Synthesis of new dehydro 2-azatryptophans and derivatives via Heck cross-coupling reactions of 3-iodoindazoles with methyl 2-(acetylamino)acrylate

Article abstract of DOI:10.1055/s-2006-950242

This paper describes the Heck cross-coupling reaction of 3-iodoindazoles with methyl 2-(acetylamino)acrylate as a general route to new dehydro 2-azatryptophans and protected amino acid derivatives after catalytic hydrogenation. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950242

3506
PAPER
Synthesis of New Dehydro 2-Azatryptophans and Derivatives via Heck Cross-
Coupling Reactions of 3-Iodoindazoles with Methyl 2-(Acetylamino)acrylate
Heck
Cross-Cr
aeactionof
n
3-Iodoindaz
ç
oles
w
ithM
o
ethyl 2-(Ac
e
i
tylami
s
no)acrylate Crestey, Valérie Collot,* Silvia Stiebing, Sylvain Rault
Centre d’Etudes et de Recherche sur le Médicament de Normandie (CERMN), UPRES EA-3915, U.F.R. des Sciences Pharmaceutiques,
Université de Caen Basse-Normandie, 5 rue Vaubénard, 14032 Caen Cedex, France
Fax +33(2)31931188; E-mail: valerie.collot@unicaen.fr
Received 28 June 2006; revised 3 July 2006
Ar
I
Abstract: This paper describes the Heck cross-coupling reaction of
3-iodoindazoles with methyl 2-(acetylamino)acrylate as a general
route to new dehydro 2-azatryptophans and protected amino acid
derivatives after catalytic hydrogenation.
R
N
R
N
N-arylation
Suzuki
N
N
R'
Ar or Het
I
Key words: dehydro 2-azatryptophans, protective amino acid de-
rivatives, catalytic hydrogenation, Heck cross-coupling reaction, 3-
iodoindazoles, 2-(acetylamino)acrylate
N
R
R''
N
R'
R' = H or protein
Sonogashira
CO2R
Amongst the heterocyclic scaffolds available for the prep-
aration of valuable new building-blocks in medicinal
chemistry, the indazole nucleus1 is probably the least
studied. In contrast to the plentiful literature on its bioisos-
teres (indole, quinoline or benzimidazole), there is a derth
of indazole chemistry literature, presumably a result of the
fact that this moiety is rather scarce in natural products.
Moreover, its utility as a starting point for the synthesis of
simple functionalized compounds is sometimes limited.
Despite these drawbacks, however, some indazole-deriv-
ative lead compounds have been developed such as
lonidamine (cytotoxic modulator),2 benzydamine (nonste-
roidal anti-inflammatory drug),3 granisetron (5HT-3 re-
ceptor antagonist),4 YC-1 (guanylyl cyclase activator),5 7-
NI (nitric oxide synthase inhibitor),6 and recently, new ki-
nase Chk1 inhibitors7 and inhibitors of the receptor ty-
rosine kinases.8
Heck
R
R
N
N
N
N
R'
R'
Scheme 1
ing program on the synthesis of functionalized indazoles,
we became interested in developing strategies for the syn-
thesis of 2-azatryptophans.11 With the aim of improving
molecular diversity, we decided to examine the Heck re-
action with methyl 2-(acetylamino)acrylate 1. Herein, we
report a methodology for the synthesis of new dehydro 2-
azatryptophans that allow access to a number of protected
amino acid derivatives.
Initially, we attempted to prepare acrylate 1 by the reac-
tion of acetamide with methyl pyruvate in the presence of
a catalytic amount of p-toluenesulfonic acid (PTSA) un-
der reflux conditions in toluene (Dean–Stark). The yields
were consistently lower than 50%, presumably due to
acrylate polymerization; however, addition of 4-methoxy-
We have long been interested in the design and synthesis
of new polyfunctionalized indazole libraries, particularly
those derived from the 2-aza bioisosteres of tryptamine,
serotonin or melatonin.9
To this end we have previously studied a number of metal- phenol (0.1%) significantly improved the yield and acry-
catalyzed reactions of 3-iodoindazoles (Scheme 1) and late 1 was then obtained with 61% yield (Scheme 2).
have reported a mild and flexible Sonogashira reaction
O
O
that allows access to new aza analogues of tryptamine de-
rivatives,9a a very efficient Suzuki cross-coupling reaction
leading to 3-arylindazoles,10a combined, selective C- and
N-arylations10b and a range of sequential cross-coupling
O
i
+
NH2
O
O
N
H
0.9 equiv
1
O
O
reactions of dihalogenated indazoles.10c We also devel- Scheme 2 Reagents and conditions: (i) PTSA (cat.), 4-methoxy-
phenol (0.001 equiv), toluene, reflux, Dean–Stark, 61%.
oped a general and versatile pathway leading to 3-inda-
zolylpropionic acid and derivatives via a straightforward
palladium-catalyzed Heck cross-coupling reaction of 3-
In our previous work we reported that a protecting group
in the N-1 position was necessary to avoid the formation
of Michael adducts.9b Indazole 6a was therefore synthe-
sised, in very good yields, by direct iodination of indazole
4a,10a followed by protection with 2-(trimethylsila-
nyl)ethoxymethyl chloride (SEM-Cl)14 in a biphasic
iodoindazoles with methyl acrylate.9b As part of our ongo-
SYNTHESIS 2006, No. 20, pp 3506–3514
1
7.
1
0
.
2
0
0
6
Advanced online publication: 10.10.2006
DOI: 10.1055/s-2006-950242; Art ID: Z13406SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Heck Cross-Coupling Reaction of 3-Iodoindazoles with Methyl 2-(Acetylamino)acrylate
3507
CH2Cl2/KOH mixture in the presence of a catalytic
amount of tetrabutylammonium bromide. Preliminary
coupling reactions were then performed by combining
protected 3-iodoindazole 6a with a slight excess of acry-
late 1, a slight excess of an amine base, 1 mol% of palla-
dium acetate and 2 mol% of triphenyl or tri(o-
tolyl)phosphine. Surprisingly, the reaction of N-SEM-3-
iodoindazole 6a with acrylate 1 using triarylphosphine
under the standard Heck conditions12 yielded none of the
desired product. Alternative conditions,9b using PdCl2(dppf)
catalyst in a mixture of DMF–H2O containing triethyl-
amine and tetrabutylammonium iodide (TBAI), gave
either unprotected 3-iodoindazole (when R = Boc) or the
deiodinated indazole along with unreacted starting mate-
rial (when R = SEM).
I
R1
R2
R1
R2
R1
ii
iii
N
N
N
N
R2
i
X
H
R
4a–f
2b–e X = NH2
3b–e X = N2 BF4–
5a–f R = H
iv
+
6a–f R = SEM
Scheme 4 Reagents and conditions: (i) aq 50% HBF4, NaNO2 aq (1
equiv), 0 °C, 84–99% (ii) KOAc (2 equiv), 18-crown-6 (0.05 equiv),
CHCl3, r.t., 44–80% (iii) I2 (2 equiv), KOH (3.75 equiv), DMF or 1,4-
dioxane, r.t. or 65 °C, 84–100% (iv) SEM-Cl (1.1 equiv), CH2Cl2/
KOH aq 50%, TBAB (0.01 equiv), r.t., 79–99%.
Table 1 Synthesis of N-SEM-3-Iodoindazoles (6a–f)
a
b
c
d
e
f
Previously reported Heck-coupling reactions of acrylate 1
have often been conducted in sealed tubes13a–h in the pres-
ence of NaHCO3 or K2CO3 as base, and a phase-transfer
agent such as a quaternary ammonium salt,13c–i in DMF,
acetonitrile or under solvent-free conditions. With this in
mind, we applied this Heck-coupling reaction to N-SEM-
3-iodoindazole 6a under the conditions described by
RajanBabu13c (1.2 equiv of acrylate 1 and TBACl, 2.7
equiv of NaHCO3 and 0.11 equiv of Pd(OAc)2 in a sealed
tube at 80 °C without solvent) and found that the reaction
gave, after 24 hours, the desired product 7a in 27% yield
(Scheme 3).
