Synthesis of 4-substituted and 3,4-disubstituted indazole derivatives by palladium-mediated cross-coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2005.06.080

The synthesis of 4-substituted indazole derivatives by palladium-mediated cross-coupling reactions was described. Suzuki, Heck, Sonogashira and Stille cross-coupling reactions were used to introduce aryl, vinyl and alkynyl substituents in 4-position of in

Full text of DOI:10.1016/j.tetlet.2005.06.080

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6163–6167
Synthesis of 4-substituted and 3,4-disubstituted indazole
derivatives by palladium-mediated cross-coupling reactions
b
a,
*
Sa¨ıd El Kazzouli,a,b Latifa Bouissane,a,b Mostafa Khouili and Gerald Guillaumet
´
a
´
´
´
Institut de Chimie Organique et Analytique, UMR CNRS 6005, Universite d’Orleans, BP 6759, 45067 Orleans Cedex 2, France
b
´ ´
Faculte des Sciences et Techniques de Beni-Mellal, Universite Cadi-Ayyad, BP 523, 23000 Beni-Mellal, Marocco
Received 11 April 2005; revised 9 June 2005; accepted 15 June 2005
Abstract—The synthesis of 4-substituted indazole derivatives by palladium-mediated cross-coupling reactions was described.
Suzuki, Heck, Sonogashira and Stille cross-coupling reactions were used to introduce aryl, vinyl and alkynyl substituents in 4-posi-
tion of indazole derivatives. The selectivity of bis-Suzuki reactions of 3,4-diiodo- and 3-bromo-4-iodoindazoles was investigated.
ꢀ 2005 Published by Elsevier Ltd.
1. Introduction
95% yield. The reaction of sulfonamide 2 with iodine
in pyridine afforded regioselectively the 4-iodoindazole
37 in excellent yield, this is due to the presence of an elec-
tron-donating N-sulfonamide at 7-position. The struc-
ture of 3 was established by 2D NMR experiments
(HMBC, HMQC). We observed, in particular, the cou-
pling between the H6 and the NH sulfonamide and the
disappearance of the coupling between H3 and H4. We
applied the known Pd(0) mediated trans-metalation
steps (Stille, Sonogashira, Suzuki) and alkene insertion
(Heck) for the synthesis of 4-alkynyl, aryl and vinyl
derivatives. Compound 3 was first converted to the
desired N-alkylated product 4 using methyl iodide in
the presence of potassium hydroxide (Scheme 1) in order
to avoid any Pd(0)-catalysed dehalogenation.
The indazole ring system is a common structural motif
found in numerous biologically active molecules. For
instance, it is found in inhibitors of platelet aggrega-
tion,1 and of HIV protease2 and in antagonists of inte-
grin avb3.3 If several procedures have been developed
for the functionalisation of indazoles at the 3-position
using palladium catalysts,4 however, no examples
involving the arylation, alkynylation of indazoles at
the 4-position by palladium-mediated cross-coupling
reactions have been described in the literature.
2. Results and discussion
In our ongoing research programme for new polyfunc-
tionalised indazoles,5 we report herein the facile
functionalisation at the 4- and 3,4-positions of N-(7-
indazolyl)-arylsulfonamide based on a palladium-medi-
ated cross-coupling reaction. Compound 4, which serves
as the central intermediate for a variety of coupling
products, was prepared from 7-nitroindazole 16 in three
steps. Thus, compound 1 was hydrogenated in the pres-
ence of 10% palladium on carbon in methanol and then
immediately treated with 4-methoxybenzenesulfonyl
chloride in pyridine to give the desired product 2 in
A Suzuki reaction8 on 4 with Pd(PPh3)4 in the presence
of 4-methoxyphenyl- or 3-thiopheneboronic acid in
refluxing dimethoxyethane afforded then the coupling
products 5a,b9 with 80% and 85%, respectively, the reac-
tion of the iodide 4 with methyl acrylate under typical
Heck conditions10 afforded the compound 5c11 in high
yield. In addition, application of the Stille12 reaction
of the heteroaryl iodide with 2-(tributylstannyl)furan
in the presence of Pd2(dba)3 and Ph3As gave the cou-
pling product 5d13 in 82% yield. Finally, we explored
the Sonogashira reaction with the 4-iodoindazole 4
and phenylacetylene, this reaction provided 5e14 in good
yield (Scheme 2 and Table 1).
