An efficient one-pot procedure for asymmetric bifunctionalization of 5,15-disubstituted porphyrins: A simple preparation of meso acyl-, alkoxycarbonyl-, and carbamoyl-substituted meso-formylporphyrins

Article abstract of DOI:10.1039/b817551a

An efficient one-pot procedure which converts 5,15-disubstituted porphyrins into their corresponding meso acyl-, alkoxycarbonyl-, and carbamoyl-substituted meso-formylporphyrins has been developed, where the procedure involves a sequential S_NAr

Full text of DOI:10.1039/b817551a

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An efficient one-pot procedure for asymmetric bifunctionalization of
5,15-disubstituted porphyrins: a simple preparation of meso acyl-,
alkoxycarbonyl-, and carbamoyl-substituted meso-formylporphyrinsw
Toshikatsu Takanami,* Atsushi Wakita, Jun Matsumoto, Sadashige Sekine and Kohji Suda*
Received (in Cambridge, UK) 6th October 2008, Accepted 31st October 2008
First published as an Advance Article on the web 19th November 2008
DOI: 10.1039/b817551a
An efficient one-pot procedure which converts 5,15-disubstituted
porphyrins into their corresponding meso acyl-, alkoxycarbonyl-,
and carbamoyl-substituted meso-formylporphyrins has been
developed, where the procedure involves a sequential SNAr reac-
tion of porphyrins with PyMe2SiCH2Li, followed by acylation or
related reactions and oxidation.
There has been continuous interest in the synthesis of por-
phyrins and their derivatives due to their ubiquitous nature
and broad spectrum of applications in different fields such as
catalysis, medicine, molecular recognition/sensing, and mate-
rials science.1,2 It is also well documented that the physical,
chemical and biological properties of porphyrins can be pre-
cisely controlled through the introduction of peripheral sub-
stituents with diverse electronic and steric environments.1 As a
consequence, intensive efforts have been dedicated to the
discovery of new synthetic intermediates and strategies for
preparing porphyrin derivatives with a variety of peripheral
substituents.3–5 Asymmetric porphyrins bearing two distinct
reactive carbonyl groups at the meso positions (their genera-
lized structure is illustrated in Fig. 1) are regarded as valuable
building blocks for more complex porphyrin systems, as each
of these carbonyl groups directly attached on the porphyrin
core can be individually replaced with other functionalities.
However, to our knowledge, there are as yet no reports on the
preparation of such asymmetric porphyrins that bear two
carbonyl groups with distinct chemical reactivities.6
Fig. 1 Asymmetric bifunctionalized porphyrins bearing two different
carbonyl groups at the meso-positions.
Recently, our research group disclosed a novel direct meso
formylation of the 5,15-disubstituted porphyrins 1 based on a
one-pot three-step procedure via the SNAr reaction of por-
phyrins with PyMe2SiCH2Li followed by hydrolysis and
oxidation with DDQ, where the PyMe2SiCH2 group works
as a latent formyl functionality in the reaction.5c As shown in
Scheme 1, the reaction proceeds through the anionic inter-
mediate I generated from the SNAr reaction of porphyrins
with PyMe2SiCH2Li, which is subsequently hydrolyzed to
form the dihydroporphyrin II and that in turn is oxidized to
Herein, we report our studies on the development of an
efficient, general one-pot procedure for the direct conversion of
the 5,15-disubstituted porphyrin 1 into the meso-acyl-, meso-
alkoxycarbonyl-, and meso-carbamoyl-substituted meso-formyl-
porphyrins 3, 5, and 7, respectively. The process involves a
sequential nucleophilic substitution (SNAr reaction)7 with
(2-pyridyldimethylsilyl)methyllithium (PyMe2SiCH2Li)8 followed
by acylation or related reactions and oxidation. This simple
one-pot procedure can be carried out under mild conditions
with a wide range of 5,15-diaryl- and 5,15-dialkyl-substituted
porphyrins, allowing direct access to a variety of asymmetric
porphyrins with formyl groups and other chemically reactive
functionalities directly attached at the meso positions in good
yields.
Meiji Pharmaceutical University, 2-522-1, Noshio, Kiyose,
Tokyo 204-8588, Japan. E-mail: takanami@my-pharm.ac.jp.
E-mail: suda@my-pharm.ac.jp; Fax: +81-42-495-8779
w Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b817551a
Scheme 1 Reaction pathway for one-pot formylation of 5,15-disubsti-
tuted porphyrins using SNAr reaction with PyMe2SiCH2Li, and our
hypothesis for their direct asymmetric bifunctionalization.
ꢀc
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Chem. Commun., 2009, 101–103 | 101

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the meso-formylporphyrin III. Thus, we envisaged that
the anionic intermediate I would be trapped by electrophiles
(FG-X) such as acyl chlorides to form the asymmetric
porphyrin IV with a formyl group and other chemically
reactive functionalities.