R1
H
H
–
OMe OBn
Br
H
I
NO2
H
R2
H
Me
99
H
84
74
84
79
Yield of 3 (%)
Yield of 4 (%)
Yield of 5 (%)
Yield of 6 (%)
98
98
80
94
99
–
a
a
–
79
100
98
44
–
92
99
100
79
100
98
a Commercially available.
a reference reaction. To this end, we modified the solvent
(DMF, toluene), the amount of acrylate 1 (1.2 to 1.7
equiv), the phase-transfer agent (TBABr or TBACl), and
the reaction temperature (110 to 135 °C). The optimum
conditions were found to be a 6b/1/TBAB/NaHCO3/
Pd(OAc)2 ratio of 1:1.6:1.9:3:0.12 in DMF at 125 °C for
two hours. Under these conditions, dehydro 2-azatryp-
tophan 7b was obtained in 54% yield. It should be noted
that the homocoupled product 8b was also isolated in 10%
yield, the structure of which was confirmed by 2D
NOESY NMR experiments.16 This minor product could
be easily separated from indazole 7b by column chroma-
tography. In order to decrease this process of homocou-
pling, the iodine atom in position 3 was replaced by
bromine, since the order of reactivity is usually I > Br >>
Cl in palladium-assisted coupling of aryl halides. Howev-
er, no reaction occurred and only starting material was re-
covered. Use of a larger excess of olefin 1 also had no
effect on either the extent of homocoupling or on the yield
of 7b. Moreover, when the reaction was conducted in the
CO2Me
I
NHAc
i
iii
N
N
N
N
N
N
H
R
4a
5a R = H
6a R = SEM
SEM
7a
ii
Scheme 3 Reagents and conditions: (i) I2 (2 equiv), KOH (3.75
equiv), DMF, r.t., 92% (ii) SEM-Cl (1.1 equiv), CH2Cl2/KOH aq
50%, TBAB (0.01 equiv), r.t., 99% (iii) acrylate 1 (1.2 equiv),
Pd(OAc)2 (0.11 equiv), TBAB (1.2 equiv), NaHCO3 (2.7 equiv),
sealed tube, 90 °C.
This encouraging result prompted us to study this reaction
with a range of other N-SEM-3-iodoindazoles 6
(Scheme 4 and Table 1). Except for indazole 4a and 5-ni-
troindazole 4f, which were both commercially available,
indazoles 4 were obtained by diazotization of 2-methyl-
anilines 2 with aqueous sodium nitrite in fluoroboric acid
(50% solution in water)15 to give the corresponding di- absence of olefin 1, compound 8b was formed as the sole
azonium tetrafluoroborate salts 3b–e in excellent yields product in 73% yield. It would appear that the competitive
(84–99%).
formation of this interesting by-product seems to be faster
than that of the desired dehydro compound.
Cyclization of these salts, promoted by potassium acetate
and 18-crown-6 in dry chloroform, gave indazoles 4b–e in When the optimized reaction conditions were applied to
good yields (44–80%). Iodination in DMF or 1,4-diox- other substituted indazoles 6 (Scheme 5 and Table 2), de-
ane,11 at room temperature or at 65 °C, followed by pro- hydro 2-azatryptophans 7 were obtained in 23–54%
yields. The nature of the substituent on the benzene moi-
ety of the indazole did not appear to influence the course
of the coupling reaction. As noted previously,13e,17 we ob-
tained dehydro compounds 7 predominantly in the Z con-
tection with the SEM group, gave indazoles 6a–f in
excellent yields (Scheme 4 and Table 1).
In order to find more efficient Heck coupling conditions,
we focused on N-SEM-3-iodo-5-methoxyindazole 6b, as
Synthesis 2006, No. 20, 3506–3514 © Thieme Stuttgart · New York

3508
F. Crestey et al.
PAPER
R2
In conclusion, we have described a method for the synthe-
sis of new dehydro 2-azatryptophans, obtained from a
Heck-coupling reaction between methyl 2-(acetylami-
no)acrylate and a range of N-SEM-3-iodoindazoles. Some
of these compounds have been hydrogenated to give the
corresponding protected amino acids derivatives. Since
orthogonal protecting groups are present, these dehydro 2-
azatryptophans and unnatural amino acid derivatives
could provide valuable building blocks for a wide range of
applications, in particular in the development of new pep-
tidomimetics with specific structural features and for the
synthesis of serotonin receptors ligands (5HT).
CO2Me
NHAc
SEM
R1
N
N
I
R1
R2
R1
i
N
N
+
N
N
N
R2
N
SEM
6
SEM
7
R1
SEM
8
R2
Scheme 5 Reagents and conditions: (i) 1 (1.6 equiv), Pd(OAc)2
(0.12 equiv), TBAB (1.9 equiv), NaHCO3 (3 equiv), DMF, sealed
tube, 125 °C.
All commercial reagents were used as received without further pu-
rification. Reaction mixtures were stirred magnetically and moni-
tored by TLC using 0.2 mm Macherey-Nagel Polygram SIL G/
UV254 coated plates. Column chromatography was performed using
CarloErba-SDS 60A 70–200 mm silica gel. Melting points (uncor-
rected) were determined on a Kofler melting point apparatus. IR
spectra were taken with a Perkin-Elmer spectrum X FT-IR spec-
Table 2 Synthesis of Protected Dehydro Indazoles (7a–f) and
Homocoupled Products (8)
a
b
c
d
e
f
R1
H
H
30
20
OMe
H
OBn
Me
45
Br
H
39
–
I
NO2
H
R2
H
1
trometer. H NMR (400 MHz) and 13C NMR (100 MHz) spectra
a
were recorded on a JEOL Lambda 400 Spectrometer instrument. 2D
NOESY NMR spectra (mixing time: 500 ms) were recorded on a
Brucker Avance DRX 400 instrument. Chemical shifts (d) are ex-
pressed in parts per million downfield from TMS as an internal stan-
dard, and the coupling constants are in Hertz. Mass spectra were
recorded on a JEOL JMS GCMate with ionising potential of 70 eV
and with perfluorokerosene as internal standard for high-resolution
measurements. Elemental analyses were performed at the Institut de
Recherche en Chimie Organique Fine (Rouen, France).
7 (%)
8 (%)
54
10
–
–
23
8
10
a Product 7e was detected with LCMS but not isolated.
figuration, except for compound 7a (R1 = R2 = H) which
proved to be an isomeric mixture in a 2:1, Z/E ratio. Im-
portantly, substrates bearing either a bromine or an iodine
atom at position 5 were exclusively functionalized at po-
sition 3. Moreover some new, potentially valuable, prod-
ucts 8 were isolated with 8–20% yields. When the
substituent at position 5 of indazole was bromine or io-
dine, however, only a small amount of de-iodinated prod-
uct was observed.
Methyl 2-(Acetylamino)acrylate (1)19
A round-bottom flask equipped with a Dean–Stark trap was charged
successively with acetamide (1.5 g, 25.4 mmol), methyl pyruvate
(2.1 mL, 22.9 mmol, 0.9 equiv), a catalytic amount of p-TsOH, 4-
methoxyphenol (4 mg, 25,4 mmol, 0.001 equiv) and toluene (50
mL). The stirred mixture was heated under reflux for 26 h then con-
centrated in vacuo. The resulting yellow oil was taken up in CH2Cl2
(100 mL), washed with sat. NaHCO3 (100 mL) and H2O (100 mL).
The organic layer was dried over MgSO4, filtered and concentrated
in vacuo to give methyl 2-(acetylamino)acrylate (1).
Efforts were then focused on the reduction of the double
bond of the dehydro compounds 7. Preliminary attempts
with sodium borohydride in the presence of Ni(II) chlo-
ride hexahydrate in methanol9b,18 gave the desired prod-
ucts albeit in low yields (<50%). However, catalytic
hydrogenation with palladium on activated carbon in
methanol13e gave amino acid derivatives 9 with very good
yields (Scheme 6). In the case of compound 7c, both the
double bond and the benzyloxy group on the aromatic nu-
cleus were reduced, leading to compound 9c.
Yield: 2.0 g (61%); light-yellow solid; mp 48 °C.
IR (KBr): 3364, 2957, 1728, 1678, 1636, 1520, 1441, 1372, 1204,
1172, 995, 904, 806 cm–1.
