A practical synthesis of 1-N-SEM-Protected 3-Iodo-7-methyl-2-piperidin-3- ylindole

Article abstract of DOI:10.1055/s-0029-1217110

A convenient procedure for the preparation of the 1-N-SEM-protected 3-iodo-7-methyl-2-piperidin-3-ylindole 3 is described. This scaffold provides access to unique and diverse 7-methyl-substituted indole libraries. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1217110

714
PRACTICAL SYNTHETIC PROCEDURES
A Practical Synthesis of 1-N-SEM-Protected 3-Iodo-7-methyl-2-
piperidin-3-ylindole
1
-N-SEM
-
Protecte
d
3
m
-Iodo-7-methyl-2-p
e
iperidin-3-
s
ylindole G. Phillips,*a Maria Jaworska,a Willard Lewb
a
Curragh Chemistries Inc., c/o Sherwin Williams Cradle, 7650 Hub Parkway, Valley View, OH 44125, USA
E-mail: contractcurragh@yahoo.com
b
Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA
PSP
Received 31 August 2009; revised 30 September 2009
No178
Abstract: A convenient procedure for the preparation of the 1-N-SEM-protected 3-iodo-7-methyl-2-piperidin-3-ylindole 3 is described.
This scaffold provides access to unique and diverse 7-methyl-substituted indole libraries.
Key words: 7-methylindoles, Fischer cyclization, 3-iodoindoles, 1,2,3,7-substituted indoles
I
H
1. PtO2, H2
N
ZnCl2
AcOH
2. NaOH, Boc2O
N
⋅HCl
3. NaH, I2
4. NaH, SEMCl
N
N
N
N
N
H
Boc
⋅HCl
SEM
1
2
3
Scheme 1
tions of aromatic heterocyclic ketones to form 2-(2-py-
ridyl) indole.5 Appropriate hydrogenation reaction
Introduction
Methodology for the preparation of N-protected 3-haloin- conditions also needed to be considered to effect only the
doles is a topic of much interest because cross-coupling saturation of the 2-pyridin-3-yl substituent in preference
reactions provide direct access to a variety of substances to the pyrrole or benzene ring of the indole. Best condi-
with significant biological activity.1 N-Protection is an tions regarding the use of solvent, catalyst, temperature,
important aspect for reactions of 3-haloindoles due to the and H2 pressure needed to be explored.6
instability of the parent compounds, and the influence of
the protecting group on subsequent chemistry. The most
commonly employed indole N-protecting groups are aryl- Scope and Limitations
sulfonyl derivatives (e.g., tosyl), carbamates (e.g., Boc),
trialkylsilyl groups (e.g., triisopropylsilyl), N,O-acetals It is important to emphasize that most of the methods and
(e.g., SEM), and some alkyl groups (e.g., benzyl).2
reaction conditions reported to yield successful Fischer
indole cyclizations between phenylhydrazines and aro-
matic methyl ketones do not work to any appreciable ex-
tent for the preparation of 2-heteroaryl-substituted 7-
methylindoles. Furthermore, Fischer cyclizations using 2-
methylphenylhydrazine are best carried out using the hy-
drochloride since the free base is not stable.7 We have
found an efficient method to prepare pure N-(1-pyridin-3-
ylethylidine)-N-o-tolylhydrazine hydrochloride (1) by the
dropwise addition of 3-acetylpyridine into a methanol so-
lution of commercially available 2-methylphenylhydra-
zine hydrochloride at room temperature followed by
heating at reflux for one hour. Compound 1 precipitates
from solution upon cooling and is collected by filtration in
89% yield. Methanol is the solvent of choice allowing for
complete reaction and easy isolation.
