Total synthesis of ibogaine, epiibogaine and their analogues

Article abstract of DOI:10.1016/j.tet.2012.06.027

Efficient total synthesis of ibogaine, epiibogaine and their analogues has been described. An intramolecular reductive-Heck type cyclization was used for the construction of seven-membered indoloazepine ring to access iboga-skeleton. Larock's heteroannula

Full text of DOI:10.1016/j.tet.2012.06.027

Tetrahedron 68 (2012) 7155e7165
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Total synthesis of ibogaine, epiibogaine and their analogues
Goutam Kumar Jana, Surajit Sinha *
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Efficient total synthesis of ibogaine, epiibogaine and their analogues has been described. An intra-
molecular reductive-Heck type cyclization was used for the construction of seven-membered in-
doloazepine ring to access iboga-skeleton. Larock’s heteroannulation reaction was employed for the
creation of suitably substituted indole and DielseAlder reaction was employed for the construction of the
isoquinuclidine ring present in iboga alkaloids.
Received 30 April 2012
Received in revised form 5 June 2012
Accepted 7 June 2012
Available online 21 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Iboga alkaloids
Reductive-Heck coupling
Indoloazepine ring
Isoquinuclidine
1. Introduction
Ibogaine exhibits a wide range of pharmacological properties
and it has been under active investigation as an anti-addictive
3
Ibogaine (2) is a naturally occurring plant indole alkaloid of
iboga family. To date about 80 structurally closely related mono-
terpenoid indole alkaloids belong to this family. Most of the iboga
alkaloids were isolated from Tabernanthe or Tabernaemontana
agent. Pharmacology of ibogaine is quite complex, affecting
4
many different neurotransmitter systems simultaneously. In
metabolic pathway ibogaine undergoes demethylation to give
noribogaine (3). The better pharmacological profile of ibogaine over
ibogamine is due to the presence of methoxy group in 5-position of
indole. However, in many cases high doses of ibogaine is required,
which causes side effects such as hallucinations, degeneration of
cerebeller purkinje cells, whole body tremors and ataxia in rats.
Apart from psychoactive properties, ibogaine and its congeners
1
species of plants belonging to the Apocynaceae family. Members of
this class of alkaloids consist of a characteristic bridgehead nitrogen
containing tricyclic framework by the fusion of seven-membered
indoloazepine ring with a rigid isoquinuclidine ring (Fig. 1).
5
Catharanthine (4) is another variant of the iboga alkaloids having
2
6
a CO
2
Me at the C16, which was isolated from Catharanthus roseus.
show a wide variety of pharmacological effects, such as antifungal
Ibogaine appears to be the most abundant and is a potent psy-
choactive substance among iboga alkaloids.
or antilipase, anti-HIV-1, anti-cholinesterasic and leishmanicide
activities (against Leishmania amazonensi).
Until now only the total synthesis of ibogaine was reported by
7
Buchi et al. in 1966. Total synthesis of ibogamine and its analogues
1
has been reported several times. However, most of the synthesis
suffers from several limitations such as less flexible to give other
members and their analogues, low yielding, harsh reaction condi-
tions and involves noncatalytic pathway. In the B u€ chi’s synthesis of
7
ibogaine, synthesis of cyclization precursor is a multistep process
and cyclization in hot acetic acid results in rearranged product
formation. Trost’s ibogamine synthesis via mixed Pd(II)eAg(I)
8
metal mediated cyclization was low yielding and not economical
as it required 1e2 equiv of palladium catalyst and 2e4 equiv of
Fig. 1. Iboga alkaloids.
4
AgBF .
The unique structure of iboga alkaloids and their potential in-
volvement in many biological activities has driven us to develop
a unified strategy towards the total synthesis of iboga alkaloids and
their analogues that might be useful for the evaluation of
*
Corresponding author. Tel.: þ91 33 2473 4971; fax: þ91 33 2473 2805; e-mail
address: ocss5@iacs.res.in (S. Sinha).
0
040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.027

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G.K. Jana, S. Sinha / Tetrahedron 68 (2012) 7155e7165
pharmacological profile. Recently, we have reported an efficient
products 7a and 7b without full consumption of starting material
approach to the synthesis of ibogamine and its analogues (Eq. 1),
employing reductive-Heck coupling as a key step. In continuation
(Scheme 3). Formation of such diiodo product was not observed
previously, when 5-position of indole was unsubstituted. Methoxy
9
9
of our interest in the synthesis of iboga alkaloids and their ana-
logues employing Pd-catalysed reactions, herein, we report the
extension of this strategy for the total synthesis of ibogaine, epi-
ibogaine and their several analogues.
group in the 5-position of indole of 8a makes 6-position more
electron rich leading to diiodinated product formation. We used
excess ICl (2.5 equiv) for full consumption of the starting material
8a, keeping in mind that inseparable mixture of mono and diiodi-
nated products will be used in the next reductive-Heck cyclization
step, which may not hamper the cyclization process. The in-
separable mixture of monoiodinated product 7a and diiodinated
product 7b, which mostly contain the diiodinated product 7b was
then subjected for the reductive-Heck coupling reaction.
Reductive-Heck coupling of this mixture provided the desired
product 5a in very good yield. Another expected cyclized product
5c was inseparable from some other unidentified products. Al-
2
. Results and discussion
The structural feature present within iboga alkaloids that
demanded immediate consideration of the bridged nitrogen con-
taining tricyclic framework. This impressive fusion of six-, six- and
seven-membered nitrogen containing rings was seen as the major
hurdle towards the total synthesis. It was realized that the poly-
cyclic framework could be drastically simplified via disconnection
of the C2eC16 bond through the realization of reductive-Heck
type cyclization to give 3-substituted indole 7, since Heck cou-
pling or oxidative-Heck coupling would lead to a highly strained
1
though we could not take a clean H NMR of 5c but mass spectra of
column collected fraction indicated the presence of product 5c in
the product mixture. It is worth to mention here that 7a was the
major component in the mixture of 7a and 7b, after cyclization, the
desired product 5a became the major component in the mixture of
products, which implies that under reductive-Heck coupling con-
dition, the diiodo compound 7b underwent cyclization at the 2-
position of indole and at the same time it underwent deiodina-
tion at the 6-position of indole (Scheme 3). Addition of catalyst
9
bridgehead olefinic system (Scheme 1). The cyclization precursor,
a suitably 3-substituted indole 7 could be obtained either via
convergent Larock’s heteroannulation reaction
10
between iso-
quinuclidine substituted internal alkyne 9 and 2-iodoaniline fol-
lowed by iodination (path a) or initial construction of the required
substituted indole part 12 prior to the connection with iso-
quinuclidine ring 11 (path b). The required isoquinuclidine ring 10
could be readily obtained via DielseAlder reaction between
dihydropyridine and methyl acrylate or methyl vinyl ketone. On
the other hand [3,2]-fused iboga analogues 6 could be realized
through similar reductive-Heck coupling of suitably 2-substituted
cyclization precursors 13. The cyclization precursors, 3-iodo
3
(10 mol %), PPh (20 mol %) and reducing agent (2 equiv) in two
batches gave 58% yield of iboga analogue 5a. Using the same re-
action sequence C19-endo-carbomethoxy substituted iboga ana-
logue 5b was obtained in 26% overall yield from Boc-protected 4-
methoxy-2-iodoaniline 16. In case of iodination of 8b with
2.2 equiv of ICl, we isolated mostly the diiodinated compound 7c.
Reductive-Heck coupling of 7c gave desired endo-carbomethoxy
substituted iboga analogue 5b in 53% yield. Another expected
cyclized product 5d was detected only by mass spectra as it was
inseparable from some other unidentified products (Scheme 3).
2
-substituted indoles 13 for the synthesis of [3,2]-fused iboga
analogues 6, could be efficiently obtained by iodocyclization of 14.
2
9
-Alkynyl anilines 14 can be easily synthesized by Sonogashira
Based on our experience while synthesizing ibogamine, we
0
reaction of terminal alkynes
-iodoaniline (Scheme 1).
For the synthesis of ibogaine and its analogues, the required
9
(when R ¼H; path c) with
realized that the replacement of carbomethoxy side chain
2
(R¼CO
2
Me) in isoquinuclidine substituted internal alkyne 9 by
ethyl side chain (R¼Et) failed to give the heteroannulation product
8c according to ‘path a’ (Scheme 4). Thus we followed ‘path b’
(Scheme 1) for the synthesis of ibogaine (2) and epiibogaine (2a)
where initial construction of the required substituted indole part 12
prior to the connection with isoquinuclidine ring 11 is considered
(Scheme 5).
