Simple Methodology for the synthesis of meso-unsubstituted β-substituted Alkyl porphyrins

Article abstract of DOI:10.1055/s-2006-950263

The MacDonald [2+2]-type condensation of meso-free β- alkyldipyrromethane with different meso-free-1,9-bis(formyl)dipyrromethanes yields new asymmetric sterically unencumbered porphyrins. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950263

2818
LETTER
Simple Methodology for the Synthesis of meso-Unsubstituted b-Substituted
Alkyl Porphyrins
Synthesis of
m
a
eso
-
Unsubs
n
tituted
b
-Su
d
bstitutedAlk
r
yl Porph
i
yrins ne Juillard, Gérard Simonneaux*
Sciences Chimiques de Rennes, ICMV, UMR CNRS 6226, Campus de Beaulieu, Université de Rennes 1, 35042 Rennes, France
Fax +33(2)23235637; E-mail: gerard.simonneaux@univ-rennes1.fr
Received 21 July 2006
Abstract: The MacDonald [2+2]-type condensation of meso-free
α
7
3
α
7
3
b-alkyldipyrromethane with different meso-free-1,9-bis(for-
myl)dipyrromethanes yields new asymmetric sterically unencum-
bered porphyrins.
α
7
3
8
2
8
2
8
2
NH
N
N
NH
N
N
N
NH
N
β
δ
β
δ
β
δ
Key words: b-alkylporphyrins, MacDonald condensation, disym-
metric b-alkyldipyrromethane, pyrroles
HN
HN
HN
12
12
18
18
12
18
γ
13
17
13
γ
13
17
γ
17
1
2
3
Sterically encumbered porphyrins have been the subject
of intensive research.1 In contrast, much less is known
about the chemistry of derivatives of porphine, bearing
only a few substituents, in particular in b-pyrrole posi-
tion.2 Despite the simple structure, there is a limited ac-
cessibility of porphine, if we discount the recent and nice
synthesis from b-pyrrole or meso-tetra(tert-butyl)porphy-
rin.3,4 Although, porphine could be a possible starting ma-
terial for simple meso-substituted porphyrins, it still
remains the fact that if the b-pyrrole substitution is neces-
sary, a different methodology is required.5 As part of our
ongoing work on reconstituted myoglobins with unen-
combered metalloporphyrins, we needed to prepare a
range of porphyrins with few b-pyrrole substituents. In
this paper, we report the synthesis of disymmetric and
symmetric porphyrins bearing methyl and ethyl group on
the b-pyrrole carbons (Figure 1), utilizing MacDonald
dipyrromethane procedure.6
In our strategy, 1,9-diformyldipyrromethanes 6c and 7c7
were the key intermediates (Figure 2). We first turned to
the new dipyrromethane diester 6a, which was prepared
from condensation of ethyl 5-acetoxymethyl-4-ethyl-3-
methylpyrrole-2-carboxylate with ethyl pyrrole-2-carbox-
ylate in the presence of p-toluenesulfonic acid in dichlo-
romethane solution. The mixture was heated under
nitrogen at 40 °C for 48 hours giving 6a in 53% yield. The
prerequisite decarboxylation can be achieved easily in one
step from the diester precursor. Compound 6a was re-
fluxed in ethylene glycol containing NaOH for 1.5 hours
giving 6b with 92% yield. The resultant dipyrromethane
was formylated with excess POCl3/DMF in dichlo-
romethane, giving the expected compound 6c with 60%
yield.
α
3
7
α
7
3
8
8
2
2
NH
N
NH
N
β
β
δ
δ
HN
N
HN
N
12
18
12
18
13
γ
17
13
γ
17
4
5
Figure 1
is summarized herein.9 Compound 7b was readily formed
in 89% yields by treatment of 1,9-bis(ethoxycarbonyl)-
3,7-diethyl-2,8-dipyrromethane (7a) with sodium hydrox-
ide.8 Reaction of 7b with excess POCl3/DMF in dichlo-
romethane produced stable 7c7 with 52% yield.
