Enantioselective synthesis of 3-substituted tryptamines as core components of central nervous system drugs and indole natural products

Article abstract of DOI:10.1139/cjc-2012-0221

Application of the MacMillan iminium ion Michael and Friedel-Crafts type reactions to γ-amino α,β-unsaturated butanals led to the corresponding β-substituted butanals in good yields and high enantioselectivities. The products could be useful intermediates

Full text of DOI:10.1139/cjc-2012-0221

13
Enantioselective synthesis of 3-substituted
tryptamines as core components of central
nervous system drugs and indole natural products
Stephen Hanessian and Elia J.L. Stoffman
Abstract: Application of the MacMillan iminium ion Michael and Friedel–Crafts type reactions to ␥-amino ␣,␤-unsaturated
butanals led to the corresponding ␤-substituted butanals in good yields and high enantioselectivities. The products could be
useful intermediates in the synthesis of indole-based central nervous system (CNS) drugs and natural products.
Key words: iminium ion alkylation, indole natural products, 3-substituted indoles.
Résumé : L’utilisation d’ions iminium de MacMillan dans des réactions de type Michael ou Friedel–Crafts sur des
␥-aminobutanals ␣,␤-insaturés conduit a la formation des butanals ␤-substitués correspondants, avec de bons rendements et
`
des énantiosélectivités élevés. Ces produits pourraient être des intermédiaires utiles dans la synthèse de produits naturels et
de médicaments pour le système nerveux central (CNS) a base d’indole.
`
Mots-clés : alkylation d’un ion iminium, produits naturels a base d’indole, indoles avec substitution en position 3.
`
[Traduit par la Rédaction]
stereoselective synthesis of ␣-branched 3-substituted indoles
(4), and its extension to other synthetically useful substrates.
The synthesis of the desired (S)-(–)-1 is outlined in
Scheme 2. The treatment of N-Boc, N-methyl acetaldehyde 5
with triethylphosphonoacetate under standard conditions fol-
lowed by reduction with diisobutylaluminum hydride
(DIBAL-H) led to allylic alcohol 6, which was oxidized to the
aldehyde 3 with the Dess–Martin periodinane reagent in an
excellent yield. The activation of 3 with the (R,R)-MacMillan
catalyst,7a followed by addition of 5-bromoindole, afforded
the adduct 7 in a quantitative yield. Reduction to the alcohol 8
and mesylation or tosylation to 9, followed by cleavage of the
N-Boc group and treatment of the product with potassium
carbonate in a mixture of tetrahydrofuran (THF) and
dimethylformamide (DMF) as the solvent led to the target
compound, (S)-(–)-1, in an excellent yield. The absolute con-
figuration was confirmed by single crystal X-ray analysis (see
ref. 3 of the Supplementary data), and stereochemical purity
(88% enantiomeric excess (ee)) was established by chiral
HPLC analysis.
The suitability of 3 as a Michael acceptor in the MacMillan
organocatalytic addition of 5-bromoindole to give ␤-branched
aldehydes such as 7 with high enantioselectivity led us to
explore the same reactions with other N substituents.
The results shown in Table 1 indicate that a variety of
N substituents can be used in the original reaction with
excellent enantioselectivities, which did not seem to vary
significantly with less sterically bulky protecting groups on
nitrogen (Table 1, entry 3) or when groups with a stronger
Introduction
The tryptamine moiety is found in a number of drugs as well
as pharmacologically active alkaloids1 that use L-tryptophan as
a biosynthetic precursor.2 Drug prototypes with demonstrated
activity against a host of central nervous system (CNS)-related
targets and containing various azacyclic rings attached to
indoles are of interest. For example, NXN274 and naratriptan3,4
are known to act on the serotonergic (5-hydroxytryptamine or
5-HT) receptors (Fig. 1).
Gelliusine E,5 a member of the diindole methane family of
alkaloids, has generated attention6 owing to the novel biolog-
ical profile of this class of symmetrical and nonsymmetrical
bisindoles.