1H NMR (CDCl3): d = 2.14 (s, 3 H), 3.85 (s, 3 H), 5.88 (s, 1 H), 6.60
(s, 1 H), 7.75 (br s, 1 H).
13C NMR (CDCl3): d = 24.7, 53.0, 108.7, 130.9, 164.6, 168.9.
MS (EI): m/z (%) = 143 (60) [M+], 113 (28), 112 (14), 102 (30), 101
(100).
CO2Me
NHAc
CO2Me
NHAc
Synthesis of 2-Methylbenzenediazonium Tetrafluoroborate
Salts (3b–e); General Procedure (GP 1)
R1
R2
R1
i
N
To a cooled solution of the 2-methylaniline 2b–e dissolved in fluo-
roboric acid (50% soln in H2O) was added at 0 °C, dropwise, a
cooled solution of NaNO2 (1 equiv in the minimum of H2O). After
the end of the addition, the mixture was stirred for 1 h at 0 °C then
for 2 h at r.t.. The resulting precipitate was filtered and washed with
Et2O (3 × 100 mL) to obtain the desired 2-methylphenyldiazonium
tetrafluoroborate salts 3b–e.
N
N
R2
N
SEM
SEM
7a–c
9a: R1 = R2 = H
85%
100%
92%
9b: R1 = OMe, R2 = H
9c: R1 = OH, R2 = Me
Scheme 6 Reagents and conditions: (i) H2, Pd/C (15 mol%), 1 atm,
MeOH, r.t.
Synthesis 2006, No. 20, 3506–3514 © Thieme Stuttgart · New York

PAPER
Heck Cross-Coupling Reaction of 3-Iodoindazoles with Methyl 2-(Acetylamino)acrylate
3509
4-Methoxy-2-methylbenzenediazonium Tetrafluoroborate Salt
(3b)
Obtained by GP 1, starting from 4-methoxy-2-methylaniline (2b;
12.8 g, 93.6 mmol), and fluoroboric acid (25 mL).
1H NMR (CDCl3): d = 2.42 (s, 3 H), 5.12 (s, 2 H), 7.10 (s, 1 H), 7.28
(s, 1 H), 7.34 (d, J = 7.3 Hz, 1 H), 7.40 (t, J = 7.3 Hz, 2 H), 7.48 (d,
J = 7.3 Hz, 2 H), 7.94 (s, 1 H), 10.04 (br s, 1 H).
13C NMR (CDCl3): d = 17.8, 70.2, 100.1, 110.7, 121.8, 127.1, 127.8,
128.5, 129.8, 134.3, 135.9, 137.4, 152.8.
MS (EI): m/z (%) = 238 (50) [M+], 147 (40), 126 (16), 91 (100).
Yield: 21.7 g (98%); pink solid; mp 144 °C.
IR (KBr): 3400, 2231, 1591, 1264, 1063 cm–1.
1H NMR (DMSO-d6): d = 2.67 (s, 3 H), 4.02 (s, 3 H), 7.32 (dd,
J = 9.3 Hz, J = 1.9 Hz, 1 H), 7.39 (d, J = 1.9 Hz, 1 H), 8.57 (d,
J = 9.2 Hz, 1 H).
Anal. Calcd for C15H14N2O: C, 75.61; H, 5.92; N, 11.76. Found: C,
75.32; H, 5.44; N, 11.25.
5-Bromo-1H-indazole (4d)
Obtained by GP 2, starting from 4-bromo-2-methylphenyldiazoni-
um tetrafluoroborate salt (3d; 12.1 g, 42.3 mmol).
4-Benzyloxy-2,5-dimethylphenyldiazonium Tetrafluoroborate
Salt (3c)
Obtained by GP 1, starting from 4-benzyloxy-2,5-dimethylaniline
(2c; 5 g, 22.0 mmol) and fluoroboric acid (6 mL).
Yield: 6.7 g (80%); orange solid; mp 122 °C; Rf = 0.45 (EtOAc–cy-
clohexane, 2:3).
Yield: 7.1 g (99%); beige solid; mp 131 °C.
IR (KBr): 3420, 2236, 1230, 1057 cm–1.
IR (KBr): 3177, 2933, 1490, 1190, 1069, 952, 878, 782 cm–1.
1H NMR (CDCl3): d = 7.41 (d, J = 8.8 Hz, 1 H), 7.48 (dd, J = 8.8
Hz, J = 1.7 Hz, 1 H), 7.92 (d, J = 1.7 Hz, 1 H), 8.02 (s, 1 H), 10.18
(br s, 1 H).
13C NMR (CDCl3): d = 111.2, 114.2, 123.4, 124.8, 130.1, 134.3,
138.7.
MS (EI): m/z (%) = 198 (97) [M + H+], 196 (100) [M – 1], 117 (51),
90 (50).
4-Bromo-2-methylbenzenediazonium Tetrafluoroborate Salt
(3d)
Obtained by GP 1, starting from 4-bromo-2-methylaniline (2d; 10
g, 53.8 mmol) and fluoroboric acid (28 mL).
Yield: 15 g (98%); beige solid; mp 176 °C.
IR (KBr): 3416, 2279, 2260, 1587, 1548, 1207, 1033 cm–1.
Anal. Calcd for C7H5BrN2: C, 42.67; H, 2.56; N, 14.22. Found: C,
42.39; H, 2.35; N, 14.13.
4-Iodo-2-methylbenzenediazonium Tetrafluoroborate Salt (3e)
Obtained by GP 1, starting from 4-iodo-2-methylaniline (2e; 5 g,
21.5 mmol) and fluoroboric acid (7 mL).
5-Iodo-1H-indazole (4e)14b
Obtained by GP 2, starting from 4-iodo-2-methylphenyldiazonium
tetrafluoroborate salt (3e; 5.7 g, 17.2 mmol).
Yield: 6 g (84%); mauve solid; mp 175 °C.
IR (KBr): 3416, 2274, 2253, 1579, 1542, 1203, 1060, 1033 cm–1.
Yield: 3.1 g (74%); yellow solid; mp 156 °C; Rf = 0.5 (EtOAc–cy-
clohexane, 2:3).
IR (KBr): 3131, 2923, 1471, 1283, 1082, 959, 892, 808 cm–1.
1H NMR (DMSO-d6): d = 7.40 (d, J = 8.7 Hz, 1 H), 7.56 (d, J = 8.7
Hz, 1 H), 8.01 (s, 1 H), 8.17 (s, 1 H), 13.23 (br s, 1 H).
Synthesis of Indazoles (4b–e); General Procedure (GP 2)
The diazonium tetrafluoroborate salt 3b–e was added in one por-
tion, under nitrogen, to a stirred mixture of KOAc (2 equiv) and 18-
crown-6 (0.05 equiv) in dry CHCl3 (500 mL). After 2 h at r.t., the
resulting precipitate was filtered, washed with CHCl3 (2 × 100 mL)
and the organic layer was concentrated in vacuo. The residual gum
was purified by column chromatography on silica gel (EtOAc–cy-
clohexane, 1:6 to 2:3) to give the desired indazoles 4b–e.
MS (EI): m/z (%) = 244 (100) [M+], 135 (27), 117 (34), 91 (39).
Anal. Calcd for C7H5IN2: C, 34.45; H, 2.07; N, 11.48. Found: C,
33.91; H, 2.19; N, 10.75.
5-Methoxy-1H-indazole (4b)15b
Obtained by GP 2, starting from 4-methoxy-2-methylphenyldiazo-
nium tetrafluoroborate salt (3b; 14 g, 59.3 mmol).
Synthesis of 3-Iodoindazoles (5); General Precedure
Method A
Iodine (2 equiv) and KOH pellets (3.75 equiv) were successively
added to a solution of the indazole 4 in DMF (60 mL) at r.t. under
stirring. After 1 h, the reaction mixture was poured into aq NaHSO3
(10%, 200 mL) and extracted with Et2O (2 × 150 mL). The com-
bined organic layers were washed with H2O (3 × 150 mL) and brine
(3 × 150 mL), dried over MgSO4, and the solvent evaporated in vac-
uo. The solid residue was washed with petroleum ether to give de-
sired 3-iodoindazoles 5.
Yield: 7 g (79%); beige solid; mp 170–171 °C; Rf = 0.2 (EtOAc–cy-
clohexane, 1:2).