Keywords: Indazoles; Palladium; 3-Bromo-4-iodoindazole.
*
In a further investigation, we developed a bis-Suzuki
cross-coupling reaction of 3,4-dihalogenoindazoles with
Corresponding author. Tel.: +33 2 38 4170 73; fax: +33 2 38 4170
78; e-mail: gerald.guillaumet@univ-orleans.fr
0040-4039/$ - see front matter ꢀ 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.06.080

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S. El Kazzouli et al. / Tetrahedron Letters 46 (2005) 6163–6167
1) H2/Pd-C, MeOH
2) p-CH3OPhSO2Cl
N
N
MeO
pyridine
N
H
N
H
95%
NH
NO2
S
I
I
2
1
O
O
N
N
I2, pyridine
98%
KOH, acetone
MeO
MeO
N
N
H
CH3I
90%
Me
N
NH
S
Me
S
O
O
O
O
3
4
Scheme 1.
R
I
Coupling Partner
Conditions
N
N
MeO
N
MeO
N
Me
Me
N
O
N
O
Me
S
Me
S
O
O
4
5(a-e)
Scheme 2.
Table 1. Results of palladium cross-coupling reactions of 4-iodoindazole
R
Conditions
Product
Yield (%)
85
5a
MeO
Pd(PPh3)4, DME, Na2CO3, reflux
S
5b
5c
5d
80
79
82
–CH2@CH–CO2CH3
PdCl2(dppf), TBAI, Et3N, DMF, 50 ꢁC
Pd2(dba)3, Ph3As, dioxane, 50 ꢁC
O
Pd Cl2(PPh3)2, CuI, Et3N, DMF, rt
5e
71
arylboronic acid as general route to 3,4-diarylindazole
derivatives. Scheme 3 outlined the synthesis of the 4-
methoxy-N-methyl-N-(3,4-diiodo-1-methyl-7-indazolyl)-
benzenesulfonamide 8.
The reaction of 8 with 1equiv of 4-methoxyphenyl-
boronic acid under Suzuki conditions afforded a mixture
of 9 (42% yield) with the unsubstituted sulfonamide 10
(26% yield). In order to improve the formation of 9,
2 equiv of boronic acid were used and the bis-arylindaz-
ole 9 was isolated in 82% yield (Scheme 5).
Mono-N-alkylation at the nitrogen in 7-position of 3
with 1equiv of methyl iodide was necessary for the regio-
selective introduction of the iodine atom at the 3-posi-
tion of the indazole derivative 6. The bis-iodinated
compound 7 was converted to 8 in 90% yield by a simple
alkylation with methyl iodide.
We thus demonstrated that the Suzuki cross-coupling
reaction of 8 is not regioselective. Consequently, we
decided to apply this sequence to the N-(3-bromo-4-
iodo-7-indazolyl)arylsulfonamide 12, obtained from 6.
Compound 6 was treated with N-bromosuccinimide in
refluxing acetonitrile to afford 11 in 80% yield. It is note-
worthy that no reaction was observed when compound
11 was reacted with 4-methoxyboronic acid under Suzuki
coupling conditions. We thus protected the N-1position
using methyl iodide. The reaction gave N-(3-bromo-4-
iodo-7-indazolyl)arylsulfonamide 12 with 89% yield.
Contrary to the results obtained for the derivative 3,4-
diiodoindazole 8, reaction of 12 with 1equiv of 4-meth-
oxyphenylboronic acid gave only the 4-monosubstituted
product 1315 in good yield. Thus, a tandem sequence
The selectivity of the monoalkylation of the NH group
at 7-position of indazole 6 was established based on
1
the H NMR data of the synthesised 4-methoxy-N-(-1-
methyl-7-indazolyl)-benzenesulfonamide 8a and 4-meth-
oxy-N-methyl-N-(7-indazolyl)-benzenesulfonamide 8b
from 7-nitroindazole (Scheme 4). The H NMR spectra
1
of 6, 8a and 8b, recorded in DMSO-d6, showed the sin-
glet at d 3.22 ppm (NCH3) for 6, d NCH3 signal at 3.48
for 8a and d NCH3 signal at 3.21for 8b. These results
served to confirm the structure of 6.

