Reactivity of Dipyrromethanes towards Azoalkenes: Synthesis of Functionalized Dipyrromethanes, Calix[4]pyrroles, and Bilanes

Article abstract of DOI:10.1002/ejoc.201402944

The introduction of side chains at the 1- and 9-positions of dipyrromethanes was explored by using the hetero-Diels-Alder reaction of azoalkenes. New 5,5′-diethyldipyrromethanes and 5-phenyldipyrromethanes that were functionalized with open-chain hydrazone moieties, including derivatives with tetrazolyl groups, were prepared. Furthermore, the synthesis of new calix[4]pyrroles and bilanes was achieved by employing the bis(hetero-Diels-Alder) reaction of azoalkenes with 5,5′-diethyldipyrromethane.

Full text of DOI:10.1002/ejoc.201402944

FULL PAPER
DOI: 10.1002/ejoc.201402944
Reactivity of Dipyrromethanes towards Azoalkenes: Synthesis of Functionalized
Dipyrromethanes, Calix[4]pyrroles, and Bilanes
Susana M. M. Lopes,[a] Américo Lemos,[b] and Teresa M. V. D. Pinho e Melo*[a]
Keywords: Synthetic methods / Cycloaddition / Nitrogen heterocycles / Azo compounds / Macrocycles
The introduction of side chains at the 1- and 9-positions of
dipyrromethanes was explored by using the hetero-Diels–
Alder reaction of azoalkenes. New 5,5Ј-diethyldipyrro-
methanes and 5-phenyldipyrromethanes that were function-
alized with open-chain hydrazone moieties, including deriv-
atives with tetrazolyl groups, were prepared. Furthermore,
the synthesis of new calix[4]pyrroles and bilanes was
achieved by employing the bis(hetero-Diels–Alder) reaction
of azoalkenes with 5,5Ј-diethyldipyrromethane.
dipyrromethanes with chlorosulfuryl isocyanate has been
reported.[5] In addition, 5,5-dialkyldipyrromethanes can un-
dergo a reaction with phenyl isocyanate to afford mono-
amide derivatives, and 1,9-bis(diazo)dipyrromethanes can
be obtained by a reaction with diazonium salts.[6] Pyrrole
can undergo a reaction with conjugated nitrosoalkenes and
azoalkenes to give open-chain oximes and hydrazones,
respectively. The formation of these products can be ex-
plained by the rearomatization of the primarily formed
cycloadduct, the bicyclic 1,2-oxazine or pyridazine (see
Scheme 1).[7]
Introduction
The research of dipyrromethanes has mainly been carried
out by groups that are focused on porphyrin chemistry, as
dipyrromethanes are particularly important building blocks
in the preparation of porphyrins and porphyrin analogues,
such as meso-substituted corroles, chlorins, expanded por-
phyrins, and calix[4]pyrroles.[1] More recently, there has
been a growing interest in the various other applications of
dipyrromethanes, and this has led to a search for efficient
strategies to functionalize dipyrromethanes, such as the syn-
thesis of its 1,9-disubstituted derivatives. Dipyrromethanes
are precursors to 4,4-difluoro-4-bora-3a,4a-diaza-s-ind-
acene (BODIPY) dyes, the photophysical properties of
which make them ideal fluorescent scaffolds for the devel-
opment of high performance imaging probes.[2] Function-
alized dipyrromethanes can function as photonic organic
based materials, are potentially attractive structures in the
development of new optical anion sensors, and have appli-
cations in biological systems and the resolution of environ-
mental problems.[1,3] In addition, calix[4]pyrroles can act as
anion sensors.[4] These macrocycles are interesting struc-
tures and can be used as anion molecular carriers to allow
anions to cross lipid bilayer membranes, a topic that is par-
ticularly relevant with regard to channelopathies.[4b]
Scheme 1. Functionalization of pyrrole through hetero-Diels–Alder
reactions (DCM = dichloromethane).[7]
The 1,9-functionalization of dipyrromethanes can be
achieved by exploring the rich electron density of the pyr-
role units. Thus, these heterocyclic compounds can undergo
acylation reactions, Vilsmeier reactions, Mannich reactions,
and addition reactions to electron-poor heterocycles.[1a,1b]
The dicyanation of 5-monosubstituted and 5-unsubstituted
This chemistry was explored as a new strategy for the
functionalization of dipyrromethanes (see Scheme 2).[8] In a
preliminary communication, we reported that 5,5Ј-diethyl-
and 5-phenyldipyrromethanes participate in hetero-Diels–
Alder reactions with nitrosoalkenes and azoalkenes to give
dipyrromethanes with side chains that contain oxime and
hydrazone groups, respectively. By controlling the stoichio-
metry of the reaction, it is possible to obtain monosubsti-
tuted or 1,9-disubstituted derivatives. More recently, we de-
scribed a new one-pot approach to 5-substituted dipyrro-
[a] Department of Chemistry, University of Coimbra,
3004-535 Coimbra, Portugal
[b] CIQA, FCT, University of Algarve,
Campus de Gambelas, 8005-139 Faro, Portugal
E-mail: tmelo@ci.uc.pt
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402944.
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S. M. M. Lopes, A. Lemos, T. M. V. D. Pinho e Melo
FULL PAPER
methanes by using an on water bis(hetero-Diels–Alder) re- water as the solvent than carrying out the reaction in
action of azo- and nitrosoalkenes with pyrrole.[9] The base- dichloromethane or in the absence of solvent.[9] In this con-
mediated dehydrohalogenation of α,α-dihalohydrazones or text, the on water cycloaddition of dipyrromethanes with
α,α-dihalooximes in the presence of pyrrole led to two con- azoalkenes was explored.
secutive Diels–Alder reactions to give the target dipyrro-
methanes.
Initially, we looked at the reactivity of 5,5Ј-diethyldipyr-
romethane (3) towards 1,2-diaza-1,3-butadienes 2a–2c (see
Table 1). Monofunctionalized dipyrromethanes 4 were pref-
erentially obtained as the major product by using an excess
amount of dipyrromethane 3 (0.5 equiv. of hydrazone),
whereas the use of an excess amount of hydrazone 1 led to
bis(functionalized) dipyrromethane 5 as the only product.
Hydrazone 1a (0.5 equiv.) was treated with sodium carb-
onate in water at room temperature for 2.5 h to give the
transient 1,2-diaza-1,3-butadiene 2a, which was trapped in
situ by dipyrromethane 3 to afford open-chain hydrazone
4a in 21% yield along with bis(functionalized) dipyrrome-
thane 5a in an isolated yield of 3% (see Table 1, Entry 1).
The target products, however, were obtained in higher
yields when dichloromethane was used as a cosolvent (see
Table 1, Entries 2 and 3). Carrying out the reaction with
0.5 equiv. of hydrazone 1a afforded open-chain hydrazones
4a and 5a in 81 and 17% yield, respectively, and the use of
2.3 equiv. of hydrazone 1a allowed for the isolation of 1,9-
disubstituted dipyrromethane 5a in 90% yield as the only
product. 1,2-Diaza-1,3-butadiene 2a was isolated by follow-
ing a general synthetic procedure,[11] and we carried out its
reaction with an excess amount of dipyrromethane 3 (see
Table 1, Entry 4). This process was less efficient than the in
situ generation of the heterodiene in the presence of di-
pyrromethane 3.
Scheme 2. Functionalization and synthesis of dipyrromethanes
through hetero-Diels–Alder reactions.[8,9]
The hetero-Diels–Alder reaction of 3-(1H-tetrazol-5-yl)-
nitrosoalkenes and 3-(1H-tetrazol-5-yl)azoalkenes was also
studied as an approach to functionalized 5-substituted-1H-
tetrazoles, which is a particularly interesting class of com-
pounds, several derivatives of which have displayed a wide
variety of biological activities.[10]
Table 1. Hetero-Diels–Alder reaction of 5,5Ј-diethyldipyrrometh-
ane (3) with 1,2-diaza-1,3-butadiene 2.
As part of our continuing investigation, we herein de-
scribe the optimization and evaluation of the scope of this
strategy to functionalize dipyrromethanes by employing the
hetero-Diels–Alder reactions of azoalkenes, including 3-
tetrazolyl-1,2-diaza-1,3-butadienes. Furthermore, the bis-
(hetero-Diels–Alder) reaction of azoalkenes with 5,5Ј-di-
ethyldipyrromethane was also explored as a route for the
preparation of calix[4]pyrroles.