On initial inspection, the synthesis of 2-substituted 3-
halo-7-methylindoles presents several obstacles. Due to
the presence of 2,7-disubstitution, steric hindrance in
these indoles excludes the use of many common N-pro-
tecting groups. Most methods for synthesizing N-protect-
ed 2- and 3-haloindoles usually use electron-withdrawing
groups with a preference in many instances for the phe-
nylsulfonyl group.3 Attempts to prepare 1-(trialkylsilyl)-
7-methoxyindoles have been shown to be unsuccessful
due to the steric hindrance of the 7-methoxy substituent.4
A review of literature revealed a paucity of reliable infor-
mation regarding the use of Fischer cyclizations to pre-
pare 2-heterocyclic-substituted 7-methylindoles. Only
recently have there been reports of useful Fischer cycliza-
A variety of common procedures and usual conditions for
the Fischer cyclization of 1 to 7-methyl-2-pyridin-3-yl-
1H-indole (2) have proven to be problematic. Heating 1 in
polyphosphoric acid (PPA) at 180 °C or using Eaton’s
SYNTHESIS 2010, No. 4, pp 0714–0717
Advanced online publication: 13.11.2009
DOI: 10.1055/s-0029-1217110; Art ID: M05109SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
9

PRACTICAL SYNTHETIC PROCEDURES
1-N-SEM-Protected 3-Iodo-7-methyl-2-piperidin-3-ylindole
715
PtO2, H2, MeOH
Boc2O
N
H
N
N
N
N
Boc
NH
H
H
⋅HCl
2
4
5
Scheme 2
acid (3% P2O5 in methanesulfonic acid–dichloromethane, as due to the failed N-phenylsulfonyl protection due to the
1:2) at 45 °C provided little product and led to formation steric hindrance of the 7-methyl and 2-piperidin-3-yl sub-
of intractable tars.8,9 Treatment of hydrazine 1 with etha- stituents and subsequent decomposition of the 3-iodoin-
nolic hydrogen chloride at reflux or with five equivalents dole 6 (Figure 1). A followup experiment in which N-
of zinc(II) chloride in dimethoxyethane at reflux or in gla- phenylsulfonyl protection of indole 5 was attempted prior
cial acetic acid at 70 °C returned mostly starting material to C-3 iodination, but failed to effect the desired protec-
after 24 hours.10,11 However, treatment of compound 1 tion to afford 8 (Figure 1).
with five equivalents of zinc(II) chloride in glacial acetic
Our observations suggested that we attempt the prepara-
acid at reflux for 17 hours provided the free base 2 in 40–
tion of indole 3 by C-3 iodination of indole 5 followed by
50% reproducible yields after a convenient workup by
subsequent N-SEM protection of indole 6 without prior
workup and isolation of 6. N-SEM protection was pro-
posed since SEMCl [2-(trimethylsilyl)ethoxymethyl chlo-
precipitation directly in water followed by a simple puri-
fication protocol (Scheme 1).
Our attempts to reduce the pyridine ring of the free base 2 ride] is a reactive alkylating agent and introduces minimal
by catalytic hydrogenation using 5% palladium on carbon steric interactions in a congested environment. A prelimi-
in acetic acid at room temperature at 50 psi as described nary experiment showed that treatment of indole 5 in N,N-
for 2-pyridin-3-yl-1H-indole gave no reaction after 48 dimethylformamide at 0 °C with 1 equivalent of sodium
hours.8 The toluenesulfonate salt of 2 was prepared, but hydride followed by quenching with SEMCl produced the
was very insoluble in methanol, and underwent very little N-SEM derivative 9 (Figure 1) in 85% isolated yield. Fol-
reduction using platinum(IV) oxide at room temperature lowing this result, treatment of indole 5 in N,N-dimethyl-
at 50 psi after 24 hours. The hydrochloride of compound formamide at –10 °C with one equivalent of sodium
2 was readily soluble in anhydrous methanol and under- hydride for 30 minutes and then dropwise addition of a
went selective hydrogenation using platinum(IV) oxide at N,N-dimethylformamide solution of one equivalent of io-
room temperature at 50 psi after 24 hours and afforded a dine afforded the intermediate C-3 iodoindole 6. This in-
95% yield of 7-methyl-2-piperidin-3-yl-1H-indole (4). termediate was directly treated with another equivalent of
Boc protection of the piperidinyl nitrogen of 4 in aqueous sodium hydride at –10 °C for 30 minutes followed by
sodium hydroxide and tert-butyl alcohol using di-tert-bu- quenching with SEMCl to afford the desired scaffold 3 in
tyl dicarbonate proceeded in 72% isolated yield to afford 70% isolated yield after purification by chromatography
indole 5 (Scheme 2).
