A new and efficient synthesis of 2-azatryptophans

Article abstract of DOI:10.1016/j.tet.2006.05.061

This paper describes a new and simple synthesis of 2-azatryptophans in five steps from 2-ethylaniline. This methodology allows to obtain either the amino acid or the amino ester, according to the treatment and the reaction time, and its scaling up for multigram synthesis.

Full text of DOI:10.1016/j.tet.2006.05.061

Tetrahedron 62 (2006) 7772–7775
A new and efficient synthesis of 2-azatryptophans
Fran c¸ ois Crestey, Val e´ rie Collot, Silvia Stiebing and Sylvain Rault
*
Centre d’Etudes et de Recherche sur le Me´dicament de Normandie (CERMN), UPRES EA-3915, U.F.R. des Sciences
Pharmaceutiques,Universite´ de Caen Basse-Normandie 5, rue Vaube´nard—14032 CAEN Cedex, France
Received 21 April 2006; revised 22 May 2006; accepted 24 May 2006
Available online 16 June 2006
Abstract—This paper describes a new and simple synthesis of 2-azatryptophans in five steps from 2-ethylaniline. This methodology allows to
obtain either the amino acid or the amino ester, according to the treatment and the reaction time, and its scaling up for multigram synthesis.
Ó 2006 Elsevier Ltd. All rights reserved.
1
0
1
. Introduction
literature described in the pioneering work of Snyder,
starting from isatine via 3-indazolecarboxylic acid (11 steps,
7% overall yield) as summarized in Scheme 1.
Among heterocyclic scaffolds that are usable to prepare new
valuable medicinal chemistry building blocks, the indazole
nucleus is always much less studied than some of its bioiso-
steres like indole, quinolines or benzimidazole. However,
some indazole derivatives have been developed to give leads
in medicinal chemistry such as 7-NI (nitric oxide synthase
inhibitor), YC-1 (guanylyl cyclase activator), granisetron
(5HT-3 receptor antagonist), lonidamine (cytotoxic modu-
lator), SE063 (HIV protease inhibitor), and recently with
new protein kinase Cb inhibitors and oestrogen receptor
ligands.
1
2. Results and discussion
Since scalability of this reported sequence is not feasible, we
reconsidered the strategy, taking into account our know-how
in the laboratory about the cyclization of indazole and the
results of bromination reported by Henke et al. The first
part of the synthesis was the preparation of N-Boc-3-bromo-
methylindazole 5, which was obtained in four steps starting
from 2-ethylaniline 1 (Scheme 2).
2
3
1
1
4
1
2
5
6
7
8
It is for this reason why our group has been interested for
a long time in the design and synthesis of new indazole
libraries, in particular synthesis of 2-aza bioisosteres of
i
ii
iii
N
9
-
+
N
tryptamine, serotonine or melatonine.
NH2
N
H
BF4
2
1
2
3
Herein, we would like to report a new efficient method for
the synthesis of both 2-azatryptophan and its corresponding
ethyl ester. One chemical pathway was found in a survey of
Br
Br
Br
iv
N
+
+
4
N
N
N
N
4
N
6
O
CO H
CON(CH3)2
5
2
O
O
O
O
O
O
O
N
N
N
N
N
ꢀ
Scheme 2. Reagents and conditions: (i) aq HBF
4
50%, aq NaNO , 0 C,
2
3
, rt, 37%; (iii) (Boc) O, Et N,
ꢀ
, 85 C, 61% of 5, 7%
H
H
H
8
4%; (ii) AcOK, 18-crown-6, CHCl
DMAP, CH
of 6, and 32% of 4.
3
2
3
CN, rt, 97%; (iv) NBS, mCPBA, CCl
4
CO Et
CO H
2
2
EtO C
2
NHCOCH3
NH2
Diazotization of 2-ethylaniline 1 with aqueous sodium
nitrite (1 equiv) in fluoroboric acid (50% solution in water)
at 0 C gave the corresponding diazonium tetrafluoroborate
N
N
N
H
N
H
ꢀ
salt 2 in 84% yield. This hygroscopic diazonium tetrafluoro-
borate salt was directly cyclized by reaction with potassium
acetate (2 equiv) and 18-crown-6 (0.05 equiv) in dry chloro-
form at room temperature to obtain compound 3 with 37%
2-azatryptophan
10
Scheme 1. Snyder’s synthesis.