Boc-protected 4-methoxy-2-iodoaniline 16 was synthesized
according to Scheme 2. Reaction of m-iodophenol with diazonium
salt of sulphanilic acid followed by reduction by sodium dithionite
1
1
provided 4-hydroxy-2-iodoaniline in good yield,
which on
methylation provided 4-methoxy-2-iodoaniline 15 in 54% yield
from m-iodophenol. Boc protection of 15 gave 16 in 89% yield.
The heteroannulation reaction of 16 with isoquinuclidine con-
Heteroannulation reaction of 4-methoxy-2-iodoaniline 15 with
disilylated alkyne 18 afforded 5-methoxy-2,3-disubstituted indole
19a and mono desilylated indole 19b in very good yields. Iodination
ꢀ
taining internal alkyne 9a at 90 C provided 2,3-disubstituted in-
dole 8a in 72% yield.1 The internal alkynes 9a and 9b were
prepared from Cbz-protected dihydropyridine following the
reported procedure.1 Iodination of 8a using 1.2 equiv of ICl
resulted in an inseparable mixture of mono and diiodinated
0b
of 19a by NIS followed by silyl deprotection using TBAF afforded
12
5-methoxy-2-iodotryptol 20, which was immediately iodinated
and purified to obtain 5-methoxy-2-iodotryptoyl iodide 12b in 58%
yield from 19a. Compound 19b was converted to 19a as iodination
0b

G.K. Jana, S. Sinha / Tetrahedron 68 (2012) 7155e7165
7157
Scheme 1. Retrosynthetic analysis.
Scheme 2. Synthesis of Boc-protected 4-methoxy-2-iodoaniline.
of 19b by NIS was not clean. The reaction between isoquinuclidine
7d and 7e was low (Scheme 5). To avoid the cyclopropane ring
formation at 3-position of indole, we tried several other conditions
by changing the reaction parameters such as temperature, solvents
and bases but in all the cases the reaction was not satisfactory.
amine 11 and 5-methoxy-2-iodotryptoyl iodide 12b in acetonitrile
9
using K
2
CO
3
as a base was not clean. We isolated the undesired
product 21 in 28% yield, where yield of the cyclization precursors

7158
G.K. Jana, S. Sinha / Tetrahedron 68 (2012) 7155e7165
Scheme 3. Synthesis of methoxy substituted [2,3]-fused iboga analogues.
Scheme 4. Initial attempt to the synthesis of ibogamine precursor.
Finally, using Cs
mation of undesired product 21. The cyclization precursors 7d and
e were obtained in 34% and 41% yields, respectively. Reductive-
Heck coupling of 7d and 7e was carried out separately in DMF
and obtained ibogaine (2) and epiibogaine (2a) in 66% and 55%
yields, respectively (Scheme 5). Such a clean and good conversion
in the synthesis of cyclization precursors 7d and 7e from 12b using
2
CO
3
as a base, we were able to suppress the for-
1). Sonogashira coupling between Boc-protected 2-iodoaniline and
isoquinuclidine containing terminal alkyne 9d afforded 2-alkynyl
aniline 14a in excellent yield. Attempted Larock’s iodocyclization
of compound 14a failed to give the desired product 2-substituted 3-
7
13
iodo indole 13a (Scheme 7). By changing solvent (such as CH
DCM, CHCl ), base (K CO , NaHCO , TBAF) and the iodinating agent
(I , ICl, NIS) we were not able to get the desired product 13a in
3
CN,
3
2
3
3
2
Cs
2
CO
3
as a base prompted us to revise the similar step in the
satisfactory yield.
synthesis of cyclization precursors for the synthesis of ibogamine
and epiibogamine. A better yield of cyclization precursors 7f (36%)
To obtain the 3-iodo cyclization precursor, we followed
a slightly different synthetic route discussed in Scheme 8. One-
pot Sonogashira reaction between Boc-protected 2-iodoaniline
and terminal alkyne 9d followed by TBAF mediated indolization
in DMF afforded 2-substituted indole 22a in 66% yield. TFA-
mediated Boc-deprotection of 22a followed by iodination using
NIS in DCM provided the desired 3-iodo cyclization precursor 13b
9
and 7g (43%) was obtained from compound 12a than earlier (7f:
9
27% and 7g: 35%) when K
2
CO
3
was used as a base (Scheme 6).
14
After the synthesis of ibogaine and epiibogaine, we were in-
terested in the synthesis of [3,2]-fused iboga analogues by applying
the reductive-Heck coupling reaction according to ‘path c’ (Scheme

G.K. Jana, S. Sinha / Tetrahedron 68 (2012) 7155e7165
7159
Scheme 5. Synthesis of ibogaine and epiibogaine.
Scheme 6. Revised synthesis of ibogamine and epiibogamine precursors.
in excellent yield. The cyclization precursor 13b was then sub-
jected to reductive-Heck coupling condition and obtained [3,2]-
3-iodo cyclization precursors 13d and 13e in very good yields. Fi-
nally, reductive-Heck cyclization of 13d and 13e furnished methoxy
substituted [3,2]-fused iboga analogues 6c and 6d in 64% and 61%
yields, respectively.
9
fused iboga analogue 6a in 78% yield. With this success in the
synthesis of 6a using reductive-Heck coupling, we were
interested to the synthesis of several other [3,2]-fused iboga
analogues using the similar reaction sequence. Accordingly,
C19-endo-carbomethoxy substituted [3,2]-fused iboga analogue
3. Conclusions
6
b was synthesized in 36% overall yield from isoquinuclidine
An efficient synthetic strategy towards the total synthesis of
ibogaine, epiibogaine and their analogues has been described.
Larock’s heteroannulation reaction was employed for the con-
struction of suitably substituted indole. An intramolecular
reductive-Heck type cyclization was used for the construction of
seven-membered indoloazepine ring to access iboga-skeleton.
DielseAlder reaction was employed for the construction of the
isoquinuclidine ring, a unique skeleton of iboga alkaloids. Most of
the steps involve Pd-catalysed reaction and are very mild and ef-
ficient. Starting from 4-methoxy-2-iodoaniline, ibogaine 2 (9.8%)
alkyne 9e (Scheme 8).
Following the same strategy, methoxy substituted [3,2]-fused
iboga analogues 6c and 6d were synthesized from Boc-protected
4
-methoxy-2-iodoaniline in good yields (Scheme 8). One-pot
Sonogashira and indolization reaction between Boc-protected 4-
methoxy-2-iodoaniline and isoquinuclidine containing terminal
alkynes 9d and 9e separately afforded 2-substituted indoles 22c
and 22d in 67% and 66% yields, respectively. Boc-deprotection fol-
lowed by iodination using NIS in DCM of 22c and 22d provided the

7160
G.K. Jana, S. Sinha / Tetrahedron 68 (2012) 7155e7165
Scheme 7. An attempt to the synthesis of cyclization precursor for [3,2]-fused analogue.
Scheme 8. Synthesis of [3,2]-fused iboga analogues.
ꢀ
and epiibogaine 2a (9.7%) were obtained in overall 19.5% yield. The
overall yield of [3,2]-fused iboga analogues was 27e41%.
to the fraction of petroleum boiling between 60 and 80 C. Organic
extracts were dried over anhydrous Na SO and then filtered prior
2
4
to removal of all volatiles under reduced pressure on rotary evap-
oration. Chromatographic purification of products was accom-
plished using column chromatography on silica gels (mesh
100w200). Thin-layer chromatography (TLC) was carried out on
aluminium sheets, Silica Gel 60 F254 (Merck; layer thickness
0.25 mm). Visualization of the developed chromatogram was per-
formed by UV light and/or vanillin stains. All melting points were
4
4
. Experimental section
.1. General
All reagents were purchased from commercial sources and used
without further purification, unless otherwise stated. All reactions
were carried out in oven-dried glassware under an argon atmo-
sphere using anhydrous solvents, standard syringe and septum
techniques unless otherwise indicated. Petroleum ether (PE) refers
1
13
uncorrected. Peak positions in H and C NMR spectra are in-
dicated in parts per million (ppm) downfield from internal TMS in
d
units. Unless otherwise indicated NMR spectra were taken in

G.K. Jana, S. Sinha / Tetrahedron 68 (2012) 7155e7165
7161
1
CDCl
3
solution at 300 and 500 MHz for H and 75 and 125 MHz for
20 min of stirring the ice-salt bath was removed and DCM
(10 mL) was added. The organic layer was washed with aq
1
3
ꢁ1
C NMR. IR spectra were reported in absorption frequency (cm ).