and subsequent recrystallization (Scheme 1). This modifi-
cation of the established Gribble procedure works effi-
ciently, is less involved experimentally as only –10 to
0 °C temperatures are required, and conveniently uses so-
dium hydride as base. The introduction of these tech-
niques provides synthetic flexibility and enables the use of
other compatible protecting groups besides Boc on the pi-
peridinyl nitrogen.
The C-3 iodination of 5 in N,N-dimethylformamide at
room temperature using potassium hydroxide and iodine
appears to proceed quantitatively (TLC analysis), but at-
tempted isolation of 6 leads to a mixture of products due
to decomposition.1 We therefore considered the prepara-
tion of the N-phenylsulfonyl derivative 7 following the
well-established procedure by Gribble.12 Treatment of in-
dole 5 at –78 °C in anhydrous tetrahydrofuran under nitro- In conclusion, we have developed an efficient, flexible,
gen with n-butyllithium followed by an iodine quench and convenient procedure for the preparation of 1-N-
appeared to give the C-3 derivative 6, but subsequent SEM-protected 3-iodo-7-methyl-2-piperidin-3-ylindole.
treatment with lithium diisopropylamide at –78 °C fol- This scaffold provides access to a host of diverse indole li-
lowed by quenching with benzenesulfonyl chloride gave braries through subsequent chemistries at C-3 and the pi-
a complex mixture of products. We rationalized this result peridinyl nitrogen.
I
I
N
N
N
N
N
N
N
N
H
Boc
Boc
Boc
SO2
SEM
Boc
SO2
6
7
8
9
Figure 1 Compounds 6–9
Synthesis 2010, No. 4, 714–717 © Thieme Stuttgart · New York

716
J. G. Phillips et al.
PRACTICAL SYNTHETIC PROCEDURES
5.20 (br s, 1 H), 6.18 (s, 1 H), 6.87 (d, J = 7.16 Hz, 1 H), 6.96 (t,
J = 7.16 Hz, 1 H), 7.35 (d, J = 7.87 Hz, 1 H), 9.37 (br s, 1 H).
HRMS: m/z calcd for (M + H)+: 215.1548; found: 215.1733.
Mps were determined using an Electrothermal capillary melting
point apparatus and are uncorrected. NMR spectra were recorded on
either a Varian Inova 300 or 400 operating at 300 and 400 MHz for
1H, respectively. Chemical shifts are reported in ppm relative to ei-
ther residual CHCl3 (d = 7.24 ppm) in CDCl3, HOD (d = 4.67 ppm)
in D2O, or CHD2S(O)CD3 (d = 2.49 ppm) in DMSO-d6. TLC was
performed on SiO2 (silica gel 60 F254, Merck). Column chromatog-
raphy was carried out on SiO2 (silica gel 60, 230–400 microns). All
reagents were purchased from Aldrich and were used without fur-
ther purification. Solvents for chromatography and recrystallization
were all ACS grade. HRMS analyses were performed at the chem-
istry department at the University of Akron. Microanalyses were
performed at Galbraith Laboratories.
3-(7-Methyl-1H-indol-2-yl)piperidine-1-carboxylic Acid tert-
Butyl Ester (5)
Boc2O (1.79 g, 8.20 mmol) was added portionwise to a suspension
of 4 (1.75 g, 8.194 mmol) in t-BuOH (6.2 mL) and aq NaOH (0.36
g NaOH, 9 mmol, in 8.2 mL of H2O) which had been cooled to 5 °C.