S. El Kazzouli et al. / Tetrahedron Letters 46 (2005) 6163–6167
6165
I
I
KOH, MeI
I2, KOH
N
N
MeO
N
H
acetone, 0°C
86%
MeO
DMF, rt
98%
N
H
NH
N
S
S
Me
O
O
O
O
3
6
I
I
I
I
KOH, MeI
N
N
Me
N
MeO
acetone, 0°C
90%
MeO
N
H
N
N
S
Me
S
Me
O
O
O
O
8
7
Scheme 3.
MeI, KOH
acetone
0 °C
N
1) H2/Pd-C
MeOH
MeO
N
N
N
Me
N
NH
N
97 %
2) 4-MeOC6H4SO2Cl
pyridine
S
H
Me
NO2
O
O
NO2
1a
92%
8a
1
1) H2/Pd-C, MeOH
2) 4-MeOC6H4SO2Cl
pyridine
95%
N
N
MeO
N
H
MeI, KOH, acetone
0 °C
MeO
N
H
NH
S
O
N
Me
98 %
S
O
O
O
1b
8b
Scheme 4.
4-MeOC6H4B(OH)2 (2 eq.)
DME, reflux
8
OMe
OMe
Na2CO3, Pd(PPh3)4
82%
OMe
4-MeOC6H4B(OH)2 (1 eq.)
DME, reflux
Na2CO3, Pd(PPh3)4
OMe
N
MeO
N
Me
N
S
Me
42 %
O
N
O
9
MeO
+
N
N
Me
MeO
N
N
S
Me
O
O
Me
N
S
Me
9
O
O
10
26 %
Scheme 5.
giving unsymmetrical 3,4-diarylindazoles seemed feasi-
ble.16 So, reaction of 13 with 1-naphthaleneboronic acid
under the same Suzuki conditions gave the desired com-
pound 1417 in 78% yield (Scheme 6).
In summary, palladium cross-coupling reactions consti-
tute a new means to functionalise 4- and 3,4-positions of
indazole. This method is especially useful for the prepa-
ration of various 4-aryl, vinyl and ethynylindazoles. The

6166
S. El Kazzouli et al. / Tetrahedron Letters 46 (2005) 6163–6167
I
I
Br
KOH, MeI
NBS, MeCN
80%
N
N
acetone, 0°C
89%
MeO
MeO
N
H
N
H
N
N
Me
S
S
Me
OMe
O
O
O
6
11
O
I
Br
Br
4-MeOC6H4B(OH)2 (1 eq.)
N
MeO
N
Me
N
Pd(PPh3)4, DME, Na2CO3
reflux, 78%
MeO
N
N
Me
S
Me
O
N
O
Me
S
OMe
12
O
O
13
B(OH)2
N
MeO
Pd(PPh3)4, DME
N
Me
Na2CO3, 80°C
78%
N
S
Me
O
O
14
Scheme 6.
(3 · 5 mL). The combined organic layers were washed
with water and brine, dried over MgSO4 and the solvent
was evaporated to give a colorless solid 3 (139 mg, 98%).
Mp 172–173 ꢁC. H NMR (DMSO-d6, 250 MHz) d 3.77
(s, 3H, OCH3), 6.73 (d, 1H, J = 7.5 Hz), 7.03 (d, 2H,
J = 8.7 Hz), 7.36 (d, 1H, J = 7.5 Hz), 7.69 (d, 2H,
J = 8.7 Hz), 7.85 (s, 1H), 10.05 (s, 1H, NH), 13.07 (s,
1H, NH). 13C NMR (DMSO-d6, 62.89 MHz) d 55.6, 95.7,
114.3, 119.5, 121.7, 128.2, 128.4, 129.1, 129.8, 130.4, 136.9,
142.6. MS (+ESI): m/z = 430 [MH+].
selectivity of sequential Suzuki–Suzuki reaction with a
3-bromo-4-iodoindazole derivative allowed us to pre-
pare 3,4-disubstituted indazole. This methodology is a
valuable and general method for the preparation of
new functionalised indazoles.
1
References and notes
1. Collot, V.; Dallemagne, P.; Bovy, P. R.; Rault, S.
Tetrahedron 1999, 55, 6917.
