Constructing iboga alkaloids via C-H bond functionalization: Examination of the direct and catalytic union of heteroarenes and isoquinuclidine alkenes

Article abstract of DOI:10.1021/jo5018102

The iboga alkaloids have attracted considerable attention in both the scientific community and popular media due to their reported ability to reverse or markedly diminish cravings for, and self-administration of, the major drugs of abuse. We have developed three new intramolecular C-H functionalization procedures leading to the core seven-membered ring of the iboga skeleton, a cyclization that proved to be highly challenging. The electrophilic palladium salt Pd(CH₃CN)₄(BF₄)₂ was effective for the cyclization of diverse N-(2-arylethyl)isoquinuclidines with yields of 10-35%. A two-step, bromination-reductive Heck reaction protocol was also effective for the synthesis of ibogamine in 42% yield. Finally, a direct Ni(0)-catalyzed C-H functionalization provided the benzofuran analogues of ibogamine (74%) and epi-ibogamine (38%). Although each approach suffers from significant shortcomings, in combination, the methods described provide practical routes to diverse ibogamine analogues.

Full text of DOI:10.1021/jo5018102

Article
pubs.acs.org/joc
Constructing Iboga Alkaloids via C−H Bond Functionalization:
Examination of the Direct and Catalytic Union of Heteroarenes and
Isoquinuclidine Alkenes
Andrew C. Kruegel, Souvik Rakshit, Xiaoguang Li, and Dalibor Sames*
Department of Chemistry, Columbia University, New York, New York 10027, United States
S
* Supporting Information
ABSTRACT: The iboga alkaloids have attracted considerable
attention in both the scientific community and popular media
due to their reported ability to reverse or markedly diminish
cravings for, and self-administration of, the major drugs of
abuse. We have developed three new intramolecular C−H
functionalization procedures leading to the core seven-
membered ring of the iboga skeleton, a cyclization that proved
to be highly challenging. The electrophilic palladium salt Pd(CH3CN)4(BF4)2 was effective for the cyclization of diverse N-(2-
arylethyl)isoquinuclidines with yields of 10−35%. A two-step, bromination-reductive Heck reaction protocol was also effective
for the synthesis of ibogamine in 42% yield. Finally, a direct Ni(0)-catalyzed C−H functionalization provided the benzofuran
analogues of ibogamine (74%) and epi-ibogamine (38%). Although each approach suffers from significant shortcomings, in
combination, the methods described provide practical routes to diverse ibogamine analogues.
Ibogaine has historically received significant attention in both
the scientific community and popular media due to widespread
anecdotal reports of its remarkable ability to reverse or
markedly attenuate drug addiction and dependence in
humans.1,2 These claims have largely been recapitulated in
rodents, where ibogaine reduces self-administration and
reinstatement of major drugs of abuse, including cocaine,
morphine, alcohol, and nicotine.1 Despite this substantial
evidence for ibogaine’s efficacy in animal models, the
mechanism of action responsible for its antiaddictive effects is
not clear. The pharmacological activity of ibogaine has been
extensively studied, and it is known to bind to a variety of CNS
receptors with micromolar potency.1,3 The complexity of
ibogaine’s pharmacological profile is further complicated by
the high doses typically used in treatment and thus the high
brain concentrations achieved.4 Therefore, even targets of low
binding affinity (>10 μM) may be of significant importance in
mediating its effects. A particularly compelling hypothesis is
that ibogaine is capable of increasing expression of glial cell
line-derived neurotrophic factor in the ventral tegmental area of
the brain and that this modulation is responsible for its
antiaddictive properties.5 However, ibogaine has also shown
binding affinity and/or functional activity at a variety of other
CNS targets, including the N-methyl-D-aspartate receptor, the
dopamine and serotonin transporters, mu-opioid receptor,
sigma 2 receptor, 5-HT2a, acetylcholine receptors, and others,
so the overall interactions and effects of its complex
pharmacology remain unclear.1,3,6
INTRODUCTION
■
Iboga Alkaloids: Background and Pharmacology. The
iboga alkaloids, represented by ibogamine and ibogaine (Figure
1A), are a class of natural products isolated from Tabernanthe
iboga, a plant used in folk and ritualistic medicine in west Africa.
Figure 1. (A) Structure of iboga alkaloids. (B) The indicated