The mixture was allowed to warm to r.t., stirred for 1 h, and then ex-
tracted with EtOAc (50 mL). The organic layer was separated, dried
(MgSO4), filtered, and concentrated. Purification of the residue ob-
tained by flash silica chromatography using CH2Cl2–EtOAc fol-
lowed by recrystallization from Et2O–hexanes gave 1.85 g of white
crystals (72%); mp 190–191 °C.
1H NMR (400 MHz, CDCl3): d = 1.41 (s, 9 H), 1.43 (m, 2 H), 1.70
(m, 2 H), 2.07 (m, 1 H), 2.54 (s, 3 H), 2.83 (m, 2 H), 3.90 (m, 1 H),
4.10 (m, 1 H), 6.30 (d, J = 2 Hz, 1 H), 6.97 (d, J = 7.08 Hz, 1 H),
7.00 (t, J = 7.08 Hz, 1 H), 7.40 (d, J = 7.57 Hz, 1 H), 8.70 (br s, 1 H).
N-(1-Pyridin-3-ylethylidene)-N-o-tolylhydrazine Hydrochlo-
ride (1)
3-Acetylpyridine (16.43 g, 0.135 mol) was added dropwise in 25
min to a MeOH solution (250 mL) of 2-methylphenylhydrazine hy-
drochloride (21.0 g, 0.132 mol) at r.t. After the addition was com-
plete, the mixture was heated at reflux for 1 h and then allowed to
cool to r.t. with stirring. The mixture was cooled further to 0 °C with
an ice bath, the precipitate was collected by filtration, the solid
washed with MeOH (2 × 20 mL), and dried under high vacuum for
several hours to give 30.9 g of a yellow solid (89%); mp 231–
235 °C (dec.).
1H NMR (300 MHz, D2O): d = 1.82 (s, 3 H), 1.91 (s, 3 H), 6.60 (t,
J = 6.9 Hz, 1 H), 6.74 (d, J = 6.9 Hz, 1 H), 6.92 (t, J = 7.8 Hz, 1 H),
7.04 (d, J = 6.9 Hz, 1 H), 7.59 (dt, J = 1.5, 7.8 Hz, 1 H), 8.16 (d,
J = 5 Hz, 1 H), 8.43 (d, J = 5 Hz, 1 H), 8.45 (s, 1 H).
HRMS: m/z calcd for (M + Na)+: 337.1891; found: 337.2131.
Anal. Calcd for C19H26N2O2 (314.42): C, 72.58; H, 8.33; N, 8.91.
Found: C, 72.29; H, 8.22; N, 8.85.
3-[3-Iodo-7-methyl-1-(2-trimethylsilylethoxymethyl)-1H-indol-
2-yl]piperidine-1-carboxylic Acid tert-Butyl Ester (3)
To a suspension of NaH (60% dispersion, 0.66 g, 0.0165 mol) in an-
hydrous DMF (30 mL) cooled to –10 °C under N2 was added a DMF
(5 mL) solution of 5 (4.78 g, 0.0152 mol) dropwise in 5 min. Stir-
ring was continued for 30 min and then a DMF (10 mL) solution of
I2 (3.84 g, 0.0151 mol) was added in 5 min. After 30 min at –10 °C,
NaH (60% dispersion, 0.66 g, 0.0165 mol) was added portionwise.
After stirring for an additional 30 min, 2-(trimethylsilyl)ethoxy-
methyl chloride (90%, 3.1 g, 0.0167 mol) was added via a syringe.
The reaction was allowed to warm to 0 °C and after 1 h, quenched
by the addition of aq NH4Cl (100 mL). Extraction with EtOAc
(2 × 60 mL), washing of the combined organic layers with 10% aq
Na2S2O3 (50 mL), followed by washing with brine (3 × 50 mL),
drying (Na2SO4), and concentration gave the crude product. Purifi-
cation by flash silica gel chromatography using EtOAc–hexanes,
followed by recrystallization from Et2O–hexanes (10:90) gave 6.06
g of white crystals (70%); mp 90–91 °C.
HRMS: m/z calcd for (M + H)+: 226.1344; found: 226.1341.
