Functionalization of dipyrromethanes via hetero-Diels-Alder reaction with azo- and nitrosoalkenes

Article abstract of DOI:10.1016/j.tetlet.2013.01.032

5,5′-Diethyl- and 5-phenyldipyrromethanes participate in cycloadditions with azo- and nitrosoalkenes giving dipyrromethanes with side chains containing open chain oximes and hydrazones. By controlling reaction stoichiometry it is possible to get mono or 1

Full text of DOI:10.1016/j.tetlet.2013.01.032

Accepted Manuscript
Functionalization of Dipyrromethanes via Hetero-Diels-Alder Reaction with
Azo- and Nitrosoalkenes
Nelson A.M. Pereira, Américo Lemos, Arménio C. Serra, Teresa M.V.D. Pinho
e Melo
PII:
S0040-4039(13)00068-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.01.032
TETL 42408
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
7 December 2012
27 December 2012
8 January 2013
Please cite this article as: Pereira, N.A.M., Lemos, A., Serra, A.C., Pinho e Melo, T.M.V., Functionalization of
Dipyrromethanes via Hetero-Diels-Alder Reaction with Azo- and Nitrosoalkenes, Tetrahedron Letters (2013), doi:
http://dx.doi.org/10.1016/j.tetlet.2013.01.032
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Functionalization of Dipyrromethanes via Hetero-Diels-Alder Reaction
with Azo- and Nitrosoalkenes
Nelson A. M. Pereira,a Américo Lemos,b Arménio C. Serra,a Teresa M. V. D. Pinho e Meloa*
aDepartment of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal,
bCIQA, FCT, University of Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
tmelo@ci.uc.pt
Abstract – 5,5’-Diethyl- and 5-phenyldipyrromethanes participate in cycloadditions with azo- and
nitrosoalkenes giving dipyrromethanes with side chains containing open chain oximes and hydrazones.
Controlling reaction stoichiometry it is possible to get mono or 1,9-dissubstituted derivatives. The
reported methodology gave access to a range of dipyrromethanes with good structural features for various
applications. It was demonstrated that reduction of dipyrromethanes containing α-oximino ester groups
opens the way to new α-amino esters.
Keywords: Dipyrromethanes, Azoalkenes, Nitrosoalkenes, Hetero-Diels-Alder Reaction.
Dipyrrolic compounds1 are of wide interest as building blocks in organic synthesis,
namely in the synthesis of porphyrins2 and porphyrin analogues such as meso-
substituted corroles,3 chlorins,4 expanded porphyrins,5 and calix[4]pyrroles.6 On the
other hand, dipyrromethanes are the precursors of BODIPY dyes (4,4-difluoro-4-bora-
3a,4a-diaza-s-indacenes) whose photophysical properties make them the ideal
fluorescent scaffold for the development of high performance imaging probes.7
Radioactive technetium complexes also have widespread application in molecular
imaging.8 Thus, we envisioned that the synthesis of dipyrromethanes with structural
requirements to act as Technetium (99mTc) ligands for application as radiotracers in
cancer detection would be of particular interest. Functionalized dipyrromethanes are
also potentially attractive structures for the development of new optical anion sensors,
for application in biological systems and in the settling of environmental problems.9 In
fact, pyrrole based anion receptors, including dipyrromethane derivatives,1b,9j have been
shown to be selective and efficient receptors for a variety of anionic species.
In this context, we decided to explore the hetero-Diels-Alder reaction of azoalkenes and
nitrosoalkenes to achieve the functionalization of dipyrromethane derivatives.
Cycloadditions of these heterodienes has been explored as a route to tetrahydro-1,2-
oxazine, tetrahydro–pyridazine, open chain oxime and hydrazone derivatives.10 Our
previous studies on hetero-Diels-Alder reactions of 3-tetrazolylnitrosoalkenes and 3-
tetrazolyl-1,2-diaza-1,3-butadienes demonstrated that it is an efficient approach for the
synthesis of functionalized 5-(substituted)-1H-tetrazoles.11 Using pyrrole as the 2π
component, open chain oximes and hydrazones are obtained. We envisaged that a
diversity of dipyrromethanes might be produced through hetero-Diels-Alder reaction
with azoalkenes and nitrosoalkenes, using 5,5’-di-substituted- and 5-mono-substituted
1

