Synthesis of new azido porphyrins and their reactivity in copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction with alkynes

Article abstract of DOI:10.1016/j.tetlet.2007.07.049

We report herein the preparation of two novel porphyrins substituted with an azido group born either on the para-position of one phenyl meso-susbtituent of a tetraaryl zinc porphyrin (1) or directly on the meso-position of a trisaryl nickel porphyrin (2).

Full text of DOI:10.1016/j.tetlet.2007.07.049

Tetrahedron Letters 48 (2007) 6518–6522
Synthesis of new azido porphyrins and their reactivity
in copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition
reaction with alkynes
Marjorie S e´ verac, Lo ¨ı c Le Pleux, Annabelle Scarpaci, Errol Blart and Fabrice Odobel*
Universit e´ de Nantes, Nantes Atlantique Universit e´ s, CNRS, Facult e´ des Sciences et des Techniques, Laboratoire de Synth e` se
Organique (LSO), UMR CNRS 6513, 2 rue de la Houssini e` re—BP 92208, 44322 Nantes Cedex 3, France
Received 23 May 2007; revised 5 July 2007; accepted 9 July 2007
Available online 13 July 2007
Abstract—We report herein the preparation of two novel porphyrins substituted with an azido group born either on the para-posi-
tion of one phenyl meso-susbtituent of a tetraaryl zinc porphyrin (1) or directly on the meso-position of a trisaryl nickel porphyrin
(
2). We studied the scope and the limitation the Huisgen cycloaddition reaction of these two porphyrins using different catalytic
conditions. We observed that the carbene (SIMes)CuBr in THF/H O 3:1 at 45 °C for 60 h gives almost quantitative yields for
2
the reaction between 1 and different alkynes, but significantly lower yields with 2 probably due to its thermal instability.
Ó 2007 Elsevier Ltd. All rights reserved.
Porphyrins are valuable compounds owing to their rich
photochemical, electrochemical and catalytic properties
that open the door to a wide range of applications in
material science, medicine, catalysis and for solar energy
conversion. The development of simple, efficient and
versatile synthetic strategy to functionalize porphyrin
is of a high interest for their broader utilizations in many
areas. The copper(I)-catalyzed 1,3-dipolar cycloaddition
of azides with alkynes has emerged as one of the most
effective synthetic reaction, since it can be conducted
in mild conditions, in various solvents, with generally
high yields and independently of the steric hindrance
and of the electronic properties of the reagents (with
rins 1 and 2 can advantageously complete the possibili-
ties offered by the b-azidotetraarylporphyrins because
the introduction of substituents on the meso-position
will certainly change the magnitude of the electronic
interactions with the porphyrin ring.
Besides, the position of the azido group in porphyrins 1
and 2 is more appropriate if one envisions to prepare
linear arrays in the direction of the meso-axis of the
porphyrin, because trans meso-disubstituted porphyrins
are much more synthetically accessible than trans beta
3
disubstituted porphyrins. The synthesis of the porphy-
rin 1 is depicted in Scheme 1. Condensation of 3 equiv
of para-tert-butylbenzaldehyde and 1 equiv of para-
nitrobenzaldehyde with 4 equiv of pyrrole using Lind-
1
both electron-rich or electron-deficient substrates). As
a consequence, we were interested to develop the synthe-
sis of azido substituted porphyrins, since these com-
pounds could certainly represent valuable substrates to
use in Huisgen reaction to easily connect various types
of molecular units. During the course of this work, Chen
and co-workers reported the synthesis and the dipolar
4
sey’s conditions afforded porphyrin 3 along with tetra-
kis(tert-butylphenyl)porphyrin and bis(nitrophenyl)
5
bis(tert-butylphenyl) porphyrins. The reaction mixture
is best purified in the next step after the reduction of
the nitro groups with tin chloride, because the desired
amino porphyrin 4 is readily separated from the other
porphyrins by column chromatography. The diazota-
tion of the amine 4 with sodium nitrite in trifluoracetic
acid followed by the addition of sodium azide at low
temperature gives the expected azido porphyrin 5 with
2
cycloaddition reaction of b-azidotetraaryl porphyrins.