*
0
Corresponding author. E-mail: sylvain.rault@unicaen.fr
040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
yield. Protection of the N1 nitrogen by (Boc) O followed
2
doi:10.1016/j.tet.2006.05.061

F. Crestey et al. / Tetrahedron 62 (2006) 7772–7775
7773
by radical bromination with NBS (1.1 equiv) and mCPBA
(
8
and monitored by TLC using 0.2 mm Macherey-Nagel
Polygram SIL G/UV254 precoated plates. Column chro-
matography was performed using CarloErba-SDS 60A
70-200 mm silica gel. Melting points (uncorrected) were
determined on a K €o fler melting point apparatus. IR spectra
were taken with a Perkin–Elmer spectrum X FTIR spectro-
meter. H NMR (400 MHz) and C NMR (100 MHz) spec-
tra were recorded on a JEOL Lambda 400 Spectrometer.
Chemical shifts (d) are expressed in parts per million down-
field from tetramethylsilane as an internal standard and the
coupling constants are given in hertz. Mass spectra were
recorded on a JEOL JMS GCMate with ionizing potential
of 70 eV and with PFK as internal standard for high-resolu-
tion. Elemental analyses were performed at the ‘Institut de
Recherche en Chimie Organique Fine’ (Rouen, France).
0.1 equiv) as free radical initiator in tetrachloromethane at
5 C provided the protected indazole bromide 5 in 61%
ꢀ
yield. This reaction, followed by TLC, not only gave the
desired brominated product 5, but also dibromo compound
6 and starting material 4 in, respectively, 61, 7, and 32%
yields (Scheme 2).
1
13
1
3
The second part was the introduction of glycine moiety.
This was accomplished by the nucleophilic substitution of
compound 5 by the carbanion of diethyl acetamidomalonate,
formed by reaction with sodium metal in ethanol, to give
a mixture of two products 7a and 7b, which were not sepa-
rated (Scheme 3).
CO H
CO Et
2
2
3.2. Synthesis of 3-methyl-1H-indazole (3)
EtO C
2
NH2 HCl
NHAc
A cooled solution of sodium nitrite (5.79 g in 6 mL H O,
2
N
N
N
ꢀ
N
H
ii
N
H
83.92 mmol) was added at 0 C dropwise to an ice solution
Br
8
7
a
of 2-ethylaniline 1 (10.17 g, 83.92 mmol) dissolved in fluo-
roboric acid (50% solution in water, 13 mL). After the end
of the addition, the mixture was stirred for 2 h, and the result-
i
N
+
CO2Et
NHAc
EtO C
CO Et
2
2
N
iii
5
Boc
NH2 HCl
ing precipitate was filtered and then washed with Et O
2
N
(
3ꢁ100 mL) to obtain 2-ethylphenyldiazonium tetrafluoro-
N
b
N
H
borate salt 2 (15.38 g, 84%) as a very hygroscopic white
7
Boc
9
ꢂ1
solid; IR (KBr): n¼3436, 2259, 1564, 1051 cm . The dia-
zonium tetrafluoroborate salt 2 (15.38 g, 69.92 mmol) was
added under nitrogen in one portion to a stirred mixture of
potassium acetate (13.72 g, 139.84 mmol) and 18-crown-6
Scheme 3. Reagents and conditions: (i) AcHNCH(CO
2
Et)
O, reflux, 4 h; (2) HCl (37%), reflux,
2
O, reflux, 1.5 h; (2) HCl (37%), reflux, 76%.
2
, Na, EtOH,
ꢀ
0 C; (ii) (1) NaOH, EtOH, H
2
7
7
0%; (iii) (1) NaOH, H
(
1.30 g, 3.49 mmol) in dry chloroform (600 mL). After
1
Indeed H NMR of the resulting reaction product indicated
that the Boc protecting group was not totally cleaved. Since
deprotection of the N-Boc group would readily occur in
the course of the following reactions, mixture of unprotected
2 h, the resulting precipitate was filtered and washed with
chloroform. The organic layer was concentrated in vacuo
and the residual gum was purified by column chromato-
graphy on silica gel (EtOAc/cyclohexane, 1:3) to give com-
ꢀ
7
a and protected 7b was used without further purification
pound 3 (3.40 g, 37%) as a beige solid. Mp 113 C. TLC
for the final step. Saponification was realized with sodium
pellets either in a water/ethanol mixture for 4 h or in water
for 1.5 h, and then decarboxylation and hydrolysis were at-
tempted in hydrochloric acid (37%) under reflux conditions.