dipyrromethanes as 2π components. On the other hand, the possibility of controlling
mono- or di-functionalization would lead to a wider range of dipyrromethane
derivatives allowing the diversification of potential applications. In this communication,
details of this new synthetic strategy for the introduction of side-chains in positions 1
and 9 of dipyrromethanes via hetero-Diels-Alder reaction are presented (Scheme 1).
X
N
R1 R2
R3
R4
XH
N
HX
NH HN
N
X = O or NR'
R4
R4
R3
R3
R2
R1
NH
HN
X = O or NR'
R1 R2
NH HN
HX
N
X
N
R4
R3
R3
R4
Scheme 1. Synthetic strategy for the functionalization of dipyrromethanes.
The heterodienes selected to carry out this study were generated in situ through base
mediated dehydrohalogenation of α-halohydrazones 2 or α-halooxime 4. These azo- and
nitrosoalkene precursors were obtained from the reaction of the corresponding
hydrazine with α-halo carbonyl compounds 1 and from the condensation of
hydroxylamine with ethyl bromopyruvate (3), respectively (Scheme 2).12
NHR1
O
N
R1NH2NH2
COR
COR
Cl
Cl
t
2a R = NMe2; R1 = CO2 Bu
1
78%
85%
89%
2b R = OEt; R1 = CONHPh
2c R = OEt; R1 = CO2 Bu
t
O
NOH
NH2OH
EtO2C
EtO2C
Br
Br
3
4 88%
Scheme 2. Synthesis of azo- and nitrosoalkene precursors.
Initially, the behaviour of 5,5’-diethyldipyrromethane (6) towards 1,2-diaza-1,3-
butadienes was explored (Scheme 3). Dipyrromethane 6 was prepared by a known
synthetic methodology involving the acid-catalyzed condensation of 3-pentanone with
pyrrole in aqueous medium.1c By treatment with sodium carbonate in dichloromethane
at room temperature, hydrazones 2 were converted into the transient 1,2-diaza-1,3-
2

butadienes 5 which were trapped in situ by dipyrromethane 6 affording the
corresponding open chain hydrazones 713 and 814. Carrying out the reaction using an
excess of pyrromethane 6 (2.25 equiv.) the mono-functionalized derivative 8 could be
isolated in moderate yield as single product whereas the reaction using a slight excess of
hydrazones 2 afforded the di-functionalized pyrromethanes 7 in good yield. These
reactions can be regarded as “formal” alkylation reactions, which are the result of
hetero-Diels-Alder reactions followed by 1,4,5,6-tetrahydropyridazine ring opening via
a 1,5-sigmatropic rearrangement and finally a enolization-type step, as previously
observed in the reaction of 1,2-diaza-1,3-butadienes with heterocycles possessing high
aromatic character such as pyrrole and indole.10,11
O
R1
N
O
R1
N
R1OC
COR1
NH
HN
NH
HN
HN
N
Na2CO3
NH HN
6
N
N
CH2Cl2, r.t.
Cl
52-80 h
O
O
COR
R
R
COR
7a R = NMe2; R1 = OtBu
7b R = OEt; R1 = NHPh 49%
7c R = OEt; R1 = OtBu
68%
5
59%
2
48 h
NH
HN
R = OEt; R1 = OtBu
6 (2.25 equiv.)
t
CO2 Bu
HN
NH HN
N
O
OEt
8 28%
Scheme 3. Hetero-Diels-Alder reaction of 5,5’-diethyldipyrromethane (6) with 1,2-
diaza-1,3-butadienes.
The work was extended to the cycloaddition of a 5-mono-substituted dipyrromethane
with 1,2-diaza-1,3-butadiene 5a (Scheme 4). The TFA catalyzed condensation of
benzaldehyde with neat excess of pyrrole afforded 5-phenyldipyrromethane (9), as
reported by Lindsey et al.1b We were pleased to observed that the conversion of
dipyrromethane 9 into 1,9-disubstituted dipyrromethane 10 showed similar efficiency to
the one observed in the cycloaddition of 5,5’-diethyldipyrromethane (6) with the same
diene. In fact, dipyrromethane 10 was obtained in 56% yield.13 Using an excess of 5-
phenyldipyrromethane (9) the mono-functionalized derivative 1114 could be obtained in
31% yield.
3