Herein, we report the synthesis and the reactivity of
new azido porphyrins, whose azido group is born either
directly on the meso-position or on the para-position of
a meso-phenyl substituent (Fig. 1). The two new porphy-
9
5% yield after purification. The free base porphyrin 5
is then metallated with zinc acetate in a quantitative
yield to afford 1.
6
*
0
Corresponding author. E-mail: fabrice.odobel@univ-nantes.fr
040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.049

M. S e´ verac et al. / Tetrahedron Letters 48 (2007) 6518–6522
6519
N
N
N
N
N
N
N
N
N
3
Zn
N
Ni
3
1
2
Figure 1. Structures of the two azido porphyrins 1 and 2 studied in this work.
Ar
CHO
CHO
a)
NH
N
N
+
+
O
2
N
Ar
N
H
HN
NO
2
3
Ar
Ar
Ar =
Ar
NH
N
N
N
N
N
b)
O
2
N
Ar
R
M
Ar
N
HN
3
Ar
c)
d)
4 : R = NH2, M = 2H
Ar
5
1
: R = N3, M = 2H
: R = N3, M = Zn(II)
Scheme 1. Synthetic route to prepare porphyrin 1. Reagents and conditions: (a) Et
2
OÆBF
3
, CH
, CH
2
Cl
2
, 12 h, rt then DDQ, 1 h, rt (11%); (b) SnCl
2
, HCl,
CHCl , AcOH, reflux, 12 h (76%); (c) NaNO , NaN , TFA, H O, 0 °C (95%); (d) Zn(OAc)
3
2
3
2
2
2
Cl , MeOH, 60 °C, 2 h (100%).
2
The second porphyrin 2 was prepared in six steps from
8 was nitrated with silver nitrite in presence of iodine at
7
10
6
(Scheme 2). First, trisaryl porphyrin 7 was obtained
0 °C. Then, the zinc nitro porphyrin 9 was demetalled
with HCl and metalled with nickel(II). The nitro group
of 11 was reduced with sodium tetrahydroborate at
room temperature and the resulting amine 12 was
8
in high yield according to Arnold’s protocol and using
Senge’s methodology by reacting an excess of phenyl
9
lithium with bisaryl porphyrin 6. Zinc trisaryl porphyrin
Ar
Ar
M
NH
N
N
a)
N
N
N
N
7
8
: M = 2H
: M = Zn(II)
Ph b)
HN
6
Ar
Ar
Ar
Ar =
Ar
M
9
1
1
: R = NO2, M = Zn(II)
0: R = NO2, M = 2H
d)
N
N
N
N
N
N
N
N
c)
Ph
R
M
Ph e)
1: R = NO , M = Ni(II)
2
f)
g)
1
2
2: R = NH2, M = Ni(II)
: R = N3, M = Ni(II)
8
Ar
Ar
Scheme 2. Synthetic route to prepare porphyrin 2. Reagents and conditions: (a) PhLi, THF, ꢀ78 °C, H
MeOH, 60 °C, 2 h (100%); (c) I , AgNO , CH CN, CH Cl , 0 °C, 1 h (73%); (d) HCl, CH Cl (100%); (e) Ni(OAc)
C, NaBH , CH Cl , MeOH, rt, 1 h (95%); (g) NaNO , NaN , H SO , THF, H O, rt, 1 h (85%).
