m),
114.5,118.9,119.0,121.4,122.6,122.9,124.4,125.3,126.7,128.8,131.0,
132.0, 133.8, 134.0, 135.6, 138.1, 138.2, 144.0, 148.1, 160.1; EIMS
(70 eV): m/z (rel int.) 353 (4.5), 352 (15), 351 (20), 350 (66, Mþ), 349
(11), 335 (14); HRMS (EI), m/z calcd for C24H18N2O: 350.1419.
Found: 350.1416. Anal. calcd for C24H18N2O$1/3H2O: C, 80.88; H,
5.28; N, 7.86. Found: C, 80.88; H, 5.20; N, 7.84.
7.34–7.7.37 (2H, m), 7.38–7.41 (2H, m), 7.42–7.46 (2H, m), 7.65–7.69
(2H, m), 7.76 (2H, s), 7.87 (1H, s), 7.99 (2H, s), 8.05 (2H, d, J¼7.5 Hz),
8.60 (2H, d, J¼7.5 Hz), 12.82 (2H, s); 13C NMR (100 MHz, d6-DMSO):
d
9.2, 61.1, 110.8, 119.0, 119.3, 121.3, 122.9, 124.5, 125.1, 125.5, 125.7,
125.96, 126.06, 127.4, 131.0, 133.9, 134.6, 137.4, 138.9, 139.0, 143.8,
147.6, 159.1; HRMS (FAB), m/z calcd for C43H32N4Oþ2 H: 637.2603.
Found: 637.2602. Anal. calcd for C43H32N4O2.H2O.1/2CHCl3: C,
73.12; H, 4.87; N, 7.84. Found: C, 72.64; H, 5.02; N, 8.22.
4.2.14. 12-(Phenylmethylene)benzo[b]indeno[1,2-f]-1,4-diazepine
(29a). Fulvene 21a (88 mg, 0.38 mmol), cerium trichloride hepta-
hydrate (150 mg), and o-phenylenediamine (61 mg, 0.56 mmol)
were reacted under the foregoing conditions. The product was
purified by column chromatography on grade 3 basic alumina,
eluting with 60% dichloromethane–hexanes, and recrystallized
from chloroform–hexanes to give the diazepine (70 mg, 0.22 mmol,
58%) as a yellow solid, mp 126 ꢁC, dec; 1H NMR (300 MHz,
4.2.11. Bis-1,4-benzodiazepine 28a. Difulvene 18a45 (97 mg,
0.25 mmol), cerium trichloride heptahydrate (194 mg), and o-
phenylenediamine (76 mg, 0.70 mmol) were reacted under the
previous conditions. Purification by column chromatography on
grade three basic alumina eluting with 60% dichloromethane–

9942
R.N. Davis, T.D. Lash / Tetrahedron 65 (2009) 9935–9943
3. Vogel, E.; Haas, W.; Knipp, B.; Lex, J.; Schmickler, H. Angew. Chem., Int. Ed. Engl.
d6-DMSO):
d 7.20–7.34 (2H, m), 7.35–7.55 (3H, m), 7.55–7.62 (3H,
1988, 27, 406–409.
4. Lash, T. D. Synlett 2000, 279–295.
5. Cyranski, M. K.; Krygowski, T. M.; Wisiorowski, M.; Hommes, N. J. R.; van, E.;
Schleyer, P.; von, R. Angew. Chem., Int. Ed. 1998, 37, 177–180.
6. Aihara, J.-i. J. Phys. Chem. A 2008, 112, 5305–5311.
m), 7.78 (1H, d, J¼7.8 Hz), 7.84 (2H, d, J¼7.5 Hz), 7.90 (1H, s), 7.96
(1H, d, J¼7.2 Hz), 8.05 (1H, s), 8.62 (1H, d, J¼7.2 Hz), 13.01 (1H, br s);
13C NMR (75 MHz, d6-DMSO):
d 110.8,119.1,119.3,121.5,122.7, 123.1,
124.4, 125.6, 127.2, 128.76, 128.85, 130.2, 131.0, 134.0, 134.8, 136.2,
137.83, 137.88, 138.6, 144.0, 147.8; EIMS (70 eV): m/z (rel int.) 322
(8.6), 321 (25), 320 (100, Mþ), 319 (57), 292 (3.1), 277 (3.8), 232
(31); HRMS (EI), m/z calcd for C23H16N2: 320.1314. Found: 320.1310.
Anal. calcd for C40H26N4$1/2CHCl3: C, 74.26; H, 4.38; N, 7.37. Found:
C, 74.22; H, 4.45; N, 7.19.