IR (KBr): 3152, 2940, 1508, 1229, 1157, 957, 810 cm–1.
1H NMR (CDCl3): d = 3.87 (s, 3 H), 7.07–7.11 (m, 2 H), 7.40 (d,
J = 8.8 Hz, 1 H), 8.00 (s, 1 H), 10.18 (br s, 1 H).
13C NMR (CDCl3): d = 55.7, 100.0, 110.6, 119.2, 123.6, 134.4,
135.9, 154.8.
MS (EI): m/z (%) = 148 (100) [M+], 133 (95), 105 (54), 78 (21).
Method B
KOH pellets (5.8 equiv) and iodine (2 equiv) were successively
added to a cooled 1,4-dioxane solution (60 mL) of indazole 4 under
stirring. The reaction mixture was stirred for 1 h at 0 °C then 2 h at
r.t.. The pH value was adjusted to pH 5 through the addition of 20%
aqueous citric acid then sat. Na2S2O3 (200 mL) was added and the
mixture was extracted with EtOAc (3 × 200 mL). The combined or-
ganic layers were washed with H2O (3 × 150 mL) and brine (3 × 150
mL), dried over MgSO4, and the solvent evaporated in vacuo. The
solid residue was washed with petroleum ether to give desired 3-io-
doindazoles 5.
Anal. Calcd for C8H8N2O: C, 64.85; H, 5.44; N, 18.91. Found: C,
64.17; H, 5.23; N, 18.33.
5-Benzyloxy-6-methyl-1H-indazole (4c)
Obtained by GP 2, starting from 4-benzyloxy-2,5-dimethylphenyl-
diazonium tetrafluoroborate salt (3c; 28.9 g, 88.6 mmol).
Yield: 9.3 g (44%); brown solid; mp 141 °C; Rf = 0.1 (EtOAc–cy-
clohexane, 1:4).
IR (KBr): 3179, 2924, 1454, 1304, 1223, 1164, 1128, 954 cm–1.
Synthesis 2006, No. 20, 3506–3514 © Thieme Stuttgart · New York

3510
F. Crestey et al.
PAPER
IR (KBr): 3436, 3122, 2893, 1464, 1255, 1234, 912, 783 cm–1.
Method C
The reaction was carried out as described in method B but the stirred
mixture was heated at 65 °C.
1H NMR (CDCl3): d = 7.38 (d, J = 8.8 Hz, 1 H), 7.53 (dd, J = 8.8
Hz, J = 1.7 Hz, 1 H), 7.68 (d, J = 1.7 Hz, 1 H), 10.62 (br s, 1 H).
Method D
13C NMR (CDCl3): d = 93.0, 111.7, 115.2, 124.2, 129.4, 131.5,
139.4.
The reaction was carried out as described in method A but the
stirred mixture was heated at 65 °C.
MS (EI): m/z (%) = 324 (97) [M + H+], 322 (100) [M – 1], 197 (57),
195 (58), 116 (46).
3-Iodo-1H-indazole (5a)10a
Obtained by method A, starting from 1H-indazole (4a; 3.8 g, 31.9
mmol).
Anal. Calcd for C7H4BrIN2: C, 26.04; H, 1.25; N, 8.67. Found: C,
26.08; H, 1.39; N, 8.63.
Yield: 6.9 g (92%); white solid; mp 141 °C; Rf = 0.5 (EtOAc–cyclo-
3,5-Diiodo-1H-indazole (5e)14b
hexane, 1:2).
IR (KBr): 3154, 2904, 1239, 1014, 739 cm–1.
Obtained by method A, starting from 5-iodo-1H-indazole (4e; 1 g,
4.1 mmol).
Yield: 1.3 g (84%); yellow solid; 198–200 °C (dec); Rf = 0.65
(EtOAc–cyclohexane, 2:3).
IR (KBr): 3426, 3150, 2928, 1460, 1257, 1236, 900, 778 cm–1.
1H NMR (CDCl3): d = 7.20 (t, J = 7.3 Hz, 1 H), 7.42 (t, J = 7.3 Hz,
1 H), 7.49 (d, J = 8.0 Hz, 1 H), 7.60 (d, J = 8.0 Hz, 1 H), 10.72 (br
s, 1 H).
13C NMR (CDCl3): d = 93.0, 110.4, 120.3, 121.5, 127.2, 127.6,
140.6.
1H NMR (CDCl3): d = 7.28 (d, J = 8.7 Hz, 1 H), 7.69 (d, J = 8.6 Hz,
1 H), 7.90 (s, 1 H), 10.55 (br s, 1 H).
MS (EI): m/z (%) = 244 (100) [M+], 117 (80), 90 (43).
MS (EI): m/z (%) = 370 (100) [M+], 243 (50), 116 (45).
Anal. Calcd for C7H5IN2: C, 34.45; H, 2.07; N, 11.48. Found: C,
34.33; H, 2.22; N, 11.27.
Anal. Calcd for C7H4I2N2: C, 22.73; H, 1.07; N, 7.57. Found: C,
23.75; H, 0.84; N, 7.41.
3-Iodo-5-methoxy-1H-indazole (5b)15a
Obtained by method B, starting from 5-methoxy-1H-indazole (4b;
3 g, 20.4 mmol).
3-Iodo-5-nitro-1H-indazole (5f)
Obtained by method D, starting from 5-nitro-1H-indazole (4f; 5 g,
30.7 mmol).
Yield: 5.6 g (100%); yellow solid; mp 178–179 °C; Rf = 0.4
Yield: 6.4 g (100%); yellow solid; mp 214 °C; Rf = 0.4 (EtOAc–cy-
(EtOAc–cyclohexane, 1:2).
clohexane, 1:2).
IR (KBr): 3184, 2902, 1506, 1483, 1288, 1172, 1028, 1004, 944,
822 cm–1.
1H NMR (DMSO-d6): d = 3.80 (s, 3 H), 6.75 (s, 1 H), 7.06 (d,
J = 8.8 Hz, 1 H), 7.45 (d, J = 9.0 Hz, 1 H), 13.37 (br s, 1 H).
13C NMR (DMSO-d6): d = 55.4, 92.2, 99.2, 111.7, 119.5, 127.1,
136.1, 154.6.
IR (KBr): 3097, 1340, 1084, 1004 cm–1.
1H NMR (DMSO-d6): d = 7.75 (d, J = 9.3 Hz, 1 H), 8.22 (dd, J = 9.3
Hz, J = 2.0 Hz, 1 H), 8.30 (d, J = 2.0 Hz, 1 H), 14.12 (br s, 1 H).
13C NMR (DMSO-d6): d = 97.2, 111.8, 118.1, 122.0, 126.3, 142.1,
142.5.
MS (EI): m/z (%) = 289 (100) [M+], 259 (16), 116 (30).
MS (EI): m/z (%) = 274 (100) [M+], 259 (13), 147 (97), 132 (10),
128 (20), 120 (25), 104 (20), 78 (20).
Anal. Calcd for C7H4IN3O2: C, 29.09; H, 1.39; N, 14.54. Found: C,
28.79; H, 1.76; N, 14.06.
Anal. Calcd for C8H7IN2O: C, 35.06; H, 2.57; N, 10.22. Found: C,
35.27; H, 2.54; N, 10.17.
Synthesis of N-SEM-3-iodoindazoles (6); General Procedure
(GP 3)
5-Benzyloxy-3-iodo-6-methyl-1H-indazole (5c)
Obtained by method C, starting from 5-benzyloxy-6-methyl-1H-in-
dazole (4c; 1.1 g, 4.6 mmol).
To a cooled solution of the 3-iodoindazole 5, TBAB (0.01 equiv)
and KOH (50% solution in H2O, 7–15 mL) in CH2Cl2 (15–20 mL)
was added at 0 °C, dropwise, SEM-Cl (1.1 equiv). After the end of
the addition, the mixture was stirred rapidly at 0 °C for 1 h then 2 h
at r.t. CH2Cl2 (50 mL) and H2O (70 mL) were added, and the organ-
ic layer was washed with brine (2 × 100 mL), dried over MgSO4, fil-
tered and evaporated in vacuo. The crude material was purified by
flash column chromatography on silica gel (EtOAc–cyclohexane,
1:6) to give a mixture of (N-1 and N-2)-SEM-3-iodoindazoles 6.