R ¼0.3 (EtOAc/cyclohexane, 2:3). IR (KBr): n¼3307,
f
ꢂ1
1
1338, 1007, 752 cm
.
H NMR (400 MHz, CDCl ):
3
d¼2.61 (s, 3H, CH ), 7.15 (t, 1H, J¼7.8 Hz), 7.37 (t, 1H, J¼
3
7.6 Hz), 7.43 (d, 1H, J¼8.6 Hz), 7.69 (d, 1H, J¼8.0 Hz),
1
3
1
1.37 (br s, 1H, NH). C NMR (100 MHz, CDCl ):
3
In this way, hydrochloride of either amino acid 8 or amino
ester 9 was obtained, respectively, in 70 and 76% yield from
d¼12.0 (CH ), 109.6, 120.1, 120.2, 122.8, 126.7, 141.1,
3
+
143.6. MS (EI): m/z (%)¼132 (M , 100), 131 (84), 104
5
according to the treatment and the reaction time (Scheme
). Finally these two compounds were obtained as racemic
(14), 77 (13). Anal. Calcd for C H N (132.17): C, 72.70;
8
8 2
1
4
3
H, 6.10; N, 21.20; found: C, 72.27; H, 6.12; N, 20.87. Lit.
mixtures from readily available starting materials under mild
reaction conditions in five steps with a 14% overall yield.
3.3. Synthesis of 1-(tert-butoxycarbonyl)-3-methyl-
indazole (4)
In summary, we have developed a straightforward and effi-
cient method to give in five steps 2-azatryptophan and its
ethyl ester in good to very good yields. The unusual 2-aza-
tryptophan residues can now be easily prepared from 3-(bro-
momethyl)-1-(tert-butoxycarbonyl)indazole 5 as described
in this paper. This method was already easily scaled up for the
synthesis of multigram amounts of amino acid or amino ester.
To a cooled solution of indazole 3 (3.56 g, 26.96 mmol) in
CH CN (110 mL) were added successively DMAP (6.59 g,
3
53.92 mmol), Et N (7.5 mL, 53.92 mmol), and (Boc) O
3
2
(11.77 g, 53.92 mmol). The resultant reaction mixture was
stirred for 1 h at 0 C and then for 2 h at room temperature.
ꢀ
The solvent was removed in vacuo, and then the crude mate-
rial was taken up in EtOAc (100 mL) and washed with H O
2
(
2ꢁ100 mL). The aqueous layer was extracted with EtOAc
3
. Experimental
(2ꢁ100 mL) and the combined organic layers were dried
over MgSO , filtered, and concentrated in vacuo. The resi-
4
3
.1. General
dual oil was purified by flash column chromatography on
silica gel (EtOAc/cyclohexane, 1:3) to give compound 4
All commercial reagents were used as received without fur-
ther purification. Reaction mixture were stirred magnetically
(6.04 g, 97%) as a pale orange oil. TLC R ¼0.5 (EtOAc/
f
cyclohexane, 1:4). IR (KBr): n¼3056, 2981, 1732, 1372,

7774
F. Crestey et al. / Tetrahedron 62 (2006) 7772–7775
ꢂ1
1
1
247, 1154, 753 cm
.
H NMR (400 MHz, CDCl3):
color, protected brominated indazole 5 (700 mg, 2.25 mmol)
in warm absolute ethanol (15 mL) was obtained. This mix-
ture was heated with stirring in an oil bath at 70 C overnight.
After being cooled to room temperature, the solution was
concentrated in vacuo, then taken up in dichloromethane,
and washed with water. The organic layer was dried over
d¼1.72 (s, 9H, C(CH ) ), 2.60 (s, 3H, CH ), 7.30 (t, 1H, J¼
3
3
3
ꢀ
7
(
(
1
.9 Hz), 7.51 (t, 1H, J¼7.4 Hz), 7.65 (d, 1H, J¼7.9 Hz), 8.11
1
3
d, 1H, J¼8.3 Hz). C NMR (100 MHz, CDCl ): d¼12.2
3
CH ), 28.2 (C(CH ) ), 84.4 (C(CH ) ), 114.6, 120.2,
3
3 3
3 3
23.1, 125.9, 128.7, 140.1, 148.4, 149.2. MS (EI): m/z
+
(
HRMS/ESI Calcd for C H N O Na [M+Na] 255.1109;
%)¼232 (M , 14), 159 (14) 132 (100), 131 (38), 77 (9).