Mass spectra were recorded by Electron Spray Ionization (ESI) or
Na
2
S
2
O
3
solution and brine. The organic part was dried over
SO and concentrated in vacuo, purified by silica
Electronic Impact (EI). The parent ions [MþH] , [MþNa]þ are
þ
ꢂ
ꢂ
anhydrous Na
2
4
quoted.
gel column chromatography (PE/EtOAc 9:1) to obtain inseparable
mixture (z3:2) (214 mg,) of compounds 7a and 7b as light
1
4
.1.1. tert-Butyl 2-iodo-4-methoxyphenylcarbamate (16). m-Iodo-
phenol (5.5 g, 25 mmol) was dissolved in water containing KOH
1.4 g, 25 mmol). A cold solution of diazotized sulfanilic acid (5.1 g,
7.5 mmol) was added to the mixture with stirring at rt for 30 min
brown foam. [Monoþdi]iodo (z3:2): R
f
z0.31 (PE/EtOAc 5:1); H
NMR (500 MHz, CDCl
3
,
d
): 8.45 (s, 1H-di), 7.87 (d, J¼9.5 Hz, 1H-
(
2
mono), 6.81 (d, J¼2.5 Hz, 1H-di), 6.75 (s, 1H-mono), 7.73 (dd,
J¼9.5, 2.5 Hz, 1H-di), 6.38 (t, J¼7.0 Hz, 1H), 6.18 (t, J¼7.0 Hz, 1H),
3.85 (s, 3H-mono), 3.78 (s, 3H-di), 3.60 (s, 3H-mono), 3.57 (s, 3H-
di), 3.18 (m, 1H), 2.72 (m, 1H), 2.62 (m, 1H), 2.50 (m, 2H), 2.37 (m,
1H), 2.24 (m, 1H), 2.12 (m, 1H), 1.88 (m, 1H), 1.62 [m, (18Hþ1H)],
followed by the addition of sodium hydrosulfite (12 g, 69 mmol).
The colour of the solution was changed immediately upon the ad-
dition of sodium hydrosulfite and the solution was stirred at 45 C
for 20 min. Diethyl ether was added to the mixture, the mixture
was filtered and the filtrate was concentrated. The solid was
recrystallized from hot water to yield needles. Methyl iodide was
added (0.98 mL, 15.7 mmol) to 4-amino-3-iodophenol (3.71 g,
ꢀ
13
3
1.35 (m, 1H); C NMR (125 MHz, CDCl , d): 175.05, 174.95, 155.86,
154.07, 149.53, 149.17, 135.35, 135.31, 133.72, 133.05, 130.87,
130.68, 130.11, 130.07, 127.92, 127.80, 126.56, 116.57, 112.81, 111.24,
99.17, 85.48, 84.90, 82.82, 79.69, 79.12, 57.08, 57.01, 56.92, 55.93,
55.45, 55.32, 54.99, 51.88, 45.48, 45.41, 31.25, 28.51, 28.45, 27.30,
27.20, 24.52.
1
5.8 mmol) in DMF (70 mL) in the presence of Cs
1.3 mmol). The reaction was left at rt for 48 h. The mixture was
then diluted with water, extracted with diethyl ether, the combined
organic extracts were washed with water, dried over Na SO , fil-
2 3
CO (13.45 g,
4
2
4
4.1.4. C19-exo-Carbomethoxy-substituted iboga analogue (5a). To
a mixture of compounds 7a and 7b (122 mg, z0.20 mmol) in dry
DMF (2 mL) was added HCOONa (27 mg, 0.4 mmol) under argon
atmosphere. The mixture was degassed and back-filled with argon
(10.5 mg, 20 mol %) were
added with stirring at 55 C. After 3 h another batch of Pd(OAc)
tered and concentrated. The product was purified by silica gel
column chromatography (PE/EtOAc 9:1) and obtained 4-methoxy-
2
-iodoaniline (15) as a light brown oil (3.36 g, 54%) from m-
iodophenol.
To a solution of 4-methoxy-2-iodoaniline (3.0 g, 12.0 mmol) in
THF (20 mL) was added di-tert-butyl dicarbonate (3.15 g,
4.5 mmol). The reaction mixture was refluxed for 2 days then
quenched with water (15 mL). The solution was extracted with Et
3ꢃ20 mL) and the combined organic extracts were dried over
anhydrous Na SO , filtered and concentrated. The crude mixture
then Pd(OAc)
2
(4.5 mg,10 mol %) and PPh
3
ꢀ
2
(4.5 mg, 10 mol %), PPh
0.4 mmol) were added to the reaction mixture, stirred for another
2
4 h at that temperature. Solvent was removed in vacuo then H O
3
(10.5 mg, 20 mol %) and HCOONa (27 mg,
1
2
O
(
(2 mL) and ethyl acetate (4 mL) were added to the residue. The
aqueous phase was extracted with ethyl acetate (2ꢃ4 mL), the
combined organic extracts were washed with brine (4 mL), dried
(Na SO ). The solvent was removed in vacuo and the crude material
2 4
was purified by column chromatography (PE/EtOAc 5:1) to afford
the desired iboga analogue 5a (51 mg, 58%) as light yellow foam.
2
4
was purified by silica gel column chromatography (2% EtOAc in PE)
to yield N-Boc-2-iodo-4-methoxy aniline as a light brown solid
(
(
(
3.72 g, 89%). 1H NMR (500 MHz, CDCl
3
,
d): 7.82 (s, 1H), 7.29
d, J¼3.0 Hz, 1H), 6.88 (dd, J¼9.0, 3.0 Hz, 1H), 6.53 (s, 1H), 3.75
13
s, 3H), 1.52 (s, 9H); C NMR (125 MHz, CDCl
3
,
d
): 156.21, 153.21,
The other expected cyclized product 5c was inseparable from im-
ꢁ1
1
132.54, 123.89, 122.24, 115.05, 80.87, 55.85, 28.48; IR (KBr, cm ):
3
purities. R
f
¼0.34 (PE/EtOAc 3:1); H NMR (500 MHz, CDCl
3
, d): 7.86
þ
þ
322, 2983, 1718; HRMS (ESI): (MþNa) calcd for C12H16INNaO3
(d, J¼9.0 Hz, 1H), 6.84 (s, 1H), 6.82 (dd, J¼9.0, 2.5 Hz, 1H), 3.96
(q, J¼5.5 Hz, 1H), 3.85 (s, 3H), 3.71 (s, 3H), 3.50 (s, 1H), 3.25e3.10
372.0067, found 372.0071.
(
m, 4H), 2.99 (m, 1H), 2.76 (m, 1H), 2.62 (m, 1H), 2.34 (m, 1H), 2.25
13
4
.1.2. Methyl 2-(2-(1-(tert-butoxycarbonyl)-5-methoxy-2-(triethyls
(m, 1H), 2.0 (m, 1H), 1.71 (m, 2H), 1.67 (s, 9H); C NMR (125 MHz,
CDCl ): 175.38, 155.93, 150.60, 143.98, 131.40, 129.90, 117.16,
116.32, 111.80, 101.01, 83.63, 56.77, 55.87, 53.61, 51.98, 50.76, 46.70,
37.80, 34.23, 28.47, 26.19, 25.61, 20.77; IR (neat, cm ): 2973, 1734,
1718, 1132; HRMS (ESI): (MþH) calcd for C25H33N O 441.2384,
ilyl)-1H-indol-3-yl)ethyl)-2-azabicyclo[2.2.2]oct-5-ene-7-carboxylate
3
, d
10b
(8a). Following the reported procedure, except slightly elevated
ꢀ
ꢁ1
temperature (90 C), the 2,3-disubstituted indole 8a was obtained
þ
þ
as a light brown sticky material (304 mg, 72%). R
f
¼0.38 (PE/EtOAc
): 7.80 (d, J¼9.5 Hz, 1H), 6.93 (d,
J¼2.5 Hz, 1H), 6.88 (dd, J¼9.5, 2.0 Hz,1H), 6.47 (t, J¼7.5 Hz,1H), 6.23
t, J¼7.0 Hz, 1H), 3.93 (m, 1H), 3.87 (s, 3H), 3.76 (s, 3H), 3.27 (dd,
J¼9.5, 2.0 Hz, 1H), 2.90 (dt, J¼12.5, 5.0 Hz, 1H), 2.76 (dt, J¼12.5,
.0 Hz, 1H), 2.56 (m, 2H), 2.48 (td, J¼10.5, 3.0 Hz, 1H), 2.36 (dt,
J¼12.5, 5.0 Hz, 1H), 2.22 (m, 2H), 1.95 (m, 1H), 1.67 (s, 9H), 1.42 (m,
H), 0.95 (m, 15H); 13C NMR (125 MHz, CDCl
): 175.08, 155.59,
51.51, 135.37, 135.18, 132.86, 132.58, 131.72, 129.82, 116.03, 113.06,
01.71, 83.32, 59.47, 56.01, 55.20, 55.06, 51.86, 45.66, 31.23, 28.38,
2
5
1
9
:1); H NMR (500 MHz, CDCl
3
,
d
found 441.2384.
