A facile one-pot preparation of meso-hydroxymethylporphyrins via a sequential SNAr reaction with (2-pyridyldimethylsilyl)methyllithium followed by hydrolysis and aerobic oxidation

Article abstract of DOI:10.1016/j.tetlet.2008.10.087

The first, direct meso-hydroxymethylation of 5,15-substituted porphyrins can effectively be obtained by a simple one-pot procedure involving a sequential S_NAr reaction of porphyrins with (2-pyridyldimethylsilyl)methyllithium, followed by hydrol

Full text of DOI:10.1016/j.tetlet.2008.10.087

Tetrahedron Letters 50 (2009) 68–70
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A facile one-pot preparation of meso-hydroxymethylporphyrins via a
sequential SNAr reaction with (2-pyridyldimethylsilyl)methyllithium
followed by hydrolysis and aerobic oxidation
*
*
Toshikatsu Takanami , Jun Matsumoto, Yoko Kumagai, Aoyo Sawaizumi, Kohji Suda
Meiji Pharmaceutical University, 2-522-1, Noshio, Kiyose, Tokyo 204-8588, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The first, direct meso-hydroxymethylation of 5,15-substituted porphyrins can effectively be obtained by a
simple one-pot procedure involving a sequential SNAr reaction of porphyrins with (2-pyridyldimethyl-
silyl)methyllithium, followed by hydrolysis and aerobic oxidation at ambient O2 pressure.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 24 September 2008
Revised 16 October 2008
Accepted 20 October 2008
Available online 1 November 2008
Porphyrins and related tetrapyrrolic macrocycles are a class of
chemically and biologically important heterocyclic compounds
that have found broad applications in the areas of catalysis, med-
icine, and material science.1,2 In this regard, a considerable effort
has been devoted to the discovery of new approaches to the syn-
thesis of various useful porphyrin systems.3–5 It is known that
hydroxymethyl-substituted porphyrins are among the most ver-
satile building blocks that allow for subsequent transformations
into more complicated porphyrin derivatives.6 The typical proce-
dure for the preparation of hydroxymethyl-substituted porphy-
1) PyMe2SiCH2Li (10 equiv)
THF, –78 °C → rt
R
R
2) aqueous HCl, 0 °C
NH
N
NH
N
DDQ
3)
(10 equiv), 65 °C
O
H
One-pot
N
HN
N
HN
R
R
1
2
= PyMe2SiCH2Li
SNAr
N
SiMe2
Oxidation
rins involves
a
stepwise process through the traditional
Li
Vilsmeier formylation of porphyrins, followed by reduction.7
However, to the best of our knowledge, no existing methods offer
a direct introduction of the hydroxymethyl group into the por-
phyrin core.8
R
NH
R
R
SiMe2Py
H
H
N
NH
N
N
NH
N
N
SiMe2Py
Oxidation
OH
Recently, we have demonstrated a novel direct meso formyl-
ation of 5,15-disubstituted porphyrins 1 based on a one-pot
three-step procedure via nucleophilic addition (SNAr reaction)4
with (2-pyridyldimethylsilyl)methyllithium (PyMe2SiCH2Li),9 fol-
lowed by hydrolysis and oxidation.5c As shown in Scheme 1, the
process involves the DDQ-promoted oxidative conversion of sily-
lmethyl-substituted dihydroporphyrins A, initially formed adducts
by the SNAr reaction, into meso-formylporphyrins 2 via the sequen-
tial generation of silylmethylporphyrins B and hydroxymethylpor-
phyrins 3.
N
HN
H
HN
HN
Oxidation
R
R
R
A
B
3
Scheme 1. Reaction pathways for the direct meso-formylation of 5,15-disubstituted
porphyrins using one-pot procedure involving SNAr reaction with PyMe2SiCH2Li,
followed by hydrolysis and DDQ oxidation.