8. Alo, B. I.; Kandil, A.; Patil, P. A.; Sharp, M. J.; Siddiqui,
M. A.; Snieckus, V. J. Org. Chem. 1991, 56, 3763.
2. Sun, J.-H.; Teleha, C. A.; Yan, J.-S.; Rodgers, J. D.;
Nugiel, D. A. J. Org. Chem. 1997, 62, 5627.
9. General procedure for Suzuki-type cross coupling reaction:
Under argon atmosphere, to a mixture of 4-iodoindazole
derivatives (0.43 mmol) and boronic acid (0.48 mmol) in
DME (8 mL), sodium carbonate (1.29 mmol) in H2O
(4 mL) and Pd(PPh3)4 (0.043 mmol) was added. The
reaction mixture was refluxed with vigorous stirring for
2 h and then the solvent was evaporated. Ethyl acetate
(5 mL) was added and the organic phase was washed with a
saturated solution of sodium chloride (10 mL), dried over
MgSO4 and the solvent was removed in vacuo. The residue
was purified by column chromatography over silica gel
(eluted with a EtOAc/EP).
3. Batt, D. G.; Petraitis, J. J.; Houghton, G. C.; Modi, D. P.;
Cain, G. A.; Corjay, M. H.; Mousa, S. A.; Bouchard, P. J.;
Forsythe, M. S.; Harlow, P. P.; Barbera, F. A.; Spitz, S. M.;
Wexler, R. R.; Jadhav, P. K. J. Med. Chem. 2000, 43, 41 .
4. (a) Amautu, A.; Collot, V.; Ros, J. C.; Alayrac, C.;
Witulski, B.; Rault, S. Tetrahedron Lett. 2002, 43, 2695;
(b) Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron Lett.
2000, 41, 9053; (c) Collot, V.; Varlet, D.; Rault, S.
Tetrahedron Lett. 2000, 41, 4363; (d) Gordon, D. W.
Synlett 1998, 1065; (e) Welch, W. M.; Hanau, C. E.;
Whalen, W. M. Synthesis 1992, 937.
4-Methoxy-N-methyl-N-[4-(4-methoxyphenyl)- 1-methyl-7-
indazolyl]-benzenesulfonamide (5a): Colorless solid 5a
(162 mg, 85%). Mp 109–110 ꢁC. 1H NMR (acetone-d6,
250 MHz) d 3.26 (s, 3H, NCH3), 3.84 (s, 3H, OCH3), 3.86
(s, 3H, OCH3), 4.45 (s, 3H, NCH3), 6.51(d, H1,
J = 7.5 Hz), 6.92 (d, 1H, J = 7.5 Hz), 6.98 (d, 2H,
5. (a) Bouissane, L.; El Kazzouli, S.; Leger, J.-M.; Jarry, C.;
Rakib, E. M.; Khouili, M.; Guillaumet, G. Tetrahedron
´
2005, 61, 8218; (b) Bouissane, L.; El Kazzouli, S.; Leonce,
S.; Pfeiffer, B.; Rakib, E. M.; Khouili, M.; Guillaumet, G.
Bioorg. Med. Chem., submitted for publication.
6. Noelting, E. Berichte 1904, 37, 2556.
7. Procedure for the synthesis of 4-methoxy-N-(4-Iodo-7-
indazolyl)-benzenesulfonamide 3: To a solution of 4-
methoxy-N-(7-indazolyl)-benzenesulfonamide 2 (100 mg,
0.33 mmol) in pyridine (10 mL), iodine (90 mg,
0.33 mmol) was added. The reaction mixture was stirred
at room temperature for 3 h and then poured into 10%
aqueous NaHSO3 (5 mL) and extracted with Et2O
J = 8.7 Hz), 7.01(d, 2H,
J = 8.1Hz), 7.57 (d, 2H,
J = 8.7 Hz), 7.64 (d, 2H, J = 8.1Hz), 8.09 (s, 1H). 13C
NMR (acetone-d6, 62.89 MHz) d 38.8, 40.0, 55.3, 55.6,
97.3, 114.1, 114.3, 119.2, 124.6, 124.7, 125.1, 128.0, À129.6,
130.5, 132.4, 131.4, 135.7, 137.4, 159.6. MS (+ESI): m/z =
438 [MH+].