(
4.1.5. Methyl 2-(2-(1-(tert-butoxycarbonyl)-5-methoxy-2-(triethyls
ilyl)-1H-indol-3-yl)ethyl)-2-azabicyclo[2.2.2]oct-5-ene-7-carboxylate
(8b). Compound 8b (214 mg, 69%) was synthesized following
5
the procedure described for the synthesis of 2,3-disubstituted
1
1
1
1
2
3
,
d
indole 8a. R
f
¼0.31 (PE/EtOAc 4:1); H NMR (500 MHz, CDCl
3
,
d
): 7.81 (d, J¼9.0 Hz, 1H), 6.99 (s, 1H), 6.89 (dd, J¼9.0, 2.5 Hz,
1H), 6.43 (t, J¼7.0 Hz, 1H), 6.18 (m, 1H), 3.89 (m, 1H), 3.86
(s, 3H), 3.65 (s, 3H), 3.15 (m, 1H), 3.04e2.91 (m, 3H), 2.70 (dt,
J¼12.5, 5.0 Hz, 1H), 2.63 (m, 1H), 2.48 (dt, J¼12.0, 5.0 Hz, 1H),
2.16 (dd, J¼7.5, 2.0 Hz, 1H), 1.81 (m, 1H), 1.74 (m, 1H), 1.67 (s,
ꢁ
1
5.20, 24.41, 8.27, 5.59; IR (neat, cm ): 2929, 1726, 1105, 729;
þ
þ
HRMS (ESI): (MþH) calcd for C31H47N O Si 555.3249, found
2
5
5
55.3248.
13
9
3
H), 0.95 (m, 15H); C NMR (125 MHz, CDCl , d): 174.62, 155.65,
4
.1.3. Methyl 2-(2-(1-(tert-butoxycarbonyl)-2-iodo-5-methoxy-1H-
151.52, 135.39, 134.76, 132.80, 132.61, 131.44, 129.90, 116.10,
113.24, 101.63, 83.42, 59.35, 56.06, 54.57, 51.88, 43.72, 30.96,
indol-3-yl)ethyl)-2-azabicyclo [2.2.2]oct-5-ene-7-carboxylate (7a)
and methyl 2-(2-(1-(tert-butoxycarbonyl)-2,6-diiodo-5-methoxy-1H-
indol-3-yl)ethyl)-2-azabicyclo[2.2.2]oct-5-ene-7-carboxylate
ꢁ
1
29.84, 28.52, 26.29, 25.12, 8.29, 5.68; IR (neat, cm ): 2951, 1726,
1105, 729; HRMS (ESI): (MþH)þ calcd for C31H47N O Si
þ
2
5
ꢀ
(
0
7b). To a cooled solution (ꢁ20 C) of compound 8a (277 mg,
555.3249, found 555.3249.
.5 mmol) in DCM and MeOH (1:1) (4 mL) was added silver tet-
rafluoroborate (152 mg, 0.55 mmol) followed by dropwise addi-
tion of ICl (1.2 mL 1 M in DCM) under argon atmosphere. After
4.1.6. Methyl 2-(2-(1-(tert-butoxycarbonyl)-2,6-diiodo-5-methoxy-
1H-indol-3-yl)ethyl)-2-azabicyclo[2.2.2]oct-5-ene-7-carboxylate

7162
G.K. Jana, S. Sinha / Tetrahedron 68 (2012) 7155e7165
(
7c). Only the diiodinated compound 7c (122 mg, 72%) was
crude product, which was used in the next step without
purification.
obtained exclusively as light brown foam according to the pro-
cedure described for the iodination of compound 8a. R
f
¼0.28 (PE/
): 8.46 (s, 1H), 6.93 (s, 1H),
.45 (t, J¼7.0 Hz, 1H), 6.15 (m, 1H), 4.02 (br s, 1H), 3.87 (s, 3H), 3.58
s, 3H), 3.21 (m, 1H), 3.14 (d, J¼10.0 Hz, 1H), 2.90 (dt, J¼11.5, 5.5 Hz,
H), 2.84 (dt, J¼11.0, 5.0 Hz, 1H), 2.71 (dt, J¼11.5, 5.0 Hz, 1H), 2.66
br s, 1H), 2.45 (dt, J¼11.5, 5.0 Hz, 1H), 2.15 (td, J¼10.0, 2.5 Hz, 1H),
To the above crude product (1 g) in dry THF (10 mL) was added
1
ꢀ
EtOAc 3:1); H NMR (500 MHz, CDCl
3
,
d
TBAF (4 mL, 1 M in THF) under argon atmosphere at 0 C and stir-
ꢀ
6
(
1
ring was continued for 2 h at 0 C. Then the reaction was quenched
with saturated aq NH
The combined organic extracts were dried over Na
4
Cl solution, extracted with Et
2
O (2ꢃ20 mL).
2
SO
4
, the solvent
(
1
was removed in vacuo to give the crude product 20 (541 mg), which
was used in the next step without purification.
13
.81 (m, 1H), 1.70 (m, 1H), 1.63 (s, 9H); C NMR (125 MHz, CDCl
3
,
d): 173.80, 154.18, 149.01, 135.77, 133.57, 130.59, 128.83, 126.55,
To a stirred solution of above crude product 20 (500 mg) in DCM
9
4
9.11, 85.55, 82.97, 79.66, 56.93, 55.99, 53.94, 53.58, 53.48, 52.00,
(5 mL) were added imidazole (245 mg, 3.6 mmol), PPh
3
(471 mg,
ꢁ1
ꢀ
2.37, 30.42, 28.34, 25.87; IR (neat, cm ): 2953, 1725, 1105, 728;
1.8 mmol) and I
2
(457 mg, 1.8 mmol) at 0 C. Stirring was continued
þ
þ
I N O
5
ꢀ
HRMS (ESI): (MþH) calcd for C25
H
693.0317, found
for 4 h at 0 C. The reaction mixture was diluted with DCM followed
31 2
2
6
93.0319.
by washing with aq Na
was dried over anhydrous Na
2
S
2
O
3
solution and brine. The organic part
SO , concentrated in vacuo and the
2
4
4
.1.7. C19-endo-Carbomethoxy substituted iboga analogue (5b). Fol
crude material was purified by silica gel column chromatography
(PE/EtOAc 19:1) to give compound 12b (514 mg) as light yellow
lowing the procedure described for the cyclization of a mixture of
a and 7b, compound 7c (1.5 g, 2.94 mmol) afforded iboga ana-
logue 5b (26 mg, 53%) as light brown foam. R
¼0.26 (PE/EtOAc 3:1);
7
crystalline solid in 58% overall yield from 19a. R
f
¼0.46 (PE/EtOAc
): 7.97 (s, 1H),
7.20 (d, J¼9.0 Hz, 1H), 6.95 (d, J¼2.0 Hz, 1H), 6.81 (dd, J¼9.5 Hz, 1H),
ꢀ
1
f
9:1); mp: 127e129 C; H NMR (500 MHz, CDCl , d
3
1
H NMR (500 MHz, CDCl
3
,
d): 7.95 (dd, J¼8.0, 2.5 Hz, 1H), 6.85
13
(
(
s, 1H), 6.83 (dd, J¼8.0, 2.5 Hz, 1H), 3.85 (s, 3H), 3.78 (m, 1H), 3.67
3.86 (s, 3H), 3.35e3.24 (m, 4H); C NMR (125 MHz, CDCl
3
, d):
s, 3H), 3.41 (s, 1H), 3.36 (m, 1H), 3.24e3.17 (m, 3H), 3.05 (m, 2H),
154.52, 134.20, 127.41, 121.30, 112.67, 111.39, 99.98, 78.64, 56.12,
ꢁ1
2
.68 (d, J¼11.0 Hz, 1H), 2.30 (m, 1H), 2.12 (m, 1H), 2.02 (m, 1H), 1.92
31.86, 4.23; IR (KBr, cm ): 3374.6, 2955.4, 1168.9, 746.3; HRMS
13
(ESI): (MþNa)þ calcd for C11
þ
(
m, 1H), 1.67 (m, 1H), 1.64 (s, 9H); C NMR (125 MHz, CDCl
3
,
d
):
H I NNaO
11 2
449.8828, found
173.34, 156.17, 150.29, 141.55, 130.30, 130.03, 117.68, 116.60, 112.68,
449.8824.