Results and discussion
In connection with a project aimed at exploiting a prac-
tical asymmetric synthesis of NXN274, we recently re-
ported3 the synthesis of an advanced intermediate, S-(–)-1,
using MacMillan’s iminium activation of ␣,␤-unsaturated al-
dehydes as a means of stereocontrolled and enantioselective
branching (Scheme 1).7
Although examples of Michael and Friedel–Crafts type
additions to ␣,␤-unsaturated aldehydes with alkyl and related
substituents at the ␥-position were known from the MacMillan
group7a,7e and others,8 we required an ␣,␤-unsaturated butanal
harbouring a functionalized amino group at the ␥-carbon, such
as 3. We now report on the details of this approach toward the
Received 12 June 2012. Accepted 24 July 2012. Published at www.nrcresearchpress.com/cjc on 20 December 2012.
S. Hanessian and E.J.L. Stoffman. Department of Chemistry, Université de Montréal, Montreal, QC H3C 3J7, Canada.
Corresponding author: Stephen Hanessian (e-mail: stephen.hanessian@umontreal.ca).
This article is part of a Special Issue dedicated to Professor Derrick L. J. Clive and wishing him the best in life and in chemistry.
Can. J. Chem. 91: 13–20 (2013)
doi:10.1139/cjc-2012-0221
Published by NRC Research Press

14
Can. J. Chem. Vol. 91, 2013
Fig. 1. Examples of 3-substituted tryptamines as drugs or natural products.
Me
N
NH2
3
H
N
S
NH
NXN274
N
H
N
H
tryptamine
Me
N
NH2
NH2
O O
S
MeHN
N
H
Br
N
H
Br
naratriptan
N
H
gelliusine E
Scheme 1. Retrosynthetic analysis of NXN274.
R
Me
N
N
H
N
S
X
NH
N
N
H
NXN274
S-(-)-1
H
R'
O
R
NMe
N
t-Bu
NH
(R,R)-(+)-2
Bn
CHO
R'
X
+
N
CHO
X
R
N
H
N
H
3
4
electron-withdrawing capability were introduced (Table 1, en-
try 2). However, when the bulkier bis-protected substrates
were used, longer reaction times were necessary (Table 1,
entries 4 and 5).
We then turned our attention to ␣,␤-unsaturated alde-
hydes containing ␥- and ␦-amino groups protected as the
tert-butylcarbamates (Scheme 4).
The use of aldehyde 16a9 under the conditions established
in Table 1 (vide supra) led to transformation of the aldehyde
to N-Boc–pyrrole, without incorporation of the indole moi-
ety. However, the homologated aldehyde 16b10 underwent
smooth conversion to the cyclized N-Boc enamine 17,
which could be converted to the O-methyl hemiaminal 18
under acid catalysis. The latter could be converted to the
achiral naratriptan precursor (19) under conditions reported by
Leonard and Woerpel11 (BF3–OEt2, Et3SiH), or by hy-
drogenation over Rh catalyst in the presence of AcOH.12 In the
absence of acetic acid, neither O-methyl hemiaminal 18
The synthesis of the bis-protected aldehyde 15 (Table 1,
entries 4 and 5) proceeded smoothly through a cross-
metathesis approach (Scheme 3). Thus, anisaldehyde (10) was
reductively aminated with allylamine (11) to give N-allyl-4-
methoxybenzylamine (12), and this was protected as the tert-
butylcarbamate 13. Cross metathesis with methyl acrylate in
the presence of the Grubbs II catalyst gave the methyl ester 14,
which was reduced to the corresponding alcohol before oxi-
dation by the Parikh–Doering method to the bis-protected
aminoaldehyde 15.
Published by NRC Research Press

Hanessian and Stoffman
15
Scheme 2. Synthesis of S-(–)-1. Reagents and conditions: (a) (i) triethylphosphonoacetate, NaH, THF, room temperature (rt), 30 min;
(ii) DIBAL-H, THF, –78 °C, 30 min, 54% (two steps); (b) Dess–Martin periodinane, CH2Cl2, rt, 2 h, 89%; (c) 5-bromoindole,
(2R,5R)-5-benzyl-2-tert-butyl-3-methylimidazolidin-4-one, trifluoroacetic acid (TFA), i-PrOH, CH2Cl2, –78 °C, 36 h, quant.; (d) NaBH4,
MeOH, rt, 2 h; (e) R ϭ Me, MsCl, CH2Cl2, Et3N, 0 °C to rt, 16 h, 80% (2 steps); R ϭ p-tolyl, TsCl, CH2Cl2, Et3N, 0 °C to rt, 16 h, 70%
(two steps); (f) (i) HCl, 1,4-dioxane, 0 °C to rt, 1.5 h; (ii) K2CO3, THF–DMF, rt, 24 h, quant. for both sulfonates.