5
3
7
4
6
5
3
7
4
6
8
2
8
2
NH
HN
9
NH
HN
9
1
1
R
R
R
R
6
7
R = CO2Et 6a
R = H
R = CHO
R = CO2Et 7a
R = H
R = CHO
6b
6c
7b
7c
Figure 2
To prepare the two porphyrins 1 and 2, we followed Mac-
Donald’s [2+2] pathway. 1,9-Bis(formyl)dipyrromethane
6c (or 7c) was condensed with dipyrromethane, a dipyr-
romethane without any substituent, in CH2Cl2 in the pres-
ence of trifluoroacetic acid. This afforded, after oxidation
with p-chloranyl and chromatographic purification,
monopyrrole-substituted porphyrin 1 (yield: 8%) and
dipyrrole-substituted porphyrin 2 (yield: 22%). In a typi-
cal experimental procedure for 1, dipyrromethane (3
Compounds 7a–c have been previously prepared by vari-
ous methods.8 The procedure used in our laboratory for 7c
SYNLETT 2006, No. 17, pp 2818–2820
1
7
.1
0
.2
0
0
6
Advanced online publication: 09.10.2006
DOI: 10.1055/s-2006-950263; Art ID: G23906ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of meso-Unsubstituted b-Substituted Alkyl Porphyrins
2819
mmol) and 1,9-diformyldipyrromethane 6c (3 mmol) dis-
solved in 1 L of distilled CH2Cl2 under argon were stirred
in the presence of 670 mL (9.2 mmol) of trifluoroacetic
acid for 14 hours at room temperature. After addition of p-
chloranyl (0.512 mmol) and 1 hour more stirring, 6.7 mL
of Et3N were added and then the solvent was removed.
The residue was purified by two subsequent column chro-
matographies on silica gel using dichloromethane as elu-
ant to give 1. Traces of porphine 5 were detected in the
mass spectra of 1. Using a similar procedure, the expected
porphine was not obtained from condensation of dipyr-
romethane with 1,9-diformyldipyrromethane.
Table 1 UV/vis Data for the Porphyrins 1–5 in Dichloromethane
Solution
l, nm (e mM–1cm–1)
Porphyrin Soret band IV
III
II
I
1
394
(158.9)
490
(8.1)
526
(2.8)
560
(3.7)
615
(0.5)
2
393
(216.9)
491
(19.1)
523
(7.4)
560
(7.8)
613
(2.7)
3
395
(180.7)
496
(10.5)
532
(6.7)
563
(5.5)
617
(1.9)
Dipyrromethane 6b was similarly condensed with di-
formyldipyrromethane 7c to give the asymmetric porphy-
rin 3 in 26% yield. It should be noted that the reverse
reaction, i.e. the condensation of 6c with 7b, gave a lower
yield of porphyrin 3 (13%). To complete the series of
these alkyl porphyrins, 4 was classically prepared by con-
densing 7c with 7b to give the previously obtained
etioporphyrin II in 40% yield. The following remarks de-
rive from these results:
4
396
(162.9)
497
(12.3)
530
(8.9)
565
(6.0)
619
(4.3)
5a
394
(272)
489
(16.4)
519
(3.2)
560
(5.4)
613
(1.1)
a Taken from ref. 3.
tons along the C2 axis. The pattern of 2 is characterized by
three singlets for the meso-protons at 10.11 (a-Hmeso),
10.19 (b and d-Hmeso) and 10.27 ppm (g-Hmeso). Such weak
structural perturbations may be useful to study the struc-
ture of some myoglobins reconstituted with unnatural
hemes.
– The porphyrin yield increases as substitution on b-pyr-
role increases, the best yield being obtained for the prepa-
ration of etioporphyrin 4,
– as the number of b-substitution in a dipyrromethane in-
creases, dipyrromethanes may become more resistant to-
ward scrambling, as expected for this MacDonald
condensation,
– the yield is higher when MacDonald condensation re-
sults from a substituted diformyldipyrromethane to dipyr-
romethane rather than the reverse situation.
In summary, we have developed a simple procedure for
the preparation of a series of simple b-alkyl porphyrins
with different symmetries using a MacDonald-type con-
densation. It may be comparable to a different and nice
route using tripyrrane as an intermediate and recently re-
ported by Taniguchi et al.11 The herein method is particu-
larly attractive owing its simplicity although the yield is
quite weak for the simplest porphyrin 1.12
The electronic spectra of porphyrins 1 and 2 exhibited a
strong Soret band near 400 nm and a phyllo-type Q band
region, as expected when four or more peripheral b-pyr-
role positions are unsubstituted.10 In contrast, the etio-
type spectrum is found both in porphyrins 3 and 4 in
which, respectively, six and eight peripheral positions car-
ry side-chains such as methyl and ethyl groups. All the
UV/vis data are summarized in Table 1.
References and Notes
(1) (a) The Porphyrin Handbook, Vol. 1–10; Kadish, K.; Smith,
K. M.; Guilard, R., Eds.; Academic Press: Boston, 2000.
(b) The Porphyrin Handbook, Vol. 11–20; Kadish, K.;
Smith, K. M.; Guilard, R., Eds.; Academic Press: San Diego,
2003.
(2) Ryppa, C.; Senge, M. O.; Hatscher, S. S.; Kleinpeter, E.;
Wacker, P.; Schilde, U.; Wiehe, A. Chem. Eur. J. 2005, 11,
3427.