1
2
00.72, 84.28, 55.91, 55.81, 54.80, 52.33, 52.22, 42.80, 33.19, 32.14,
ꢁ
1
8.37, 25.55, 21.75, 20.19; IR (neat, cm ): 2971, 1732, 1716, 1134;
4.1.10. 7-Ethyl-2-(2-(2-iodo-5-methoxy-1H-indol-3-yl)ethyl)-2-
azabicyclo[2.2.2]oct-5-ene (7d) and 7-ethyl-2-(2-(2-iodo-5-methoxy-
1H-indol-3-yl)ethyl)-2-azabicyclo[2.2.2]oct-5-ene (7e). A suspen-
þ
þ
HRMS (ESI): (MþH) calcd for C25H33N O
441.2384, found
2
5
4
41.2382.
2 3 3
sion of Cs CO (568 mg, 1.75 mmol) in anhydrous CH CN (6 mL)
4
.1.8. 5-Methoxy-2-(triethylsilyl)-3-(2-(triethylsilyloxy)ethyl)-1H-in-
containing deprotected isoquinuclidine 11 (205 mg, 0.77 mmol)
and diiodo compound 12b (300 mg, 0.70 mmol) was heated at
60 C for 10 h then the reaction mixture was cooled to rt and
filtered through a pad of Celite and washed with EtOAc (10 mL). The
filtrate was concentrated in vacuo and purified by column chro-
matography on silica gel (DCM/MeOH as eluent with gradual
increase in concn of MeOH from 0.5% to 1.5%) to give 7d (103 mg,
dole (19a). A dry flask was charged with 4-methoxy-2-iodoaniline
1.13 g, 4.56 mmol), disilylated alkyne 18 (1.63 g, 5.48 mmol),
palladium(II)acetate (101 mg, 0.456 mmol), Na CO (1.43 g,
ꢀ
(
2
3
13.68 mmol) and DMF (12 mL) under argon atmosphere and
ꢀ
heated at 90 C for 8 h. DMF and volatiles were removed in vacuo.
Ethyl acetate (15 mL) and water (15 mL) were added to the residue.
The aqueous phase was extracted with ethyl acetate (3ꢃ15 mL).
34%) and 7e (125 mg, 41%) as light yellow foam.
1
The combined organic extract was washed with 5% NaHCO
3
Compound 7d: H NMR (500 MHz, CDCl
3
,
d
): 8.0 (br s, 1H),
(
20 mL) and brine (30 mL), and solvent was removed by rotary
7.17 (m, 1H), 7.01 (s, 1H), 6.77 (dd, J¼8.5, 2.5 Hz, 1H), 6.31 (m,
2H), 3.85 (s, 3H), 3.32 (br s, 1H), 3.20 (br s, 1H), 2.79 (m, 2H),
2.68 (m, 1H), 2.46 (br s, 2H), 2.01 (d, J¼9.5 Hz, 1H), 1.64e1.57 (m,
2H), 1.49 (t, J¼11.0 Hz, 1H), 1.31 (br m, 1H), 0.95 (dd, J¼13.0,
evaporation. The crude product was purified by silica gel column
chromatography (PE/EtOAc) to give indole 19a (918 mg, 48%) as
a light brown oil and 19b (376 mg, 27%) as a light brown sticky
material.
13
6.5 Hz, 1H), 0.88 (t, J¼7.0 Hz, 3H); C NMR (125 MHz, CDCl
3
, d):
To a stirred solution of 19b (305 mg, 1 mmol) and imidazole
154.16, 134.32, 133.06, 132.74, 128.05, 112.14, 11.12, 104.14,
100.54, 78.39, 58.54, 56.52, 56.15, 55.90, 41.09, 31.69, 29.80,
(
340 mg, 5 mmol) in DCM (4 mL) was added TESCl (251.7 mL,
ꢀ
ꢁ1
1
.5 mmol) under argon atmosphere at 0 C. Stirring was continued
27.24, 19.18, 12.61; IR (neat, cm ): 3243, 2951, 1647, 1446, 747;
ꢀ
þ
þ
for another 2 h at 0 C then the reaction was quenched with ice-
water, organic part was separated, dried over Na SO , the solvent
was removed by rotary evaporation. The crude product was puri-
HRMS (ESI): (MþH) calcd for C20H26IN O 437.1084, found
2
2
4
437.1084.
Compound 7e: 1H NMR (500 MHz, CDCl
, d): 8.54 (br s, 1H),
3
fied by silica gel column chromatography to give indole 19a
7.17 (d, J¼8.5 Hz, 1H), 7.07 (s, 1H), 6.76 (dd, J¼8.5, 2.5 Hz, 1H),
6.48 (t, J¼7.5 Hz, 1H), 6.16 (t, J¼7.5 Hz, 1H), 3.85 (s, 3H), 3.71 (br
s, 1H), 3.28 (d, J¼10.0 Hz, 1H), 3.00 (td, J¼12.5, 4.5 Hz, 1H), 2.88
(m, 2H), 2.64 (s, 1H), 2.60 (td, J¼11.0, 3.5 Hz, 1H), 2.28 (br d,
1
(
394 mg, 94%) as a light brown oil. R
f
¼0.52 (PE/EtOAc 25:1).
H
NMR (500 MHz, CDCl
3
,
d
): 7.73 (s, 1H), 7.16 (dd, J¼8.5, 2.5 Hz, 1H),
.97 (d, J¼2.0 Hz, 1H), 6.76 (dd, J¼8.5, 2.5 Hz, 1H), 3.78 (s, 3H), 3.72
t, J¼7.5 Hz, 3H), 3.00 (t, J¼7.5 Hz, 3H), 0.92 (m, 18H), 0.80
6
(
J¼10.5 Hz, 2H), 1.87 (td, J¼11.0, 2.0 Hz, 1H), 1.22 (m, 2H), 1.03
ꢁ
1
13
(
q, J¼8.0 Hz, 6H), 0.56 (q, J¼8.0 Hz, 6H); IR (neat cm ): 3398,
(m, 1H), 0.86 (t, J¼7.0 Hz, 3H); C NMR (125 MHz, CDCl
3
, d):
þ
þ
NO Si
2
2
4
955, 1620, 736; HRMS (ESI): (MþH) calcd for C
H
154.37, 135.27, 135.20, 134.26, 127.83, 123.43, 112.49, 111.32,
100.14, 78.37, 57.24, 57.07, 56.21, 53.54, 38.59, 30.95, 30.03,
8.58, 24.87, 11.53; IR (neat, cm ): 3305, 2937, 1642, 745;
HRMS (ESI): (MþH) calcd for C20H26IN O 437.1084, found
2
3
42
2
20.2749, found 420.2748.
ꢁ
1
2
þ
þ
4
.1.9. 2-Iodo-3-(2-iodoethyl)-5-methoxy-1H-indole (12b). To a cooled
2
ꢀ
(
0 C) solution of compound 19a (868 mg, 2.06 mmol) in dry
437.1084.
DCM (15 mL) was added NIS (558 mg, 2.48 mmol) under argon
ꢀ
4.1.11. 2 -Iodo-5 -methoxyspiro[cyclopropane-1,3 -indole] (21). 1
NMR (500 MHz, CDCl
): 7.57 (d, J¼9.0 Hz, 1H), 6.84 (dd, J¼8.5,
2.5 Hz, 1H), 6.57 (d, J¼2.5 Hz, 1H); 3.81 (s, 3H), 1.83 (dd, J¼8.5,
0
0
0
atmosphere. Stirring was continued for 40 min at 0 C. DCM
10 mL) was added to the reaction mixture and washed with aq
Na solution and brine. The organic part was dried over
anhydrous Na SO and concentrated in vacuo to give 1.1 g of
H
(
3
, d
2 2 3
S O
13
2
4
4.5 Hz, 2H), 1.62 (dd, J¼8.0, 4.5 Hz, 2H); C NMR (125 MHz,

G.K. Jana, S. Sinha / Tetrahedron 68 (2012) 7155e7165
7163
CDCl
3
,
d
): 158.27, 150.68, 143.15, 121.10, 112.17, 104.13, 55.91,
(3 mL) was added to a flask containing compound 22a (200 mg,
0.48 mmol) at 0 C under argon atmosphere with stirring. The so-
ꢀ
4
3.25, 19.17.
lution was warmed to rt and stirring was continued for another 3 h
at rt. DCM and volatiles were removed in vacuo. Saturated aq
4.1.12. Ibogaine (2) and epiibogaine (2a). To a solution of com-
pound 7d (70 mg, 0.16 mmol) in dry DMF (2 mL) was added
3
NaHCO solution (3 mL) and ethyl acetate (5 mL) were added to the
HCOONa (27 mg, 0.4 mmol) under argon atmosphere. The mixture
residue. The aqueous phase was extracted with ethyl acetate
was degassed and back-filled with argon then Pd(OAc)
0 mol %) and PPh (8 mg, 20 mol %) were added with stirring at
5 C. The reaction mixture was heated for 6 h at that temperature.
Solvent was removed in vacuo then H O (2 mL) and DCM (4 mL)
2
(3.5 mg,
(3ꢃ5 mL). The combined organic extracts were washed with brine
1
5
3
2 4
(10 mL) and dried (Na SO ). Solvent was removed in vacuo to give
ꢀ
the crude product (142 mg, 95%) as light yellow foam, which was
2
used in the next step without purification.