Ph
Ph
t
t
CO2 Bu
CO2 Bu
t
tBuO2C
CO2 Bu
NH
Na2CO3
CH2Cl2, r.t.
HN
HN
N
N
NH
HN
N
NH HN
9
N
N
Cl
- HCl
62 h
O
O
CONMe2
CONMe2
Me2N
NMe2
5a
2a
Ph
10 56%
48 h
Ph
NH
HN
9 (3 equiv.)
t
CO2 Bu
HN
NH HN
O
N
NMe2
11 31%
Scheme 4. Hetero-Diels-Alder reaction of 5-phenyldipyrromethane (9) with 1,2-diaza-
1,3-butadiene 5a.
We have also explored the hetero-Diels–Alder reaction of nitrosoalkene 12, generated in
situ from the corresponding bromooxime 4, with dipyrromethane 6 (Scheme 5). In this
case, it was observed that carrying out the mono-functionalization to give 13, followed
by the subsequent cycloaddition leading to the target compound 14, was more efficient
than a one-pot procedure. In fact, the latter led to a more difficult isolation since the
formation of derivative 13 was also observed. Under the optimized reaction conditions
dipyrromethane 13 was isolated in 59% yield and di-functionalized derivative 14 was
obtained from 13 in 48% yield. It is noteworthy that compounds 13 and 14 have the
structural requirements to act as Technetium (99mTc) ligands for application in cancer
radioimaging.
Na2CO3
CH2Cl2, r.t.
24 h
NOH
CO2Et
O
NH
HN
N
6
NH HN
13 59%
CO2Et
NOH
CO2Et
12
Br
4
Na2CO3
CH2Cl2, r.t.
48 h
Na2CO3
CH2Cl2, r.t.
66 h
4
6
NH HN
EtO2C
HON
CO2Et
NOH
23%
48%
14
Scheme 5. Hetero-Diels-Alder reaction of 5,5’-diethyldipyrromethane (6) with
nitrosoalkene 12.
The reaction of nitrosoalkene 12 with 5-phenyldipyrromethane (9) was not as
straightforward as with the 5,5’-diethyldipyrromethane (6), which prompted us to
prepare dipyrromethane 17 using different strategies (Scheme 6). The hetero-Diels–
4

Alder reaction requires long reaction times leading to oxidation of the dipyrromethanes
making the isolation of the target compounds harder. The one-pot approach afforded the
di-functionalized dipyrromethane 17 in 19% yield. Reacting oxime 4 with an excess of
5-phenyldipyrromethane (9) in the presence of sodium carbonate led to the formation of
dipyrromethane 16 in 42% yield. This heterocyclic compound, when subjected to
another cycloaddition with nitrosoalkene 12, gave compound 17 in moderate yield
(34%). Finally, an alternative strategy was devised. Dipyrromethane 17 was obtained in
18% yield from the condensation of benzaldehyde with two equivalents of pyrrole 1512f
in dichloromethane, in the presence of a catalytic amount of TFA, a general procedure
described by Lindsey et al.15
NOH
CO2Et
HON
O
Na2CO3
CH2Cl2 r.t.
N
H
N
CO2Et
- HBr
N
CO2Et
12
Br
H
15 61%
4
CH2Cl2, r.t.
20 h
PhCHO
TFA
Ph
48 h
24 h
18%
NH
HN
19%
9
4
NH
HN
HN
NH
CO2Et
NOH
EtO2C
HON
CO2Et
NOH
Na2CO3
CH2Cl2
r.t., 48 h
34%
16 42%
17
Scheme 6. Synthesis of dipyrromethane 17.
The functionalities introduced on the dipyrromethane nucleus can be used for other useful
transformations, as in the case of the reduction of α-oximino ester to α-amino esters.12f,11a
Therefore, the reduction of α-oximino ester 13 was carry out using aluminum amalgam in
aqueous THF giving the corresponding α-amino ester which underwent N-protection with di-t-
butyldicarbonate to afford compound 18 in 67% overall yield16 (Scheme 7).
5