2
O, DDQ (85%); (b) Zn(OAc)
2 2 2
, CH Cl ,
2
2
3
2
2
2
2
2
, DMF, 110 °C, 2 h (97%); (f) Pd/
4
2
2
2
3
2
4
2

6520
M. S e´ verac et al. / Tetrahedron Letters 48 (2007) 6518–6522
subsequently transformed into the diazonium salt that
was finally reacted with sodium azide to give 2. The
the expected bisporphyrin 14 did not form at all (entry
1). Highly polar solvents increase the solubility of the
1
1
1
strong azide band could be detected by IR spectroscopy
‘ligand free’ copper catalyst and they were reported to
facilitate the coordination of copper by alkyne. The
ꢀ1
ꢀ1
14
at 2120 cm and 2105 cm , respectively, for azido por-
phyrins 1 and 2. It is worth noting that the amino por-
phyrin 12 is not very stable and should be used rapidly
in the next step after its preparation. Similarly, but in
a less extent, the azido porphyrin 2 is relatively prone
to decomposition if not stored in the dark and at low
temperature.
latter reaction is known to be a crucial step in the cata-
lytic mechanism, but the utilization of the mixture
DMSO/CH Cl /Et N 10:5:1 did not change the out-
2
2
3
come of the reaction (entry 2). The low stability of the
azido porphyrin 1 and 2 and their triazole derivatives
as observed during the mass spectroscopy analyses
prompted us to try the very recent conditions reported
by Sharpless and co-workers which give good results
Attempts to prepare the azido free base porphyrin cor-
responding to 2 by the same route failed in the last step.
Furthermore, the recently published coupling reaction
of aryl halides with sodium azide using the catalytic mix-
ture CuI-L-proline also failed to produce 2 when applied
3
when the C–N bond of the triazole tends to brakes eas-
1
5
ily. However, these conditions also failed to give
detectable amount of 14 (entry 3).
1
2
to zinc iodo porphyrin. With reference to other
The first success came when the organo-soluble copper
catalysts Cu(PPh ) Br and Cu[P(OEt) ]I were used
1
3
works, we reasoned that the metal complexed in the
porphyrin controls the stability of the directly meso-
substituted azido porphyrin such as 2. The mass
spectroscopy analyses clearly showed the facile fragmen-
tation of the azido porphyrins 1 and 2 as well as the
triazole derivatives resulting from the coupling of 1 or
3
3
3
(entries 4–5). It is notable to observe the formation of
porphyrin 15 with an appreciable yield (33%) as a side
product when Cu(PPh ) Br was used (Fig. 2). The for-
3
3
mation of this by-product can be certainly rationalized
on the account of Staudinger reaction between the free
1
6
2
with alkynes. During most mass analyses, the frag-
triphenylphosphine and azide 1. The copper carbene
complex with SIMes ligand, recently reported by Nolan
and co-workers, proved to be the best catalyst for this
mentation of these compounds occurs readily with loss
of nitrogen.
1
7
reaction with the porphyrin azides 1 and 2 substrates.
In a second stage, the successful preparation of the azido
porphyrins 1 and 2 allowed us to study their reactivities
with different alkynes using several copper-based cata-
lysts. It is worthy of noticing that a free base porphyrin
tends to be metallated by copper when subjected to most
of the conditions listed in Table 1. Conversely, no
transmetalation seems to occur using zinc porphyrin 1
or nickel porphyrin 2. We started to investigate the
coupling of zinc porphyrin 1 with ethynylphenyl zinc
porphyrin 13 using different reaction conditions
These porphyrins being not soluble in water, we investi-
gated other reaction mixture and found that the mixture
THF/water 3:1 was satisfying to conduct the reaction
with this catalyst and with water insoluble reagents.
With these conditions, the isolated yield of 14 reaches
44% after 60 h of reaction at 45 °C (entry 7). Then, we
turn our attention to other alkynes to investigate the ori-
gin of the modest yield obtained with porphyrin 1.
Three different aryl–ethynyl substrates, spanning differ-
ent electronic properties from neutral (16) to electron-
rich (17) to electron-deficient (18), were reacted with
the azido porphyrin 1 (Scheme 3).