ꢀ
were added to the residue. The aqueous phase was extracted with
To a cold (0 C), stirred solution of the above crude material
DCM (2ꢃ4 mL), the combined organic extracts were washed with
(120 mg, 0.38 mmol) in dry DCM (4 mL) was added NIS (90 mg,
0.40 mmol) under argon atmosphere. Stirring was continued for
30 min at 0 C. To the reaction mixture about 10 mL of DCM was
2 4
brine (4 mL) and dried (Na SO ). The solvent was removed in vacuo
ꢀ
and the crude material was purified by column chromatography
DCM/MeOH gradual increase in concn of MeOH from 1% to 2%) to
afford ibogaine (2) (33 mg, 66%) as light yellow dense oil. R
¼0.37
): 7.69 (br s, 1H),
.16 (d, J¼9.0 Hz, 1H), 6.91 (s, 1H), 6.78 (d, J¼8.5 Hz, 1H), 3.85
s, 3H), 3.51 (m, 1H), 3.31e3.19 (m, 3H), 3.08 (d, J¼10.0 Hz, 1H),
.97 (m, 2H), 2.86 (d, J¼13.5 Hz, 1H), 2.11 (m, 1H), 1.92 (m, 3H),
(
added, washed with aq Na
part was dried over anhydrous Na
2
S
2
O
3
solution and brine. The organic
SO , concentrated in vacuo, the
f
2
4
1
(
7
(
DCM/MeOH 14:1); H NMR (500 MHz, CDCl
3
,
d
crude product was purified by column chromatography on silica gel
(PE/EtOAc, 5:1) to give cyclization precursor 13b (139 mg, 84%) as
1
light yellow foam. R
CDCl
f
¼0.44 (PE/EtOAc 3:1); H NMR (500 MHz,
2
3
,
d
): 10.59 (br s, 1H), 7.61 (d, J¼8.0 Hz, 1H), 7.37 (d, J¼7.5 Hz,
1
3
1
(
5
2
.67e1.61 (m, 4H), 1.29 (m, 1H), 0.91 (t, J¼7.0 Hz, 3H); C NMR
125 MHz, CDCl ): 154.30, 129.98, 129.92, 111.32, 111.11, 108.87,
8.32, 56.19, 55.91, 54.84, 50.18, 41.73, 33.88, 29.84, 27.54, 26.03,
1H), 7.18 (t, J¼7.5 Hz, 1H), 7.13 (t, J¼7.5 Hz, 1H), 6.54 (m, 1H), 6.30
(m, 1H), 3.77 (m, 1H), 3.65 (s, 3H), 3.33 (dd, J¼10.0, 2.0 Hz, 1H),
2.89e2.76 (m, 3H), 2.70 (m, 1H), 2.55 (m, 2H), 2.15 (td, J¼13.0,
3
, d
ꢁ
1
13
0.40, 12.07; IR (neat, cm ): 3383, 2922, 1612, 1461; HRMS (ESI):
2.5 Hz, 1H), 2.00 (dd, J¼7.0, 2.5 Hz, 1H), 1.56 (m, 1H); C NMR
þ
þ
(
MþH) calcd for C20H27N O 311.2118, found 311.2118.
3
(125 MHz, CDCl , d): 176.42, 140.50, 136.47, 135.32, 130.10, 129.90,
2
Similarly, epiibogaine (2a) was obtained as light yellow dense oil
121.96, 120.05, 120.00, 111.95, 56.71, 56.60, 55.99, 54.12, 52.45,
ꢁ
1
(
27 mg, 55%), which was crystallized on standing. R
f
¼0.31 (DCM/
44.99, 30.79, 25.11, 24.53; IR (neat, cm ): 3219, 2947, 1724, 743;
ꢀ
1
þ
þ
MeOH 9:1); mp: 176e179 C; H NMR (500 MHz, CDCl
3
,
d
): 7.80 (br
HRMS (ESI): (MþH) calcd for C19H22IN O
437.0720, found
2
2
s, 1H), 7.16 (d, J¼9.0 Hz, 1H), 6.91 (s, 1H), 6.78 (dd, J¼8.5, 1.5 Hz,
437.0721.
1
2
2
H), 3.85 (s, 3H), 3.38 (m, 2H), 3.29 (m, 2H), 3.10 (d, J¼10.5 Hz,
H), 3.02 (s, 1H), 2.76 (d, J¼16.0 Hz, 1H), 2.15 (br s, 1H), 2.07 (m,
H), 1.94 (br s, 1H), 1.65 (dd, J¼11.0, 2.5 Hz, 1H), 1.39 (m, 2H), 1.10
4.1.15. Iboga analogue (6a). General procedure: following the
reductive-Heck coupling procedure described for the synthesis of
ibogaine (2), iboga analogue 6a was obtained in 78% (43 mg) yield.
13
(
dd, J¼13.0, 5.5 Hz, 1H), 0.93 (t, J¼7.5 Hz, 3H); C NMR (125 MHz,
CDCl
3
,
d
): 154.34,129.71, 129.60, 111.33,111.24,109.62,100.29, 57.74,
Only exception is that mixed solvent system DMF and CH
3
CN (3:1)
ꢀ
1
5
6.15, 55.14, 49.68, 34.64, 32.93, 31.21, 28.10, 25.82, 19.95, 12.07; IR
were used. R
(500 MHz, CDCl
J¼8.0 Hz, 1H), 7.02 (m, 2H), 3.63 (s, 3H), 3.56 (m, 1H), 3.39 (m, 1H),
.24 (ddd, J¼11.0, 4.5, 1.5 Hz, 1H), 3.14 (m, 2H), 3.00 (m, 1H), 2.94
(m, 1H), 2.73 (m, 1H), 2.40 (td, J¼16.5, 3.0 Hz, 1H), 2.28 (m, 1H), 2.10
f
¼0.52 (CH
2
Cl
2
/MeOH 20:1); mp: 99e100 C; H NMR
ꢁ1
þ
(
KBr, cm ): 3401, 2926, 1613, 1463; HRMS (ESI): (MþH) calcd for
3
,
d
): 7.58 (br s, 1H), 7.37 (d, J¼7.5 Hz, 1H), 7.18 (d,
þ
C20H27N O 311.2118, found 311.2117.
2
3
4.1.13. Methyl 2-(2-(1-(tert-butoxycarbonyl)-1H-indol-2-yl)ethyl)-2-
13
azabicyclo[2.2.2]oct-5-ene-7-carboxylate (22a). General procedure:
to a mixture of N-Boc-2-iodoaniline (450 mg, 1.41 mmol), terminal
(m, 1H), 1.90 (m, 1H), 1.71 (m, 1H), 1.48 (m, 1H); C NMR (75 MHz,
CDCl ): 175.7, 134.7, 133.2, 128.6, 121.1, 119.1, 117.5, 110.2, 58.3,
3
, d
ꢁ
1
alkyne 9d (370 mg, 1.69 mmol) and Et
were added Pd(PPh Cl (49 mg, 0.071 mmol) and CuI (27 mg,
.141 mmol) under argon. The reaction mixture was stirred at rt for
3
N (3 mL) in DMF (6 mL)
52.4, 51.9, 49.6, 46.4, 35.1, 34.7, 26.1, 26.0, 25.32; IR (KBr, cm ):
)
2
2
3397, 2928, 2858, 1727, 1460 cm ; HRMS (ESI): (MþH)þ calcd for
ꢁ1
3
þ
0
6
4
C19H22N O H 311.1754, found 311.1754.