a
Boc
Boc
OH
b
Boc
N
CHO
N
N
CHO
Me
Me
Me
5
6
3
c
Boc
Boc
Me
Me
N
N
N
N
d
OH
CHO
Br
Br
H
H
7
8
e
Boc
Me
N
Me
N
OSO2R
Br
Br
f
N
H
N
H
9a:R=Me
9b:R=p-tolyl
S-(-)-1
Table 1. Organocatalytic MacMillan indole alkylation using nitrogen-containing aldehydes.
Pg
R
N
O
NMe
NH
t-Bu
CHO
Bn
R
Br
N
CHO
+
Br
N
H
TFA, i-PrOH, DCM,
-70 °C, 1-2 days
Pg
N
H
Entry
Pg
R
Br position
Yield (%)a
ee (%)b
Time (days)
1
2
3
4
5
Boc
Bus
COOMe
Boc
Me
Me
Me
PMB
PMB
5
5
5
5
6
Quant.
89c
97
80
65 (83)d
82
92
91
88
81
1
1
1
2
2
Boc
Note: PMB, p-methoxybenzyl ether; quant., quantitative.
aPure isolated yield unless otherwise indicated.
bBased on chiral HPLC analysis of the corresponding alcohols obtained by NaBH4 reduction. The opposite
enantiomer was obtained by running the reaction using the enantiomeric MacMillan catalyst.
cPure isolated material (61%) and 28% in a mixture with starting aldehyde as determined by 1H NMR.
dCorrected for recovered 6-bromoindole.
11
nor enamine 17 were reduced by catalytic hydrogenation using
either Rh-on-carbon or Crabtree’s catalyst13 at 8 atm (1 atm ϭ
101.325 kPa) of hydrogen for 24 h. The treatment of 18
with allyltrimethylsilane in the presence of BF3–OEt2 af-
forded the 2-allyl naratripan analog 20, an asymmetric
naratriptan analog.
Published by NRC Research Press

16
Can. J. Chem. Vol. 91, 2013
Scheme 3. Synthesis of bis-protected aminoaldehyde 15. Reagents and conditions: (a) (i) MgSO4, dichloromethane (DCM); (ii) NaBH4,
MeOH, 4 Å molecular sieves, 54% (two steps); (b) Boc2O, THF, 50 °C, 91%; (c) methyl acrylate, Grubbs II, DCM, 52%; (d) (i) DIBAL-H,
PhMe, –78 °C, 52%; (ii) SO3-pyridine, triethylamine (TEA), dimethyl sulfoxide (DMSO), DCM, 74%.
CHO
N
a
H
+
MeO
H2N
11
MeO
PMB
10
12
b
N
Boc
c
Boc
N
CO2Me
MeO
14
15
13
d
Boc
N
CHO
PMB
Scheme 4. Synthesis of naratriptan analogs. Reagents and conditions: (a) (2R,5R)-5-benzyl-2-tert-butyl-3-methylimidazolidin-4-one, TFA,
i-PrOH, CH2Cl2, –70 °C, 1 day; (b) TsOH–H2O, MeOH, 70% (two steps); (c) H2 (8 atm; 1 atm ϭ 101.325 kPa), Rh-C, AcOH, 62% or
BF3–OEt2, Et3SiH, 58%; (d) BF3–OEt2, allyltrimethylsilane, 23%.
Boc
N
Br
Boc
a
Br
N
H
CHO
n
+
N
H
N
4
n=1:16a
n=2:16b
17
H
n=2;
for n=1 only product was N-Boc-pyrrole
b
Boc
Boc
N
N
OMe
c
Br
Br
N
N
H
H
19
18
d
Boc
N
Br
N
H
20
Published by NRC Research Press

Hanessian and Stoffman
17
Scheme 5. The use of bis-protected aldehyde 15 to generate a substrate suitable for indole-3-pyrrolidine synthesis. Reagents and conditions:
(a) 15, (2R,5R)-5-benzyl-2-tert-butyl-3-methyl-imidazolidin-4-one, TFA, i-PrOH, CH2Cl2, –70 °C, 1.5 day; (b) NaBH4, MeOH, 84%;
(c) (i) MsCl, TEA, 70%; (ii) HCl, EtOAc; (iii) K2CO3, DMF, 85%; (d) (i) ␣-chloroethylchloroformate, CH2Cl2; (ii) MeOH, reflux, 45%.