(
Table 1). In a first experiment, we tried the classical
conditions using copper sulfate with ascorbic acid in tri-
ethylamine and dichloromethane as solvent mixture, but
Table 1. Yield of isolated product 14 resulting from the reaction of the porphyrins 1 and 13 using the conditions listed below
Ar =
Ar
Ar
N
N
N
Ar
N
N
N
N
N
N
N
conditions
Zn
1
+
Zn
Ar
Ar
N
Ar
N
N
Zn
N
13
14
N
Ar
Ar
Ar
Entry
Reaction conditions
Yield (%)
1
2
3
4
5
6
7
CuSO
CuSO
CuI, 4H
Cu(PPh
Cu[P(OEt)
4
, 4H
, 4H
2
O, ascorbic acid, CH
O, ascorbic acid, 40 °C DMSO/CH
, 0 °C, 12 h, then rt 72 h
2
Cl
2
/Et
3
N 5:1, 60 °C, 12 h
0
0
0
23
29
32
44
4
2
2
Cl /Et N 10:5:1, 4 h
2
3
2
O, 1,6-dimethyl-pyridine, CHCl
Br, DIEA/THF 1:5, 50 °C, 3 h
]I, DIEA/THF/H O 1:1:5, 50 °C, 12 h
3
3
)
3
3
2
(SIMes)CuBr, THF/H
(SIMes)CuBr, THF/H
2
O 3:1, 45 °C, 12 h
O 3:1, 45 °C, 60 h
2
0
DIEA = diisopropylethylamine. SIMes = N,N -bis(2,4,6-trimethylphenyl)-4,5-dihydro-imidazol-2-ylidene.

M. S e´ verac et al. / Tetrahedron Letters 48 (2007) 6518–6522
6521
N
N
N
N
N
N
N
N
N
Ph
3
P
N
Zn
N
N
Ni
1
5
26
Figure 2. Structures of porphyrins 15 and 26.
Ar
N
N
N
N
THF/H O, 45˚C
2
N
R
1
+
R
Zn
N
(SIMes)CuBr
Ar
N
1
1
1
6: R = H
7: R = N(Hex)2
8: R = CN
19: R = H
20: R = N(Hex)2
21: R = CN
Ar =
Ar
Scheme 3. Huisgen reaction of azido porphyrin 1 with the alkynes 16–18.
The coupled products 19–21 were isolated with a yield
above of 95% after 60 h of reaction. Therefore, the lower
yield of 14 is certainly not ascribed to a steric factor, be-
cause Huisgen reaction is known to be relatively insensi-
tive to sterically hindered substrates and the substitution
in para-position of the phenyl leaves a large free space
above conditions. The coupled products 26 and 24 were
formed with 41% and 18% yield, respectively, (Fig. 2
and Scheme 4). The lower yield for the zinc porphyrin
containing compound 24 compared to that of 26 and
25 is also explained by the degradation of the ZnP unit
during silica gel column chromatography. Unlike por-
phyrins 1 and 13 which are strictly insoluble in DMF,
the significant solubility of the porphyrins 2, 22 and 23
in this latter solvent allowed us to test the conditions re-
ported by Chen and co-workers for b-azidotetraaryl
porphyrins (CuSO , 4H O, ascorbic acid, 50 °C, DMF,
1
around the azido or ethynyl group. Second, the high
yields of formation of 19–21 clearly show that electronic
factor can be also excluded. More certainly, the low
yield of 14 is due to the presence of zinc porphyrin that
partly degrades during the silica gel column chromatog-
raphy. This phenomenon is particularly accentuated
with the zinc porphyrin dimer 14 compared to mono
zinc porphyrin 19–21. A good support of this assump-
tion is that the purification of the crude after demetala-
tion of the porphyrins by HCl permitted us to obtain the
expected bis(free base porphyrin) analagous of 14 with a
4
2
2
50 h). In these conditions, 24 and 25 were effectively
formed with 18% and 41% yields, respectively. These lat-
ter experiments, firstly show that the conditions reported
here with (SIMes)CuBr are at least as efficient and prob-
ably superior than those using CuSO , 4H O in DMF
4
2
and secondly they confirm that the presence of zinc por-
phyrin reduces the isolated yield, since 25 is formed with
more than a fold yield relative to that of 24.