2
2
h and then tetra-butylammonium fluoride (TBAF) (1.0 M in THF,
.23 mmol) was added dropwise to the reaction mixture. The re-
4.1.16. Methyl 2-(2-(1-(tert-butoxycarbonyl)-1H-indol-2-yl)ethyl)-2-
azabicyclo[2.2.2]oct-5-ene-7-carboxylate (22b). Following the gen-
eral procedure described for the synthesis of compound 22a
ꢀ
action mixture was heated at 80 C for 4 h and concentrated in
vacuo. The resulting residue was partitioned between water and
dichloromethane. The aqueous layer was further extracted with
dichloromethane (2ꢃ10 mL). The combined organic extracts were
(above), compound 22b was obtained as light yellow oil in 64%
1
(116 mg) yield. R
d
f
¼0.37 (PE/EtOAc, 3:1); H NMR (300 MHz, CDCl
3
,
dried over Na
2
SO
4
, evaporated in vacuo to give the crude product,
): 8.06 (d, J¼8.4 Hz, 1H), 7.43 (dm, J¼6.6 Hz, 1H), 7.21 (td, J¼8.1,
which was purified by column chromatography on silica gel
1.5 Hz, 1H), 7.16 (td, J¼7.2, 1.5 Hz, 1H), 6.42 (t, J¼6.9 Hz, 1H), 6.36
(s, 1H); 6.20 (ddd, J¼8, 5.4,1.2 Hz, 1H), 3.87 (ddd, J¼5.4, 3.3,
1.2 Hz, 1H), 3.64 (s, 3H), 3.23e3.10 (m, 3H), 3.03e2.99 (dd, J¼9.3,
1.8 Hz, 1H), 2.93e2.86 (m, 1H), 2.64e2.55 (m, 2H), 2.11e2.03 (dt,
(
(
(
(
PE/EtOAc 6:1) to afford the isoquinuclidine containing indole 22a
1
384 mg, 66%) as a light yellow oil. R
500 MHz, CDCl
): 8.06 (d, J¼7.8 Hz, 1H), 7.44 (m, 1H), 7.24e7.14
m, 2H), 6.47 (t, J¼6.6 Hz, 1H), 6.37 (s, 1H), 6.27 (m, 1H), 3.90 (ddd,
f
¼0.46 (PE/EtOAc, 4:1); H NMR
3
, d
13
J¼9.3, 2.4 Hz, 1H), 1.80e1.71 (m, 2H), 1.68 (s, 9H); C NMR
J¼5.7, 2.7, 1.2 Hz, 1H), 3.60 (s, 3H), 3.20 (dd, J¼9.0, 2.1 Hz, 1H),
(75 MHz, CDCl ): 174.5, 150.5, 140.2, 136.5, 134.8, 129.6, 129.4,
3
, d
3
2
.12e3.10 (m, 2H), 2.18 (ddd, J¼12.6, 4.2, 2.4 Hz, 1H), 1.93 (dt, J¼9.3,
123.3, 122.6, 119.8, 115.6, 107.5, 83.8, 57.2, 54.6, 54.2, 51.8, 43.9,
13
ꢁ1
.4 Hz, 1H), 1.69 (s, 9H), 1.44e1.34 (ddt, J¼12.9, 11.1, 2.7 Hz, 1H);
): 174.8, 150.5, 140.5, 136.4, 135.1, 130.0,
29.5, 123.1, 122.5, 119.7, 115.5, 107.5, 83.6, 57.1, 55.0, 54.9, 51.7, 45.3,
C
30.8, 29, 28.44, 28.35, 28.24, 26.1; IR (neat, cm ): 2926, 2949,
1732, 1454; HRMS (ESI): (MþH)þ calcd for C24H30N O H
þ
NMR (125 MHz, CDCl
1
3
(
3
,
d
2
4
411.2278, found 411.2275.
ꢁ
1.6, 28.9, 28.3, 24.4; IR (neat, cm ): 2947, 1732, 1454, 1329; HRMS
1
þ
þ
ESI): (MþH) calcd for C24H30N O H 411.2278, found 411.2274.
4.1.17. Methyl 2-(2-(3-iodo-1H-indol-2-yl)ethyl)-2-azabicyclo[2.2.2]
oct-5-ene-7-carboxylate (13c). Following the general procedure as
described for the synthesis of compound 13b (above), compound
13c was obtained as light yellow foam in 77% yield from compound
2
4
4.1.14. Methyl 2-(2-(3-iodo-1H-indol-2-yl)ethyl)-2-azabicyclo[2.2.2]
oct-5-ene-7-carboxylate (13b). General procedure: 30% TFA in DCM

7164
G.K. Jana, S. Sinha / Tetrahedron 68 (2012) 7155e7165
2
2b. R
f
¼0.32 (PE/EtOAc, 3:1); 1H NMR (500 MHz, CDCl
3
,
d
): 10.40
3.72 (m, 1H), 3.62 (s, 3H), 3.29 (d, J¼9.0 Hz, 1H), 2.81 (m, 2H),
2.75e2.67 (m, 2H), 2.53 (m, 2H), 2.12 (m, 1H), 1.96 (d, J¼9.5 Hz, 1H),
(
br s, 1H), 7.39 (d, J¼7.5 Hz, 1H), 7.30 (d, J¼8.0 Hz, 1H), 7.16 (m, 2H),
13
6
3
2
1
.52 (t, J¼7.5 Hz, 1H), 6.23 (t, J¼7.0 Hz, 1H), 3.90 (s, 1H), 3.66 (s,
H), 3.15 (m, 1H), 3.07 (dd, J¼9.5, 1.5 Hz, 1H), 2.95e2.84 (m, 3H),
.67 (m, 2H), 2.15 (dd, J¼10.0, 2.5 Hz, 1H), 1.89 (m, 1H), 1.80 (m,
3
1.50 (m, 1H); C NMR (125 MHz, CDCl , d): 176.38, 154.73, 141.05,
135.27, 131.41, 130.47, 129.84, 129.76, 112.69, 112.19, 101.82, 56.65,
56.60, 56.00, 54.03, 52.40, 44.96, 30.96, 25.10, 24.47; IR (neat,
13
ꢁ1
þ
H); C NMR (125 MHz, CDCl
3
,
d): 174.05, 140.67, 135.88, 135.32,
cm ): 3246, 2947, 1724, 719; HRMS (ESI): (MþH) calcd for
þ
130.40, 129.35, 122.24, 120.39, 120.36, 111.18, 57.65, 56.37, 54.41,
C
20
H24IN
2
O
3
467.0826, found 467.0826.
ꢁ
1
¼0.31 (PE/EtOAc, 2:1); 1H NMR (500 MHz,
5
1
3.72, 52.01, 43.97, 30.71, 26.30, 25.46; IR (neat, cm ): 3332, 2942,
Compound 13e: R
CDCl
f
726, 745; HRMS (ESI): (MþH)þ calcd for C19H22IN O 437.0720,
þ
,
d
): 7.47 (br s, 1H), 7.18 (d, J¼8.5 Hz, 1H), 6.82 (m, 2H), 6.51
2
2
3
found 437.0719.
(t, J¼7.0 Hz, 1H), 6.22 (m, 1H), 3.91 (m, 1H), 3.88 (s, 3H), 3.64 (s,
H), 3.14 (m, 1H), 3.04 (dd, J¼9.5, 2.0 Hz, 1H), 2.93e2.84 (m, 3H),
2.69 (m, 2H), 2.13 (td, J¼9.5, 2.5 Hz, 1H), 1.88 (m, 1H), 1.80 (m, 1H);
3
4.1.18. Iboga analogue (6b). Following the reductive-Heck coupling
13
procedure as for the synthesis of iboga analogue 6a, compound 13c
3
C NMR (125 MHz, CDCl , d): 173.99, 154.97, 141.14, 135.40, 130.92,
was converted to the iboga analogue 6b in 74% (38 mg) yield as
130.85, 129.29, 112.48, 112.05, 102.25, 563,56.05, 54.42, 53.71,
ꢀ
ꢁ1
a light brown solid. R
f
¼0.42 (CH
H NMR (500 MHz, CDCl
.25 (d, J¼8.0 Hz, 1H), 7.09 (m, 2H), 3.70 (s, 3H), 3.64e3.59 (m, 1H),
.35 (m, 3H), 3.22 (m, 1H), 3.15 (m, 2H), 3.05 (m, 1H), 2.56
2
Cl
2
/MeOH, 20:1); mp:149e151 C;
52.01, 43.88, 30.70, 26.27, 25.56; IR (neat, cm ): 3284, 2946, 1723,
1
þ
þ
3
,
d): 7.74 (br s, 1H), 7.40 (d, J¼7.5 Hz, 1H),
HRMS (ESI): (MþH) calcd for C20H24IN O
2
3
467.0826, found
7
3
467.0822.
(
(
1
td, J¼16.5, 3.0 Hz, 1H), 2.21 (m, 2H), 2.00 (m, 1H), 1.92 (m, 1H), 1.48
4.1.21. C19-Carbomethoxy substituted [3,2]-fused iboga analogues
(6c) and (6d). Following the reductive-Heck coupling procedure
described for the synthesis of ibogaine (2), compounds 13d and 13e
were converted separately to the iboga analogues 6c (32 mg) and
6d (30 mg) in 64% and 61% yields, respectively, as a light brown
solid.
m, 1H); 13C NMR (75 MHz, CDCl
,
d): 175.0, 134.6, 133.3, 128.5,
3
21.3, 119.3, 119.0, 117.6, 110.2, 57.2, 52.7, 52.0, 49.54, 46.2, 35.2,
ꢁ1
3
0.7, 26.0, 25.8, 25.0; IR (KBr, cm ): 3339, 2931, 1732, 1458;
þ
þ
HRMS(ESI): (MþH) calcd for C19H22N O H 311.1754, found
2
2
3
11.1759.