Herein, we report an aerobic oxidation version of this reaction,
which can effectively afford meso-hydroxymethylporphyrins 3 and
not meso-formylporphyrins 2. The crucial element of the reaction is
the use of molecular oxygen instead of DDQ as an oxidizing
agent,10 which effectively brings about the conversion of A into 3
but without further oxidation of the hydroxymethyl functionality
to the CHO group, thereby facilitating the unprecedented direct
meso-hydroxymethylation of the porphyrin core. This reported
reaction proceeds at ambient O2 pressure, and these mild, green,
and economic conditions have been employed for a range of
5,15-diaryl- and 5,15-dialkyl-substituted free-base porphyrins as
well as their metal complexes, providing a new series of porphy-
rins with a hydroxymethyl functionality attached at the meso posi-
tion in good yields.
* Corresponding authors. Tel.: +81 42 495 8780; fax: +81 42 495 8779.
E-mail addresses: takanami@my-pharm.ac.jp (T. Takanami), suda@my-pharm.
ac.jp (K. Suda).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.087

T. Takanami et al. / Tetrahedron Letters 50 (2009) 68–70
69
1) PyMe2SiCH2Li (10 equiv)
Ph
Ph
[O]
O2
O2
air
hydrolysis
time (h)
3a
THF, -78 °C → rt
2) hydrolysis, 0 °C
3) [O], rt, time
NH
N
N
1 M HCl
H2O
2
1.5
8
56 %a)
76 %a)
71 %a)
NH
N
OH
One-pot
HN
N
HN
H2O
Ph
Ph
1a
3a
a) Isolated yield.
Scheme 2. Direct meso-hydroxymethylation of 5,15-diphenylporphyrin by SNAr reaction using PyMe2SiCH2Li, hydrolysis, and aerobic oxidation.
In previous work, the sequential treatment of 5,15-diph-
enylporphyrin 1a with 10 equiv of PyMe2SiCH2Li at À78 °C,
followed by 1 M HCl at 0 °C and 10 equiv of DDQ at 65 °C, afforded
the corresponding 10-formyl-5,15-diphenylporphyrin 2a in 91%
yield.5c On the other hand, a similar reaction using dioxygen in-
stead of DDQ as an oxidizing agent at ambient temperature and
pressure resulted in the formation of 10-hydroxymethyl-5,15-
diphenylporphyrin 3a in 56% yield along with an inseparable com-
plex mixture of byproducts (Scheme 2).11 Upon further investiga-
tion of the reaction conditions, conducting the aerobic oxidation
under nearly neutral conditions was found to produce a substantial
improvement. Thus, a solution of 1a in tetrahydrofuran was trea-
ted in the following order: 10 equiv of PyMe2SiCH2Li at À78 °C to
room temperature, H2O at 0 °C, and aerobic oxidation for 1.5 h at
ambient temperature and O2 pressure. Under these conditions,
the reaction proceeded cleanly to provide a 76% yield of the desired
meso-hydroxymethylporphyrin 3a without byproducts other than
a trace amount (<5%) of the meso-formylporphyrin 2a, which could
be detected in the 1H NMR spectrum of the crude reaction mixture.
Essentially, the same result was also obtained using air in lieu of
pure dioxygen as an oxidizing agent, although a prolonged oxida-
tion reaction time (8 h) was necessary to complete the reaction.
The hydroxymethylation reaction with various porphyrins is
summarized in Table 1.12 As can be observed, this process was
found to have a wide scope with regard to the central metal ions
and peripheral substituents of the porphyrin ring. For example,
5,15-diarylporphyrins with electron-rich, electron-neutral, and
electron-poor aromatic moieties on the porphyrin core are all com-
patible with the reaction conditions (entries 1–5). The hydroxyme-
thylation was applicable to the substrate 1f containing a silyl
functionality, leaving the functional group untouched (entry 6).