7
0% yield.
Finally, we investigated the reaction of the meso-azido
porphyrin 2 with phenyl acetylene 16 and meso-ethynyl
zinc porphyrin 22 using (SIMes)CuBr as catalyst in the
Overall, the general lower yields of the Huisgen reaction
with porphyrin 2 relative to those obtained with porphy-
Ar
Ni
Ar
M
Ar
Ar
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Ph
N
3
+
Ph
N
M
Ni
N
N
N
Ph
Ph
N
Ar
Ar
Ar
2
2
2: M = Zn(II)
3: R =Ni(II)
Ar =
Ar
2
2
2
4: M = Zn(II)
5: M = Ni(II)
Scheme 4. Huisgen reaction of the azido porphyrin 2 with the ethynylporphyrins 22 and 23.

6522
M. S e´ verac et al. / Tetrahedron Letters 48 (2007) 6518–6522
rin 1 are most probably correlated with the thermal
instability of the azido porphyrin 2, which may partly
decompose during the reaction with the alkyne.
Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew.
Chem., Int. Ed. 2002, 41, 2596–2599; (c) Tornoe, C. W.;
Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057–
3
064.
. Shen, D.-M.; Liu, C.; Chen, Q.-Y. Eur. J. Org. Chem.
007, 9, 1419–1422.
2
3
In summary, we report the successful preparation of new
azido porphyrins 1 and 2 with relatively good yields.
When the azido group is directly connected to the por-
phyrin core (compound 2), we observed that its stability
is highly dependent of the metal inside the porphyrin.
The reactions of these azido porphyrins 1 and 2 with
several terminal alkynes were investigated using different
catalytic systems. We found that the recently reported
2
. (a) Lindsey, J. S. J. Org. Chem. 2000, 65, 1084–1092; (b)
Littler, B. J.; Ciringh, Y.; Lindsey, J. S. J. Org. Chem.
1
999, 64, 2864–2872.
4. Lindsey, J. S.; Schreiman, I. C.; Hsu, H. C.; Kearney, P.
C.; Marguerettaz, A. M. J. Org. Chem. 1987, 52, 827–
836.
5
. Liu, X.; Liu, J.; Jin, K.; Yang, X.; Peng, Q.; Sun, L.
1
7
Tetrahedron 2005, 61, 5655–5662.
copper carbene (SIMes)CuBr was a better catalyst than
most of the usual copper complexes used for this trans-
formation. The former proved to be particularly efficient
with azido phenyl porphyrin 1, but the yields obtained
with meso-substituted azido porphyrin 2 were much
lower probably due to its thermal decomposition during
the course of the reaction. However, using (SIMes)CuBr
catalyst in the solvent mixture THF/water 3:1, several
adducts with porphyrins 1 and 2 were formed, opening
thus the possibility to click probably numerous terminal
alkynes on azido porphyrins 1 and 2 in very mild condi-
tions. We believe that these latter synthons could be
useful to prepare new porphyrin-based systems in view
of various applications.
1
6
. Analytical data of 1: H NMR (CDCl
3
, 300 MHz) d: 1.62
), 7.76 (d, 6H, H-m-
t
(
s, 27H, Bu), 7.39 (d, 2H, H-m-aryl-N
aryl- Bu), 8.15 (d, 6H, H-o-aryl- Bu), 8.21 (d, 2H, H-o-
3
t
t
aryl-N ), 8.89 (d, 2H, H ), 9.00 (m, 6H, H ), MS MALDI-
3
b
b
TOF, m/z calculated for C56
found, 859.2.