NH HN
CO2Et
NOH
13
1. Al/Hg
THF/10% H2O
2. Boc2O, NEt3
NH HN
CO2Et
t
HN
CO2 Bu
18 67%
Scheme 7. Reduction of α-oximino ester 13.
A new synthetic strategy for the introduction of side-chains in positions 1 and 9 of
dipyrromethanes via hetero-Diels-Alder reaction with azo- and nitrosoalkenes is
reported. This allowed the synthesis of new 5,5’-diethyl- and 5-phenyldipyrromethanes
functionalized with side chains containing open chain oximes and hydrazones.
Furthermore, it was demonstrated that reduction of dipyrromethanes containing α-
oximino ester groups opens the way to new α-amino esters.
The new dipyrromethanes have good structural features for various applications, namely
for the synthesis of BODIPY dyes and Technetium (99mTc) ligands to be used as
radiotracers, the synthesis of porphyrin analogues and the development of new optical
anion sensors.
Acknowledgments
Thanks are due to Fundação para a Ciência e a Tecnologia (PEst-C/QUI/UI0313/2011
and SFRH/BD/61573/2009) for financial support. We acknowledge the Nuclear
Magnetic Resonance Laboratory of the Coimbra Chemistry Center (www.nmrccc.uc.pt),
University of Coimbra for obtaining the NMR data.
Supplementary Material
1
Experimental procedures and characterization data all new compounds. H and 13C NMR
spectra for all new compounds. Supplementary data associated with this article can be
found, in the online version, at XXX.
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13. 1-(2’-t-Butoxycarbonylhydrazono-1’-ethoxycarbonylpropyl)-5,5’-diethyldipyrromethane
(8). Obtained in 28% yield (0.018 g) from dipyrromethane 6 (0.060 g, 0.30 mmol) and
hydrazone 2c (0.041 g, 0.15 mmol) as a yellow solid. Mp 43-45 ºC. 1H NMR (400 MHz,
CDCl3) δ = 8.33 (s, 1H, NH), 8.06 (s, 1H, NH), 7.53 (s, 1H, NH), 6.63 (bs, 1H, α-H
pyrrolic), 6.11-6.10 (m, 1H, β-H pyrrolic), 6.05 (bs, 1H, β-H pyrrolic), 5.97 (bs, 1H, β-H
pyrrolic), 4.65 (s, 1H, CH), 4.16 (q, J = 7.0 Hz, 2H, CH2), 1.95-1.92 (m, 4H, CH2), 1.77
(s, 3H, Me), 1.50 and 1.46 (2s, 9H, Me), 1.23 (t, J = 7.0 Hz, 3H, Me), 0.73 - 0.68 (m, 6H,
Me) ppm. 13C NMR (100 MHz, CDCl3) δ = 170.0, 152.4, 148.0, 137.3, 136.2, 129.4,
128.2, 123.1, 116.7, 107.2, 105.8, 105.5, 81.2, 61.4, 53.2, 43.5, 29.6, 28.1, 13.3, 13.2, 8.3
ppm. HRMS (ESI): calcd. 467.2629 for C24H36N4NaO4 [M + Na]+, found 467.2618. 1-(2’-
t-Butoxycarbonylhydrazono-1’-dimethylaminocarbonylpropyl)-5-phenyldipyrromethane
(11). Obtained in 31% yield (0.038 g) yield from dipyrromethane 9 (0.140 g, 0.63 mmol)
and hydrazone 2a (0.07 g, 0.28 mmol) as a purple solid. Mp 97-99 ºC [from diethyl ether
8