Results and Discussion
Usually, nitroso and azoalkenes are generated in situ by
treating the corresponding α-halooximes and α-halohydraz-
ones with sodium carbonate, which has a low solubility in Entry Hydrazone [equiv.] Time [h]
Products [% yield]
1a (0.5)[a]
1a (0.5)
1a (2.3)
1a (0.5)[b]
1b (0.5)
1b (2.3)
1c (0.5)
1c (2.3)
2.5
2
3
2
2
3
2
3
4a (21)
4a (81)
–
5a (3)
dichloromethane to ensure a slow rate of 1,4-dehydrohalo-
genation, thus preventing side reactions. These conditions
were used for the previously described Diels–Alder reac-
tions of these heterodienes with dipyrromethanes.[8] How-
ever, the bis(hetero-Diels–Alder) reaction of pyrrole with
nitrosoalkenes and azoalkenes, which were generated by the
base-mediated dehydrohalogenation of α,α-dihalooximes
and α,α-dihalohydrazones to give 5-substituted dipyrro-
1
2
3
4
5
6
7
8
5a (17)
5a (90) (49)[8]
5a (8)
4a (45)
4b (27)
–
5b (31)
5b (76) (59)[8]
4c (53) (28)[7] 5c (13)
–
5c (73) (68)[8]
[a] Without CH2Cl2 as cosolvent. [b] Reaction of isolated azoalkene
methanes, was accelerated and gave higher yields by using 2a with dipyrromethane 3.
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Functionalized Dipyrromethanes, Calix[4]pyrroles, and Bilanes
The optimized reaction conditions were then applied to The transient 1,2-diaza-1,3-butadiene 10 was generated in
the Diels–Alder reactions of dipyrromethane 3 and hetero- situ by treating bromohydrazone 9[10c] with sodium carb-
dienes 2b and 2c (see Table 1, Entries 5–8). The expected onate in either dichloromethane or water/dichloromethane.
1,9-disubstituted dipyrromethanes 5b and 5c were again ob- The Diels–Alder reaction was first carried out at room tem-
tained as single products (73–76% yield) by using 2.3 equiv. perature for 24 h in dichloromethane to afford the two
of the corresponding hydrazone 1. The use of an excess monofunctionalized dipyrromethanes 11 and 12 in 16 and
amount of the hydrazone afforded the bis(functionalized) 53% yield, respectively (see Table 3, Entry 1).
dipyrromethanes in good overall yields. All of these reac-
tions were carried out at room temperature for 2 to 3 h to
give good yields of the desired products (see Table 1). In
dichloromethane, the Diels–Alder reaction of dipyrro-
methane 3 required significantly longer reaction times (48–
80 h)[8] and led to lower yields.
Table 2. Hetero-Diels–Alder reaction of 5-phenyldipyrromethane
(6) with 1,2-diaza-1,3-butadiene 2.
This work was extended to the cycloaddition of the 1,2-
diaza-1,3-butadienes 2 with 5-phenyldipyrromethane (6),
which showed the same chemical behavior as that of the
reaction with 5,5Ј-diethyldipyrromethane (3, see Table 2).
Using the optimized reaction conditions with an excess
amount of hydrazones 1 afforded 1,9-disubstituted dipyrro-
methanes 8 in high yields (71–92%) in only 3 h (see Table 2,
Entries 2, 5, and 7). By carrying out the reaction with an
excess amount of dipyrromethane 6, we obtained mono-
functionalized derivatives 7 in good isolated yields (42–
68%) along with 1,9-disubstituted dipyrromethanes 8 as the
minor products (5–18% yield, see Table 2, Entries 1, 4, and
6). The results confirmed the advantage of using water/
dichloromethane as the solvent system over dichlorometh-
ane, as significantly higher yields were obtained with
shorter reaction times. On the other hand, the Diels–Alder
reaction of hydrazone 1b and dipyrromethane 6 with water
as the solvent led to product 7b in very low yield (see
Table 2, Entry 3).
Entry Hydrazone [equiv.] Time [h]
Products [% yield]
1
2
3
4
5
6
7
1a (0.5)
1a (2.3)
1b (0.5)[a]
1b (0.5)
1b (2.3)
1c (0.5)
1c (2.3)
2
3
24
2
3
2
7a (42)
8a (18)
8a (71)
–
–
7b (trace)
7b (58) (31)[7] 8b (18)
–
8b (92) (56)[8]
7c (64)
8c (5)
8c (71)
3
–
The reactivity of dipyrromethane 3 towards tetrazolyl-
1,2-diaza-1,3-butadiene 10 was also explored (see Table 3). [a] Without CH2Cl2 as cosolvent.
Table 3. Hetero-Diels–Alder reaction of 5,5Ј-diethyldipyrromethane (3) with tetrazolyl-1,2-diaza-1,3-butadiene 10.
Entry
9 [equiv.]
Reaction conditions
11
12
13
1
2
3
4
5
0.5
0.5
0.5
2.3
2.7
DCM, 24 h
H2O/DCM (9:1.5 mL), 2 h
H2O, 24 h
DCM, 7 d
H2O/DCM (9:1.5 mL), 4 h
16%
14%
trace
–
53%
38%
–
–
–
–
7%
–
44%
33%
–
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1
The H NMR spectrum of compound 12 shows signals same products, compounds 11 (14%) and 12 (38%) along
that indicate a bicyclic structure. In particular, four double with difunctionalized dipyrromethane 13 (7%, see Table 3,
doublets (δ = 2.50, 2.78, 3.05, and 3.30 ppm) are present, Entry 2). The employment of water as the solvent afforded
and their chemical shifts and coupling constants are consis- trace amounts of compound 11 (see Table 3, Entry 3). Di-
tent with those expected for the geminal protons in the six- substituted dipyrromethane 13, which incorporating an
membered ring and those of the five-membered ring. Two open-chain hydrazone and a 1,4,5,6-tetrahydropyridazine
additional multiplets are present at δ = 4.42–4.47 and δ = unit, was isolated as a single product by using an excess
4.53–4.58 ppm, which correspond to the methine protons amount of hydrazone 9 (see Table 3, Entries 4 and 5). In
that are attached to the ring-fused carbons (see Supporting this case, the reaction that was performed in dichlorometh-
Information). Compound 12, with
a
1,4,5,6-tetra- ane gave a higher product yield (44%) than the one in
hydropyridazine ring incorporated into it, is formed by a water/dichloromethane (33%), although a longer reaction
prototropic rearrangement of the primary cycloadduct. time was required.
This result indicates that compound 11 is also formed
The deprotection of the tetrazolyl group of dipyrro-
through the Diels–Alder reaction followed by an opening methane 11 was efficiently carried out by using ammonium
of the 1,4,5,6-tetrahydropyridazine ring. In fact, the conver- formate in the presence of 10% Pd/C as a catalytic hydrogen
sion of 12 into 11 was quantitative by heating 12 in meth-
anol at reflux for 30 h (see Scheme 3). This type of bicyclic
imine has been obtained from the reaction of 2,5-dimeth-
ylpyrrole and azoalkenes, as the rearomatization to give a
functionalized pyrrole is blocked. However, open-chain
hydrazones are usually obtained by using pyrrole. Only in
the case of the reaction of pyrrole with a heterodiene that
was derived from bromopyruvate tert-butoxycarbonyl-
hydrazone was the same type of bicyclic structure detected
by NMR, although its lack of stability precluded its isola-
tion.[7e]
Scheme 3. Ring opening of compound 12 to afford hydrazone 11.
The reaction of dipyrromethane 3 with 1,2-diaza-1,3-
butadiene 10 in water/dichloromethane for 2 h gave the 11 and 12.
Scheme 4. Deprotection of the tetrazolyl group in dipyrromethanes
Scheme 5. Synthesis of dipyrromethane 17.
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Functionalized Dipyrromethanes, Calix[4]pyrroles, and Bilanes
transfer system, according to a reported procedure.[6] The
deprotection of compound 12 gave a mixture (1:1) of dipyr-
romethanes 14 and 15. However, by heating the mixture in
methanol at reflux for 2 h, we were able to convert it into
open-chain hydrazone 14 in an isolated yield of 63% (see
Scheme 4).