7. Berlin, K. Angew. Chem., Int. Ed. 1996, 35, 1820–1822.
8. Lash, T. D.; Hayes, M. J. Angew. Chem., Int. Ed. 1997, 36, 840–842.
9. (a) Lash, T. D.; Hayes, M. J.; Spence, J. D.; Muckey, M. A.; Ferrence, G. M.;
Szczepura, L. F. J. Org. Chem. 2002, 67, 4860–4874; (b) Liu, D.; Lash, T. D. J. Org.
Chem. 2003, 68, 1755–1761.
10. Muckey, M. A.; Szczepura, L. F.; Ferrence, G. M.; Lash, T. D. Inorg. Chem. 2002, 41,
4840–4842.
11. Lash, T. D.; Colby, D. A.; Szczepura, L. F. Inorg. Chem. 2004, 43, 5258–5267.
12. Lash, T. D.; Rasmussen, J. M.; Bergman, K. M.; Colby, D. A. Org. Lett. 2004, 6,
549–552.
13. Hayes, M. J.; Spence, J. D.; Lash, T. D. Chem. Commun. 1998, 2409–2410.
14. Lash, T. D.; Muckey, M. A.; Hayes, M. J.; Liu, D.; Spence, J. D.; Ferrence, G. M.
J. Org. Chem. 2003, 68, 8558–8570.
15. Morganthaler, J. B.; Peters, S. J.; Ceden˜o, D. L.; Constantino, M. H.; Edwards, K.
A.; Kamowski, E. M.; Passini, J. C.; Butkus, B. E.; Young, A. M.; Lash, T. D.; Jones,
M. A. Bioorg. Med. Chem. 2008, 16, 7033–7038.
16. Lash, T. D. In The Porphyrin Handbook; Kadish, K. M., Smith, K. M., Guilard, R.,
Eds.; Academic: San Diego, 2000; Vol. 2, pp 125–199.
4.2.15. 12-(2,4-Dimethoxyphenylmethylene)benzo[b]indeno[1,2-f]-
1,4-diazepine (29d). Fulvene 21d (202 mg, 0.69 mmol), cerium tri-
chloride heptahydrate (281 mg), and o-phenylenediamine (79 mg,
0.73 mmol) were reacted under the previous conditions. The product
was purified by column chromatography on grade three basic alu-
mina, eluting with 60% dichloromethane–hexanes, and recrystal-
lized from chloroform–hexanes to give the diazepine (150 mg,
0.39 mmol, 57%) as a yellow solid, mp 246–247 ꢁC; 1H NMR
17. Lash, T. D. Eur. J. Org. Chem. 2007, 5461–5481.
18. (a) Lash, T. D.; Chaney, S. T. Tetrahedron Lett. 1996, 37, 8825–8828; (b) Bergman,
K. M.; Ferrence, G. M.; Lash, T. D. J. Org. Chem. 2004, 69, 7888–7897.
19. Lash, T. D. Angew. Chem., Int. Ed. Engl. 1995, 34, 2533–2535.
20. Lash, T. D.; Chaney, S. T.; Richter, D. T. J. Org. Chem. 1998, 63, 9076–9088.
21. Richter, D. T.; Lash, T. D. Tetrahedron 2001, 57, 3659–3673.
22. El-Beck, J. A.; Lash, T. D. Org. Lett. 2006, 8, 5263–5266.
23. Hayes, M. J.; Lash, T. D. Chem.d Eur. J. 1998, 4, 508–511.
24. Lash, T. D.; Chaney, S. T. Angew. Chem., Int. Ed. 1997, 36, 839–840.
25. (a) Lash, T. D.; Colby, D. A.; Graham, S. R.; Chaney, S. T. J. Org. Chem. 2004, 69,
8851–8864; (b) Lash, T. D.; El-Beck, J. A.; Ferrence, G. M. J. Org. Chem. 2007, 72,
8402–8415.
(400 MHz, d6-DMSO):
d 3.89 (3H, s), 3.93 (3H, s), 6.74 (1H, s), 6.76
(1H, d, J¼8.4 Hz), 7.20–7.30 (2H, m), 7.30–7.42 (2H, m), 7.55 (1H, d,
J¼8 Hz), 7.76–7.82 (2H, m), 7.88 (1H, d, J¼7.6 Hz), 7.92 (1H, s), 7.93
(1H, s), 8.60 (1H, d, J¼7.6 Hz), 12.93 (1H, s); 13C NMR (75 MHz, d6-
DMSO): d 55.3, 55.7, 98.3, 106.2, 110.7, 117.8, 118.8, 119.0, 121.3, 122.5,
122.9, 124.9, 125.3, 126.0, 126.6, 132.1, 133.3, 134.0, 135.6, 137.7, 138.4,
144.0, 148.1, 159.5, 162.0; EIMS (70 eV): m/z (rel int.) 382 (7.9), 381
(28), 380 (100, Mþ), 379 (10), 365 (12); HRMS (EI), m/z calcd for
C25H20N2O2: 380.1525. Found: 380.1520. Anal. calcd for C25H20N2O2:
C, 78.93; H, 5.30; N, 7.36. Found: C, 78.43; H, 5.30; N, 7.15.