Boc
PMB
N
a
CHO
Br
Br
N
N
H
21
H
b
Boc
R
N
PMB
N
N
OH
Br
Br
c
N
H
H
22
23R = PMB
24R = H
d
Scheme 6. Synthesis of enantioenriched phenethylamines and 2-ethylamino furans.
Boc
O
NMe
N
OMe
t-Bu
OMe
Me
NH
3,
Bn
CHO
N
TFA, CH2Cl2, -40 °C, 1.5 days
N
25
26
84%; er = 91:9a
O
NMe
t-Bu
Boc
NH
Me
Me
3,
Bn
N
O
O
Me
CHO
HCl, EtOAc, -40 °C, 1.5 days
27
60%; er = 94:6b
To circumvent the acid-induced decomposition of aldehyde
16a to N-Boc–pyrrole, we investigated an alternative approach
(Scheme 5) now utilizing the enantiomeric MacMillan catalyst
ent-(–)-(2).
3-substituted butanals. Thus, the treatment of 3 with 3-pyrrolidino
anisole in the presence of the MacMillan (S,S) imidazolinone
catalyst ent-2 in methylene chloride at –40 °C led to the
phenethylamine derivative 26 in an 84% yield and 91:9
enantiomeric ratio (Scheme 6). A similar reaction with
2-methylfuran, albeit using EtOAc as the solvent, led to the
substituted 2-methylfuran derivative 27 in a 60% yield and
94:6 enantiomeric ratio.
Starting from 21 (Table 1, entry 5), we first reduced the
aldehyde to the primary alcohol 22. Mesylation of alcohol 22
and removal of the Boc group resulted in a spontaneous cyclization
to the pyrrolidine 23. Removal of the PMB protecting group was
easily accomplished using ␣-chloroethylchloroformate14 to furnish
24, the des-N-methyl enantiomer of S-(–)-1.
Conclusion
Paras and MacMillan7e reported Friedel–Crafts type conju-
gate additions of electron-rich aromatics and heterocyclics to
␣,␤-unsaturated aldehydes. The extension of this reaction to
4-N-Boc-N-methyl butanal provided access to enantioenriched
Butanals containing N substituents at the ␥-carbon atom
are excellent substrates for Michael and Friedel–Crafts type
conjugate additions of indoles and electron-rich aromatics,
Published by NRC Research Press

18
Can. J. Chem. Vol. 91, 2013
respectively, affording suitably functionalized adducts in
high diastereomeric ratios. The extension of MacMillan’s
organocatalytic indole alkylation to nitrogen-containing al-
dehydes was realized and has found application in our
concise synthesis of S-(–)-1, a late-stage intermediate in the
synthesis of the dual action migraine drug prototype
NXN274. We expect that this methodology will also find
applications in alkaloid synthesis and in the synthesis of
other indole-containing compounds of medicinal interest.
appear to arise from a single C, but doubled owing to Boc
carbamate). Exact mass m/z calcd for C18H25NNaO5:
358.16249 (M ϩ Na); found: 358.16086.
(4-Methoxy-benzyl)-(4-oxo-but-2-enyl)carbamic acid
tert-butyl ester (15)
DIBAL-H (1.6 mL, 1 mol/L in hexanes, 1.6 mmol) was
added via syringe to a stirred and cooled (–78 °C) solution of
14 (0.2426 g, 0.7432 mmol) in PhMe (2.2 mL) under Ar. After
30 min, the cooling bath was removed and the mixture was
quenched by the addition of saturated aqueous Rochelle’s salt
(1.5 mL), diluted with Et2O (20 mL), and washed once with
saturated aqueous Rochelle’s salt (5 mL). The organic layer
was allowed to stand overnight and the next day the gel that
formed was filtered through Celite. Filtration of the residue
through a pad of SiO2 (2 cm ϫ 2 cm) using 40% EtOAc–
hexanes afforded the allylic alcohol (0.1152 g, 52%), which
was oxidized using the Parikh–Doering method.