Table 2 One-pot preparation of meso-alkoxycarbonyl-substituted
formylporphyrins 5 using chloroformates 4 as an electrophile
In order to confirm our hypothesis, we initially examined
the asymmetric bifunctionalization of 5,15-diphenylporphyrin
1a by using a one-pot procedure involving a SNAr reaction
with PyMe2SiCH2Li followed by the trapping of the resulting
anion with benzoylchloride 2a as an electrophile and oxida-
tion. Thus, a solution of 1a in THF was treated in the
following order with: 10 equiv. of PyMe2SiCH2Li at À78 1C
to room temperature, 10 equiv. of 2a at À40 1C to room
temperature, aqueous HCl at 0 1C, and then 10 equiv. of DDQ
at 65 1C. The one-pot sequential reaction proceeded smoothly,
enabling the direct conversion of 1a into the desired
asymmetric bifunctionalized product 5-benzoyl-15-formyl-
10,20-diphenylporphyrin 3aa in 85% yield (Table 1, entry 1).
To determine the scope of the above procedure, different
5,15-substituted free-base porphyrins 1a–e and acylchlorides
2a–e were employed as substrates (Table 1). The benzoyl-
chloride derivatives 2b and 2c with methoxy and trifluoro-
methyl substituents on their aromatic ring are compatible with
the asymmetric bifunctionalization of 1a to afford the corres-
ponding meso acyl-substituted formylporphyrins 3ab and 3ac
in good yields (entries 2 and 3). Both the primary and the
secondary aliphatic acylchlorides could also participate as
substrates in the transformation (entries 4 and 5). With regard
to 5,15-diarylporphyrins, substrates with electron-rich,
electron-neutral, and electron-poor aromatic moieties on the
porphyrin core are all compatible with the asymmetric
bifunctionalization conditions (entries 6–8). The 5,15-dialkyl-
substituted porphyrin 1e also yielded a favorable reaction
(entry 9).
Entry Porphyrin
Acylchloride
Product Yielda (%)
1
2
3
4
5
6
7
1a (R1 = Ph)
4a (R2 = Me)
4b (R2 = iPr)
5aa
5ab
76
70
46
65
62
60
60
1a (R1 = Ph)
1a (R1 = Ph)
1b (R1 = p-Tol)
4c (R2 = CH2Ph) 5ac
4a (R2 = Me)
5ba
5ca
5da
5ea
1c (R1 = 3-MeOPh) 4a (R2 = Me)
1d (R1 = 3-CF3Ph) 4a (R2 = Me)
1e (R1 = iBu)
4a (R2 = Me)
a
Isolated yield.
4a (10 equiv.), aqueous HCl, and DDQ (10 equiv.) led to the
formation of 5-formyl-15-methoxycarbonyl-10,20-diphenyl-
porphyrin 5aa in 76% yield (entry 1). Likewise, other
porphyrins 1b–e and chloroformates including isopropyl-
chloroformate 4b and benzylchloroformate 4c readily
participated in the transformation as substrates, furnishing
the corresponding meso-alkoxycarbonyl-substituted formyl-
porpyrins in good to moderate yields (entries 2–7).
The one-pot procedure can also be applied to the synthesis
of the meso-carbamoyl-substituted formylporphyrins 7 by
using isocyanates 6 as an electrophile (Table 3). For example,
subjecting the diphenylporphyrin 1a and phenylisocyanates
6a–c substituted with electron-rich, electron-neutral, and
electron-poor arenes to the asymmetric bifunctionalization
conditions led to the desired meso-carbamoyl-substituted
formylporphyrins in 73–60% yields (entries 1–3). The process
is not limited to arylisocyanates. Nonbranched, branched,
and cyclic alkylisocyanates were all compatible with the
With the use of the chloroformate 4 as an electrophile, the
meso-alkoxycarbonyl-substituted formylporphyrins 5 can also
be prepared similarly (Table 2). For example, the sequential
treatment of 1a with PyMe2SiCH2Li (10 equiv.) followed by
Table
porphyrins 3 using acylchloride 2 as an electrophile
1
One-pot preparation of meso-acyl-substituted formyl-
Table 3 One-pot preparation of meso-carbamoyl-substituted formyl-
porphyrins 7 using isocyanates 6 as an electrophile
Entry Porphyrin
Acylchloride
Product Yielda (%)
Entry Porphyrin
Isocyanate
Product Yielda (%)
1
2
3
4
5
6
7
8
9
1a (R1 = Ph)
2a (R2 = Ph)
3aa
85
70
77
68
61
70
74
72
71
1
2
3
4
5
6
7
8
9
1a (R1 = Ph)
6a (R2 = Ph)
7aa
73
65
60
85
74
71
66
68
67
1a (R1 = Ph)
1a (R1 = Ph)
1a (R1 = Ph)
1a (R1 = Ph)
1b (R1 = p-Tol)
2b (R2 = 4-MeOPh) 3ab
2c (R2 = 4-CF3Ph) 3ac
1a (R1 = Ph)
1a (R1 = Ph)
1a (R1 = Ph)
1a (R1 = Ph)
1a (R1 = Ph)
6b (R2 = 4-MeOPh) 7ab
6c (R2 = 4-BrPh)
6d (R2 = Et)
7ac
7ad
7ae
7af
7cd
7dd
7ed
2d (R2 = Me)
2e (R2 = iPr)
2a (R2 = Ph)
3ad
3ae
3ba
3ca
3da
3ea
6e (R2 = iPr)
6f (R2 = c-C6H11
)
1c (R1 = 3-MeOPh) 2a (R2 = Ph)
1d (R1 = 3-CF3Ph) 2a (R2 = Ph)
1c (R1 = 3-MeOPh) 6d (R2 = Et)
1d (R1 = 3-CF3Ph) 6d (R2 = Et)
1e (R1 = iBu)
2a (R2 = Ph)
1e (R1 = iBu)
6d (R2 = Et)
a
a
Isolated yield.
