Efficient Synthesis of 5-(Bromomethyl)-and 5-(Aminomethyl)-1-THP-Indazole

Full text of DOI:10.1021/jo970375b

J . Org. Chem. 1997, 62, 5627-5629
5627
Sch em e 1a
Efficien t Syn th esis of 5-(Br om om eth yl)-
a n d 5-(Am in om eth yl)-1-THP -In d a zole
J ung-Hui Sun,* Christopher A. Teleha, J ia-Sheng Yan,
J ames D. Rodgers, and David A. Nugiel*
The DuPont Merck Pharmaceutical Company,
P.O. Box 80500, Wilmington, DE 19880-0500
Received February 27, 1997
The indazole ring system has an interesting chemistry
and is an effective pharmacophore in medicinal chemis-
try.1 Recently, we disclosed an extremely potent cyclic
urea-based human immunodeficiency virus protease
(
i
HIVPR) inhibitor (K ) 0.018 nM) with excellent anti-
viral activity (IC90 ) 8 nM), using 5-methyl-1H-indazole
as the P2/P2′ substituent (1). Molecular modeling of 1
a
Reagents and conditions: (a) Ac2O/AcOH, NaNO2, HNO3, HCl
2
hydrolysis, 30%; (b) DHP, PPTS, CH Cl , 69%; (c) NBS, AIBN,
2
2
CCl4, 31%.
Sch em e 2a
Bn
Bn
bound in the active site of HIVPR showed key hydrogen
bonds between each indazole nitrogen and backbone NH
and carbonyl groups of Asp 30. Unlike other benzofused
heterocycles examined, the potent enzyme inhibitory
activity of 1 translated efficiently to whole cell antiviral
activity. These favorable properties make the indazole
moiety an attractive target for future analogs. Therefore,
we needed an expedient synthesis of the title indazole 4;
a key intermediate in the synthesis of 1. In addition,
we prepared the analogous aminomethyl derivative 9.
This allows introduction of the indazole moiety in a
complimentary nucleophilic fashion compared to an elec-
trophilic process used with bromide 4.
a
Reagents and conditions: (a) H2, Pd/C, EtOH, 97%; (b) Ac2O/
KOAc, n-amyl nitrite, cat. 18-crown-6, CHCl3, 58%; (c) 48%
aqueous HBr, 92%; (d) DHP, THF, reflux, 79%.
protected analog. The final product was difficult to
handle and had to be stored as a frozen benzene solution
to prevent polymerization. Radical bromination of 3,
using NBS in refluxing CCl
4
, gave bromide 4 in 31%
Our initial approach to the desired indazole 4 is shown
in Scheme 1. This strategy relied on a radical-promoted
benzylic bromination late in the synthetic scheme. Using
the same reaction conditions reported by Huisgen and
yield. The low yield was probably due to the reactivity
of the aminal hydrogen on the THP group, leading to
decomposition of the starting material.
This initial sequence had two major problems we
wished to address: (i) inefficient assembly of the indazole
ring system and (ii) inefficient installation of the bro-
momethyl functionality. Both of these issues were ad-
dressed in our second approach shown in Scheme 2.
Commercially available 3-methyl-4-nitrobenzyl alcohol
provides a versatile benzylic alcohol handle for conversion
to the bromomethyl entity using non-radical-based meth-
odology. In addition, the indazole ring system is as-
3
Bast, 2,4-dimethylaniline was converted to 5-methyl-1H-
indazole (2) in 30% yield. Next, the indazole 1-nitrogen
was regioselectively functionalized with a tetrahydro-
pyranyl (THP) protecting group in 69% yield. The acidic
reaction media results in high regioselectivity.4 Attempts
at introducing other acid-labile protecting groups (MEM,
SEM), requiring base-promoted reaction conditions, gave
a mixture of N-1- and N-2-protected indazoles. Initially,
this did not seem to be a problem since the protecting
group would ultimately be removed in subsequent chemi-
cal manipulations. Unfortunately, the radical-promoted
bromination step proceeded in modest yield for the SEM-
5
sembled using a phase-transfer-promoted protocol. Fac-
ile reduction of the nitro group was accomplished using
hydrogen and 10% palladium on carbon to give the
aniline 5 in 97% yield.6 Preforming the diacetate of 5
with acetic anhydride, followed by nitrosation with
n-amyl nitrite in the presence of catalytic amounts of 18-
crown-6, gave the desired indazole 6 in 58% yield. The
phase-transfer protocol allows for anilide nitrosation and
rearrangement under mild conditions without the use of
a strong acid. To our knowledge, this is the first example
of this transformation with a benzylic ester-containing
substrate.