SO3–pyridine (0.12 g, 0.75 mmol) was added in one portion
to a stirred and cooled (0 °C) solution of allylic alcohol (from
the DIBAL reduction; 0.1152 g, 0.3748 mmol), Et3N
(0.10 mmol), and DMSO (0.22 mL) in CH2Cl2 (3 mL). Stir-
ring was continued for 10 min before the ice bath was removed
and stirring was then continued for a further 2 h. The mixture
was then diluted with CH2Cl2 (5 mL) and the mixture was
washed once with water (6 mL), dried (MgSO4), and evaporated.
Flash chromatography of the residue over SiO2 (1.5 cm ϫ
20 cm) using 20% EtOAc–hexanes afforded 15 (85.1 mg,
74%) as a colourless oil. 1H NMR (400 MHz, CDCl3) ␦: 9.52
(d, J ϭ 7.8 Hz, 1H), 7.14 (br s, 2H), 6.85 (d, J ϭ 8.6 Hz, 2H),
6.67 (br s, 1H), 6.08 (dd, J ϭ 7.4, 15.4 Hz, 1H), 4.36 (br s,
2H), 3.97–4.05 (m, 2H), 3.79 (s, 3H), 1.48 (s, 9H). 13C NMR
(CDCl3, 100 MHz) ␦: 28.4, 47.1, 49.7 and 50.1 (doubled
peak), 55.3, 80.6, 114.0, 128.8, 129.5, 132.5, 152.9, 155.3,
Experimental
General
The J values are spacings measured directly from the
spectrum. Dry solvents were purified using a sodium dode-
cyl sulfate (SDS) system or purchased as such (Sigma-
Aldrich). Column sizes are quoted as (width ϫ height).
Melting points were measured on a Büchi melting point
B-540 apparatus and are uncorrected. Optical rotations were
recorded on a PerkinElmer model 343 polarimeter at am-
bient temperature.
N-Allyl-N-4-methoxybenzylamine (12)
Anisaldehyde (0.44 mL, 3.6 mmol), allylamine (0.29 mL,
1.1 equiv), and MgSO4 (0.5 g) in CH2Cl2 (5.4 mL) were mixed and
the solution was stirred for 3 h (TLC control) and then the mixture
was filtered and the filtrate solution was concentrated in vacuo.15
The crude aldimine was then taken up in MeOH (6 mL) and
4 Å molecular sieves (1 g), followed by NaBH4 (0.13 g,
3.4 mmol) were added with stirring. The flask was flushed with
Ar and stirring was continued for 2 h, then the mixture was
diluted with Et2O (25 mL) and extracted twice with 10% HCl
(10 mL each). The combined acidic extracts were basified with 3 N
NaOH and extracted twice with Et2O (30 mL total). The combined
ethereal extracts were dried (Na2SO4) and evaporated to afford 12
(0.34 g, 54%), which had data identical to that previously reported.15
159.1, 193.2. Exact mass m/z calcd for C17H23NNaO4:
328.15193 (M ϩ Na); found: 328.15163.
4-(5-Bromo-1H-indol-3-yl)-3,4-dihydro-2H-pyridine-1-
carboxylic acid tert-butyl ester (17)
N-tert-Butylcarbonyl-N-allyl-N-4-methoxybenzylamine (13)
Boc2O (0.49 mL, 1.1 equiv) was added to a stirred solution
of 12 (0.3421 g, 1.930 mmol) in THF (6 mL) under Ar and the
mixture was stirred at rt overnight. Removal of the volatiles in
vacuo afforded 13 (0.4865 g, 91%), having spectral data
identical to that previously reported.16
A flask was charged with MacMillan’s catalyst (2R,5R)-5-
benzyl-2-tert-butyl-3-methyl-imidaolidin-4-one (6.8 mg,
0.13 mmol) and then TFA (0.04 mL, 0.03 mmol) was intro-
duced via syringe. The flask was flushed with Ar, cooled
to –70 °C (cooling machine), and 16b (0.4012 g, 2.014 mmol)
in CH2Cl2 (1.3 mL) and i-PrOH (0.2 mL) were introduced via
syringe. The mixture was stirred for 5 min, then 5-bromoindole
(0.13 g, 0.67 mmol) was added in one portion. The flask