10. Ruhland, B.; Bombrun, A.; Gallop, M. A. J. Org. Chem.
1997, 62, 7820.

S. El Kazzouli et al. / Tetrahedron Letters 46 (2005) 6163–6167
6167
11. Procedure for the synthesis of (E)-(7-[(4-methoxy-
benzenesulfonyl)-methyl-)-methylamino]-1H-4-indazolyl]-
acrylic acid methyl ester (5c): To a mixture of compound 4
(200 mg, 0.43 mmol), methyl acrylate (50 lL, 0.86 mmol)
and tetrabutylammonium iodide (324 mg, 0.86 mmol) in a
mixture of DMF/TEA (8 mL, 5/5, v/v) under argon was
added PdCl2(dppf) (30 mg, 0.043 mmol). The reaction
mixture was stirred overnight at 45 ꢁC and then the
solution was evaporated. Ethyl acetate (5 mL) was added
and the organic phase, washed with water and brine, was
dried over MgSO4. The solvent was removed in vacuo and
the residue was purified by column chromatography over
silica gel (eluted with a EtOAc/EP) to give 5c (143 mg,
79%). Mp 155–156 ꢁC. 1H NMR (acetone-d6, 250 MHz) d
3.23 (s, 3H, NCH3), 3.76 (s, 3H, OCH3), 3.88 (s, 3H,
OCH3), 4.32 (s, 3H, NCH3), 6.59 (d, 1H, J = 7.8 Hz), 6.80
(d, 1H, J = 16.0 Hz), 7.18 (d, 2H, J = 9.1Hz), 7.44 (d, 1H,
J = 7.8 Hz), 7.59 (d, 2H, J = 9.1Hz), 7.96 (d, 1H, J =
16.0 Hz), 8.50 (s, 1H). 13C NMR (acetone-d6, 62.89 MHz)
d 38.4, 39.4, 51.6, 55.7, 96.7, 114.5, 120.5, 121.5, 124.4,
125.4, 127.2, 127.6, 130.2, 131.2, 140.7, 136.8, 143.1, 166.4.
MS (+ESI): m/z = 416 [MH+].
14. Procedure for the synthesis of 4-methoxy-N-methyl-N-(4-
phenylethynyl-1-methyl-7-indazolyl)-benzenesulfonamide
(5e). To a solution of 4 (200 mg, 0.43 mmol), phenylacet-
ylene (70 lL, 0.63 mmol) and CuI (17 mg, 0.09 mmol) in a
mixture of DMF/TEA (8 mL, 5/5, v/v) under argon was
added Pd(PPh3)2Cl2 (30 mg, 0.043 mmol). The reaction
mixture was stirred at room temperature overnight and
then the solvent was evaporated. Ethyl acetate (5 mL) was
added and the organic phase, washed with water and
brine, was dried over MgSO4. The solvent removed in
vacuo and the residue was purified by column chroma-
tography over silica gel (eluted with a EtOAc/EP) to give
5e (132 mg, 71%). Mp 84–85 ꢁC. 1H NMR (acetone-d6,
250 MHz) d 3.32 (s, 3H, NCH3), 3.95 (s, 3H, OCH3), 4.39
(s, 3H, NCH3), 6.61(d, 1H, J = 7.5 Hz), 7.15–7.19 (m,
3H), 7.44–7.47 (m, 3H), 7.62–7.67 (m, 4H), 8.09 (s, 1H).
13C NMR (acetone-d6, 62.89 MHz) d 39.0, 40.1, 56.2, 94.4,
86.9, 115.1, 116.5, 124.9, 125.3, 128.0, 128.3, 128.7, 129.5,
129.8, 131.4, 132.5, 132.6, 137.9, 142.5. MS (+ESI):
m/z = 432 [MH+].