Yield: 1.7 g (100%); beige solid; mp 152 °C; Rf = 0.25 (EtOAc–cy-
clohexane, 1:4).
IR (KBr): 3256, 1728, 1474, 1446, 1281, 1192, 1137, 991, 870
cm–1.
1H NMR (DMSO-d6): d = 2.32 (s, 3 H), 5.17 (s, 2 H), 6.82 (s, 1 H),
7.33 (d, J = 8.0 Hz, 1 H), 7.36 (s, 1 H), 7.41 (t, J = 8.0 Hz, 2 H),
7.51 (d, J = 8.0 Hz, 2 H), 13.24 (br s, 1 H).
13C NMR (DMSO-d6): d = 17.3, 69.4, 92.1, 99.5, 111.3, 125.5,
127.3, 127.7, 128.4, 129.4, 135.9, 137.4, 152.4.
3-Iodo-1-[2-(trimethylsilanyl)ethoxymethyl]-1H-indazole (6a)
Obtained by GP 3, starting from 3-iodo-1H-indazole (5a; 1.5 g, 6.2
mmol).
Yield: 2.3 g (99%); light-yellow oil; Rf = 0.8 (EtOAc–cyclohexane,
1:3).
MS (EI): m/z (%) = 364 (26) [M+], 273 (11), 91 (100).
Anal. Calcd for C15H13IN2O: C, 49.47; H, 3.60; N, 7.69. Found: C,
49.47; H, 2.91; N, 7.02.
IR (KBr): 3060, 2952, 1615, 1490, 1460, 1317, 1249, 1194, 1174,
1081, 860, 836, 745 cm–1.
1H NMR (CDCl3): d = –0.11 (s, 9 H), 0.83 (t, J = 8.3 Hz, 2 H), 3.53
(t, J = 8.3 Hz, 2 H), 5.65 (s, 2 H), 7.15 (t, J = 7.8 Hz, 1 H), 7.34–
7.41 (m, 2 H), 7.46 (d, J = 8.6 Hz, 1 H).
5-Bromo-3-iodo-1H-indazole (5d)
Obtained by method A, starting from 5-bromo-1H-indazole (4d; 1.1
g, 5.5 mmol).
13C NMR (CDCl3): d = –1.4, 17.6, 66.5, 77.8, 93.2, 109.7, 121.5,
121.9, 127.8, 128.9, 140.1.
Yield: 1.7 g (94%); yellow solid; mp 196 °C; Rf = 0.3 (EtOAc–cy-
clohexane, 1:3).
Synthesis 2006, No. 20, 3506–3514 © Thieme Stuttgart · New York

PAPER
Heck Cross-Coupling Reaction of 3-Iodoindazoles with Methyl 2-(Acetylamino)acrylate
3511
MS (EI): m/z (%) = 374 (23) [M+], 331 (10), 329 (20), 316 (26), 258
(55), 257 (36), 243 (43), 175 (35), 174 (86), 131 (52), 130 (30), 103
(30), 73 (100).
3,5-Diiodo-1-[2-(trimethylsilanyl)ethoxymethyl]-1H-indazole
(6e)14b
Obtained by GP 3, starting from 3,5-diiodo-1H-indazole (5e; 0.8 g,
2 mmol).
HRMS (ESI): m/z [M + H]+ calcd for C13H20IN2OSi: 375.0390;
found: 375.0375.
Yield: 0.8 g (79%); orange oil; Rf = 0.7 (EtOAc–cyclohexane, 1:4).
IR (KBr): 2952, 2895, 1470, 1256, 1190, 1080, 858, 835 cm–1.
3-Iodo-5-methoxy-1-[2-(trimethylsilanyl)ethoxymethyl]-1H-
indazole (6b)
Obtained by GP 3, starting from 3-iodo-5-methoxy-1H-indazole
(5b; 3.5 g, 12.8 mmol).
1H NMR (CDCl3): d = –0.06 (s, 9 H), 0.86 (t, J = 8.3 Hz, 2 H), 3.54
(t, J = 8.3 Hz, 2 H), 5.68 (s, 2 H), 7.34 (d, J = 8.8 Hz, 1 H), 7.71 (dd,
J = 8.6 Hz, J = 1.7 Hz, 1 H), 7.87 (d, J = 1.7 Hz, 1 H).
13C NMR (CDCl3): d = –1.4, 17.7, 66.8, 78.2, 85.3, 91.4, 111.7,
130.6, 131.4, 136.3, 139.4.
MS (EI): m/z (%) = 500 (23) [M+], 442 (24), 384 (37), 300 (40), 257
(33), 256 (16), 150 (16), 103 (30), 101 (25), 74 (100).
HRMS (EI): m/z [M]+ calcd for C13H18I2N2OSi: 499.9278; found:
499.9272.
Yield: 5.1 g (98%); orange solid; mp <46 °C; Rf = 0.7 (EtOAc–cy-
clohexane, 1:6).
IR (KBr): 2953, 1500, 1285, 1249, 1062, 860 cm–1.
1H NMR (CDCl3): d = –0.05 (s, 9 H), 0.87 (t, J = 8.7 Hz, 2 H), 3.56
(t, J = 8.7 Hz, 2 H), 3.99 (s, 3 H), 5.64 (s, 2 H), 6.72 (d, J = 1.7 Hz,
1 H), 7.06 (dd, J = 9.0 Hz, J = 1.7 Hz, 1 H), 7.36 (d, J = 9.0 Hz,
1 H).
13C NMR (CDCl3): d = –0.9, 18.5, 56.1, 66.3, 78.6, 92.6, 100.8,
111.5, 120.7, 130.0, 136.4, 156.3.
3-Iodo-5-nitro-1-[2-(trimethylsilanyl)ethoxymethyl]-1H-
indazole (6f)
Obtained by GP 3, starting from 3-iodo-5-nitro-1H-indazole (5f;
1.8 g, 6.1 mmol).
MS (EI): m/z (%) = 404 (58) [M+], 359 (25), 346 (42), 288 (23), 287
(37), 205 (31), 204 (50), 189 (17), 161 (33), 160 (27), 145 (15), 102
(18), 73 (100).
Yield: 2.5 g (98%); yellow solid; 88–90 °C (dec); Rf = 0.7 (EtOAc–
cyclohexane, 1:4).
Anal. Calcd for C14H21IN2O2Si: C, 41.59; H, 5.24; N, 6.93. Found:
C, 41.36; H, 4.87; N, 6.49.
IR (KBr): 2953, 1500, 1285, 1249, 1062, 860 cm–1.
1H NMR (CDCl3): d = –0.08 (s, 9 H), 0.87 (t, J = 8.6 Hz, 2 H), 3.58
(t, J = 8.6 Hz, 2 H), 5.75 (s, 2 H), 7.65 (d, J = 9.3 Hz, 1 H), 8.30 (dd,
J = 9.3 Hz, J = 1.9 Hz, 1 H), 8.40 (d, J = 2.0 Hz, 1 H).
13C NMR (CDCl3): d = –1.4, 17.6, 67.1, 78.4, 95.4, 110.6, 119.2,
122.7, 128.6, 143.2, 143.8.
5-Benzyloxy-3-Iodo-6-methyl-1-[2-(trimethylsilanyl)ethoxy-
methyl]-1H-indazole (6c)
Obtained by GP 3, starting from 5-benzyloxy-3-iodo-6-methyl-1H-
indazole (5c; 1.7 g, 4.6 mmol).
MS (EI): m/z (%) = 419 (12) [M+], 376 (34), 374 (19), 361 (51), 303
(87), 302 (23), 219 (51), 176 (25), 175 (18), 103 (14), 74 (100).
Yield: 1.8 g (79%); light-brown solid; 74–76 °C (dec); Rf = 0.6
(EtOAc–cyclohexane, 1:4).
IR (KBr): 2952, 2920, 1475, 1277, 1204, 1160, 1077, 830 cm–1.