MgSO , filtered, and concentrated in vacuo, and yellow solid
4
+
obtained was placed in water (10 mL), ethanol (4 mL), and
sodium hydroxide pellets (1.60 g) and heated under reflux
for 4 h. Then 37% hydrochloric acid (20 mL) was added
and the reaction mixture was heated under reflux conditions
for 68 h. Solvent was completely evaporated, and the residue
was extracted with boiling ethanol (4ꢁ15 mL). The com-
bined extracts were concentrated in vacuo and cooled to give
1
3 16 2 2
1
2
found 255.1110. Lit.
3.4. Synthesis of 3-(bromomethyl)-1-(tert-butoxycarbo-
nyl)indazole (5) and 3-(dibromomethyl)-1-(tert-butoxy-
carbonyl)indazole (6)
ꢀ
To a solution of protected indazole 4 (1.65 g, 7.10 mmol)
heated in CCl (90 mL) in an oil bath at 65 C were added
compound 8 (380 mg, 70%) as a white solid. Mp>260 C. IR
ꢀ
half of a mixture of NBS (1.39 g, 7.81 mmol) and mCPBA
ꢂ1
1
(KBr): n¼3435, 1626, 1438 cm . H NMR (400 MHz,
4
d -DMSO + 3 D O): d¼3.03 (dd, 1H, J¼15.1 and 9.6 Hz,
6
2
ꢀ
(
123 mg, 0.71 mmol). Then other half was added at 85 C.
The resulting solution was heated in reflux conditions for
.5 h and then cooled in an ice-bath. Then the reaction mix-
ture was filtered through a pad of Celite and the solvent was
evaporated in vacuo. The residual material was purified by
column chromatography on silica gel (EtOAc/cyclohexane,
CH ), 3.39 (dd, 1H, J¼15.0 and 3.7 Hz, CH ), 3.54 (dd,
2
2
1H, J¼9.4 and 3.6 Hz, CH), 7.06 (t, 1H, J¼7.3 Hz), 7.32
(t, 1H, J¼7.2 Hz), 7.45 (d, 1H, J¼8.4 Hz,), 7.78 (d, 1H,
6
1
3
J¼8.2 Hz). C NMR (100 MHz, d -DMSO + 3 D O):
6
2
d¼27.3 (CH ), 51.9 (CH), 110.9, 120.2, 121.0, 122.1,
2
127.3, 139.9, 141.3, 170.4 (CO H). Anal. Calcd for
2
1:6) to give, after trituration with petroleum ether, compound
5 (1.34 g, 61%) as a pale yellow solid, compound 6 (200 mg,
7%) as a white solid, and compound 4 (528 mg, 32%).
C H N O $HCl$0.5H 0 (250.69): C, 47.91; H, 5.23; N,
1
16.76; found: C, 48.03; H, 5.33; N, 16.90.
0
12
3
2
2
3.6. Synthesis of 2-amino-3-(1H-indazol-3-yl)propanoic
acid ethyl ester hydrochloride (9)
ꢀ
Compound 5: mp 84 C. TLC R ¼0.5 (EtOAc/cyclohexane,
f
1
1
:6). IR (KBr): n¼3030, 2980, 1737, 1433, 1370, 1252,
ꢂ1
3
1
153, 1010, 748 cm
.
H NMR (400 MHz, CDCl ):
In a three-necked flask under nitrogen was placed succes-
sively absolute ethanol (25 mL) and sodium (323 mg,
11.05 mmol). To this solution was added diethyl acetamido-
malonate (1.61 g, 7.39 mmol) in absolute ethanol (20 mL),
and after few minutes of stirring and apparition of a yellow
color, protected brominated indazole 5 (2.30 g, 7.39 mmol)
in warm absolute ethanol (15 mL) was obtained. This mix-
d¼1.70 (s, 9H, C(CH ) ), 4.77 (s, 2H, CH ), 7.33 (t, 1H,
3
3
2
J¼7.6 Hz), 7.52 (t, 1H, J¼7.3 Hz), 7.82 (d, 1H,
1
3
J¼8.0 Hz), 8.10 (d, 1H, J¼8.6 Hz). C NMR (100 MHz,
CDCl ): d¼22.9 (CH ), 28.1 (C(CH ) ), 85.3 (C(CH ) ),
3
2
3 3
3 3
1
(
14.9, 120.7, 123.7, 124.0, 129.3, 140.7, 147.2, 148.9. MS
EI): m/z (%)¼312 (M+1, 17), 310 (Mꢂ1, 17), 239 (8),
ꢀ
2
1
37 (8), 212 (32), 211 (14), 210 (33), 209 (11), 187 (14),
31 (100), 102 (43), 77 (18). Anal. Calcd for C H BrN O
2 2
ture was stirred in an oil bath at 70 C overnight. After being
cooled to room temperature, the solution was concentrated
in vacuo, then taken up in dichloromethane, and washed with
water. The organic layer was dried over MgSO , filtered, and
1
3
15
(
4
311.18): C, 50.18; H, 4.86; N, 9.00; found: C, 50.14; H,
.44; N, 8.86. Lit.