Bis(functionalized) dipyrromethane 13 was also obtained
from the Diels–Alder reaction of dipyrromethane 12 with
an excess amount of 1,2-diaza-1,3-butadiene 10 to give bis-
(hydrazone) 16. The deprotection of the tetrazolyl groups
gave 1,9-bis(2Ј-ethoxycarbonylhydrazono-2Ј-1H-tetrazol-5-
ylethyl)-5,5Ј-diethyldipyrromethane (17) in 99% yield (see
Scheme 6. Hetero-Diels–Alder reaction of hydrazone 9 with 5-
phenyldipyrromethane (6).
Scheme 5). Compound 17 was very unstable upon standing ence of sodium carbonate, two products were obtained, the
at room temperature. expected calix[4]pyrroles 23 along with bilanes 22. By start-
Monofunctionalized dipyrromethane 18 was obtained in ing from hydrazine 19a (0.5 equiv.), we achieved the best
low yield (18–27%) by employing the Diels–Alder reaction overall yield (32%) with a reaction time of 96 h (see Table 4,
of hydrazone 6 with 5-phenyldipyrromethane (6) in either Entry 3). Performing the reaction at room temperature for
dichloromethane or water/dichloromethane as the solvent 2 h in water/dichloromethane afforded bilane 22a and
(see Scheme 6). Unfortunately, all attempts to obtain the calix[4]pyrrole 23a in 15 and 5% yield, respectively (see
bis(functionalized) dipyrromethane derivatives were unsuc- Table 4, Entry 4). Increasing the amount of hydrazone 19a
cessful.
(2 equiv.) provided only trace amounts of bilane 22a, and
The possibility to access tetrapyrrolic macrocycles by compound 24 was formed as a result of the self-condensa-
using the bis(hetero-Diels–Alder) approach was also investi- tion reaction of hydrazone 19a (see Table 4, Entry 5). In
gated (see Table 4). Thus, the base-mediated dehydrohaloge- fact, hydrazone 19a was converted into compound 24 in
nation of α,α-dichlorohydrazones 19 in the presence of di- 90% yield by employing triethylamine (see Scheme 7). A
pyrromethane 3 was carried out. Interestingly, when the re- similar result was obtained by carrying out the reaction of
actions were performed at room temperature in the pres- hydrazone 19a and dipyrromethane 3 in the presence of tri-
Table 4. Synthesis of bilanes 22 and calix[4]pyrroles 23 through the bis(hetero-Diels–Alder) reaction of azoalkenes with dipyrrometh-
ane 3.
Entry
Hydrazone
[equiv.]
Reaction conditions
Products [% yield]
1
2
3
4
5
6
7
8
19a (0.5)
19a (0.5)
19a (0.5)
19a (0.5)
19a (2.0)
19a (0.5)
19b (0.5)
19b (1.0)
DCM, Na2CO3, r.t, 47 h
DCM, Na2CO3, r.t, 72 h
DCM, Na2CO3, r.t, 96 h
H2O/DCM (6:1 mL), Na2CO3, r.t, 2 h
H2O/DCM (6:1 mL), Na2CO3, r.t, 2 h
DCM, NEt3, r.t, 1.5 h
DCM, Na2CO3, r.t, 96 h
DCM, Na2CO3, r.t, 96 h
22a (7)
23a (13)
23a (11)
23a (16)
23a (5)
–
22a (14)
22a (16)
22a (15)
22a (Ͻ2)[a]
22a (2)[a]
22b (8)
–
23b (7)
23b (6)
22b (5)
[a] Azoalkene self-condensation product 24 was also isolated.
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S. M. M. Lopes, A. Lemos, T. M. V. D. Pinho e Melo
FULL PAPER
were recorded with a Finnigan MAT95 S instrument. Melting
points were recorded on a Melting Point Device Falc R132467.
Flash column chromatography was performed with Merck 9385
silica gel as the stationary phase. Hydrazones 1a–1c,[13] 1-(1-benzyl-
1H-tetrazol-5-yl)-2-bromoethanone ethoxycarbonyl hydrazone
(9),[10c] 1,1-dichloroacetone tert-butoxycarbonyl hydrazone (19a),[14]
2,2-dichloro-4Ј-bromoacetophenone tert-butoxycarbonyl hydrazone
(19b),[9] 5,5Ј-diethyldipyrromethane,[15] and 5-phenyldipyrrometh-
ane[16] were prepared as described in the literature.
ethylamine (see Table 4, Entry 6). Bilane 22b and calix[4]
pyrrole 23b could also be obtained from hydrazone 19b,
although in low yields (see Table 4, Entries 7 and 8).
General Procedure for the Difunctionalization of Dipyrromethanes
Method A – On-Water: Dipyrromethane 3 or 6 (0.335 mmol) and
a solution of hydrazone 1 or 9 (0.67 mmol) in dichloromethane
(1.5 mL) were added to a solution of Na2CO3 (3.35 mmol) in water
(9 mL). The reaction mixture was stirred at room temperature for
2 h. After this time, additional hydrazone 1 (0.1 mmol) or 9
(0.23 mmol) was added in three portions. The reaction mixture was
Scheme 7. Self-condensation of azoalkene 19a.
The synthesis of calix[4]pyrroles 23 can be explained by
the initial formation of bis(functionalized) dipyrromethane
21 followed by dehalogenation to give the corresponding
azoalkenes, which can undergo a reaction with another stirred for the time indicated, and the progress of the reaction was
monitored by TLC. Upon completion, the mixture was extracted
with dichloromethane (3ϫ 20 mL), and the combined extracts were
dried with Na2SO4. The solvent was evaporated to give the crude
product, which was purified by flash chromatography.
molecule of dipyrromethane 3 through a hetero-Diels–
Alder reaction. Bilanes 22 are formed through monofunc-
tionalized dipyrromethane 20. Bilanes are interesting
heterocycles, as they are important precursors of corroles
and asymmetrically-substituted porphyrins.[12]
Method B – In Dichloromethane: Dipyrromethane 3 (0.23 mmol)
and hydrazone 9 (0.54 mmol) were added to a suspension of
Na2CO3 (2.3 mmol) in dichloromethane (30 mL). The reaction
mixture was stirred at room temperature for the time indicated.
The progress of the reaction was monitored by TLC. Upon comple-
tion, the mixture was filtered through a pad of Celite, which was
washed with dichloromethane. The solvent was evaporated, and the
product was purified by flash chromatography.
Conclusions
The synthetic strategy to introduce side chains at the 1-
and 9-positions of dipyrromethanes was further explored
by employing the hetero-Diels–Alder reaction of dipyrro-
methanes with azoalkenes. Employing water as the solvent
and dichloromethane as the cosolvent allowed for the syn-
thesis of new 5,5Ј-diethyldipyrromethanes and 5-phenyldi-
pyrromethanes with side chains that contained open-chain
hydrazones.
1,9-Bis(2Ј-phenylcarbamoylhydrazono-1Ј-ethoxycarbonylpropyl)-5,5Ј-
diethyldipyrromethane (5a): Hydrazone 1a (229 mg, 0.77 mmol) and
dipyrromethane 3 (67 mg, 0.335 mmol) were employed as described
in the general procedure for method A (reaction time of 3 h). Puri-
fication by flash chromatography (ethyl acetate/hexane, 1:1) af-
forded compound 5a[9] (215.4 mg, 90%) as a white solid.
The reaction of ethyl 3-(1-benzyl-1H-tetrazol-5-yl)-1,2-
diaza-1,3-butadiene-1-carboxylate with 5,5Ј-diethyldipyrro-
methane afforded the corresponding dipyrromethane, but
1,9-Bis(2Ј-tert-butoxycarbonylhydrazono-1Ј-dimethylaminocarbon-
ylpropyl)-5,5Ј-diethyldipyrromethane (5b): Hydrazone 1b (214 mg,
0.77 mmol) and dipyrromethane 3 (67 mg, 0.335 mmol) were em-
ployed as described in the general procedure for method A (reac-
tion time of 3 h). Purification by flash chromatography (ethyl acet-
ate/hexane, 3:1) afforded compound 5b[9] (174 mg, 76%) as a white
solid.
bicyclic derivatives that contained
a
1,4,5,6-tetra-
hydropyridazine ring were also obtained by a prototropic
rearrangement of the primary cycloadduct. Under ther-
molysis these compounds were converted into the corre-
sponding open-chain hydrazones, and deprotection of the
tetrazolyl group of the functionalized dipyrromethane was
successfully carried out. The base-mediated dehydrohaloge-
nation of α,α-dichlorohydrazones in the presence of 5,5Ј-
diethyldipyrromethane allowed for the syntheses of new
calix[4]pyrroles and bilanes through this hetero-Diels–Alder
reaction.