(
1) (a) Elderfield, R. C. In Heterocyclic Compounds; Elderfield, R.
C., Ed.; J ohn Wiley & Sons, Inc.: New York, 1957; Vol. 5, p 162. (b)
Behr, L. C.; Fusco, R.; J arobe, C. H. In Pyrazoles, Pyrazolines,
Pyrazolidines, Indazoles and Condensed Rings; Wiley, R. H., Ed.;
International Wiley Science: New York, 1969; p 289. (c) Elguero, J .
In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C.
W., Eds.; Pergamon Press: New York, 1984; Vol. 5, p 167. For more
recent examples see: Ruchardt, C.; Hassman, V. Liebigs Ann. Chem.
1
1
980, 908. Dell’Erba, C.; Novi, M.; Petrillo, G.; Tavani, C. Tetrahedron
992, 48, 325.
(
2) Rodgers, J . D.; J ohnson, B. L.; Wang, H.; Greenberg, R. A.;
Erickson-Viitanen, S.; Klabe, R. M.; Cordova, B. C.; Rayner, M. M.;
Lam, G. N.; Chang, C.-H. BioMed. Chem. Lett. 1996, 6, 2919.
(5) Bartsch, R. A.; Yang, I.-W. J . Heterocycl. Chem. 1984, 21, 1063.
Phase-transfer-promoted indazole formation was also observed as a
byproduct in the synthesis of biarenes. See: Beadle, J . R.; Korzenio-
wski, S. H.; Rosenberg, D. E.; Garcia-Slanga, B. J .; Gokel, G. W. J .
Org. Chem. 1984, 49, 1594.
(6) Nayar, M. R. G.; Francis, J . D. Indian J . Chem. Sect. B 1983,
22B, 776.
(
3) Huisgen, R.; Bast, K. Organic Syntheses; Wiley: New York, 1973;
Collect. Vol. V, p 650.
4) Alonso, G.; Diez, C.; Garcia-Munoz, G.; De las Heras, F. G.;
Navarro, P. J . Carbohydr., Nucleosides, Nucleotides 1976, 3(3), 157-
7.
(
6
S0022-3263(97)00375-7 CCC: $14.00 © 1997 American Chemical Society

5
628 J . Org. Chem., Vol. 62, No. 16, 1997
Notes
Sch em e 3a
5-Meth yl-1H-in d a zole (2). Using the procedure reported by
3
Huisgen and Bast, 2,4-dimethylaniline was converted to 5-meth-
4
yl-1H-indazole in 30% yield. 2: mp 103-107 °C (lit. mp 111
1
°
8
C); H NMR (CDCl
3
) δ 8.00 (s, 1 H), 7.53 (s, 1 H), 7.40 (d, J )
.9 Hz, 1 H), 7.22 (d, J ) 8.9 Hz, 1 H), 2.40 (s, 3 H).
-Meth yl-1-(2-tetr a h yd r op yr a n yl)in d a zole (3). A mixture
of 2 (6.63 g, 0.05 mol), 3,4-dihydro-2H-pyran (10.3 mL, 0.113
mol), and PPTS (0.12 g, 0.6 mmol) in CH Cl (50 mL) was heated
to reflux for 5 h. The reaction was poured into saturated
NaHCO (100 mL), the layers were separated, and the aqueous
layer was extracted with CH Cl
(2 × 50 mL). The combined
organic layers were washed with 5% aqueous citric acid (50 mL)
and brine (100 mL), dried (MgSO ), and concentrated. Chro-
matography (silica gel, 10% EtOAc/hexane) gave the product as
5
2
2
3
2
2
a
4
Reagents and conditions: (a) NaN3, DMF, 90 °C, quant; (b)
LAH, THF, 0 °C, 98%.