1
2
4
concentrated in vacuo, and yellow solid obtained was placed
in water (30 mL) and sodium hydroxide pellets (1.60 g) and
heated under reflux for 1.5 h. Then 37% hydrochloric acid
(20 mL) was added and the reaction mixture was heated
under reflux for 20 h. Solvents were completely evaporated,
and the residue was extracted with boiling ethanol (4ꢁ
15 mL). The combined extracts were concentrated in vacuo
and cooled to give compound 9 (1.51 g, 76%) as a white
ꢀ
Compound 6: mp 91–93 C. TLC R ¼0.8 (EtOAc/cyclohex-
f
ane, 1:6). IR (KBr): n¼3031, 2978, 1733, 1613, 1505, 1360,
ꢂ1 1
1
342, 1292, 1248, 1151, 1075, 851, 764, 739, 613 cm . H
NMR (400 MHz, CDCl ): d¼1.73 (s, 9H, C(CH ) ), 6.97 (s,
3
3 3
1
8
H, CH), 7.44 (t, 1H, J¼7.6 Hz), 7.59 (t, 1H, J¼7.3 Hz),
1
3
.16 (d, 1H, J¼8.3 Hz), 8.23 (d, 1H, J¼7.8 Hz). C NMR
(
100 MHz, CDCl ): d¼28.1 (C(CH ) ), 30.3 (CH), 85.7
3
3 3
ꢀ
(
1
C(CH ) ), 115.0, 121.8, 122.4, 123.7, 129.5, 141.2, 148.7,
3 3
solid. Mp 212 C (dec). IR (KBr): n¼3423, 2896, 1743,
+
ꢂ1
1
48.9. MS (EI): m/z (%)¼392 (M+2, 2), 390 (M , 4), 388
1637, 1515, 1436 cm . H NMR (400 MHz, d -DMSO):
6
(
Mꢂ2, 2), 311 (5), 309 (5), 212 (10), 211 (97), 210 (11),
d¼1.01 (t, 3H, J¼7.1 Hz, CH ), 3.38 (q, 2H, J¼7.1 Hz,
3
2
09 (100), 101 (19). Anal. Calcd for C H Br N O
1
OCH ), 3.43–3.60 (m, 2H, CH ), 4.25–4.31 (m, 1H, CH),
2
3
14
2
2
2
2
(
3
390.08): C, 40.03; H, 3.62; N, 7.18; found: C, 40.22; H,
.80; N, 7.16.
7.07 (t, 1H, J¼7.3 Hz), 7.32 (t, 1H, J¼7.3 Hz), 7.49 (d,
1H, J¼8.3 Hz), 7.78 (d, 1H, J¼8.1 Hz), 8.63 (br s, 3H).
1
3
C NMR (100 MHz, d -DMSO): d¼18.7 (CH ), 27.3
6
3
3.5. Synthesis of 2-amino-3-(1H-indazol-3-yl)propanoic
acid hydrochloride (8)
(CH ), 51.6 (CH), 56.1 (OCH ), 110.4, 120.0, 120.1,
2 2
121.8, 126.4, 139.3, 140.9, 170.2 (CO ). Anal. Calcd for
2
C H N O $HCl$0.5H O (278.74): C, 51.71; H, 6.15; N,
1
2
15
3
2
2
In a three-necked flask under nitrogen were placed succes-
sively absolute ethanol (12 mL) and sodium (52 mg,
15.07; found: C, 51.76; H, 6.21; N, 15.16.
2
.25 mmol). To this solution was added diethyl acetamido-
Acknowledgements
malonate (489 mg, 2.25 mmol) in absolute ethanol (16 mL),
and after few minutes of stirring and apparition of a yellow
We thank Dr. Christophe Philippo for helpful discussions.

F. Crestey et al. / Tetrahedron 62 (2006) 7772–7775
7775
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