Isolated yield.
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102 | Chem. Commun., 2009, 101–103

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asymmetric bifunctionalization conditions, and gave the
corresponding asymmetric porphyrins in good yields (entries
4–6). As expected, the reactions of other porphyrins 1c–e with
ethylisocyanate 6e proceeded smoothly to furnish the corres-
ponding meso-carbamoyl-substituted formylporphyrins 7cd,
7dd, and 7ed in 68–66% yields (entry 7–9).
3 For some examples of leading works on functionalization reactions
of porphyrins, see: (a) S. G. DiMagno, V. S.-Y. Lin and
M. J. Therien, J. Am. Chem. Soc., 1993, 115, 2513;
(b) S. G. DiMagno, V. S.-Y. Lin and M. J. Therien, J. Org. Chem.,
1993, 58, 5983; (c) R. W. Boyle, C. K. Johnson and D. Dolphin,
J. Chem. Soc., Chem. Commun., 1995, 527; (d) Y. Chen and
X. P. Zhang, J. Org. Chem., 2003, 68, 4432; (e) G. Y. Gao,
A. J. Colvin, Y. Chen and X. P. Zhang, Org. Lett., 2003, 5, 3261;
(f) G. Y. Gao, Y. Chen and X. P. Zhang, Org. Lett., 2004, 6, 1837;
(g) G. Y. Gao, A. J. Colvin, Y. Chen and X. P. Zhang, J. Org.
Chem., 2004, 69, 8886; (h) H. Hata, H. Shinokubo and A. Osuka,
J. Am. Chem. Soc., 2005, 127, 8264; (i) C. Liu, D.-M. Shen and
Q.-Y. Chen, J. Org. Chem., 2007, 72, 2732; (j) G.-Y. Gao,
J. V. Ruppel, D. B. Allen, Y. Chen and X. P. Zhang, J. Org. Chem.,
2007, 72, 9060; (k) Y. Matano, T. Shinokura, K. Matsumoto,
H. Imahori and H. Nakano, Chem.–Asian J., 2007, 2, 1417;
(l) S. Horn, N. N. Sergeeva and M. O. Senge, J. Org. Chem.,
2007, 72, 5414; (m) Y. Matano, K. Matsumoto, Y. Nakao, H. Uno,
S. Sakaki and H. Imahori, J. Am. Chem. Soc., 2008, 130, 4588.
4 (a) M. O. Senge, Acc. Chem. Res., 2005, 38, 733; (b) M. O. Senge,
S. S. Hatscher, A. Wiehe, K. Dahms and A. Kelling, J. Am. Chem.
Soc., 2004, 126, 13634; (c) K. Dahms, M. O. Senge and M. B. Bakar,
Eur. J. Org. Chem., 2007, 3833; (d) X. Feng and M. O. Senge,
Tetrahedron, 2000, 56, 587; (e) Y. M. Shaker and M. O. Senge,
Heterocycles, 2005, 65, 2441; and references cited therein.