26. (a) Lash, T. D. Chem. Commun. 1998, 1683–1684; (b) Colby, D. A.; Ferrence, G. M.;
Lash, T. D. Angew. Chem., Int. Ed. 2004, 43, 1346–1349.
27. (a) Colby, D. A.; Lash, T. D. Chem.dEur. J. 2002, 8, 5397–5402; (b) Lash, T. D.;
Colby, D. A.; Ferrence, G. M. Eur. J. Org. Chem. 2003, 4533–4548; (c) El-Beck, J. A.;
Lash, T. D. Eur. J. Org. Chem. 2007, 3981–3990.
4.2.16. 12-(5-Bromo-2,4-dimethoxyphenylmethylene)benzo[b]indeno[1,2-
f]-1,4-diazepine (29e). Fulvene 35d (51 mg, 0.14 mmol), cerium tri-
chloride heptahydrate (53 mg), and o-phenylenediamine (18 mg,
0.17 mmol) were reacted under the previous conditions. The product
was purified by column chromatography on grade three basic alumina,
eluting with 60% dichloromethane–hexanes, and recrystallized from
chloroform–hexanes to give the diazepine (43 mg, 0.094 mmol, 67%) as
28. (a) Stepien, M.; Latos-Grazynski, L. Chem.dEur. J. 2001, 7, 5113–5117; (b) Ste-
pien, M.; Latos-Grazynski, L. Acc. Chem. Res. 2005, 38, 88–98.
29. (a) Szymanski, J. T.; Lash, T. D. Tetrahedron Lett. 2003, 44, 8613–8616; (b) Lash,
T. D.; Szymanski, J. T.; Ferrence, G. M. J. Org. Chem. 2007, 72, 6481–6492.
30. (a) Graham, S. R.; Ferrence, G. M.; Lash, T. D. Chem. Commun. 2002, 894–895; (b)
Lash, T. D.; Colby, D. A.; Graham, S. R.; Ferrence, G. M.; Szczepura, L. F. Inorg.
Chem. 2003, 42, 7326–7338; (c) Liu, D.; Ferrence, G. M.; Lash, T. D. J. Org. Chem.
2004, 69, 6079–6093.
31. (a) Stepien, M.; Latos-Grazynski, L.; Lash, T. D.; Szterenberg, L. Inorg. Chem.
2001, 40, 6892–6900; (b) Venkatraman, S.; Anand, V. G.; Pushpan, S. K.; Sankar,
J.; Chandrashekar, T. K. Chem. Commun. 2002, 462; (c) Stepien, M.; Latos-Gra-
zynski, L.; Szterenberg, L.; Panek, J.; Latajka, Z. J. Am. Chem. Soc. 2004, 126,
4566–4580.
an orange solid, mp 285–286 ꢁC; 1H NMR (400 MHz, d6-DMSO):
d 4.00
(3H, s), 4.01 (3H, s), 6.91 (1H, s), 7.20–7.30 (2H, m), 7.30–7.42 (2H, m), 7.59
(1H, d, J¼8.0 Hz), 7.77 (1H, d, J¼8.0 Hz), 7.82–7.90 (3H, m), 7.90 (1H, s),
8.63 (1H, d, J¼7.6 Hz), 13.04 (1H, s); 13C NMR (100 MHz, d6-DMSO):
d
56.2, 56.5, 97.5, 101.7, 110.8, 118.7, 118.9, 119.0, 121.4, 122.7, 123.0, 124.1,
32. Lash, T. D. Macroheterocycles 2008, 1, 9–20.
33. Latos-Grazynski, L. In The Porphyrin Handbook; Kadish, K. M., Smith, K. M.,
Guilard, R., Eds.; Academic: San Diego, 2000; Vol. 2, pp 361–416.
34. Srinivasan, A.; Furuta, H. Acc. Chem. Res. 2005, 38, 10–20.
35. Harvey, J. D.; Ziegler, C. J. Coord. Chem. Rev. 2003, 247, 1–19.
36. (a) Liu, B. Y.; Bru¨ckner, C.; Dolphin, D. Chem. Commun. 1996, 2141–2142; (b)
Lash, T. D.; Richter, D. T.; Shiner, C. M. J. Org. Chem. 1999, 64, 7973–7982; (c)
Lash, T. D.; Von Ruden, A. L. J. Org. Chem. 2008, 73, 9417–9425.