1
3
an oil (7.57 g, 69%). 3: H NMR (CDCl ) δ 7.93 (s, 1 H), 7.47
(
m, 2 H), 7.21(d, J ) 9.5 Hz, 1 H), 5.68 (dd, J ) 9.4, 2.4 Hz, 1
The next reaction removes both acetate groups and
introduces the benzylic bromide in one step. Treating
H), 4.02 (br, 1 H), 3.72 (dd, J ) 10.6, 3.0 Hz, 1 H), 2.57 (m, 1 H),
7
13
2.44 (s, 3 H), 2.2-2.0 (m, 2 H), 1.8-1.6 (m, 3 H); C NMR
indazole 6 with 48% aqueous HBr at 25 °C for 16 h gave
the desired 5-(bromomethyl)-1H-indazole (7) in 92% yield
as the HBr salt. It was critical to isolate 7 as the salt to
reduce the indazole nitrogen’s nucleophilicity and sup-
press polymerization. This salt was taken on crude to
the next step. Any attempt to purify this material as its
free base led to decomposition. Heating indazole 7 with
3
(CDCl ) δ 139.6, 134.7, 131.9, 129.9, 126.5, 121.4, 111.1, 86.7,
+
4
),
6
2
8.8, 30.8, 26.6, 24.0, 22.6; CIMS (NH
3
) m/ z 234 (M + NH
+
17 (M + H ). Anal. Calcd for C13
H N O: C, 72.39; H, 7.46;
16 2
N, 12.95. Found: C, 72.66; H, 7.42; N, 13.05.
-(Hyd r oxym eth yl)-2-m eth yla n ilin e (5). A mixture of
-methyl-4-nitrobenzyl alcohol (21.05 g, 0.126 mol) and 10%
4
3
palladium on carbon (2.0 g) in 200 mL of EtOH was hydroge-
nated at rt. After completion of the reaction, the catalyst in the
reaction mixture was removed by filtration. The solvent was
3
,4-dihydro-2H-pyran in refluxing THF gave the desired
evaporated and the residue dried in a vacuum to give 5 as a
product 4 in 79% yield. The importance of the THP
protecting group becomes evident. Any attempt at
introducing nitrogen protecting groups, using base-
promoted reaction conditions, would lead to decomposi-
tion of 7. Bromide 4 could be stored indefinitely at 0 °C
without much evidence of decomposition.
1
yellow solid (17.22 g, 97%). 5: mp 72-75 °C; H NMR (CDCl
3
)
δ 7.06 (s, 1 H), 7.03 (d, J ) 8.0 Hz, 1 H), 6.66 (d, J ) 7.7 Hz, 1
H), 4.53 (s, 1 H), 3.62 (br, 2 H), 2.17 (s, 3 H); CIMS (NH ) m/ z
3
+
+
4
172 (M + 2 X NH + H , 100), 155 (M + NH ).
3
1-Acetyl-5-(a cetoxym eth yl)in d a zole (6). A mixture of 5
(
16.58 g, 0.12 mol), acetic anhydride (34.0 mL, 0.36 mol) and
potassium acetate (23.71 g, 0.24 mol) in 240 mL of CHCl was
3
Scheme 3 details the conversion of bromide 4 to amine
. Facile displacement of the benzylic bromide was
stirred at rt for 3 h, refluxed for 2 h, and stirred at rt overnight.
Then n-amyl nitrite (32 g, 0.27 mol) and 18-crown-6 (1.59 g, 6.0
mmol) were added and the mixture heated at reflux for 28 h.
After being cooled to rt, the reaction mixture was added to acetic
anhydride (10 mL) and stirred at rt overnight. The reaction
9
accomplished using sodium azide in DMF to give 8 in
quantitative yield. The crude azide was carried onto the
next step without purification. Reduction of the azide
was accomplished with LAH in THF to give the desired
amine 9 in 98% yield. This material was of sufficient
purity (96.8% by HPLC) to be used in subsequent
reactions without further purification and could be stored
at 0 °C indefinitely.
In conclusion, we presented a short, efficient synthesis
of two useful intermediates on a multigram scale. The
indazole ring system was assembled using a phase-
transfer-catalyzed protocol, further expanding this reac-
tion’s scope. A one-pot conversion provided 5-(bromo-
methyl)-1H-indazole from intermediate 6 in 92% yield.
Regioselective introduction of the THP protecting group
gave the title compound 4. An efficient conversion of
bromide 4 to amine 9 proceeded in 98% yield without
chromatography. These intermediates should provide
easy and useful ways of introducing the indazole moiety
into future medicinal targets.
mixture was diluted with CH
saturated NaHCO (200 mL), water, and brine, and dried (Na
SO ) and the solvent evaporated to give a dark brown solid.