(3) Neya, S.; Funasaki, N. Tetrahedron Lett. 2002, 43, 1057.
(4) Neya, S.; Quan, J.; Hoshino, T.; Hata, M.; Funasaki, N.
Tetrahedron Lett. 2004, 45, 8629.
(5) Nguyen, L. T.; Senge, M. O.; Smith, K. M. J. Org. Chem.
1996, 61, 998.
In the NMR spectra of 1–4, the regiochemical arrange-
ment and substitution pattern was easily obtained from 2D
spectra, such as COSY, HMQC and HMBC. Thus, if we
consider the 1H NMR spectrum of 1, the magnetic aniso-
tropy of the porphyrin ring due to the two different alkyl
groups on a pyrrole ring, although very weak, is enough to
see the four different meso-protons at 500 MHz
(d = 10.24, 10.25, 10.33 and 10.34 ppm). Many 1H NMR
studies have investigated the effects of substituents on the
porphyrin-ring-current effect.2 A general conclusion from
previous studies is that substitution at the meso-position
appears to decrease the ring current more than substitution
at the pyrrole ring. Thus it is quite surprising that methyl
vs. ethyl substitution affects sufficiently the whole current
flow to detect the four different meso-H in 1. If we consid-
er porphyrins 1 and 2, the changes in symmetry are clearly
(6) Arsenault, G. P.; Bullock, E.; MacDonald, S. F. J. Am.
Chem. Soc. 1960, 82, 4384.
(7) Chong, R.; Clezy, P. S.; Liepa, A. J.; Nichol, A. W. Aust. J.
Chem. 1969, 22, 229.
(8) Helms, A.; Heiler, D.; McLendon, G. J. Am. Chem. Soc.
1992, 114, 6227.
(9) Young, R.; Chang, C. K. J. Am. Chem. Soc. 1985, 107, 898.
(10) Porphyrins and Metalloporphyrins; Smith, K. M., Ed.;
Elsevier: Amsterdam, 1975.
1
reflected in the H NMR spectra. For example, the por-
(11) Taniguchi, S.; Hasegawa, H.; Nishimura, M.; Takahashi, H.
phyrin 2 shows characteristic splitting of the meso-pro-
Synlett 1999, 73.
Synlett 2006, No. 17, 2818–2820 © Thieme Stuttgart · New York

2820
S. Juillard, G. Simonneaux
LETTER
617 (1.9) nm. HRMS: m/z calcd for C29H33N4 [M + H]+:
(12) Selected Data
Compound 1: 1H NMR (500 MHz, CDCl3): d = –3.94 (br s,
437.2705; found: 437.2694.
2 H, NH), 1.93 (t, 3 H, CH2CH3), 3.71 (s, 3 H, CH3), 4.18 (q,
2 H, CH2CH3), 9.46 (m, 4 H, 7,8,17,18-Hpyrrolic), 9.54 (s, 2 H,
12,13-Hpyrrolic), 10.24 (s, 1 H, a- or d-Hmeso), 10.25 (s, 1 H, a-
or d-Hmeso), 10.33 (s, 1 H, b- or g-Hmeso), 10.34 (s, 1 H, b- or
g-Hmeso) ppm. 13C NMR (125 MHz, CDCl3): d = 11.45
(CH3), 17.53 (CH2CH3), 19.78 (CH2CH3), 99.89 (Ca,d),
104.37 (Cb,g), 129.00 (C12,13), 132.96 (C7,8,17,18),
142.07 (C3), 153,03 (C2) ppm. UV/vis (CH2Cl2): lmax (e
mM–1cm–1): 394 (158.9), 490 (8.1), 526 (2.8), 560 (3.7), 615
(0.5) nm. HRMS: m/z calcd for C23H21N4 [M + H]+:
353.1766; found: 353.1766.
Compound 4: 1H NMR (500 MHz, CDCl3): d = –3.72 (br s,
2 H, NH), 1.91 (t, 12 H, CH2CH3), 3.67 (s, 12 H, CH3), 4.13
(q, 8 H, CH2CH3), 10.12 (s, 2 H, Hmeso), 10.13 (s, 2 H, Hmeso
)
ppm. 13C NMR (125 MHz, CDCl3): d = 11.59 (CH3), 17.75
(CH2CH3), 19.92 (CH2CH3), 96.29 (Cmeso), 135.03 (C2),
142.12 (C3) ppm. UV/vis (CH2Cl2): lmax (e mM–1cm–1): 396
(162.9), 497 (12.3), 530 (8.9), 565 (6.0), 619 (4.3) nm.
HRMS: m/z calcd for C39H39N4 [M + H]+: 479.3175; found:
479.3174.