37. For related N-confused pyriporphyrins and pyrazole-containing analogues of
the porphyrins, see: (a) Lash, T. D.; Pokharel, K.; Serling, J. M.; Yant, V. R.;
Ferrence, G. M. Org. Lett. 2007, 9, 2863–2866; (b) Lash, T. D.; Young, A. M.; Von
Ruden, A. L.; Ferrence, G. M. Chem. Commun. 2008, 6309–6311.
38. (a) Furuta, H.; Asano, T.; Ogawa, T. J. Am. Chem. Soc. 1994, 116, 767–768; (b)
Chmielewski, P. J.; Latos-Grazynski, L.; Rachlewicz, K.; Glowiak, T. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 779–781.
39. Lash, T. D.; Romanic, J. L.; Hayes, M. J.; Spence, J. D. Chem. Commun. 1999,
819–820.
40. Furuta, H.; Maeda, H.; Osuka, A. J. Am. Chem. Soc. 2000, 122, 803–807.
41. Maeda, H.; Osuka, A.; Furuta, H. J. Am. Chem. Soc. 2003, 125, 15690–15691.
42. Graham, S. R.; Colby, D. A.; Lash, T. D. Angew. Chem., Int. Ed. 2002, 41, 1371–
1374.
124.4,125.5,126.9,133.7,134.0,134.1,136.5,137.6,138.5,143.9,147.9,157.4,
158.9; HRMS (EI), m/z calcd for C25H19BrN2O2: 458.0630. Found:
458.0628. Anal. calcd for C25H19BrN2O2.H2O: C, 62.90; H, 4.43; N, 5.87.
Found: C, 63.11; H, 4.19; N, 5.86.
Acknowledgements
This material is based upon work supported by the National
Science Foundation under Grant No. CHE-0616555 and the Petro-
leum Research Fund, administered by the American Chemical So-
ciety. Funding for a 500 MHz Bruker Avance III NMR spectrometer
was provided by the National Science Foundation under grant no.
CHE-0722385.
Supplementary data
43. The synthesis of resorcinol-derived dicarbaporphyrinoids has also been noted:
Xu, L.; Lash, T. D. Tetrahedron Lett. 2006, 47, 8863–8866.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.10.013.
44. Miyake, K.; Lash, T. D. Chem. Commun. 2004, 178–179.
45. Lash, T. D.; Colby, D. A.; Idate, A. S.; Davis, R. N. J. Am. Chem. Soc. 2007, 129,
13801–13802.
46. Zhang, Z.; Ferrence, G. M.; Lash, T. D. Org. Lett. 2009, 11, 101–104.
47. Lash, T. D. Chem.dEur. J. 1996, 2, 1197–1200.
48. These results were presented, in part, at the following meetings: (a)
231st National American Chemical Society Meeting, Atlanta, GA, March
2006 (Davis, R.N.; Lash, T.D. Book of Abstracts, ORGN 535); (b) Great
Lakes Regional Meeting of the American Chemical Society, Milwaukee,
References and notes
1. Milgrom, L. R. The Colours of Life; Oxford University: New York, NY, 1997.
2. Medforth, C. J. In The Porphyrin Handbook; Kadish, K. M., Smith, K. M., Guilard, R.,
Eds.; Academic: San Diego, 2000; Vol. 5, pp 1–80.

R.N. Davis, T.D. Lash / Tetrahedron 65 (2009) 9935–9943
9943
Wisconsin, June 2006 (Davis, R.N.; Lash, T.D. Program & Abstracts, Ab-
stract No. 64).
53. The sodium sulfate presumably absorbs trace amounts of water and thereby
aids in fulvene formation. However, the effect was not general and the pres-
ence of anhydrous Na2SO4 did not improve the yields for the other fulvenes
described in this paper.
54. Paine, J. B., III; Woodward, R. B.; Dolphin, D. J. Org. Chem. 1976, 41, 2826–2835.
55. Sessler, J. L.; Hemmi, G.; Mody, T. D.; Murai, T.; Burrell, A.; Young, S. W. Acc.
Chem. Res. 1994, 27, 43–50.
49. Enamine 14 was prepared by a literature procedure in one step from indene:
Arnold, Z. Collect. Czech. Chem. Commun. 1965, 2783–2792.
50. Hafner, K.; Bernhard, C. Liebigs Ann. Chem. 1959, 625, 108–123.
51. Hong, B.-C.; Gupta, A. K.; Wu, M.-F.; Liao, J.-H.; Lee, G.-H. Org. Lett. 2003, 5,
1689–1692.
52. Sinnema, P. J.; Ho¨hn, B.; Hubbard, R. L.; Shapiro, P. J.; Twamley, B.; Blumenfeld,
A.; Vij, A. Organometallics 2002, 21, 182–191.
56. Kobayashi, K.; Shimizu, H.; Itoh, M.; Suginome, H. Bull. Chem. Soc. Jpn. 1990, 63,
2435–2437.