5,15-Di(iso-butyl)porphyrin 1g could also participate as a substrate
in the reaction, furnishing the hydroxymethylporphyrin in 66%
yield (entry 7). This process is not limited to free-base porphyrins;
both nickel and zinc complexes could be substituted to obtain the
meso hydroxymethyl-substituted complexes in good yields (entries
8–15). It is of note that the central metal ions of these metal com-
plexes were entirely preserved during the hydroxymethylation
(entries 12–15); in contrast, complete demetallation from zinc por-
phyrin complexes was observed in our previous meso-formylation
with DDQ as an oxidizing agent.5c
While the detailed mechanism has not yet been experimentally
confirmed, we tentatively assume the reaction pathway of the
hydroxymethylation as shown in Scheme 3. In this reaction path-
way, the oxidative conversion of the intermediary B into the
meso-hydroxymethylporphyrin 3 proceeds by a Fleming-Tamao
oxidation mechanism,13 in which hydrogen peroxide, generated
in situ from aerobic oxidation of dihydroporphyrin A, is mainly
responsible for the oxidation of the silyl group to the hydroxyl
group.14 Indeed, a brief experiment using aqueous hydrogen
peroxide as an oxidant under an anaerobic condition resulted in
the transformation of porphyrin 1a into the meso-hydroxymethyl
derivative 3a in 53% yield, although the reaction conditions
have not yet been optimized. Further experiments will be
necessary to obtain insights into the precise mechanism of the
hydroxymethylation.
In summary, we have developed an efficient one-pot procedure
for the first, direct hydroxymethylation of 5,15-disubstituted por-
phyrins at the meso position. This involves a sequential SNAr reac-
Table 1
One-pot conversion of 5,15-disubstituted porphyrins into meso-hydroxymethylpor-
phyrins by SNAr reaction using PyMe2SiCH2Li, hydrolysis, and aerobic oxidation
1) PyMe2SiCH2Li (10 equiv)
R
R
M
R
THF, -78 °C → rt
2) H2O, 0 °C
3) O2, rt
1) PyMe2SiCH2Li (10 equiv)
R
R
THF, –78 °C → rt
2) H2O, 0 °C
3) O2, rt
N
N
N
N
N
N
N
N
OH
M
NH
N
NH
N
OH
One-pot
One-pot
N
HN
N
HN
R
1
3
R
R
1
Entry
Substrate
M
R
Product
Yielda (%)
3
Si-OH
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1a
1b
1c
1d
1e
1f
1g
Ni-1a
Ni-1b
Ni-1d
Ni-1f
Zn-1a
Zn-1c
Zn-1f
Zn-1g
2H
2H
2H
2H
2H
2H
2H
Ni
Ni
Ni
Ni
Zn
Zn
Zn
Zn
Ph
p-Tolyl
3a
3b
3c
3d
3e
3f
3g
Ni-3a
Ni-3b
Ni-3d
Ni-3f
Zn-3a
Zn-3c
Zn-3f
Zn-3g
76
70
75
55
56
71
66
82
70
72
72
57
83
62
65
PyMe2SiCH2Li
SNAr
The Fleming-
Tamao Oxidation
3-MeOC6H4
3,4,5-(MeO)3C6H2
3-CF3C6H4
4-(i-Pr3SiC„C)C6H4
i-Bu
H
2O2
R
R
Ph
p-Tolyl
NH
N
N
SiMe2Py
H
H
NH
N
SiMe2Py
3,4,5-(MeO)3C6H2
4-(i-Pr3SiC„C)C6H4
Ph
3-MeOC6H4
4-(i-Pr3SiC„C)C6H4
i-Bu
HN
N
HN
H
O2
R
R
B
A
Scheme 3. Plausible reaction pathway for the one-pot meso-hydroxymethylation of
a
Isolated yield.
5,15-disubstituted porphyrins.

70
T. Takanami et al. / Tetrahedron Letters 50 (2009) 68–70
Crossley, M. J.; Gosper, J. J.; Harding, M. M.; Officer, D. L.; Reid, D. C. W. J.