Compound 6a: 1H NMR (500 MHz, CDCl3): d = 1.06 and
1.33 (all t, 9 H, 3 CH2CH3), 2.32 (s, 3 H, CH3), 2.45 and 4.29
(two q, 6 H, 3 CH2CH3), 3.98 (s, 2 H, CH2), 6.04 and 7.29
(two s, 2 H, 2 Hpyrrolic), 9.60 and 10.00 (two br s, 2 H, 2 NH)
ppm. 13C NMR (125 MHz, CDCl3): d 10.55, 14.42, 15.53,
17.22, 24.67, 59.86, 60.53, 108.87, 116.26, 117.28, 122.01,
124.20, 127.02, 129.62, 134.87, 161.65, 162.50 ppm.
HRMS: m/z calcd for C18H24N2O4 [M+·]: 332.1736; found:
332.1704.
Compound 2: 1H NMR (500 MHz, CDCl3): d = –3.81 (br s,
2 H, NH), 1.92 (t, 6 H, CH2CH3), 3.65 (s, 6 H, CH3), 4.12 (q,
4 H, CH2CH3), 9.45 (dd, 4 H, Hpyrrolic), 10.11 (s, 1 H, a-
H
meso), 10.19 (s, 2 H, b,d-Hmeso), 10.27 (s, 1 H, g-Hmeso) ppm.
13C NMR (125 MHz, CDCl3): d = 11.52 (CH3), 17.71
(CH2CH3), 19.90 (CH2CH3), 95.57 (Ca), 100.19 (Cb,d),
104.71 (Cg), 130.21 (C11,19), 130.50 (C12,13,17,18),
136.15 (C2,8), 142.74 (C3,7) ppm. UV/vis (CH2Cl2): lmax
(e mM–1cm–1): 393 (216.9), 491 (19.1), 523 (7.4), 560 (7.8),
613 (2.7) nm. HRMS: m/z calcd for C26H27N4 [M + H]+:
395.2236; found: 395.2243.
Compound 6b: 1H NMR (500 MHz, CDCl3): d = 1.13 (t, 3
H, CH2CH3), 2.08 (s, 3 H, CH3), 2.48 (q, 2 H, CH2CH3), 3.94
(s, 2 H, 5-CH2), 6.04, 6.17, 6.41, 6.68 (all m, 4 H, 4 Hpyrrolic),
7.49, 7.87 (two br s, 2 H, 2 NH) ppm. 13C NMR (125 MHz,
CDCl3): d = 10.31, 16.00, 17.40, 24.51, 106.26, 108.50,
113.90, 116.99, 117.90, 121.22, 124.32, 129.21. HRMS:
m/z calcd for C12H16N2 [M+·]: 188.1313; found: 188.1313.
Compound 6c: 1H NMR (500 MHz, CDCl3): d = 0.91 (t, 3 H,
CH2CH3), 2.32 (s, 3 H, CH3), 2.50 (q, 2 H, CH2CH3), 4.06 (s,
2 H, 5-CH2), 6.19, 6.91, 9.42, 9.55 (all m, 4 H, 4 Hpyrrolic),
10.99, 11.36 (two br s, 2 H, 2 NH). 13C NMR (125 MHz,
CDCl3): d = 8.86, 15.32, 16.98, 24.79, 110.37, 122.83,
125.31, 128.74, 133.23, 135.51, 138.18, 177.04, 179.04.
HRMS: m/z calcd for C14H16N2O2 [M+·]: 244.1212; found:
244.1198.
Compound 3: 1H NMR (500 MHz, CDCl3): d = –3.50 (br s,
2 H, NH), 1.91 (m, 9 H, CH2CH3), 3.64 (s, 3 H, 8-CH3), 3.69
(s, 6 H, 2,12-CH3), 4.10 (q, 2 H, 7-CH2CH3), 4.16 (m, 4 H,
3,13-CH2CH3), 9.43 (s, 2 H, Hpyrrolic), 10.14 (s, 1 H, a- or b-
H
meso), 10.15 (s, 1 H, a- or b-Hmeso), 10.20 (s, 1 H, d- or g-
Hmeso), 10.21 (s, 1 H, d- or g-Hmeso) ppm. 13C NMR (125
MHz, CDCl3): d = 11.51 (CH3), 17.65 (CH2CH3), 19.85
(CH2CH3), 96.02 (Ca,b), 100.64 (Cd,g), 131.73 (C17,18),
133.86 (C12), 134.69 (C2), 136.73 (C8), 141.00 (C3),
141.70 (C13), 143.81 (C7) ppm. UV/vis (CH2Cl2): lmax
(e mM–1cm–1): 395 (180.7), 496 (10.5), 532 (6.7), 563 (5.5),
Synlett 2006, No. 17, 2818–2820 © Thieme Stuttgart · New York