15. 4-Methoxy-N-methyl-N-(3-bromo-4-(4-methoxyphenyl)-1-
methyl-7-indazolyl)-benzenesulfonamide (13): Colorless
solid, yield 78%. Mp 178–179 ꢁC. 1H NMR (acetone-d6,
250 MHz) d 3.33 (s, 3H, NCH3), 3.87 (s, 3H, OCH3),
3.94 (s, 3H, OCH3), 4.39 (s, 3H, NCH3), 6.69 (d,
1H, J = 7.5 Hz), 6.86 (d, 1H, J = 7.5 Hz), 7.02 (d, 2H,
J = 8.7 Hz), 7.17 (d, 2H, J = 8.9 Hz), 7.36 (d, 2H,
J = 8.7 Hz), 7.67 (d, 2H, J = 8.9 Hz). 13C NMR (ace-
tone-d6, 62.89 MHz) d 39.4, 40.2, 55.6, 56.2, 113.9, 115.1,
117.4, 118.9, 123.6, 126.3, 126.4, 128.9, 129.1, 130.3, 131.4,
132.2, 137.3, 140.7, 164.5. MS (+ESI): m/z = 517.5 [MH+].
16. During the submission of this article, similar results were
published. Witulski, B.; Azcon, J. R.; Alayrac, C.;
Arnautu, A.; Collot, V.; Rault, S. Synthesis 2005, 771.
17. 4-Methoxy-N-[4-(4-methoxyphenyl)-1-methyl-3-naphtalen-
yl-7-indazolyl]-N-methylbenzenesulfonamide (14): Yellow
solid, yield 78%. Mp 109–110 ꢁC. 1H NMR (CDCl3,
250 MHz) d 3.35 (s, 3H, NCH3), 3.55 (s, 3H, OCH3), 3.89
(s, 3H, OCH3), 4.58 (s, 3H, NCH3), 6.14 (d, 2H, J =
7.8 Hz), 6.57 (d, 1H, J = 7.5 Hz), 6.71(d, 2H, J = 8.8 Hz),
6.82 (d, 1H, J = 7.5 Hz), 7.02 (d, 1H, J = 8.8 Hz), 7.22–
7.32 (m, 4H), 7.67–7.75 (m, 5H). 13C NMR (CDCl3,
62.89 MHz) d 39.1, 40.3, 55.2, 55.8, 112.2, 114.2, 121.1,
124.3, 124.7, 125.4, 125.8, 126.1, 127.6, 128.4, 128.7, 129.8,
130.5, 131.5, 132.7, 133.3, 137.8, 138.4, 143.5, 158.5, 163.5.
MS (+ESI): m/z = 564.0 [MH+].
12. Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebes-
kind, L. S. J. Org. Chem. 1994, 59, 5905.
13. Procedure for the synthesis of 4-methoxy-N-methyl-N-[4-
(furan-2-yl)-1-methyl-7-indazolyl]-benzenesulfonamide (5d):
To a solution of 4 (100 mg, 0.21 mmol), 2-(tributylstan-
nyl)furan (77 mg, 0.25 mmol) and triphenylarsin (153 mg,
0.5 mmol) in 1,4-dioxan (5 mL) under argon was added
Pd2(dba)3-CHCl3 (21mg, 0.021mmol). The reaction
mixture was heated at 80 ꢁC overnight and then the
solvent was evaporated. Ethyl acetate (5 mL) was added
and the organic phase, washed with water and brine, was
dried over MgSO4. The solvent was removed in vacuo
and the residue was purified by column chromatography
over silica gel (eluted with a EtOAc/EP) to give 5d
(70 mg, 82%). Mp 126–127 ꢁC. 1H NMR (acetone-d6,
250 MHz) d 3.32 (s, 3H, NCH3), 3.95 (s, 3H, OCH3),
4.40 (s, 3H, NCH3), 6.61(d, 1H, J = 7.8 Hz), 6.66 (dd,
1H, J = 1.5, 3.4 Hz), 7.11 (d, 1H, J = 3.4 Hz), 7.18 (d,
2H, J = 9.1Hz), 7.33 (d, 1H, J = 7.8 Hz), 7.65 (d, 2H,
J = 9.1Hz), 7.78 (d, 1H, J = 1.5 Hz), 8.44 (s, 1H). 13C
NMR (acetone-d6, 62.89 MHz) d 39.0, 40.2, 56.2, 109.2,
112.0, 115.1, 116.9, 122.8, 124.6, 125.5, 126.4, 129.1,
131.4, 133.0, 144.2, 138.6, 143.3, 153.3. MS (+ESI): m/z =
397 [MH+].