Porphyrins Phthalocyanines 2002, 6, 708–719; (f) Higuchi, H.; Shimizu, K.;
Takeuchi, M.; Ojima, J.; Sugiura, K.; Sakata, Y. Bull. Chem. Soc. Jpn. 1997, 70,
1923–1933; (g) Torpey, J. W.; Ortiz de Montellano, P. R. J. Org. Chem. 1996, 60,
2195–2199; (h) Arnold, D.; Johnson, A. W.; Winter, M. J. Chem. Soc., Perkin
Trans. 1 1977, 1643–1647.
tion with PyMe2SiCH2Li, followed by hydrolysis and aerobic oxida-
tion at ambient O2 pressure. This process can readily accommodate
a wide variety of substrates including 5,15-dialkyl- and 5,15-dia-
ryl-substituted free-base porphyrins and their metal complexes,
affording the corresponding meso-hydroxymethylporphyrins in
good yields. Further investigations into the utility of the products,
that is, meso-hydroxymethylporphyrins, as building blocks for the
construction of porphyrin derivatives that show various useful
functions are currently underway.
7. This stepwise method also presents the following limitations: The substrate
porphyrins are restricted to only Ni(II) and Cu(II) complexes which lack acid-
sensitive functional groups, as the Vilsmeier formylation and related reactions
require the use of strong acidic conditions. For reviews, see: (a) Balakumar, A.;
Muthukumaran, K.; Lindsey, J. S. J. Org. Chem. 2004, 69, 5112–5115; (b)
Ponomarev, G. V. Chem. Heterocycl. Compd. 1994, 30, 1444–1465.
8. Multi-step total syntheses of hydroxymethyl-substituted porphyrins have been
reported by Lindsey et al. (see Refs. 5a,b).
Acknowledgments
9. (a) Itami, K.; Mitsudo, K.; Yoshida, J. Tetrahedron Lett. 1999, 40, 5533–5536; (b)
Itami, K.; Mitsudo, K.; Yoshida, J. Tetrahedron Lett. 1999, 40, 5537–5540; (c)
Itami, K.; Kamei, T.; Mitsudo, K.; Nokami, T.; Yoshida, J. J. Org. Chem. 2001, 66,
3970–3976.
10. The choice of oxidation conditions is of critical importance to the syntheses of
porphyrins via dihydroporphyrins, and a variety of oxidants and oxidative acid
catalysts have been exploited for this purpose, see: (a) Lindsey, J. S. In The
Porphyrin Handbook; Kadish, K. M., Smith, K. M., Guilard, R., Eds.; Academic
Press: San Diego, 2000; Vol. 1, p 45; (b) Johnstone, R. A. W.; Nunes, M. L. P. G.;
Pereira, M. M.; Gonsalves, M. d’A. R.; Serra, A. C. Heterocycles 1996, 43, 1423–
1437 and references cited therein.
This work was partly supported by a Grant-in-Aid for Scientific
Research (KAKENHI) from JSPS and by a Special Grant (GAKUCHO-
GRANT) from Meiji Pharmaceutical University.
References and notes
1. The Porphyrin Handbook; Smith, K. M., Guilard, R., Eds.; Academic Press: San
Diego, 1999–2003, Vols. 1–20.
11. These reaction conditions seem to lead to decomposition of porphyrin
derivatives involved in the reaction; oxidative ring-opening degradation of
porphyrins to linear tetrapyrrolic compounds under aerobic conditions has
been reported: (a) Asano, N.; Uemura, S.; Kinugawa, T.; Akasaka, H.; Mizutani,
T. J. Org. Chem. 2007, 72, 5320–5326; (b) Yamauchi, T.; Mizutani, T.; Wada, K.;
Horii, S.; Furukawa, H.; Masaoka, S.; Chang, H.-C.; Kitagawa, S. Chem. Commun.
2005, 1309–1311; (c) Kumar, D.; de Visser, S. P.; Shaik, S. J. Am. Chem. Soc. 2005,
2. We have developed porphyrin-based Lewis acid catalysts that can promote
regio- and stereo selective isomerization of epoxides to carbonyl compounds
and Claisen rearrangement of allylvinyl ethers, see: (a) Suda, K.; Baba, K.;
Nakajima, S.; Takanami, T. Chem. Commun. 2002, 2570–2571; (b) Suda, K.;
Kikkawa, T.; Nakajima, S.; Takanami, T. J. Am. Chem. Soc. 2004, 126, 9554–9555;
(c) Takanami, T.; Hayashi, M.; Suda, K. Tetrahedron Lett. 2005, 46, 2893–2896;
(d) Takanami, T.; Hayashi, M.; Iso, K.; Nakamoto, H.; Suda, K. Tetrahedron 2006,
62, 9467–9474; (e) Takanami, T.; Nakajima, S.; Nakadai, S.; Hino, F.; Suda, K.