Chromatography (silica gel, 15% EtOAc/hexane) gave 6 as a
2 2
Cl (400 mL), washed with
3
2
-
4
1
3
yellow solid (16.98 g, 58%). 6: mp 73-74 °C; H NMR (CDCl )
δ 8.44 (d, J ) 8.8 Hz, 1 H), 8.13 (d, J ) 0.8 Hz, 1 H), 7.75 (d, J
) 0.7 Hz, 1 H), 7.56 (dd, J ) 8.8, 1.5 Hz, 1 H), 5.23 (s, 2 H),
2
+
6
.79, (s, 3 H), 2.12 (s, 3 H); CIMS (NH
3
) m/ z 267 (M + 2 X NH
3
+
+
H , 100), 250 (M + NH
4
). Anal. Calcd for C12 : C,
12 2 3
H N O
2.06; H, 5.22; N, 12.06. Found: C, 62.07; H, 5.07; N, 11.91.
5
-(Br om om eth yl)-1H-in d a zole Hyd r ogen Br om id e (7). A
mixture of 6 (10 g, 0.043 mol) in 50 mL of 48% HBr was stirred
at rt for 16 h. The solid was collected on a Buchner funnel,
washed with 48% HBr, and dried in a vacuum desiccator with
P
2
O
5
and NaOH to give 7 as a light tan solid (11.58 g, 92%),
which was used for the next reaction without further purifica-
1
tion. 7: mp >300 °C; H NMR (DMSO-d
Hz, 1 H), 7.86 (s, 1 H), 7.55 (d, J ) 8.4 Hz, 1 H), 7.43 (dd, J )
.8, 1.5 Hz, 1 H), 4.87 (s, 2 H); CIMS (NH ) m/ z 230, 228 (M +
NH4 ), 213, 211 (M + H ).
-(Br om om eth yl)-1-(2-tetr a h yd r op yr a n yl)in d a zole (4). A
6
) δ 8.09 (d, J ) 0.8
8
3
+
+
5
mixture of 7 (16.54 g, 0.057 mol) and 3,4-dihydro-2H-pyran (9.53
g, 0.113 mol) in THF (400 mL) was refluxed for 2 h and stirred
at rt overnight. The reaction solution was diluted with 1 L of
Exp er im en ta l Section
All reactions were carried out with continuous stirring under
an atmosphere of dry nitrogen. Commercial reagents were used
as received without additional purification. THF was distilled
CH
dried (MgSO
(silica gel, EtOAc/hexane 0-20%) gave 4 as a beige solid (13.3
2
Cl
2
, washed with saturated NaHCO
3
, water, and brine, and
4
) and the solvent evaporated. Chromatography
1
13
from sodium benzophenone ketyl. H NMR (300 MHz) and
C
1
NMR (75 MHz) spectra were recorded using tetramethylsilane
as an internal standard. Melting points are uncorrected. TLC
was performed on E. Merck 15719 silica gel plates. Flash
chromatography was carried out using EM Science silica gel 60
230-400 mesh). Elemental analysis was performed by Quan-
titative Technologies, Inc., Bound Brook, NJ .
3
g, 79%). 4: mp 66-68 °C; H NMR (CDCl ) δ 8.00 (s, 1 H), 7.73
(s, 1 H), 7.59 (d, J ) 8.8 Hz, 1 H), 7.45 (dd, J ) 8.8, 1.5 Hz, 1 H),
5.72 (dd, J ) 9.4, 2.4 Hz, 1 H), 4.66 (s, 2 H), 4.04-4.00 (m, 1 H),
3.79-3.70 (m, 1 H), 2.62-2.49 (m, 1 H), 2.18-2.06 (m, 2 H),
1.84-1.57 (m, 3 H); 13C NMR (CDCl
) δ 139.2, 134.0, 130.9,
128.0, 124.8, 121.4, 110.8, 85.5, 67.4, 34.5, 29.4, 25.1, 22.5; CIMS-
(
3
+
+
(
(
1
NH
KBr) 3406, 3208, 2938, 2864, 2528, 1692, 1640, 1538, 1440,
364, 1308, 1282, 1246, 1200, 1136, 1078, 1038, 1012, 908, 816
3
) m/ z 314, 312 (M + NH
4
, 100), 297, 295 (M + H ); IR
(
7) Initially, a two-step protocol was used to produce indazole 7 from
, which involved removing the acetate groups with K CO /MeOH and
treating the subsequent 5-(hydroxymethyl)-1H-indazole with 48% HBr
6
2
3
-
1
cm . Anal. Calcd for C13
2
H15BrN O: C, 52.90; H, 5.12; N, 9.49;
in 42% overall yield.
Br, 27.07. Found: C, 52.62; H, 5.31; N, 9.35; Br, 27.03.