1,9-Bis(2Ј-tert-butoxycarbonylhydrazono-1Ј-ethoxycarbonylpropyl)-
5,5Ј-diethyldipyrromethane (5c): Hydrazone 1c (215 mg, 0.77 mmol)
and dipyrromethane 3 (67 mg, 0.335 mmol) were employed as de-
scribed in the general procedure for method A (reaction time of
3 h). Purification by flash chromatography (ethyl acetate/hexane,
1:2) afforded compound 5c[9] (168 mg, 73%) as a white solid.
1,9-Bis(2Ј-phenylcarbamoylhydrazono-1Ј-ethoxycarbonylpropyl)-5-
phenyldipyrromethane (8a): Hydrazone 1a (229 mg, 0.77 mmol) and
dipyrromethane 6 (74 mg, 0.335 mmol) were employed as described
in the general procedure for method A (reaction time of 3 h). Puri-
fication by flash chromatography (ethyl acetate/hexane, 1:2) af-
Experimental Section
1
General Methods: The H NMR spectroscopic data were recorded
forded compound 8a (177 mg, 71%) as a red foam. IR (KBr): ν =
˜
with an instrument that operated at 400 MHz. The 13C NMR spec-
troscopic data were recorded with an instrument that operated at
100 MHz. The NMR solvent was deuterochloroform, except where
indicated otherwise. The chemical shifts are reported in parts per
million relative to TMS (δ = 0 ppm) as the internal standard, and
the coupling constants (J) are reported in Hz. IR spectra were re-
corded with a Nicolet 6700 FTIR spectrometer. HRMS spectra
754, 1448, 1533, 1595, 1685, 1731, 3369 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 1.15–1.18 (m, 6 H, 16-H and 27-H), 1.80–1.81 (m, 6
H, 17-H and 28-H), 4.10–4.13 (m, 4 H, 15-H and 26-H), 4.48–4.50
(m, 2 H, 13-H and 24-H), 5.33 (s, 1 H, 5-H), 5.71 (s, 1 H, 3-H),
5.72 (s, 1 H, 7-H), 5.90 (s, 2 H, 2-H and 8-H), 6.95 (t, J = 8.0 Hz,
2 H, ArH), 7.11–7.20 (m, 9 H, ArH), 7.31–7.34 (m, 4 H, ArH),
7.98 (s, 2 H, NH, 22-H and 33-H), 8.55–8.61 (m, 2 H, NH, 10-H
7044
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 7039–7048

Functionalized Dipyrromethanes, Calix[4]pyrroles, and Bilanes
and 11-H), 8.88–8.91 (m, 2 H, NH, 20-H and 31-H) ppm. 13C
1,9-Bis(2Ј-ethoxycarbonylhydrazono-1Ј-benzyl-1H-tetrazol-5-yl)-
NMR (100 MHz, CDCl3): δ = 14.1 (C-16 and C-27), 14.4 (C-17 5,5Ј-diethyldipyrromethane (16): Compound 13 (78 mg, 0.100 mmol)
and C-28), 44.2 (C-5), 53.4 (C-13 and C-24), 61.7 (C-15 and C-26), was dissolved in dry methanol (20 mL), and the resulting mixture
107.5 (C-3), 107.6 (C-7), 108.6 (C-2 and C-8), 119.2 (CH-Ar), 119.3 was heated at reflux for 9 h. The solvent was evaporated, and the
(CH-Ar), 123.4 (CH-Ar), 123.5 (C-1), 123.6 (C-9), 127.0 (CH-Ar), crude product was purified by flash chromatography (ethyl acetate/
128.3 (CH-Ar), 128.6 (CH-Ar), 129.0 (CH-Ar), 133.6 (C-4), 133.7
hexane, 1:1) to give compound 16 (44 mg, 57%) as a white solid;
(C-6), 138.0 (C-23 and 34), 141.8 (C-12), 146.5 (C-18 and C-29), m.p. 114.6–116.1 °C (diethyl ether/hexane). IR (KBr): ν = 723,
˜
153.8 (C-21 and C-32), 170.2 (C-14 and C-25) ppm. HRMS (ESI):
calcd. for C41H45N8O6 [M + H]+ 745.34566; found 745.34690.
1064, 1221, 1412, 1498, 1616, 1720, 1751, 2968, 3267, 3342,
1
3409 cm–1. H NMR (400 MHz, CDCl3): δ = 0.61 (t, J = 8.0 Hz,
6 H, 13-H and 15-H), 1.32 (t, J = 8.0 Hz, 6 H, 22-H and 32-H),
1.80 (q, J = 8.0 Hz, 4 H, 12-H and 14-H), 4.00 (s, 4 H, 16-H and
26-H), 4.32 (q, J = 8.0 Hz, 4 H, 21-H and 31-H), 5.74 (s, 2 H, 2-
H and 8-H), 5.86 (s, 2 H, 3-H and 7-H), 6.01 (s, 4 H, 24-H and 34-
H), 7.28–7.29 (m, 6 H, ArH), 7.42 (br. s, 4 H, ArH), 8.25 (br. s, 2
H, NH, 10-H and 11-H), 8.89 (s, 2 H, NH, 19-H and 29-H) ppm.
13C NMR (100 MHz, CDCl3): δ = 8.3 (C-13 and C-15), 14.4 (C-
22 and C-32), 26.7 (C-16 and C-26), 29.4 (C-12 and C-14), 43.5 (C-
5), 52.8 (C-24 and C-34), 62.7 (C-21 and C-31), 106.5 (C-3 and C-
7), 106.8 (C-2 and C-8), 121.0 (C-1 and C-9), 128.6 (CH-Ar), 128.7
(CH-Ar), 134.4 (C-25 and C-35), 136.8 (C-17 and C-27), 137.3 (C-
4 and C-6), 150.7 (C-23 and C33), 153.3 (C-20 and C-30) ppm.
HRMS (ESI): calcd. for C39H47N14O4 [M + H]+ 775.38992; found
775.38906.
1,9-Bis(2Ј-tert-butoxycarbonylhydrazono-1Ј-dimethylaminocarbonyl-
propyl)-5-phenyldipyrromethane (8b): Hydrazone 1b (214 mg,
0.77 mmol) and dipyrromethane 6 (74 mg, 0.335 mmol) were em-
ployed as described in the general procedure for method A (reac-
tion time of 3 h). Purification by flash chromatography (ethyl acet-
ate/hexane, 3:1) afforded compound 8b[9] (218 mg, 92%) as a pink
solid.
1,9-Bis(2Ј-tert-butoxycarbonylhydrazono-1Ј-ethoxycarbonylpropyl)-
5-phenyldipyrromethane (8c): Hydrazone 1c (215 mg, 0.77 mmol)
and dipyrromethane 6 (74 mg, 0.335 mmol) were employed as de-
scribed in the general procedure for method A (reaction time of
3 h). Purification by flash chromatography (ethyl acetate/hexane,
1:2) afforded compound 8c (168 mg, 71%) as a red solid; m.p. 98.5–
100.1 °C (from diethyl ether/hexane). IR (KBr): ν = 769, 1161,
˜
General Procedure for the Monofunctionalization of Dipyrrometh-
anes
1244, 1369, 1496, 1728, 1732, 1979, 3352 cm–1 1H NMR
.
(400 MHz, CDCl3): δ = 1.24 (t, J = 7.2 Hz, 6 H), 1.46 and 1.50 (s,
18 H), 1.79 (s, 6 H), 4.17 (q, J = 7.2 Hz, 4 H), 4.69 (s, 2 H), 5.34–
5.39 (m, 1 H), 5.74–5.82 (m, 2 H), 5.97 (s, 2 H), 7.17–7.31 (m, 5
H), 7.53 and 7.56 (s, 2 H, NH), 8.55 and 8.63 (br. s, 2 H, NH) ppm.
13C NMR (100 MHz, CDCl3): δ = 13.1, 14.1, 28.3, 44.2, 53.3, 61.5,
81.3, 107.6, 108.0, 124.0, 126.9, 128.4, 128.5, 133.3, 141.8, 148.4,
152.6, 170.1 ppm. HRMS (ESI): calcd. for C37H51N6O8 [M + H]+
707.37629; found 707.37519.