ꢀ
1
Compound 6c: R
NMR (500 MHz, CDCl , d
f
¼0.44 (CH
2
Cl
2
/MeOH, 15:1); mp: 84e86 C; H
4
.1.19. Methyl 2-(2-(1-(tert-butoxycarbonyl)-5-methoxy-1H-indol-2-
3
): 7.55 (br s, 1H), 7.15 (d, J¼9.0 Hz, 1H), 6.88
yl)ethyl)-2-azabicyclo[2.2.2] oct-5-ene-7-carboxylate (22c) and
methyl 2-(2-(1-(tert-butoxycarbonyl)-5-methoxy-1H-indol-2-yl)eth
yl)-2-azabicyclo[2.2.2]oct-5-ene-7-carboxylate (22d). Following the
general procedure described for the synthesis of compound 22a,
compounds 22c (176 mg) and 22d (173 mg) were synthesized
from N-Boc-4-methoxy-2-iodoaniline in 67% and 66% yields, re-
(d, J¼2.5 Hz, 1H), 6.78 (dd, J¼8.5, 2.5 Hz, 1H), 3.85 (s, 3H), 3.72
(s, 3H), 3.60 (m, 1H), 3.49 (s, 1H), 3.25 (m, 3H), 3.15 (d, J¼8.5 Hz,
1H), 3.01 (d, J¼9.5 Hz, 1H), 2.82 (ddd, J¼11.5, 5.5, 2.0 Hz, 1H), 2.50
(d, J¼16.5 Hz, 1H), 2.35 (m, 1H), 2.17 (m, 1H), 2.00 (m, 1H), 1.80
13
3
(m, 1H), 1.55 (m, 1H); C NMR (125 MHz, CDCl , d): 175.69, 154.12,
134.38, 133.06, 129.92, 129.13, 119.27, 110.91, 100.13, 58.41, 56.15,
52.55, 51.92, 49.69, 46.52, 35.22, 34.88, 26.26, 26.02, 25.48; IR (KBr,
spectively, as light yellow oil.
1
ꢁ1
þ
Compound 22c: H NMR (500 MHz, CDCl
3
,
d
): 7.93 (d, J¼9.0 Hz,
cm ): 3335, 2942, 1726, 747; HRMS (ESI): (MþH) calcd for
þ
1
(
3
(
(
(
1
5
H), 6.91 (d, J¼2.5 Hz, 1H), 6.81 (dd, J¼9.0, 2.5 Hz, 1H), 6.45
t, J¼7.5 Hz, 1H), 6.28 (s, 1H), 6.26 (m, 1H), 3.88 (m, 1H), 3.82 (s, 3H),
.58 (s, 3H), 3.19 (dd, J¼9.0, 2.0 Hz, 1H), 3.10e2.97 (m, 2H), 2.78
m, 1H), 2.55 (m, 1H), 2.44 (m, 2H), 2.16 (td, J¼10.0, 2.5 Hz, 1H), 1.92
C20
H
25
N O 341.1860, found 341.1860.
2
3
ꢀ
Compound 6d: R
H NMR (500 MHz, CDCl
f
¼0.42 (CH
2 2
Cl /MeOH, 9:1); mp: 115e118 C;
): 7.59 (br s, 1H), 7.15 (d, J¼8.5 Hz, 1H),
1
3
,
d
6.82 (d, J¼2.5 Hz, 1H), 6.78 (dd, J¼8.5, 2.0 Hz, 1H), 3.83 (s, 3H), 3.71
(s, 3H), 3.58 (m, 1H), 3.39e3.31 (m, 3H), 3.19e3.13 (m, 3H), 3.06
(d, J¼10.0 Hz, 1H), 2.58 (d, J¼16.5 Hz, 1H), 2.23 (m, 2H), 2.02 (m,
13
td, J¼10.5, 2.5 Hz, 1H), 1.66 (s, 9H), 1.37 (m, 1H); C NMR
125 MHz, CDCl ): 174.81, 155.73, 150.42, 141.26, 135.09, 131.14,
3
, d
13
30.27, 129.95, 116.20, 111.47, 107.48, 102.56, 83.44, 57.05, 55.65,
3
1H), 1.95 (m, 1H), 1.50 (m, 1H); C NMR (125 MHz, CDCl , d): 174.74,
ꢁ
1
4.89, 51.70, 45.31, 31.03, 28.91, 28.27, 24.37; IR (neat, cm ): 2947,
154.33, 134.10, 129.82, 128.91, 118.81, 111.25, 111.03, 100.28, 57.28,
56.27, 53.06, 52.11, 49.86, 45.71, 35.10, 30.44, 25.94, 25.80, 25.04; IR
þ
þ
1
4
730, 1223, 847; HRMS (ESI): (MþH) calcd for C25H33N O
2
5
ꢁ
1
þ
41.2384, found 441.2383.
(KBr, cm ): 3365, 2945, 1724, HRMS (ESI): (MþH) calcd for
1
þ
Compound 22d: H NMR (500 MHz, CDCl
3
,
d
): 7.96 (d, J¼9.0 Hz,
C20H25N O 341.1860, found 341.1862.
2
3
1
(
3
2
1
1
1
3
H), 6.93 (d, J¼2.5 Hz, 1H), 6.85 (dd, J¼9.0, 2.5 Hz, 1H), 6.46
t, J¼7.5 Hz, 1H), 6.31 (s, 1H), 6.22 (m, 1H), 3.88 (m, 1H), 3.84 (s,
Acknowledgements
H), 3.65 (s, 3H), 3.19e3.12 (m, 3H), 3.03 (dd, J¼9.0, 2.0 Hz, 1H),
.90 (m, 1H), 2.61 (m, 2H), 2.10 (td, J¼9.0, 2.5 Hz, 1H), 1.80 (m, 1H),
We thank Council of Scientific and Industrial Research, New Delhi
for the award of a research fellowship to G.K.J. and Department of
Science and Technology (DST), India, for financial support.
13
3
.75 (m, 1H), 1.69 (s, 9H); C NMR (125 MHz, CDCl , d): 174.52,
55.85, 150.42, 141.04, 134.70, 131.20, 130.23, 129.68, 116.33, 111.74,
07.45, 102.62, 83.63, 57.25, 55.70, 54.63, 54.28, 51.75, 43.98,
ꢁ1
0.88, 29.26, 28.33, 26.12; IR (neat, cm ): 2949, 1726, 1122, 846;
þ
þ
Supplementary data
HRMS (ESI): (MþH) calcd for C25H33N O
441.2384, found
2
5
4
41.2384.
1H and 13C NMR spectra for all the new compounds described
herein are available free of charge via the Internet. Supplementary
data related to this article can be found online at http://dx.doi.org/
4
.1.20. Methyl 2-(2-(3-iodo-5-methoxy-1H-indol-2-yl)ethyl)-2-
azabicyclo[2.2.2]oct-5-ene-7-carboxylate (13d) and methyl 2-(2-(3-
iodo-5-methoxy-1H-indol-2-yl)ethyl)-2-azabicyclo[2.2.2] oct-5-ene-
10.1016/j.tet.2012.06.027.
7
-carboxylate (13e). Following the general procedure described
earlier for the synthesis of cyclization precursor 13b, compounds
3d (94 mg) and 13e (85 mg) were synthesized from 22c and 22d in
References and notes
1
7
5% and 68% yields, respectively, as light yellow foam.
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Compound 13d: R
CDCl
1
f
¼0.33 (PE/EtOAc 3:1). 1H NMR (500 MHz,
2
. (a) Gorman, M.; Neuss, N.; Svoboda, G. H.; Barnes, A. J., Jr.; Cone, N. J. J. Am.
Pharm. Assoc. Sci. Ed. 1959, 48, 256; (b) Gorman, M.; Neuss, N.; Svoboda, G. H. J.
Am. Chem. Soc. 1959, 81, 4745.
3
,
d
): 10.49 (br s, 1H), 7.48 (d, J¼9.0 Hz, 1H), 6.81 (d, J¼7.5 Hz,
H), 6.80 (s, 1H), 6.50 (t, J¼7.5 Hz, 1H), 6.28 (m, 1H), 3.87 (s, 3H),

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2
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(
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