7-Methyl-2-pyridin-3-yl-1H-indole (2)
Compound 1 (10.16 g, 0.038 moles) and anhydrous ZnCl2 (26 g, 0.19
mol) in glacial AcOH (100 mL) were heated at reflux under N2 for
17 h. The reaction mixture was cooled to r.t. and added to ice water
(600 g). After stirring for 2 h, the solids were filtered and washed
with H2O (50 mL). The solids were suspended in 1 N aq NaOH (100
mL, pH 11–12), extracted with EtOAc (2 × 150 mL), the combined
organic layers were dried (Na2SO4), filtered, and concentrated to
give a solid. Trituration with MTBE followed by filtration gave
3.56 g of a tan solid; mp 194–196 °C. Average yields over 3 runs
were 40–50%. Additional product (approximately 5–10%) could be
obtained from the aqueous filtrate by neutralization with NaOH and
extraction with EtOAc, but this protocol was not optimized.
1H NMR (300 MHz, CDCl3): d = 0.0 (s, 3 H), 0.96 (m, 2 H), 1.46
(s, 9 H), 1.62 (m, 2 H), 1.90 (m, 2 H), 2.60 (m, 1 H), 2.77 (s, 3 H),
2.85 (m, 1 H), 3.16 (m, 1 H), 3.58 (t, J = 7.57 Hz, 2 H), 4.18 (m, 2
H), 5.60 (ABq, J = 11.48 Hz, 2 H), 7.02 (d, J = 6.84 Hz, 1 H), 7.10
(t, J = 7.81 Hz, 1 H), 7.36 (d, J = 7.81 Hz, 1 H).
1H NMR (400 MHz, DMSO-d6): d = 2.52 (s, 3 H), 6.90 (m, 2 H),
7.0 (d, J = 2.15 Hz, 1 H), 7.35 (m, 1 H), 7.46 (ddd, J = 0.87, 4.75,
8.01 Hz, 1 H), 8.27 (ddd, J = 1.61, 2.37, 8.01 Hz, 1 H), 8.47 (dd,
J = 1.61, 4.75 Hz, 1 H), 9.14 (ABq, J = 0.87, 2.37 Hz, 1 H).
HRMS: m/z calcd for (M + Na)+: 593.1672; found: 593.1842.
HRMS: m/z calcd for (M + H)+: 209.1078; found: 209.1196.
Anal. Calcd for C25H39IN2O3Si (570.58): C, 51.89; H, 6.53; N, 5.04.
Found: C, 52.10; H, 6.67; N, 4.89.
Anal. Calcd for C14H12N2·0.2 H2O: C, 79.37; H, 5.91; N, 13.22.
Found: C, 79.66; H, 5.71; N, 13.11.
Acknowledgment
7-Methyl-2-piperidin-3-yl-1H-indole (4)
7-Methyl-2-pyridin-3-yl-1H-indole hydrochloride (2·HCl; 2.11 g,
8.65 mmol) was dissolved in anhydrous MeOH (200 mL) at r.t. The
solution was degassed, PtO2·H2O (0.20g) was added and the mix-
ture hydrogenated at 35 psi at r.t. for 18 h. The catalyst was removed
by filtration through Celite and the filtrate concentrated. The dry
foam was dissolved in CH2Cl2 (30 mL), was washed with 10% aq
Na2CO3 (30 mL), the organic layer separated, dried (Na2SO4), fil-
tered, and concentrated to give 1.75 g of a tan foam (95%). This ma-
terial was not further purified, but used directly.
The authors would like to thank Professor Gribble for helpful sug-
gestions and encouragement. We would also like to thank Dr. Dale
Ray (Department of Chemistry at Case Western Reserve Universi-
ty) for NMR assistance.
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(m, 1 H), 2.48 (s, 3 H), 2.60 (m, 2 H), 3.20 (m, 2 H), 3.68 (m, 1 H),
Synthesis 2010, No. 4, 714–717 © Thieme Stuttgart · New York

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717
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Synthesis 2010, No. 4, 714–717 © Thieme Stuttgart · New York