Method A – On-Water: Dipyrromethane 3 or 6 (1.08 mmol) and a
solution of hydrazone 1 or 9 (0.54 mmol) in dichloromethane
(1.5 mL) were added to a solution of Na2CO3 (2.7 mmol) in water
(9 mL). The reaction mixture was stirred at room temperature for
2 h. The mixture was then extracted with dichloromethane (3ϫ
20 mL), and the combined extracts were dried with Na2SO4. The
solvent was evaporated to give the crude product, which was puri-
fied by flash chromatography.
Ethyl 3-(1-Benzyl-1H-tetrazol-5-yl)-6-[3-(5-{2-(1-benzyl-1H-
tetrazol-5-yl)-2-[2-(ethoxycarbonyl)hydrazono]ethyl}-1H-pyrrol-2-
yl)pentan-3-yl]-4,4a,7,7a-tetrahydro-1H-pyrrolo[3,2-c]pyridazine-1-
carboxylate (13): Hydrazone 9 [method A (332 mg, 0.90 mmol),
method B (194 mg, 0.53 mmol)] and dipyrromethane 3 [method A
(67 mg, 0.335 mmol), method B (47 mg, 0.23 mmol)] were em-
ployed as described in the general procedure for method A (reac-
tion time of 4 h) and method B (reaction time of 7 d). Purification
by flash chromatography (ethyl acetate/hexane, 1:1 and 1:2) af-
forded compound 13 [method A (86 mg, 33%), method B (79 mg,
44%)] as a white solid; m.p. 102.4–103.5 °C (diethyl ether/hexane).
Method
B – In Dichloromethane: Dipyrromethane 3 or 6
(1.08 mmol) and hydrazone 1 or 9 (0.54 mmol) were added to a
suspension of Na2CO3 (2.7 mmol) in dichloromethane (30 mL).
The reaction mixture was stirred at room temperature for the time
indicated, and the progress of the reaction was monitored by TLC.
Upon completion, the mixture was filtered through a pad of Celite,
which was washed with dichloromethane. The solvent was evapo-
rated, and the product was purified by flash chromatography.
1-(2Ј-Phenylcarbamoylhydrazono-1Ј-ethoxycarbonylpropyl)-5,5Ј-di-
ethyldipyrromethane (4a) and 1,9-Bis(2Ј-phenylcarbamoylhydrazono-
1Ј-ethoxycarbonylpropyl)-5,5Ј-diethyldipyrromethane (5a): Hydraz-
IR (KBr): ν = 723, 1136, 1201, 1226, 1321, 1412, 1631, 1680, 1728,
˜
2979, 3263, 3411 cm–1. 1H NMR (400 MHz, CDCl3): δ = 0.61–0.64 one 1a (161 mg, 0.54 mmol) and dipyrromethane 3 (218 mg,
(m, 6 H, 16-H and 18-H), 1.29 (t, J = 8.0 Hz, 6 H, 10-H and 33- 1.08 mmol) were employed as described in the general procedure
H), 1.88–1.95 (m, 4 H, 15-H and 17-H), 2.63–2.68 (m, 1 H, 7-H),
for method A. Purification of the crude product by flash
chromatography (ethyl acetate/hexane, 1:1) gave, in order of elu-
2.78 (dd, 1J = 20.0 Hz, 2J = 8.0 Hz, 4-H), 3.15–3.20 (m, 1 H, 7-H),
3.33–3.38 (m, 1 H, 4-H), 4.03 (d, J = 16.0 Hz, 1 H, 24-H), 4.14 (d, tion, 4a (204 mg, 81%) as a yellowish solid and 5a[9] (65 mg, 17%)
J = 16.0 Hz, 1 H, 24-H), 4.26–4.35 (m, 4 H, 9-H and 32-H), 4.58 as a white solid. Data for 4a: M.p. 72.5–74.2 °C (diethyl ether/hex-
(br. s, 2 H, 4a-H and 7a-H), 5.81 (s, 1 H, 21-H), 5.85 (s, 1 H, 20-
ane). IR (KBr): ν = 754, 1034, 1228, 1448, 1533, 1689, 1728, 2968,
˜
1
H), 5.95–6.06 (m, 4 H, 12-H and 27-H), 7.27–7.43 (m, 10 H, ArH), 3371 cm–1. H NMR (400 MHz, CDCl3): δ = 0.70 (t, J = 7.6 Hz,
8.93 (s, 1 H, NH, 30-H), 10.4 (br. s, 1 H, NH, 23-H) ppm. 13C 6 H), 1.26 (t, J = 7.2 Hz, 3 H), 1.88 (s, 3 H), 1.93 (q, J = 7.6 Hz,
NMR (100 MHz, CDCl3): δ = 8.2 (C-16), 8.3 (C-18), 14.4 (C-10), 4 H), 4.19–4.22 (m, 2 H), 4.57 (s, 1 H), 6.01 (dd, J = 9.2 Hz, J =
14.4 (C-33), 25.6 (C-4), 26.5 (C-24), 27.2 (C-15), 27.3 (C-17), 41.8 2.8 Hz, 2 H), 6.08–6.11 (m, 2 H), 6.60 (d, J = 0.8 Hz, 1 H), 7.05
1
2
(C-7), 48.7 (C-14), 52.4 (C-12 and C-27), 52.8 (C-7a), 61.6 (C-4a),
62.6 (C-31), 63.6 (C-8), 107.3 (C-20), 107.5 (C-21), 123.1 (C-22),
(t, J = 7.6 Hz, 1 H), 7.29 (t, J = 7.6 Hz, 2 H), 7.45 (d, J = 7.6 Hz,
2 H), 7.78 (br. s, 1 H, NH), 8.07 (s, 1 H, NH), 8.23 (br. s, 1 H,
128.3 (CH-Ar), 128.4 (CH-Ar), 128.6 (CH-Ar), 128.7 (CH-Ar), NH), 8.78 (s, 1 H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ =
128.7 (CH-Ar), 131.6 (C-19), 134.5 (C-13 and C-28), 136.8 (C-25),
137.2 (C-3), 149.5 (C-11), 150.7 (C-26), 153.2 (C-31), 154.0 (C-8),
187.7 (C-6) ppm. HRMS (ESI): calcd. for C39H47N14O4 [M + H]+
775.38992; found 775.38795.
8.4, 14.1, 29.5, 43.6, 53.5, 61.6, 105.9, 106.2, 107.6, 107.8, 116.8,
119.3, 123.1, 123.3, 128.9, 136.3, 137.8, 138.0, 146.4, 153.7,
170.1 ppm. HRMS (ESI): calcd. for C26H34N5O3 [M + H]+
464.26562; found 464.26458.
Eur. J. Org. Chem. 2014, 7039–7048
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7045

S. M. M. Lopes, A. Lemos, T. M. V. D. Pinho e Melo
FULL PAPER
1-(2Ј-tert-Butoxycarbonylhydrazono-1Ј-dimethylaminocarbonylprop-
hydrazono-1Ј-ethoxycarbonylpropyl)-5-phenyldipyrromethane (8c):
yl)-5,5Ј-diethyldipyrromethane (4b) and 1,9-Bis(2Ј-tert-Butoxycarb- Hydrazone 1c (151 mg, 0.54 mmol) and dipyrromethane 6 (240 mg,
onylhydrazono-1Ј-dimethylaminocarbonylpropyl)-5,5Ј-diethyldipyr- 1.08 mmol) were employed as described in the general procedure
romethane (5b): Hydrazone 1b (150 mg, 0.54 mmol) and dipyrro- for method A. Purification of the crude product by flash
methane 3 (218 mg, 1.08 mmol) were employed as described in the
general procedure for method A. Purification of the crude product
by flash chromatography (ethyl acetate/hexane, 3:1) gave, in order
of elution, 4b (65 mg, 27%) as yellowish solid and 5b[9] (115 mg,
31%) as a white solid. Data for 4b: M.p. 136.3–136.9 °C (diethyl
chromatography (ethyl acetate/hexane, 1:2) gave, in order of elu-
tion, 7c (161 mg, 64%) as a red solid and 8c (19 mg, 5%) as a
red solid. Data for 7c: M.p. 68.9–70.4 °C (diethyl ether/hexane). IR
1
(KBr): ν = 727, 1161, 1244, 1369, 1496, 1724, 2979, 3367 cm–1. H
˜
NMR (400 MHz, CDCl3): δ = 1.20–1.26 (m, 3 H), 1.46 and 1.50
ether/hexane). IR (KBr): ν = 761, 1169, 1241, 1511, 1643, 1724,
(s, 9 H), 1.78 and 1.81 (s, 3 H), 4.11–4.19 (m, 2 H), 4.66 (s, 1 H),
˜
2971, 3303, 3384 cm–1. 1H NMR (400 MHz, CDCl3): δ = 0.68–0.73 5.41 (d, J = 3.6 Hz, 1 H), 5.76–5.83 (m, 1 H), 5.87 (br. s, 1 H), 5.98
(m, 6 H), 1.50 (s, 9 H), 1.73 (s, 3 H), 1.90–1.97 (m, 4 H), 2.92 (s, 3
(br. s, 1 H), 6.12 (br. s, 1 H), 6.69 (br. s, 1 H), 7.18–7.38 (m, 5 H),
H), 3.03 (s, 3 H), 4.98 (s, 1 H), 5.97 (br. s, 2 H), 6.04 (br. s, 1 H), 7.51 (s, 1 H, NH), 8.25 (br. s, 1 H, NH), 8.66 (br. s, 1 H, NH) ppm.