1H NMR (CDCl3): d = –0.08 (s, 9 H), 0.85 (t, J = 8.6 Hz, 2 H), 2.40
(s, 3 H), 3.52 (t, J = 8.7 Hz, 2 H), 5.22 (s, 2 H), 5.63 (s, 2 H), 6.79
(s, 1 H), 7.32 (s, 1 H), 7.33 (d, J = 7.3 Hz, 1 H), 7.39 (t, J = 7.3 Hz,
2 H), 7.48 (d, J = 7.3 Hz, 2 H).
Anal. Calcd for C13H12IN3O3Si: C, 37.24; H, 4.33; N, 10.02. Found:
C, 37.42; H, 4.18; N, 10.04.
Heck Cross-Coupling of Protected Dehydro 2-Azatryptophans
(7); General Procedure (GP 4)
A mixture of NaHCO3 (3 equiv), methyl 2-(acetylamino)acrylate
(1; 1.6 equiv), TBAB (1.9 equiv), N-SEM-3-iodoindazoles 6, and
DMF (3–4 mL) was flushed with argon in a sealed tube. After 10
min, palladium acetate (0.12 equiv) was added and the mixture was
heated at 130 °C in an oil bath for 2 h. After cooling to r.t., the re-
sulting mixture was taken up in EtOAc (80 mL) and washed with
H2O (3 × 150 mL). The aqueous layer was extracted with EtOAc (2
× 80 mL), and the combined organic layers were filtered through
Celite then concentrated in vacuo. The residual brown oil was puri-
fied by column chromatography on silica gel (EtOAc–cyclohexane,
1:6 to 1:1) to afford desired protected dehydro 2-azatryptophans 7
and homocoupling products 8.
13C NMR (CDCl3): d = –1.4, 17.8, 17.9, 66.5, 70.3, 78.0, 91.2,
100.4, 110.9, 127.1, 127.8, 127.8, 128.5, 131.1, 135.7, 137.0, 153.7.
MS (EI): m/z (%) = 494 (45) [M+], 436 (14), 377 (23), 345 (84), 287
(17), 251 (17), 203 (22), 91 (100), 73 (67).
Anal. Calcd for C21H27IN2O2Si: C, 51.01; H, 5.50; N, 5.67. Found:
C, 51.46; H, 5.44; N, 5.43.
5-Bromo-3-iodo-1-[2-(trimethylsilanyl)ethoxymethyl]-1H-
indazole (6d)
Obtained by GP 3, starting from 5-bromo-3-iodo-1H-indazole (5d;
6 g, 18.6 mmol).
Yield: 8.3 g (99%); orange oil; Rf = 0.7 (EtOAc–cyclohexane, 1:3).
IR (KBr): 2952, 2895, 1473, 1251, 1192, 1083, 859, 796 cm–1.
1H NMR (CDCl3): d = –0.06 (s, 9 H), 0.87 (t, J = 8.3 Hz, 2 H), 3.55
(t, J = 8.3 Hz, 2 H), 5.70 (s, 2 H), 7.44 (d, J = 8.8 Hz, 1 H), 7.54 (dd,
J = 8.8 Hz, J = 1.7 Hz, 1 H), 7.66 (d, J = 1.7 Hz, 1 H).
(Z)-2-Acetylamino-3-{1-[2-(trimethylsilanyl)ethoxymethyl]-
1H-indazol-3-yl}acrylic Acid Methyl Ester (7a) and 1,1¢-Bis[2-
(trimethylsilanyl)ethoxymethyl]-[3,3¢]biindazolyl (8a)
Obtained by GP 4, starting from 3-iodo-1-[2-(trimethylsila-
nyl)ethoxymethyl]-1H-indazole (6a; 2.5 g, 6.7 mmol).
13C NMR (CDCl3): d = –1.3, 17.9, 67.0, 78.4, 91.8, 111.6, 115.5,
124.4, 130.8, 131.3, 139.2.
7a
Yield: 0.8 g (30%); yellow oil; Rf = 0.6 (EtOAc–cyclohexane, 1:1).
MS (EI): m/z (%) = 454 (13) [M + H]+, 452 (12) [M – 1], 396 (21),
394 (21), 338 (28), 337 (19), 336 (28), 335 (18), 255 (16), 254 (39),
253 (16), 252 (37), 211 (20), 210 (17), 209 (23), 208 (15), 74 (100).
HRMS (EI): m/z [M]+ calcd for C13H18BrIN2OSi: 451.9416; found:
451.9426.
IR (KBr): 3310, 2953, 1732, 1694, 1644, 1506, 1347, 1248, 1080,
837, 749 cm–1.
1H NMR (CDCl3): d = –0.07 (s, 9 H), 0.90 (t, J = 8.3 Hz, 2 H), 2.22
(s, 3 H), 3.57 (t, J = 8.3 Hz, 2 H), 3.90 (s, 3 H), 5.76 (s, 2 H), 6.85
(s, 1 H), 7.27 (t, J = 7.8 Hz, 1 H), 7.48 (t, J = 7.8 Hz, 1 H), 7.58 (d,
J = 8.5 Hz, 1 H), 7.79 (d, J = 8.1 Hz, 1 H), 9.87 (br s, 1 H).
Synthesis 2006, No. 20, 3506–3514 © Thieme Stuttgart · New York

3512
F. Crestey et al.
PAPER
13C NMR (CDCl3): d = –1.4, 17.7, 23.6, 52.6, 66.9, 78.1, 108.7,
109.8, 119.9, 122.3, 124.2, 127.8, 130.1, 139.9, 141.0, 165.5, 168.6.
Anal. Calcd for C28H42N4O4Si2: C, 60.61; H, 7.63; N, 10.10. Found:
C, 59.44; H, 7.92; N, 9.98.
MS (EI): m/z (%) = 389 (9) [M+], 289 (13), 167 (14), 149 (35), 73
(100).
HRMS (EI): m/z [M]+ calcd for C19H27N3O4Si: 389.1771; found:
389.1753.
(Z)-2-Acetylamino-3-{5-benzyloxy-6-methyl-1-[2-(trimethylsi-
lanyl)ethoxymethyl]-1H-indazol-3-yl}acrylic Acid Methyl Ester
(7c) and 5,5¢-Dibenzyloxy-6,6¢-dimethyl-1,1¢-bis[2-(trimethylsi-
lanyl)ethoxymethyl]-[3,3¢]biindazolyl (8c)
Obtained by GP 4, starting from 5-benzyloxy-3-iodo-6-methyl-1-
[2-(trimethylsilanyl)ethoxymethyl]-1H-indazole (6c; 3.1 g, 6.2
mmol).
8a
Yield: 0.6 g (20%); light-orange solid; 82–84 °C (dec).
IR (KBr): 2955, 1464, 1379, 1303, 1249, 1079, 836, 744 cm–1.
1H NMR (CDCl3): d = –0.09 (s, 18 H), 0.93 (t, J = 8.3 Hz, 4 H), 3.67
(t, J = 8.3 Hz, 4 H), 5.84 (s, 4 H), 7.28 (t, J = 8.3 Hz, 2 H), 7.46 (t,
J = 8.3 Hz, 2 H), 7.59 (d, J = 8.3 Hz, 2 H), 8.53 (d, J = 8.3 Hz, 2 H).
13C NMR (CDCl3): d = –1.4, 17.7, 66.5, 77.7, 109.4, 121.8, 123.1
127.6, 134.0, 139.7, 140.6.
MS (EI): m/z (%) = 494 (8) [M+], 377 (10), 203 (26), 177 (20), 175
(73), 148 (40), 132 (73), 131 (100), 103 (16), 84 (25), 74 (89).
7c
Yield: 1.4 g (45%); pale-yellow solid; 102–104 °C (dec).
IR (KBr): 3273, 2950, 2917, 1735, 1665, 1525, 1489, 1434, 1305,
1256, 1223, 1082, 858, 835 cm–1.
1H NMR (CDCl3): d = –0.06 (s, 9 H), 0.90 (t, J = 8.3 Hz, 2 H), 2.21
(s, 3 H), 2.43 (s, 3 H), 3.55 (t, J = 8.3 Hz, 2 H), 3.90 (s, 3 H), 5.13
(s, 2 H), 5.69 (s, 2 H), 6.81 (s, 1 H), 7.12 (s, 1 H), 7.37 (s, 1 H), 7.34
(d, J = 6.8 Hz, 1 H), 7.41 (t, J = 7.1 Hz, 2 H), 7.49 (d, J = 7.3 Hz,
2 H), 9.87 (br s, 1 H).
13C NMR (CDCl3): d = –1.5, 17.6, 17.8, 23.5, 52.5, 66.7, 70.1, 78.1,
98.8, 108.6, 110.8, 123.0, 127.0, 127.9, 128.5, 129.3, 130.8, 135.4,
136.9, 140.0, 153.8, 165.6, 168.5.