H
51
7 2
N Zn ꢀ N + 2H: 859.3;
7. Odobel, F.; Suresh, S.; Blart, E.; Nicolas, Y.; Quintard, J.-
P.; Janvier, P.; Questel, J.-Y. L.; Illien, B.; Rondeau, D.;
Richomme, P.; H a¨ upl, T.; Wallin, S.; Hammarstr o¨ m, L.
Chem. Eur. J. 2002, 8, 3027–3046.
. Hartnell, R. D.; Edwards, A. J.; Arnold, D. P. J.
Porphyrins Phthalocyanines 2002, 6, 695–707.
8
9
. Feng, X.; Senge, M. O. J. Chem. Soc., Perkin Trans. 1
2
001, 1030–1038; Senge, M. O. Acc. Chem. Res. 2005, 38,
7
33–743; Senge, M. O.; Kalisch, W. W.; Bischoff, I.
Chem.-Eur. J. 2000, 6, 2721–2738.
General Procedure for Huisgen reaction: Azido porphy-
rin (0.03 mmol, 1 equiv) and alkyne (1 equiv) were solu-
bilized in 3 mL of THF. SIMesCuBr (15 lmol) and
1
0. Yoshida, N.; Ishizuka, T.; Yofu, K.; Murakami, M.;
Miyasaka, H.; Okada, T.; Nagata, Y.; Itaya, A.; Cho, H.
S.; Kim, D.; Osuka, A. Chem.-Eur. J. 2003, 9, 2854–
1
mL of water were added. The mixture was stirred at
2866.
1
1
1. Analytical data of 2: H NMR (CDCl
3
, 300 MHz) d: 1.47
4
5 °C for 72 h. After cooling to room temperature, the
t
(
s, 36H, Bu), 7.67 (m, 3H, H-m-p-phenyl), 7.73 (t, 2H,
crude mixture was evaporated to dryness and the residue
was purified by silica gel flash column chromatography
to give the coupled product.
t
t
H-p-aryl- Bu), 7.83 (d, 4H, H-o-aryl- Bu), 7.98 (dd,
2
H, H-o-phenyl), 8.66 (d, 2H, H
b b
), 8.70 (d, 2H, H ),
8
.83 (d, 2H, H ), 9.40 (d, 2H, H ), ESI-MS, m/z calculated
b
b
for C H N Ni ꢀ N + 2H, 833.4; found, 833.5.
5
4
55
7
2
1
1
2. Zhu, W.; Ma, D. Chem. Commun. 2004, 888–889.
3. (a) Ortiz de Montellano, P. R.; David, S. K.; Ator, M. A.;
Tew, D. Biochem. 1988, 27, 5470–5476; (b) Smith, K. M.;
Barnett, G. H.; Evans, B.; Martynenko, Z. J. Am. Chem.
Soc. 1979, 101, 5953–5961.
Acknowledgements
The French Research Ministry is gratefully acknowl-
edged for the financial support of these researches
through the ANR program entitled ‘PhotoCumElec’
and Region Pays de la Loire for CER program. FO
thanks Benoit Colasson (Univ. Paris 5) for fruitful dis-
cussion about the preparation of azido derivatives.
1
1
4. Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.;
Noodleman, L.; Sharpless, K. B.; Fokin, V. V. J. Am.
Chem. Soc. 2005, 127, 210–216.
5. Yoo, E. J.; Ahlquist, M.; Kim, S. H.; Bae, I.; Fokin, V. V.;
Sharpless, K. B.; Chang, S. Angew. Chem., Int. Ed. 2007,
4
6, 1730–1733.
1
1
6. Gololobov, Y. G.; Zhmurova, I. N.; Kasukhin, L. F.
Tetrahedron 1981, 37, 437–472.
7. D ´ı ez-Gonz a´ lez, S.; Correa, A.; Cavallo, L.; Nolan, S. P.
Chem. Eur. J. 2006, 12, 7558–7564.
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. (a) Bock, V. D.; Hiemstra, H.; van Maarseveen, J. H. Eur.
J. Org. Chem. 2006, 2006, 51–68; (b) Rostovtsev, V. V.;