6.10 (d, J = 2.8 Hz, 1 H), 6.61 (br. s, 1 H), 7.44 (br. s, 1 H, NH), 13C NMR (100 MHz, CDCl3): δ = 13.6, 14.1, 28.3, 44.1, 53.3, 61.6,
7.91 (br. s, 1 H, NH), 8.62 (br. s, 1 H, NH) ppm. 13C NMR 81.5, 107.1, 107.3, 108.0, 108.2, 117.4, 123.8, 126.8, 128.4, 128.5,
(100 MHz, CDCl3): δ = 8.4, 12.9, 28.3, 29.5, 29.6, 35.8, 37.8, 43.6,
50.4, 81.2, 105.7, 106.1, 107.3, 107.5, 116.6, 124.2, 136.4, 137.2,
150.6, 152.7, 170.0 ppm. HRMS (ESI): calcd. for C24H38N5O3 [M
+ H]+ 444.29692; found 444.29605.
132.4, 133.5, 142.3, 152.6, 170.1 ppm. HRMS (ESI): calcd. for
C26H33N4O4 [M + H]+ 465.24963; found 465.24934.
1-(2Ј-Ethoxycarbonylhydrazono-1Ј-benzyl-1H-tetrazol-5-yl)-5,5Ј-di-
ethyldipyrromethane (11), Ethyl 6-[3-(1H-Pyrrol-2-yl)pentan-3-yl]-3-
(1-benzyl-1H-tetrazol-5-yl)-4,4a,7,7a-tetrahydro-1H-pyrrolo[3,2-c]-
pyridazine-1-carboxylate (12), and Ethyl 3-(1-Benzyl-1H-tetrazol-5-
yl)-6-[3-(5-{2-(1-benzyl-1H-tetrazol-5-yl)-2-[2-(ethoxycarbonyl)-
hydrazono]ethyl}-1H-pyrrol-2-yl)pentan-3-yl]-4,4a,7,7a-tetrahydro-
1H-pyrrolo[3,2-c]pyridazine-1-carboxylate (13): hydrazone 9
(200 mg, 0.54 mmol) and dipyrromethane 3 (218 mg, 1.08 mmol)
were employed as described in the general procedure for method A
or B (reaction time of 24 h). Purification of the crude product by
flash chromatography (ethyl acetate/hexane, 1:2) gave, in order of
elution, 11 [method A (36 mg, 14%), method B (43 mg, 16%)] as
a white solid, 12 [method A (101 mg, 38%), method B (139 mg,
53%)] as a white solid, and 13 [method A (29 mg, 7%)] as a white
1-(2Ј-tert-Butoxycarbonylhydrazono-1Ј-ethoxycarbonylpropyl)-5,5Ј-
diethyldipyrromethane (4c) and 1,9-Bis(2Ј-tert-butoxycarbonyl-
hydrazono-1Ј-ethoxycarbonylpropyl)-5,5Ј-diethyldipyrromethane
(5c): Hydrazone 1c (151 mg, 0.54 mmol) and dipyrromethane 3
(218 mg, 1.08 mmol) were employed as described in the general
procedure for method A. Purification of the crude product by flash
chromatography (ethyl acetate/hexane, 1:2) gave, in order of elu-
tion, 4c[9] (127 mg, 53%) as yellow solid and 5c[9] (48 mg, 13%) as
a white solid.
1-(2Ј-Phenylcarbamoylhydrazono-1Ј-ethoxycarbonylpropyl)-5-phen-
yldipyrromethane (7a) and 1,9-Bis(2Ј-phenylcarbamoylhydrazono-1Ј-
ethoxycarbonylpropyl)-5-phenyldipyrromethane (8a): Hydrazone 1a
(161 mg, 0.54 mmol) and dipyrromethane 6 (240 mg, 1.08 mmol)
were employed as described in the general procedure for method A.
Purification of the crude product by flash chromatography (ethyl
acetate/hexane, 1:2) gave, in order of elution, 7a (110 mg, 42%) as
a red solid and 8a (72 mg, 18%) as a red foam. Data for 7a: M.p.
solid. Data for 11: M.p. 154.2–154.7 °C (diethyl ether/hexane). IR
1
(KBr): ν = 723, 1064, 1187, 1319, 1430, 1600, 1691, 3388 cm–1. H
˜
NMR (400 MHz, CDCl3): δ = 0.65 (t, J = 8.0 Hz, 6 H, 13-H and
15-H), 1.33 (t, J = 8.0 Hz, 3 H, 22-H), 1.88 (q, J = 8.0 Hz, 4 H,
12-H and 14-H), 4.05 (s, 2 H, 16-H), 4.32 (q, J = 8.0 Hz, 2 H, 21-
H), 5.81 (s, 1 H, 2-H), 5.92 (d, J = 4.0 Hz, 1 H, 3-H), 5.99 (s, 2 H,
24-H), 6.03 (s, 1 H, 7-H), 6.08 (d, J = 4.0 Hz, 1 H, 8-H), 6.56 (s, 1
H, 9-H), 7.29–7.30 (m, 3 H, ArH), 7.41 (br. s, 2 H, ArH), 7.74 (br.
s, 1 H, NH, 10-H), 8.24 (br. s, 1 H, NH, 11-H), 8.57 (br. s, 1 H,
NH, 19-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 8.2 (C-13 and
C-15), 14.5 (C-22), 27.0 (C-16), 29.1 (C-12 and C-14), 43.4 (C-5),
52.8 (C-24), 62.8 (C-21), 105.9 (C-7), 106.4 (C-3), 106.9 (C-2), 107.5
(C-8), 116.9 (C-9), 121.1 (C-1), 128.5 (CH-Ar), 128.6 (CH-Ar),
128.7 (CH-Ar), 134.4 (C-25), 136.1 (C-6), 136.8 (C-17), 138.3 (C-
4), 150.6 (C-23), 153.1 (C-20) ppm. HRMS (ESI): calcd. for
C26H33N8O2 [M + H]+ 489.27210; found 489.27107. Data for 12:
83.3–84.8 °C (diethyl ether/hexane). IR (KBr): ν = 727, 1448, 1533,
˜
1595, 1685, 1728, 3369 cm–1. 1H NMR (400 MHz, CDCl3): δ =
1.23–1.27 (m, 3 H, 15-H), 1.90 (s, 3 H, 16-H), 4.19–4.21 (m, 2 H,
14-H), 4.59 (s, 1 H, 12-H), 5.42 (s, 1 H, 5-H), 5.80 (d, J = 4.0 Hz,
1 H, 2-H), 5.89 (s, 1 H, 8-H), 6.00 (s, 1 H, 3-H), 6.11 (t, J = 4.0 Hz,
1 H, 7-H), 6.63 (s, 1 H, 9-H), 7.04 (t, J = 8.0 Hz, 1 H, ArH), 7.17–
7.29 (m, 7 H, ArH), 7.41 (d, J = 8.0 Hz, 2 H, ArH), 7.96 (br. s, 1
H, NH, 10-H), 8.05 (s, 1 H, NH, 21-H), 8.61 (d, J = 8.0 Hz, 1 H,
NH, 11-H), 8.91 (d, J = 4.0 Hz, 1 H, NH, 19-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 14.2 (C-15), 14.4 (C-16), 44.1 (C-5), 53.5
(C-12), 61.7 (C-14), 107.2 (C-8), 107.6 (C-2), 108.4 (C-7), 108.6 (C-
3), 117.3 (C-9), 119.3 (CH-Ar), 123.3 (CH-Ar), 123.5 (C-1), 127.0
(CH-Ar), 128.4 (CH-Ar), 128.6 (CH-Ar), 128.7 (CH-Ar), 129.0
(CH-Ar), 132.4 (C-6), 133.8 (C-23), 138.0 (C-22), 142.0 (C-4), 146.4
(C-17), 153.8 (C-20), 170.1 (C-13) ppm. HRMS (ESI): calcd. for
C28H30N5O3 [M + H]+ 484.23432; found 484.23368.