Anal. Calcd for C26H38N4O2Si2: C, 63.12; H, 7.74; N, 11.32. Found:
C, 63.03; H, 7.71; N, 10.87.
(Z)-2-Acetylamino-3-{5-methoxy-1-[2-(trimethylsila-
nyl)ethoxymethyl]-1H-indazol-3-yl}acrylic Acid Methyl Ester
(7b) and 5,5¢-Dimethoxy-1,1¢-bis[2-(trimethylsilanyl)ethoxy-
methyl]-[3,3¢]biindazolyl (8b)
MS (EI): m/z (%) = 510 (16) [M+], 328 (19), 300 (17), 270 (16), 258
(30), 91 (55), 84 (19), 76 (43), 74 (100).
Obtained by GP 4, starting from 3-iodo-5-methoxy-1-[2-(trimethyl-
silanyl)ethoxymethyl]-1H-indazole (6b; 2.2 g, 5.4 mmol).
Anal. Calcd for C27H35N3O5Si: C, 63.63; H, 6.92; N, 8.24. Found:
C, 63.26; H, 6.22; N, 7.94.
7b
8c
Yield: 1.2 g (54%); pale-yellow solid; 68–70 °C (dec); Rf = 0.1
Yield: 0.7 g (10%); light-brown solid; mp 139 °C; Rf = 0.7 (EtOAc–
cyclohexane, 2:3).
(EtOAc–cyclohexane, 1:3).
IR (KBr): 3342, 2953, 2923, 2902, 1732, 1699, 1496, 1328, 1306,
1277, 1086, 1044, 839 cm–1.
IR (KBr): 3430, 2948, 2914, 1479, 1462, 1249, 1157, 1083, 864,
834 cm–1.
1H NMR (CDCl3): d = –0.07 (s, 9 H), 0.88 (t, J = 8.0 Hz, 2 H), 2.21
(s, 3 H), 3.55 (t, J = 8.0 Hz, 2 H), 3.85 (s, 3 H), 3.89 (s, 3 H), 5.69
(s, 2 H), 6.80 (s, 1 H), 7.07 (d, J = 2.2 Hz, 1 H), 7.11 (dd, J = 9.0
Hz, J = 2.2 Hz, 1 H), 7.45 (d, J = 9.0 Hz, 1 H), 9.79 (br s, 1 H).
13C NMR (CDCl3): d = –1.5, 17.6, 23.5, 52.4, 55.6, 66.7, 78.2, 98.8,
108.4, 110.8, 119.9, 124.7, 129.3, 135.6, 140.0, 155.8, 165.5, 168.5.
1H NMR (CDCl3): d = –0.09 (s, 18 H), 0.92 (t, J = 8.3 Hz, 4 H), 2.44
(s, 6 H), 3.63 (t, J = 8.3 Hz, 4 H), 5.19 (s, 4 H), 5.79 (s, 4 H), 7.33
(d, J = 7.1 Hz, 2 H), 7.39 (s, 2 H), 7.40 (t, J = 7.7 Hz, 4 H), 7.52 (d,
J = 7.6 Hz, 4 H), 7.93 (s, 2 H).
13C NMR (CDCl3): d = –1.4, 17.8, 17.9, 66.3, 70.3, 78.0, 102.6,
110.5, 121.8, 127.4, 127.8, 128,5, 129.7, 136.2, 137.6, 139,2, 153.5.
MS (EI): m/z (%) = 735 (1) [M+], 469 (70), 467 (66), 427 (33), 425
(33), 411 (20), 409 (19), 369 (63), 367 (61), 353 (36), 352 (69), 350
(59), 310 (25), 308 (27), 304 (27), 294 (26), 292 (23), 256 (31), 245
(17), 142 (8), 74 (100).
MS (EI): m/z (%) = 419 (54) [M+], 361 (15), 319 (37), 302 (44), 260
(22), 85 (55), 73 (100).
Anal. Calcd for C20H29N3O5Si: C, 57.26; H, 6.97; N, 10.02. Found:
C, 57.32; H, 6.87; N, 9.94.
Anal. Calcd for C42H54N4O4Si2: C, 68.63; H, 7.40; N, 7.62. Found:
C, 68.67; H, 7.01; N, 7.23.
8b
Yield: 0.3 g (10%); light-orange solid; mp 110–112 °C; Rf = 0.6
(EtOAc–cyclohexane, 2:3).
(Z)-2-Acetylamino-3-{5-bromo-1-[2-(trimethylsilanyl)ethoxy-
methyl]-1H-indazol-3-yl}acrylic Acid Methyl Ester (7d)
Obtained by GP 4, starting from 5-bromo-3-iodo-1-[2-(trimethylsi-
lanyl)ethoxymethyl]-1H-indazole (6d; 2.7 g, 6 mmol).
IR (KBr): 3430, 2952, 2927, 1625, 1490, 1449, 1305, 1247, 1206,
1167, 1071, 1053, 1033, 834, 801 cm–1.
1H NMR (CDCl3): d = –0.07 (s, 18 H), 0.92 (t, J = 8.0 Hz, 4 H), 3.66
(t, J = 8.0 Hz, 4 H), 3.95 (s, 6 H), 5.83 (s, 4 H), 7.15 (dd, J = 8.8 Hz,
J = 2.2 Hz, 2 H), 7.51 (d, J = 9.0 Hz, 2 H), 7.94 (d, J = 2.3 Hz, 2 H).
13C NMR (CDCl3): d = –1.4, 17.8, 55.8, 66.5, 78.1, 102.7, 110.5,
119.1, 123.5, 136.5, 139.0, 155.6.
MS (EI): m/z (%) = 554 (22) [M+], 438 (19), 278 (39), 233 (19), 220
(33), 178 (28), 162 (61), 161 (92), 148 (16), 118 (17), 84 (38), 74
(100).
Yield: 1.1 g (39%); yellow oil.
1H NMR (CDCl3): d = –0.07 (s, 9 H), 0.88 (t, J = 8.3 Hz, 2 H), 2.21
(s, 3 H), 3.54 (t, J = 8.3 Hz, 2 H), 3.89 (s, 3 H), 5.72 (s, 2 H), 6.76
(s, 1 H), 7.46 (d, J = 8.8 Hz, 1 H), 7.55 (dd, J = 8.8 Hz, J = 1.7 Hz,
1 H), 7.94 (d, J = 1.7 Hz, 1 H), 9.69 (br s, 1 H).
MS (EI): m/z (%) = 469 ([M + 1], 7), 467 ([M – 1], 7), 389 (14), 352
(5), 350 (5), 142 (15), 85 (67), 83 (100), 74 (32).
HRMS (EI): m/z [M+] Calcd for C19H26BrN3O4Si: 467.0876; found
467.0871.
Synthesis 2006, No. 20, 3506–3514 © Thieme Stuttgart · New York

PAPER
Heck Cross-Coupling Reaction of 3-Iodoindazoles with Methyl 2-(Acetylamino)acrylate
3513
(Z)-2-Acetylamino-3-{5-nitro-1-[2-(trimethylsilanyl)ethoxy-
methyl]-1H-indazol-3-yl}acrylic Acid Methyl Ester (7f) and
5,5¢-Dinitro-1,1¢-bis[2-(trimethylsilanyl)ethoxymethyl]-[3,3¢]bi-
indazolyl (8f)
Obtained by GP 4, starting from 3-iodo-5-nitro-1-[2-(trimethylsila-
nyl)ethoxymethyl]-1H-indazole (6f; 2.5 g, 6.1 mmol).
HRMS (EI): m/z [M]+ calcd for C19H29N3O4Si: 391.1928; found
391.1930.
2-Acetylamino-3-{5-methoxy-1-[2-(trimethylsilanyl)ethoxy-
methyl]-1H-indazol-3-yl}propanoic Acid Methyl Ester (9b)
Obtained by GP 5, starting from 2-acetylamino-3-{5-methoxy-1-[2-
(trimethylsilanyl)ethoxymethyl]-1H-indazol-3-yl}acrylic acid me-
thyl ester (7b; 1.2 g, 2.7 mmol).