Notes
J . Org. Chem., Vol. 62, No. 16, 1997 5629
+
P r ep a r a tion of 4 by Ra d ica l Br om in a tion of 3. A solution
of NBS (1.065 g, 5.99 mmol) and AIBN (13.5 mg, 0.08 mmol) in
CCl (80 mL) was heated to 60 °C, and a solution of 3 (0.99 g,
.58 mmol) in CCl (20 mL) was added. After continued heating
at this temperature overnight, the reaction was cooled to 0 °C
and filtered and the filtrate washed with water. After the
ESIMS m/ z 258 (M + H , 100); HRMS calcd for C13
H
16
N
5
O
1
(M
+
+ H ) 258.1355, found: 258.1360.
4
5
-(Am in om eth yl)-1-(2-tetr a h yd r op yr a n yl)in d a zole (9).
4
4
A solution of azide 8 (2.6 g, 0.01 mol) in THF (30 mL) was cooled
to 0 °C using an ice bath and treated with LAH (10.2 mL, 1.0 M
in THF) via syringe over 10 min. After 1 h, the reaction mixture
was quenched by the dropwise addition of a 1.0 M solution of
NaOH (1.5 mL). The reaction mixture was allowed to reach rt,
organic layer was dried (MgSO
4
) and the solvent removed at
reduced pressure, the residue was chromatographed (silica gel,
1
3
7% EtOAc/hexane) to give the product as a yellow oil (414 mg,
1% yield), which slowly crystallized upon standing, mp 64-67
diluted with EtOAc (60 mL), dried with Na
Celite). The filter cake was washed with an additional portion
2 4
SO , and filtered
(
°C. This material was identical in every respect to that prepared
of EtOAc (20 mL), and the organic layers were combined and
evaporated to give essentially pure amine 9 (2.31 g, 98%). An
analytical sample was purified by chromatography (silica, 10%
from 7.
5
-(Azid om eth yl)-1-(2-tetr a h yd r op yr a n yl)in d a zole (8). A
solution of bromide 4 (3.0 g, 0.01 mol) in dry DMF (30 mL) was
treated with sodium azide (2.64 g, 0.041 mol) in one portion and
heated to 90 °C for 30 min. The reaction mixture was cooled
and poured into water (100 mL) and extracted with ether (150
OH). 9: oil; 1H NMR (CDCl
2 2 4 3
Cl /1% concd NH ) δ
MeOH/CH
.92 (s, 1 H), 7.53 (s, 1 H), 7.48 (d, J ) 8.8 Hz, 1 H), 7.29 (d, J
8.8 Hz, 1 H), 5.62 (dd, J ) 9.4, 2.4 Hz, 1 H), 3.97-3.93 (m, 1
7
)
H), 3.85 (s, 2 H), 3.70-3.62 (m, 1 H), 2.83 (bs, 2 H), 2.56-2.43
mL). The organic phase was separated, dried (MgSO
4
), and
13
(
m, 1 H), 2.09-1.96 (m, 2 H), 1.76-1.50 (m, 3 H); C NMR
CDCl ) δ 138.8, 135.2, 133.7, 126.8, 124.8, 119.0, 110.3, 85.3,
7.4, 46.0, 29.4, 25.1, 22.6; ESIMS m/ z 232 (M + H , 33), 215
evaporated to give azide 8 as an oil (2.6 g, quant). No further
(
3
1
purification was needed. 8: oil; H NMR (CDCl
3
) δ 8.00 (s, 1
+
6
(
H), 7.63 (s, 1 H), 7.59 (d, J ) 8.8 Hz, 1 H), 7.32 (d, J ) 8.8 Hz,
+
+
M + H - 17, 100); HRMS calcd for C13
32.1500, found 232.1447. Anal. Calcd for C13
H, 7.42; N, 18.17. Found: C, 67.18; H, 7.31; N, 18.45.
H
H
18
N
3
O (M + H )
O: C, 67.51;
1
1
H), 5.72 (dd, J ) 9.4, 2.4 Hz, 1 H), 4.38 (s, 2 H), 4.04-4.00 (m,
H), 3.76-3.68 (m, 1 H), 2.62-2.49 (m, 1 H), 2.15-2.03 (m, 2
2
17
N
3
1
3
3
H), 1.99-1.52 (m, 3 H); C NMR (CDCl ) δ 139.3, 133.9, 128.4,
1
27.1, 124.8, 120.8, 110.8, 85.4, 67.4, 55.0, 29.4, 25.1, 22.5;
J O970375B