M.p. 149.4–150.9 °C (ethyl acetate/hexane). IR (KBr): ν = 723,
˜
1126, 1322, 1381, 1406, 1624, 1720, 2966, 3250 cm–1 1H NMR
.
(400 MHz, CDCl3): δ = 0.60 (t, J = 8.0 Hz, 3 H, 15-H), 0.63 (t, J
= 8.0 Hz, 3 H, 17-H), 1.30 (t, J = 8.0 Hz, 3 H, 20-H), 1.87–1.91
1
2
(m, 4 H, 14-H and 16-H), 2.50 (dd, J = 16.0 Hz, J = 4.0 Hz, 1
1
2
1-(2Ј-tert-Butoxycarbonylhydrazono-1Ј-dimethylaminocarbonylprop-
yl)-5-phenyldipyrromethane (7b) and 1,9-Bis(2Ј-tert-butoxycarbon-
ylhydrazono-1Ј-dimethylaminocarbonylpropyl)-5-phenyldipyrrometh-
ane (8b): Hydrazone 1b (150 mg, 0.54 mmol) and dipyrromethane
6 (240 mg, 1.08 mmol) were employed as described in the general
procedure for method A. Purification of the crude product by flash
chromatography (ethyl acetate/hexane, 3:1) gave, in order of elu-
tion, 7b[9] (145 mg, 58%) as a purple solid and 8b[9] (69 mg, 18%)
as a pink solid.
H, 7-H), 2.78 (dd, J = 20.0 Hz, J = 4.0 Hz, 1 H, 4-H), 3.05 (dd,
1J = 16.0 Hz, J = 4.0 Hz, 1 H, 7-H), 3.30 (dd, J = 16.0 Hz, J =
4.0 Hz, 1 H, 4-H), 4.33 (q, J = 8.0 Hz, 2 H, 19-H), 4.42–4.47 (m,
1 H, 4-Ha), 4.53–4.58 (m, 1 H, 7-Ha), 5.95 (s, 1 H, 10-H), 6.01 (s,
2 H, 22-H), 6.10 (d, J = 4.0 Hz, 1 H, 11-H), 6.60 (d, J = 4.0 Hz, 1
H, 12-H), 7.27–7.29 (m, 3 H, ArH), 7.37–7.38 (m, 2 H, ArH), 9.16
(br. s, 1 H, NH, 13-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 8.5
(C-15), 8.6 (C-17), 14.5 (C-20), 26.6 (C-4), 29.0 (C-14), 29.1 (C-16),
41.9 (C-7), 48.1 (C-8), 52.3 (C-22), 53.6 (C-7a), 63.2 (C-4a), 63.3
(C-19), 105.3 (C-10), 107.8 (C-11), 116.6 (C-12), 128.3 (CH-Ar),
128.5 (CH-Ar), 128.8 (CH-Ar), 133.4 (C-9), 134.6 (C-23), 137.9 (C-
2
1
2
1-(2Ј-tert-Butoxycarbonylhydrazono-1Ј-ethoxycarbonylpropyl)-5-
phenyldipyrromethane (7c) and 1,9-Bis(2Ј-tert-butoxycarbonyl-
7046
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 7039–7048

Functionalized Dipyrromethanes, Calix[4]pyrroles, and Bilanes
3), 149.8 (C-21), 154.2 (C-18), 183.2 (C-6) ppm. HRMS (ESI): vent was evaporated, and the product was purified by flash
calcd. for C26H33N8O2 [M + H]+ 489.27210; found 489.27075.
chromatography.
1-(2Ј-Ethoxycarbonylhydrazono-1Ј-benzyl-1H-tetrazol-5-yl)-5-phen-
yldipyrromethane (18): Hydrazone 9 (200 mg, 0.54 mmol) and di-
pyrromethane 6 (240 mg, 1.08 mmol) were employed as described
in the general procedures for methods A and B (reaction time of
22 h). Purification by flash chromatography (ethyl acetate/hexane,
1:2) gave 18 [method A (49 mg, 18%), method B (74 mg, 27%)] as
5,5Ј,15,15Ј-Tetraethyl-10-(1Ј-tert-butoxycarbonylhydrazonoethyl)-
bilane (22a) and 5,5Ј,15,15Ј-Tetraethyl-10,20-bis(1Ј-tert-butoxycarb-
onylhydrazonoethyl)calix[4]pyrrole (23a): Hydrazone 19a (100 mg,
0.41 mmol) and dipyrromethane 3 (167 mg, 0.82 mmol) were em-
ployed as described in the general procedure. Purification of the
crude product by flash chromatography (ethyl acetate/hexane, 1:4)
gave, in order of elution, 22a (38 mg, 16%) as yellow solid and 23a
(49 mg, 16 %) as yellow solid. Data for 22a: M.p. 58.6–59.4 °C
a yellow solid; m.p. 107.4–109.1 °C (diethyl ether/hexane). IR
1
(KBr): ν = 723, 1064, 1223, 1430, 1685, 1701, 1709, 3340 cm–1. H
˜
NMR (400 MHz, CDCl3): δ = 1.35 (t, J = 7.2 Hz, 3 H), 4.06 (s, 2
H), 4.34 (q, J = 7.2 Hz, 2 H), 5.34 (s, 1 H), 5.75 (s, 1 H), 5.84 (s,
1 H), 5.87 (s, 1 H), 5.99 (s, 2 H), 6.11 (d, J = 2.8 Hz, 1 H), 6.66 (s,
1 H), 7.13–7.16 (m, 2 H), 7.23–7.30 (m, 6 H), 7.44 (br. s, 2 H), 7.88
(ethyl acetate/hexane). IR: ν = 714, 764, 1039, 1157, 1234, 1367,
˜
1491, 1717, 2964, 3360 cm–1. 1H NMR (400 MHz, CDCl3): δ =
0.66–0.72 (m, 12 H), 1.51 (s, 9 H), 1.71 (s, 3 H), 1.87–1.92 (m, 8
H), 4.85 (s, 1 H), 5.81 (s, 2 H), 5.95 (t, J = 2.8 Hz, 2 H), 6.03 (s, 2
H), 6.10 (d, J = 2.8 Hz, 2 H), 6.62 (s, 2 H), 741 (s, 1 H, NH), 8.02
(br. s, 2 H, NH), 8.09 (br. s, 2 H, NH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 8.4, 28.3, 29.5, 29.6, 43.5, 47.0, 81.3, 105.6, 105.8,
106.3, 107.3, 116.8, 128.1, 136.6, 136.8, 152.0, 152.8 ppm. HRMS
(ESI): calcd. for C34H48N6NaO2 [M + Na]+ 595.37310; found
595.37324. Data for 23a: M.p. Ͼ160 °C (dec., ethyl acetate/hexane).
(br. s, 1 H, NH), 8.50 (br. s, 1 H, NH), 8.59 (s, 1 H, NH) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 14.5, 26.7, 44.0, 52.8, 62.9, 107.3,
107.5, 107.6, 108.4, 117.3, 121.5, 127.1, 128.3, 128.6, 128.7, 128.8,
132.1, 134.1, 134.3, 141.7, 150.7 ppm. HRMS (ESI): calcd. for
C28H29N8O2 [M + H]+ 509.24080; found 509.24052.