7f
Yield: 0.6 g (23%); light-brown oil; Rf = 0.4 (EtOAc–cyclohexane,
2:3).
Yield: 1.2 g (100%); white solid; mp 92–94 °C.
IR (KBr): 3284, 3076, 2953, 1757, 1652, 1548, 1506, 1315, 1239,
1075, 1035, 859, 833 cm–1.
1H NMR (CDCl3): d = –0.04 (s, 9 H), 0.90 (t, J = 8.0 Hz, 2 H), 2.01
(s, 3 H), 3.45–3.59 (m, 4 H), 3.67 (s, 3 H), 3.86 (s, 3 H), 5.01–5.05
(m, 1 H), 5.64 (s, 2 H), 6.81 (d, J = 7.6 Hz, 1 H), 7.01 (s, 1 H), 7.09
(d, J = 9.0 Hz, 1 H), 7.42 (d, J = 9.0 Hz, 1 H).
13C NMR (CDCl3): d = –1.5, 17.7, 23.1, 28.6, 51.5, 52.3, 55.6, 66.2,
77.6, 99.1, 110.7, 119.2, 124.3, 136.3, 140.5, 155.0, 169.7, 171.7.
MS (EI): m/z (%) = 421 (51) [M+], 362 (65), 317 (24), 305 (23), 304
(100), 303 (63), 302 (26), 246 (45), 245 (83), 233 (82), 232 (26),
187 (18), 161 (20), 73 (90).
IR (KBr): 3331, 2951, 1738, 1700, 1520, 1330, 1250, 1082, 837
cm–1.
1H NMR (CDCl3): d = –0.13 (s, 9 H), 0.82 (t, J = 8.0 Hz, 2 H), 2.15
(s, 3 H), 3.50 (t, J = 8.0 Hz, 2 H), 3.83 (s, 3 H), 5.73 (s, 2 H), 6.70
(s, 1 H), 7.60 (d, J = 9.3 Hz, 1 H), 8.25 (dd, J = 9.8 Hz, J = 2.1 Hz,
1 H), 8.65 (d, J = 2.1 Hz, 1 H), 9.51 (br s, 1 H).
13C NMR (CDCl3): d = –1.6, 17.6, 23.4, 52.7, 67.3, 78.6, 105.8,
110.4, 117.5, 122.6, 123.2, 131.6, 141.6, 143.1, 143.3, 164.9, 168.3.
MS (EI): m/z (%) = 434 (25) [M+], 392 (21), 376 (14), 334 (22), 317
(21), 259 (12), 215 (18), 103 (12), 74 (100).
HRMS (EI): m/z [M]+ Calcd for C19H26N4O6Si: 434.1621; found
434.1601.
Anal. Calcd for C20H31N3O5Si: C, 56.98; H, 7.41; N, 9.97. Found:
C, 56.65; H, 7.47; N, 9.84.
8f
2-Acetylamino-3-{5-hydroxy-6-methyl-1-[2-(trimethylsila-
nyl)ethoxymethyl]-1H-indazol-3-yl}propanoic Acid Methyl
Ester (9c)
Yield: 0.3 g (8%); yellow solid; mp 170 °C; Rf = 0.6 (EtOAc–cyclo-
hexane, 1:3).
IR (KBr): 3435, 3097, 2953, 1612, 1520, 1343, 1251, 1105, 1076,
859, 836 cm–1.
1H NMR (CDCl3): d = –0.08 (s, 18 H), 0.91 (t, J = 8.3 Hz, 4 H), 3.70
(t, J = 8.3 Hz, 4 H), 5.88 (s, 4 H), 7.70 (d, J = 9.0 Hz, 2 H), 8.37 (dd,
J = 9.0 Hz, J = 2.0 Hz, 2 H), 9.46 (d, J = 2.0 Hz, 2 H).
13C NMR (CDCl3): d = –1.5, 17.8, 67.3, 78.6, 110.4, 120.9, 122.2,
122.6, 140.8, 142.4, 143.7.
Obtained by GP 5, starting from 2-acetylamino-3-{5-benzyloxy-6-
methyl-1-[2-(trimethylsilanyl)ethoxymethyl]-1H-indazol-3-
yl}acrylic acid methyl ester (7c; 1.4 g, 2.7 mmol).
Yield: 1.1 g (92%); brown oil; Rf = 0.5 (CHCl3–MeOH, 9:1).
IR (KBr): 3372, 2953, 1743, 1652, 1536, 1435, 1373, 1250, 1080,
838 cm–1.
1H NMR (CDCl3): d = –0.07 (s, 9 H), 0.88 (t, J = 8.0 Hz, 2 H), 2.00
(s, 3 H), 2.37 (s, 3 H), 3.41–3.52 (m, 4 H), 3.65 (s, 3 H), 4.94–5.01
(m, 1 H), 5.60 (s, 2 H), 6.29 (br s, 1 H), 6.63–6.72 (m, 1 H), 6.99 (s,
1 H), 7.24 (s, 1 H).
MS (EI): m/z (%) = 584 (10) [M+], 468 (37), 409 (11), 350 (23), 74
(100).
Anal. Calcd for C26H36N6O6Si2: C, 53.40; H, 6.21; N, 14.37. Found:
C, 53.32; H, 6.49; N, 14.09.
13C NMR (CDCl3): d = –1.6, 17.6, 17.9, 22.8, 30.7, 51.8, 52.2, 66.0,
76.8, 101.5, 110.4, 122.8, 127.6, 136.0, 139.7, 150.9, 170.5, 171.6.
Hydrogenation of Protected 2-Azatryptophans (9); General
Procedure (GP 5)
A mixture of protected dehydro 2-azatryptophan 7 and palladium on
activated carbon (15–20 mol%) in MeOH (80–100 mL) was hydro-
genated in a Parr apparatus at 1 atm at r.t. for 24 h. The solution was
filtered through Celite then concentrated in vacuo to give desired
protected amino acids 9.
MS (EI): m/z (%) = 421 (10) [M+], 304 (35), 245 (27), 233 (27), 208
(28), 165 (37), 163 (29), 123 (26), 86 (33), 84 (42), 74 (100).
HRMS (EI): m/z [M]+ calcd for C20H31N3O5Si: 421.2033; found
421.2041.
Acknowledgment
2-Acetylamino-3-{1-[2-(trimethylsilanyl)ethoxymethyl]-1H-in-
dazol-3-yl}propanoic Acid Methyl Ester (9a)
Obtained by GP 5, starting from 2-acetylamino-3-{1-[2-(trimethyl-
silanyl)ethoxymethyl]-1H-indazol-3-yl}acrylic acid methyl ester
(7a; 0.5 g, 1.2 mmol).
We thank Dr. Christophe Philippo for helpful discussions and Dr.
Rémi Legay for high-resolution mass spectrometry measurements
and 2D NOESY NMR studies.
References
Yield: 0.4 g (85%); yellow oil.
1H NMR (CDCl3): d = –0.05 (s, 9 H), 0.90 (t, J = 8.0 Hz, 2 H), 2.01
(s, 3 H), 3.44–3.60 (m, 4 H), 3.67 (s, 3 H), 5.03–5.07 (m, 1 H), 5.69
(s, 2 H), 6.54 (d, J = 7.6 Hz, 1 H), 7.21 (t, J = 7.6 Hz, 1 H), 7.43 (t,
J = 7.7 Hz, 1 H), 7.54 (d, J = 8.1 Hz, 1 H), 7.65 (d, J = 8.0 Hz, 1 H).
13C NMR (CDCl3): d = –1.5, 17.8, 23.2, 28.6, 51.5, 52.4, 66.4, 77.5,
110.7, 120.0, 121.2, 124.1, 127.1, 140.5, 141.4, 169.7, 171.7.
MS (EI): m/z (%) = 391 (42) [M+], 319 (21), 287 (20), 278 (32), 277
(51), 274 (95), 273 (94), 272 (42), 216 (86), 215 (100), 203 (56),
202 (18), 132 (17), 74 (98).
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Synthesis 2006, No. 20, 3506–3514 © Thieme Stuttgart · New York