5 We have reported several functionalization reactions of porphyrins:
(a) T. Takanami, M. Hayashi, F. Hino and K. Suda, Tetrahedron
Lett., 2003, 44, 7353; (b) T. Takanami, M. Hayashi, H. Chijimatsu,
W. Inoue and K. Suda, Org. Lett., 2005, 7, 3937; (c) T. Takanami,
A. Wakita, A. Sawaizumi, K. Iso, H. Onodera and K. Suda, Org.
Lett., 2008, 10, 685; (d) T. Takanami, M. Yotsukura, W. Inoue,
N. Inoue, F. Hino and K. Suda, Heterocycles, 2008, 76, 439.
6 Multi-step total syntheses of asymmetric bifunctionalized por-
phyrins that bear two different functional groups, such as acyl
and hydroxymethyl, borolanyl and alkynyl, vinyl and alkynyl, and
so on, at the meso-positions have been reported, see:
(a) T.-G. Zhang, Y. Zhao, I. Asselberghs, A. Persoons, K.
Clays and M. J. Therien, J. Am. Chem. Soc., 2005, 127, 9710;
(b) S. Shanmugathasan, C. K. Johnson, C. Edwards,
E. K. Matthews, D. Dolphin and R. W. Boyle, J. Porphyrins
Phthalocyanines, 2000, 4, 228; (c) M. Yeung, A. C. H. Ng, M. G.
B. Drew, E. Vorpagel, E. M. Breitung, R. J. McMahon and D. K.
P. Ng, J. Org. Chem., 1998, 63, 7143; (d) T. S. Balaban, A. D. Bhise,
M. Fischer, M. Linke-Schaetzel, C. Roussel and N. Vanthuyne,
Angew. Chem., Int. Ed., 2003, 42, 2140; (e) Z. Yao, J. Bhaumik,
S. Dhanalekshmi, M. Ptaszek, P. A. Rodriguez and J. S. Lindsey,
Tetrahedron, 2007, 63, 10657.
Although most of the reactions described above were
performed on a 0.1 mmol scale (see ESIw), they can easily be
scaled up if needed. For example, the reaction employing the
porphyrin 1a and the ethylisocyanate 6e as substrates can be
carried out on a 1 mmol scale under similar reaction condi-
tions, furnishing the desired porphyrin 7ae at 515 mg and in
92% yield, which is virtually the same yield as that on a
0.1 mmol scale (cf. Table 3, entry 4).
In summary, we have developed a novel and facile one-pot
procedure for the direct asymmetric bifunctionalization of
5,15-disubstituted free base porphyrins via a sequential SNAr
reaction with PyMe2SiCH2Li followed by acylation or related
reactions and oxidation. This simple one-pot procedure pro-
vides an efficient approach to the synthesis of a variety of
asymmetric free base porphyrins which bear a formyl group
and other chemically reactive functional groups, such as acyl,
alkoxycarbonyl, and carbamoyl functionalities, at the meso
positions in good yields. The operational simplicity as well as
the mild reaction conditions and the broad substrate scope
render this method attractive for the synthesis of more
complicated porphyrin derivatives, which could find potential
applications in areas such as catalysis, medicine, and mole-
cular recognition/sensing. Such studies are currently under
way in our laboratory, the results from which will be reported
in due course.
This work was supported by a Grant-in-Aid for Scientific
Research (KAKENHI) from JSPS and a Special Grant
(GAKUCHO-GRANT) from Meiji Pharmaceutical University.
Notes and references
1 The Porphyrin Handbook, ed. K. M. Kadish, K. M. Smith and
R. Guilard, Academic Press, San Diego, 1999–2003, vol. 1–20.
2 We have developed porphyrin-based Lewis acid catalysts that can
promote regio- and stereoselective isomerization of epoxides to
carbonyl compounds and Claisen rearrangement of allylvinyl ethers,
see: (a) K. Suda, K. Baba, S. Nakajima and T. Takanami, Chem.
Commun., 2002, 2570; (b) K. Suda, T. Kikkawa, S. Nakajima and
T. Takanami, J. Am. Chem. Soc., 2004, 126, 9554; (c) T. Takanami,
M. Hayashi, F. Hino and K. Suda, Tetrahedron Lett., 2005, 46,
2893; (d) T. Takanami, M. Hayashi, K. Iso, H. Nakamoto and
K. Suda, Tetrahedron, 2006, 62, 9467.
7 Porphyrin modification based on the SNAr strategy with organo-
lithium reagents was pioneered by the research group of Senge.
They have widely applied the strategy to the preparation of
various asymmetric porphyrins bearing different alkyl and/or aryl
substituents at the meso positions, see ref. 4.
8 (a) K. Itami, K. Mitsudo and J. Yoshida, Tetrahedron Lett., 1999,
40, 5533; (b) K. Itami, K. Mitsudo and J. Yoshida, Tetrahedron
Lett., 1999, 40, 5537; (c) K. Itami, T. Kamei, K. Mitsudo,
T. Nokami and J. Yoshida, J. Org. Chem., 2001, 66, 3970.
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Chem. Commun., 2009, 101–103 | 103