was reflushed with Ar and stirring was continued for 1.5 days,
at which point condensing atmospheric water had caused the
acetone cooling bath to reach –65 °C. The mixture was re-
moved from the cooling bath, diluted with CH2Cl2 (10 mL),
washed once with water, and dried (MgSO4). Flash chroma-
tography of the residue over SiO2 (1.5 cm ϫ 20 cm) using
25% EtOAc–hexanes afforded 17 (66 mg), which was con-
verted directly to 18 (see the following section). An analytical
4-[tert-Butoxycarbonyl-(4-methoxy-benzyl)amino]but-2-
enoic acid methyl ester (14)
The Grubbs II catalyst (34 mg, 0.040 mmol) was added to
a stirred solution of 13 (0.4159 g, 1.500 mmol) and methyl
acrylate (5.4 mL) in CH2Cl2 (6.6 mL). The flask was flushed
with Ar and stirring was continued overnight. The mixture was
filtered through a plug of SiO2 (2 cm ϫ 2 cm) using 5%
EtOAc–hexanes to wash the plug and then the volatiles were
removed in vacuo. Flash chromatography over SiO2 (1.5 cm ϫ
25 cm) using 5% EtOAc–hexanes afforded 14 (0.2594 g,
52%) as a colourless oil. 1H NMR (400 MHz, CDCl3) ␦: 7.14
(br s, 2H), 6.85 (d, J ϭ 8.44 Hz, 2H), 6.82–6.86 (m overlap-
ping with previous, 1H), 5.81–5.85 (m, 1H), 4.36 (br s, 2H),
3.94 (br s, 1H), 3.79 (s, 3H), 7.74–3.80 (m overlapping, 1H),
3.74 (s, 3H), 1.48 (s, 9H). 13C NMR (CDCl3, 100 MHz) ␦:
28.4, 46.6, 49.2, 51.6, 55.3, 80.3, 114.0, 121.6, 128.8, 129.3,
129.6, 144.1, 155.4, 159.0, 166.5 (peaks at 128.8 and 129.3
sample had [α]2D5 ϩ14.6° (c 0.77, CHCl3). FT-IR (film
cast, cm–1): 3431, 1678, 1648, 1458, 1406, 1367, 1299, 1235,
1
1164, 1120, 987. H NMR (400 MHz, CDCl3) ␦: 8.07 (br s,
1H), 7.76 (s, 1H), 7.29 (d, J ϭ 1.8 Hz, 1H), 7.24 (dd, J ϭ 8.2,
0.4 Hz, 1H), 6.91–7.07 (m, 1H), 6.97 (d, J ϭ 2.1 Hz, 1H),
4.97–5.09 (m, 1H), 3.66–3.73 (overlapping m, 2H), 3.42–3.50
Published by NRC Research Press

Hanessian and Stoffman
19
(m, 1H), 2.18 and 1.96 (two br s, 1H), 1.61 and 1.50 (two s,
9H). 13C NMR (CDCl3, 100 MHz) ␦: 28.2, 28.6, 28.9, 39.0,
40.0, 80.7, 107.1, 107.5, 112.4, 112.5, 119.4, 121.3, 123.0,
123.3, 124.8, 125.5, 125.8, 127.8, 128.2, 135.1, 152.1, 152.7.
Exact mass m/z calcd for C18H21BrN2NaO2: 399.06786
(M ϩ Na); found: 399.06807.
9H), 0.81–0.95 (m, 1H). Exact mass m/z calcd for
C21H27BrN2NaO2: 441.11481 (M ϩ Na); found: 441.11557.
Supplementary data
Supplementary data are available with the article through
the journal Web site at http://nrcresearchpress.com/doi/suppl/
10.1139/cjc-2012-0221. CCDC 898223 contains the X-ray
data in CIF format for this manuscript. These data can be
obtained, free of charge, via http://www.ccdc.cam.ac.uk/
products/csd/request. (Or from the Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge CB2 1EZ,
UK; fax: ϩ44 1223 33603; or e-mail: deposit@ccdc.cam.
ac.uk.)
4-(5-Bromo-1H-indol-3-yl)-2-methoxypiperidine-1-
carboxylic acid tert-butyl ester (18)
TsOH–H2O (2 mg, 0.01 mmol) was added to a stirred
solution of 17 (66 mg, assumed to be 0.67 mmol from the
previous transformation) in MeOH (2 mL). The flask was
flushed with Ar and stirring was continued for 1 day. Evapo-
ration of the solvent and flash chromatography over SiO2
(1.5 cm ϫ 20 cm) using 20% EtOAc–hexanes afforded 18 as
a mixture of diasteromers (39.4 mg, 72%).