Heterocycles, 2008 [COM-08-S(F)27]. Available from: http://www.heterocycles.
jp/library.
_
127, 8204–8213; (d) Kalish, H.; Lee, H. M.; Olmstead, M. M.; Latos-Grazyn´ ski,
L.; Rath, S. P.; Balch, A. L. J. Am. Chem. Soc. 2003, 125, 4674–4675 and references
cited therein.
12. Typical procedure for the one-pot hydroxymethylation of 5,15-disubstituted
porphyrins: An oven-dried 100 mL round-bottomed flask equipped with a
magnetic stirring bar and a three-way stopcock was charged with a porphyrin
1 (0.1 mmol). The flask was evacuated and flushed with argon (three times),
and then absolute THF (40 mL) was added. To the solution was added an
ethereal solution of PyMe2SiCH2Li (prepared by adding 0.65 mL of 1.58 M tBuLi
in pentane to a solution of 1.2 mmol 2-pyridyltrimethylsilane in 1.5 mL of
ether, followed by stirring at À78 °C for 2 h)9 via a cannula at À78 °C. After
being stirred at À78 °C for 5 min, the cooling bath was removed and the
mixture was stirred at room temperature. The reaction was complete within
3 h, having been monitored by TLC. Upon completion of the reaction, the
mixture was cooled to 0 °C, and then 5 mL of H2O was added. After being
stirred at 0 °C for 10 min, the mixture was stirred under O2 (using a balloon) at
room temperature for 1–5 h, and poured into brine. The organic layer was
separated, and the aqueous layer was extracted with CH2Cl2. The organic layers
were combined, concentrated in vacuo, and subjected to chromatography on
silica gel using 2–10% hexane/CH2Cl2 as an eluent to give the meso-
hydroxymethylporphyrin 3. All the compounds reported herein showed
spectral data consistent with the assigned structures. Selected data: For 3a:
1H NMR (CDCl3) d: 10.20 (1H, s), 9.66 (2H, d, J = 4.7 Hz), 9.30 (2H, d, J = 4.4 Hz),
9.04 (2H, d, J = 4.7 Hz), 8.98 (2H, d, J = 4.4 Hz), 8.22 (4H, d, J = 6.6 Hz), 7.86–7.74
(6H, m), 7.02 (2H, s), 3.73 (1H, br), À3.14 (2H, s); IR (KBr): 3308, 1597, 1561,
3. For some examples of recent leading works on porphyrin functionalization
reactions, see: (a) Chen, Y.; Zhang, X. P. J. Org. Chem. 2003, 68, 4432–4438; (b)
Gao, G. Y.; Colvin, A. J.; Chen, Y.; Zhang, X. P. Org. Lett. 2003, 5, 3261–3264; (c)
Hata, H.; Shinokubo, H.; Osuka, A. J. Am. Chem. Soc. 2005, 127, 8264–8265; (d)
Liu, C.; Shen, D.-M.; Chen, Q.-Y. J. Org. Chem. 2007, 72, 2732–2736; (e) Gao, G.-
Y.; Ruppel, J. V.; Allen, D. B.; Chen, Y.; Zhang, X. P. J. Org. Chem. 2007, 72, 9060–
9066; (f) Matano, Y.; Shinokura, T.; Matsumoto, K.; Imahori, H.; Nakano, H.
Chem. Asian J. 2007, 2, 1417–1429; (g) Horn, S.; Sergeeva, N. N.; Senge, M. O. J.