/ hexane] (obtained as mixture of two conformers) 1H NMR (400 MHz, CDCl3) δ = 8.97
(s, 1H, NH), 8.17 and 8.12 (2s, 1H, NH), 7.46 (s, 1H, NH), 7.28 - 7.15 (m, 5H, Ph), 6.68
(bs, 1H, α-H pyrrolic), 6.12 (bs, 1H, β-H pyrrolic), 5.97-5.96 (m, 1H, β-H pyrrolic), 5.86-
5.74 (m, 2H, β-H pyrrolic), 5.40 (s, 1H, CH meso), 5.00 (s, 2H, CH), 3.05 and 3.04 (2s,
3H, Me), 2.92 and 2.91 (2s, 3H, Me), 1.77 and 1.76 (2s, 3H, Me), 1.49 (s, 9H, Me) ppm.
13C NMR (100 MHz, CDCl3) δ = 170.0, 152.7, 150.6, 142.3, 133.3, 132.5, 132.4, 128.6,
128.5, 128.4, 128.3, 126.8, 124.7, 124.6, 117.3, 117.2, 108.2, 107.9, 107.6, 107.5, 107.2,
107.1, 81.3, 50.2, 50.2, 44.2, 37.9, 35.9, 28.3, 13.1, 13.0 ppm. HRMS (ESI): calcd. for
C26H34N5O3 [M + H]+ 464.2656, found 464.2652.
14. 5,5’-Diethyl-1,9-bis(1’-dimethylaminocarbonyl-2’-
phenylaminocarbonylhydrazonopropyl)-dipyrromethane (7b). Obtained in 49% yield
(0.087 g) from dipyrromethane 6 (0.05 g, 0.25 mmol) and hydrazone 2b (0.240 g, 0.86
1
mmol) as a white solid. Mp 92-94 ºC [from diethyl ether / hexane] H NMR (400 MHz,
CDCl3) δ = 8.29 (s, 2H, NH), 8.12 (s, 1H, NH), 8.04 (s, 3H, NH), 7.46 (d, J = 7.6 Hz, 4H,
Ph), 7.30 (t, J = 7.6 Hz, 4H, Ph), 7.08 - 7.04 (m, 2H, Me), 6.01-5.99 (m, 4H, β-H
pyrrolic), 4.56 (s, 1H, CH), 4.53 (s, 1H, CH), 4.22 - 4.19 (m, 4H, CH2), 1.93-1.92 (m, 4H,
CH2), 1.81 (s, 3H, Me), 1.79 (s, 3H, Me), 1.28-125 (m, 6H, Me), 0.72 - 0.70 (m, 6H, Me)
ppm. 13C NMR (100 MHz, CDCl3) δ = 170.1, 153.3, 153.2, 146.4, 146.3, 137.9, 137.4,
129.0, 123.4, 122.9, 122.9, 119.4, 119.3, 108.2, 108.0, 106.3, 61.6, 53.2, 43.8, 43.7, 29.8,
14.2, 13.8, 8.5, 8.4 ppm HRMS (ESI): calcd. for C39H49N8O6 [M + H]+ 725.3769, found
725.3746.
1,9-Bis(2’-t-butoxycarbonylhydrazono-1’-dimethylaminocarbonylpropyl)-5-
phenyldipyrromethane (10). Obtained in 56% yield (0.090 g) from dipyrromethane 9
(0.055 g, 0.16 mmol) and hydrazone 2a (0.150 g, 0.54 mmol) as a pink solid. Mp 130-
1
132 ºC [from diethyl ether / hexane]. H NMR (400 MHz, CDCl3) δ = 8.91 (s, 1H, NH),
8.87 (s, 1H, NH), 7.48 (s, 2H, NH), 7.28 - 7.15 (m, 5H, Ph), 5.96 (bs, 2H, β-H pyrrolic),
5.73-5.69 (m, 2H, β-H pyrrolic), 5.34 (s, 1H, CH meso), 5.01 (s, 2H, CH), 3.05 (s, 6H,
Me), 2.92 (s, 6H, Me), 1.79 (s, 3H, Me), 1.77 (s, 3H, Me), 1.50 (s, 18H, Me) ppm. 13C
NMR (100 MHz, CDCl3) δ = 170.0, 152.7, 151.0, 150.9, 142.0, 133.1, 133.0, 128.6,
128.5, 128.4, 128.3, 126.9, 124.8, 108.0, 107.9, 107.8, 107.7, 107.6, 81.3, 81.2, 50.1,
44.3, 37.9, 35.8, 28.3, 13.0, 12.9 ppm. HRMS (ESI): calcd. for C37H53N8O6 [M + H]+
705.4082, found 705.4077.
15. Wagner, R. W.; Lindsey, J. S. Pure & Appl. Chem. 1996, 68, 1373-1380.
16. 1-(2-t-Butoxycarbonylamino-2-ethoxycarbonylethyl)-5,5’-diethyldipyrromethane
(18)
1
was obtained as a yellow oil in 67% yield. H NMR (400 MHz, CDCl3) δ = 8.12 (s, 1H,
NH), 7.64 (s, 1H, NH), 6.65 (s, 1H, α-H pyrrolic), 6.12-6.11 (m, 1H, β-H pyrrolic), 6.07
(s, 1H, β-H pyrrolic), 5.95 (bs, 1H, β-H pyrrolic), 5.84 (bs, 1H, β-H pyrrolic), 5.06-5.05
(m, 1H, NH), 4.38-4.37 (m, 1H, CH), 4.12-4.05 (m, 2H, CH2), 3.02-287 (m, 2H, CH2),
1.92-187 (m, 4H, CH2), 1.40 (s, 9H, Me), 1.24-1.21 (m, 3H, Me), 0.72-0.68 (m, 6H, Me)
ppm. 13C NMR (100 MHz, CDCl3) δ = 171.9, 155.1, 136.7, 136.4, 132.8, 129.5, 128.3,
125.1, 116.8, 107.4, 107.3, 106.3, 105.6, 79.9, 61.5, 53.7, 43.6, 31.3, 29.9, 29.7, 28.3,
14.1, 8.4 ppm. HRMS (ESI): calcd. for C23H35N3NaO4 [M + Na]+ 440.2520, found
440.2514.
9

Graphical Abstract (for review)