Acknowledgements
We thank the Natural Sciences and Engineering Research
Council of Canada (NSERC) and the Fonds de Recherche
du Québec (FQRNT) for financial assistance and Benoît
Deschênes-Simard (Hanessian group) for X-ray structure
determination.
4-(5-Bromo-1H-indol-3-yl)-piperidine-1-carboxylic acid
tert-butyl ester (19)
Et3SiH (0.3 mL, 5% v/v in CH2Cl2, 0.1 mmol) followed by
BF3-OEt2 (0.14 mL, 5% v/v in CH2Cl2, 0.057 mmol) were
added via syringe to a stirred and cooled (–78 °C) solution of
18 (9.7 mg, 0.024 mmol) in CH2Cl2 (0.5 mL) under Ar. The
mixture was stirred for 1 h and then quenched by the addition
of saturated aqueous NaHCO3 (0.5 mL). The aqueous phase
was extracted once with CH2Cl2 (5 mL) and dried (MgSO4).
Flash chromatography over SiO2 (0.5 cm ϫ 10 cm) using 20%
EtOAc–hexanes afforded 19 (5.2 mg, 58%); mp 199–200 °C.
1H NMR (400 MHz, CDCl3) ␦: 8.03 (br s, 1H), 7.72 (m, 1H),
7.19–7.26 (overlapping m, 2H), 6.93–6.94 (m, 1H), 4.21 (ddd,
J ϭ 13.3, 2.1, 2.1 Hz, 2H), 2.84–2.95 (m overlapping with
next, 1H), 2.85 (ddd, J ϭ 13.0, 13.0, 2.4 Hz, 1H), 2.02–1.96
(m, 2H), 1.54–1.67 (m, 2H), 1.46 (s, 9H). 13C NMR (CDCl3,
100 MHz) ␦: 21.4, 22.0, 39.4, 123.9, 126.4, 127.0, 128.1,
128.2, 129.3, 142.1, 143.9, 155.5 (signals from Boc t-Bu did
not appear). Exact mass m/z calcd for C18H23BrN2NaO2:
401.08351 (M ϩ Na); found: 401.08548. X-ray crystallo-
graphic data are given in Appendix 1 in the Supplementary
data. Compounds 18 and 19 had the same Rf by TLC; how-
ever, 19 stained purple with anisaldehyde.
References
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(R)-2-Allyl-(5-bromo-1H-indol-3-yl)piperidine-1-carboxylic
acid tert-butyl ester (20)
Allyltrimethylsilane (0.02 mL, 0.13 mmol) followed by
BF3-OEt2 (0.22 mL, 5% v/v in CH2Cl2, 0.089 mmol) were
added via syringe to a stirred and cooled (–78 °C) solution of
18 (16.1 mg, 0.039 mmol) in CH2Cl2 (0.5 mL) under Ar. The
mixture was stirred for 1 h, then quenched by the addition of
saturated aqueous NaHCO3 (0.5 mL). The aqueous phase was
extracted once with CH2Cl2 (5 mL) and dried (MgSO4). Flash
chromatography over SiO2 (0.5 cm ϫ 10 cm) using 20%
EtOAc–hexanes afforded 20 (3.7 mg, 23%). Compounds 18
and 20 had the same Rf by TLC; however, 20 stained a
different colour using anisaldehyde. 1H NMR (400 MHz,
CDCl3) ␦: 7.98 (br s, 1H), 7.71 (m, 1H), 7.19–7.27 (overlap-
ping m, 2H), 6.92–6.93 (m, 1H), 5.79 (dddd, J ϭ 17.1, 10.1,
7.2, 7.2 Hz, 1H), 5.12 (dddd, J ϭ 18.4, 1.9, 1.9, 1.9 Hz),
5.05–5.09 (m, 1H), 4.42 (app br s, 1H), 4.13 (app br s, 1H),
2.95–3.20 (m, 1H), 2.36–2.58 (m, 1H), 1.71 (ddd, J ϭ 13.3,
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Published by NRC Research Press

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Published by NRC Research Press