General Procedure for N-Deprotection of Compounds 11 and 16: An-
hydrous ammonium formate (2.5 mmol) was added in a single por-
tion under nitrogen to a stirred suspension of compound 11 or 16
(0.25 mmol) and an equal mass of 10 % Pd/C in dry methanol
(20 mL). The resulting mixture was stirred, heated at reflux for 1 h,
and then cooled to room temperature. The catalyst was removed
by filtration through a pad of Celite, which was washed with meth-
anol. The combined filtrates were concentrated under reduced pres-
sure to give a residue that was triturated with diethyl ether and
filtered to give the final product.
IR: ν = 763, 1045, 1156, 1239, 1367, 1491, 1708, 2967, 3306 cm–1.
˜
1H NMR (400 MHz, CDCl3): δ = 0.62 (t, J = 7.2 Hz, 6 H), 0.71
(t, J = 7.2 Hz, 6 H), 1.50 (s, 18 H), 1.81 (s, 6 H), 1.84–1.89 (m, 8
H), 4.96 (s, 2 H), 5.85 (s, 4 H), 5.91 (s, 4 H), 7.38 (s, 2 H, NH),
8.18 (br. s, 4 H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 8.28,
8.32, 28.3, 43.1, 46.9, 81.3, 105.4, 106.1, 128.6, 137.3, 151.7,
153.1 ppm. HRMS (ESI): calcd. for C42H61N8O4 [M + H]+
741.48103; found 741.47976.
5,5Ј,15,15Ј-Tetraethyl-10-[1Ј-tert-butoxycarbonylhydrazono-1Ј-(p-
bromophenyl)methyl]bilane (22b) and 5,5Ј,15,15Ј-Tetraethyl-10,20-
bis[1Ј-tert-butoxycarbonylhydrazono-1Ј-(p-bromophenyl)methyl]-
calix[4]pyrrole (23b): Hydrazone 19b (157 mg, 0.41 mmol) and di-
pyrromethane 3 (167 mg, 0.82 mmol) were employed as described
in the general procedure. Purification of the crude product by flash
chromatography (ethyl acetate/hexane, 1:5) gave, in order of elu-
tion, 23b (29 mg, 7%) as yellow solid and 22b (23 mg, 8%) as yel-
low solid. Data for 22b: M.p. 72.6–74.2 °C (ethyl acetate/hexane).
1-(2Ј-Ethoxycarbonylhydrazono-1Ј-1H-tetrazol-5-yl)-5,5Ј-diethyldi-
pyrromethane (14): Compound 11 (122 mg, 0.25 mmol) was em-
ployed as described in the general procedure to give 14 (91 mg,
91%) as grey solid; m.p. Ͼ160 °C (dec., diethyl ether). IR (KBr): ν
˜
= 771, 1051, 1248, 1385, 1523, 1720, 2968, 3411 cm–1. 1H NMR
(400 MHz, [D6]DMSO): δ = 0.53–0.58 (m, 6 H), 1.24–1.28 (m, 3
H), 1.86–1.90 (m, 4 H), 3.99 (s, 1 H), 4.17 (s, 1 H), 4.19–4.23 (m,
2 H), 5.50 (s, 1 H), 5.65 (s, 1 H), 5.80 (s, 1 H), 5.87–5.89 (m, 1 H),
6.55–6.57 (m, 1 H), 9.96–10.05 (m, 1 H, NH), 10.13 (s, 1 H, NH),
10.74 (s, 1 H, NH), 11.86 (br. s, 1 H, NH) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 8.4, 14.4, 25.7, 28.7, 42.8, 61.2, 104.8,
105.0, 105.2, 106.2, 116.6, 122.2, 136.4, 153.4 ppm. HRMS (ESI):
calcd. for C19H27N8O2 [M + H]+ 399.22515; found 399.22437.
IR: ν = 714, 753, 1086, 1154, 1232, 1480, 1731, 2963, 3362 cm–1.
˜
1H NMR (400 MHz, CDCl3): δ = 0.68 (t, J = 7.2 Hz, 12 H), 1.46
(s, 9 H), 1.85–1.92 (m, 8 H), 5.14 (s, 1 H), 5.76 (s, 2 H), 5.92 (s, 2
H), 6.02 (s, 2 H), 6.10 (d, J = 2.4 Hz, 2 H), 6.63 (br. s, 4 H), 7.37
(br. s, 1 H, NH), 7.46 (d, J = 8.0 Hz, 2 H), 7.96 (br. s, 2 H, NH),
8.10 (br. s, 2 H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 8.4,
28.2, 29.1, 43.3, 46.6, 81.7, 105.5, 105.9, 107.0, 107.3, 116.8, 127.4,
129.1, 132.5, 136.7, 137.1, 151.9, 152.5 ppm. HRMS (ESI): calcd.
for C39H50BrN6O2 [M + H]+ 713.31731; found 713.31697. Data for
1,9-Bis(2Ј-ethoxycarbonylhydrazono-1Ј-1H-tetrazol-5-yl)-5,5Ј-di-
ethyldipyrromethane (17): Compound 16 (194 mg, 0.25 mmol) was
employed as described in the general procedure to give 17 (147 mg,
23b: M.p. Ͼ180 °C (dec., ethyl acetate/hexane). IR: ν = 750, 1091,
˜
99%) as grey solid; m.p. Ͼ140 °C (dec., diethyl ether). IR (KBr): ν
˜
1154, 1226, 1482, 1739, 2969, 3362 cm–1 1H NMR (400 MHz,
.
= 771, 1038, 1257, 1400, 1539, 1593, 1724, 2981, 3163 cm–1. 1H
NMR (400 MHz, [D6]DMSO): δ = 0.48–0.58 (m, 6 H), 1.21–1.26
(m, 6 H), 1.80–1.82 (m, 4 H), 3.94 (s, 4 H), 4.08–4.18 (m, 4 H),
5.51–5.54 (m, 1 H), 5.57 (br. s, 2 H), 5.62 (br. s, 1 H), 8.41 (s, 3 H,
NH), 10.06 (br. s, 2 H, NH), 12.84 (br. s, 1 H, NH) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 8.5, 14.4, 14.5, 24.8, 26.1, 28.6, 29.1,
33.0, 42.6, 42.8, 60.0, 60.4, 61.0, 64.9, 104.6, 104.8, 104.9, 126.7,
126.8, 135.3, 135.4, 157.6, 160.6, 165.5 ppm. HRMS (ESI): calcd.
for C25H35N14O4 [M + H]+ 595.29602; found 595.29584.
CDCl3): δ = 0.63 (t, J = 7.2 Hz, 12 H), 1.44 (s, 18 H), 1.70–1.83
(m, 8 H), 5.18 (s, 2 H), 5.87 (s, 4 H), 5.89 (s, 4 H), 6.90 (d, J =
8.4 Hz, 4 H), 7.43 (s, 2 H, NH), 7.49 (d, J = 8.4 Hz, 4 H), 8.20 (br.
s, 4 H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 8.3, 28.2,
28.7, 43.1, 46.6, 81.6, 105.4, 106.7, 123.9, 128.2, 129.2, 131.7, 132.6,
137.4, 150.9, 152.6 ppm. HRMS (ESI): calcd. for C52H63Br2N8O4
[M + H]+ 1021.33335; found 1021.33080.
tert-Butyl 6-Methyl-1,2-dihydro-1,2,3,4-tetrazine-2-carboxylate
(24): Triethylamine (1.23 mmol) was added to a solution of hydraz-
one 19a (0.41 mmol) in dichloromethane (20 mL). The reaction
mixture was stirred at room temperature for 3 h. The mixture was
then extracted with dichloromethane (3ϫ 20 mL), and the com-
bined extracts were dried with Na2SO4. The solvent was evapo-
rated, and the resulting residue was purified by flash chromatog-
General Procedure for the Synthesis of Bilanes and Calix[4]pyrroles:
Dipyrromethane 3 (0.82 mmol) and hydrazone 19a or 19b
(0.41 mmol) were added to a suspension of Na2CO3 (4.1 mmol) in
dichloromethane (20 mL). The reaction mixture was stirred at
room temperature for 96 h. The mixture was then filtered through
a pad of Celite, which was washed with dichloromethane. The sol-
Eur. J. Org. Chem. 2014, 7039–7048
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7047

S. M. M. Lopes, A. Lemos, T. M. V. D. Pinho e Melo
FULL PAPER
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Thanks are given to the Fundação para a Ciência e a Tecnologia
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2014 and SFRH/BPD/84413/2012) for financial support. The au-
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Received: July 17, 2014
Published Online: September 19, 2014
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Eur. J. Org. Chem. 2014, 7039–7048