Org. Chem. 2007, 72, 5414–5417; (h) Matano, Y.; Matsumoto, K.; Nakao, Y.; Uno,
H.; Sakaki, S.; Imahori, H. J. Am. Chem. Soc. 2008, 130, 4588–4589; (i) Gao, G.-Y.;
Ruppel, J. V.; Fields, K. B.; Xu, X.; Chen, Y.; Zhang, X. P. J. Org. Chem. 2008, 73,
4855–4858; (j) Yamada, H.; Kushibe, K.; Mitsuogi, S.; Okujima, T.; Uno, H.; Ono,
N. Tetrahedron Lett. 2008, 49, 4731–4733; (k) Mizumura, M.; Shinokubo, H.;
Osuka, A. Angew. Chem., Int. Ed. 2008, 47, 5378–5381 and references cited
therein.
4. Senge et al. have developed a unique, yet useful, method for the preparation of
meso-substituted porphyrins utilizing an SNAr reaction with organolithium
reagents: (a) Senge, M. O. Acc. Chem. Res. 2005, 38, 733–743; (b) Senge, M. O.;
Hatscher, S. S.; Wiehe, A.; Dahms, K.; Kelling, A. J. Am. Chem. Soc. 2004, 126,
13634–13635; (c) Dahms, K.; Senge, M. O.; Bakar, M. B. Eur. J. Org. Chem. 2007,
3833–3848 and references cited therein.
5. We have reported several functionalization reactions of porphyrins: (a)
Takanami, T.; Hayashi, M.; Hino, F.; Suda, K. Tetrahedron Lett. 2003, 44, 7353–
7357; (b) Takanami, T.; Hayashi, M.; Chijimatsu, H.; Inoue, W.; Suda, K. Org.
Lett. 2005, 7, 3937–3940; (c) Takanami, T.; Wakita, A.; Sawaizumi, A.; Iso, K.;
Onodera, H.; Suda, K. Org. Lett. 2008, 10, 685–687; (d) Takanami, T.; Yotsukura,
M.; Inoue, W.; Inoue, N.; Hino, F.; Suda, K. Heterocycles 2008, 76, 439–453.
6. (a) Yao, Z.; Bhaumik, J.; Dhanalekshmi, S.; Ptaszek, M.; Rodriguez, P. A.; Lindsey,
J. S. Tetrahedron 2007, 63, 10657–10670; (b) Tamiaki, H.; Kumon, K.; Shibata, R.
J. Porphyrins Phthalocyanines 2007, 11, 434–441; (c) Carcel, C. M.; Laha, J. K.;
Loewe, R. S.; Thamyongkit, P.; Schweikart, K.-H.; Misra, V.; Bocian, D. F.;
Lindsey, J. S. J. Org. Chem. 2004, 69, 6739–6750; (d) Balaban, T. S.; Bhise, A. D.;
Fischer, M.; Linke-Schaetzel, M.; Roussel, C.; Vanthuyne, N. Angew. Chem., Int.
Ed. 2003, 42, 2140–2144; (e) Bonfantini, E. E.; Burrell, A. K.; Campbell, W. M.;
1484, 1440, 1406, 976, 957, 921, 850, 794, 724, 704 cmÀ1
;
HRMS-FAB+
([M+H]+): calcd for C33H25N4O: 493.2028. Found 493.2023. For 3f: 1H NMR
(CDCl3) d: 10.21 (1H, s), 9.68 (2H, d, J = 4.9 Hz), 9.32 (2H, d, J = 4.8 Hz), 9.03 (2H,
d, J = 4.9 Hz), 8.97 (2H, d, J = 4.8 Hz), 8.16 (4H, d, J = 7.9 Hz), 7.90 (4H, d,
J = 7.9 Hz), 7.03 (2H, s), 3.73 (1H, br), 1.33–1.01 (42H, m), À3.16 (2H, s); IR
(KBr): 3614, 2943, 2866, 2152, 1651, 1550, 1466, 1068, 995, 798, 671 cmÀ1
HRMS-FAB+ ([M+H]+): calcd for C55H65N4OSi2: 853.4697. Found 853.4703.
;
13. Kurti, L.; Czako, B. In Strategic Applications of Named Reactions in Organic
Synthesis; Elsevier: Oxford, 2005; p 174.
14. It is known that molecular oxygen and hydrogen peroxide can serve as
an oxidant for the conversion of dihydroporphyrins into porphyrins, see
Ref. 10