disconnection unlocks a rapid and modular approach to ibogamine
analogues. The key C−H functionalization is however highly
challenging as described in this report.
Received: August 5, 2014
© XXXX American Chemical Society
A
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Synthesis of Iboga Alkaloids via C−H Functionaliza-
tion. In light of their interesting pharmacological and clinical
properties, the iboga alkaloids have attracted considerable
interest from the synthetic community, with several total
syntheses of the desmethoxy analogue ibogamine (Figure 1A)
reported in the literature.7 In the context of a research program
studying the pharmacology and cell signaling biology of iboga
alkaloids, we required a modular and robust synthesis for the
preparation of ibogamine and unnatural analogues. Finding
existing synthetic strategies poorly suited to this task, we
endeavored to develop new synthetic methods providing access
to the iboga skeleton.
Scheme 1. Synthesis of Isoquinuclidine Building Blocks via
Diels−Alder Reaction
For many years, we have been advancing “C−H bond
functionalization” as a general concept in chemical synthesis to
provide new strategic opportunities in the construction of
complex molecular skeletons.8 In the context of iboga alkaloid
synthesis, we were interested in rapid construction of the
polycyclic core structure by formation of the seven-membered
ring, via C−H bond/alkene coupling, as the key strategic step
(Figure 1B). This is a powerful disconnection that would
enable modular and convergent synthesis of ibogamine
analogues from a diverse set of readily available isoquinuclidines
and bromoethylheteroarenes.
Scheme 2. Synthesis of N-(Heteroarylalkyl)isoquinuclidines
by Alkylation
This approach was employed by Trost in the synthesis of
ibogamine and related systems.9−11 Unfortunately, the original
conditions reported by Trost for this cyclization suffer from
several significant disadvantages. First, stoichiometric quantities
of both palladium and silver are required, making the
transformation quite costly. More importantly, we found this
procedure inconsistent and low yielding, and yields over 15%
were never obtained despite extensive variation of the reaction
conditions. Our results are in agreement with those of
Hodgson, reported independently.12 Therefore, we set out to
systematically examine this powerful, but challenging, C−H
functionalization step for cyclization of the iboga skeleton, with
the main goal of developing new catalytic procedures to provide
ibogamine analogues for our chemical biology project.
RESULTS AND DISCUSSION
■
Synthesis of Starting Materials. A collection of
cyclization substrates was first prepared via a modular route.
To prepare the isoquinuclidine fragment, exo- and endo-
tosylhydrazones 1a and 1b were prepared according to the
method of Krow (Scheme 1).13 It should be noted that the
stereochemistry of these products was incorrectly assigned in
this original report, as noted and corrected by Hodgson based
on crystallographic results.12 We have independently confirmed
the corrected stereochemistry of both hydrazones based on
NMR experiments. Finding the reported reduction procedures
of the hydrazones to be low yielding, we developed alternative
conditions. Interestingly, the two isomers required different
reduction conditions, with the exo isomer 1a being much more
resistant to reduction. By our modified conditions, both exo-
and endo-7-ethylisoquinuclidines 2a and 2b were successfully
obtained (Scheme 1).
These were then deprotected and the resulting amine
hydroiodide salts alkylated with various bromoalkylheteroar-
enes S2a−e (for synthesis, see Experimental Section and
Supporting Information, Scheme S1) to obtain a collection of
N-(heteroarylalkyl)isoquinuclidines 3a−g (Scheme 2).
Indole C−H Bond Functionalization: Electrophilic
Approach. Initially, it was hoped that a catalytic electrophilic
activation strategy could be developed under acidic conditions.
*
For synthesis of bromoalkylheteroarenes, see Experimental Section
(compounds S2a−e) and Supporting Information (Scheme S1)
Electrophilic palladium(II) species are known to activate arenes
for addition to olefins in oxidative couplings (effectively
stoichiometric Heck reactions).14,15 Likewise, Trost9−11 and
others16 have shown that the intermediate alkyl-palladium
species in these reactions can be reduced to afford a reductive
coupling process. Therefore, it was hoped that in the iboga
system, where oxidative cyclization is not feasible due to strain
considerations, the intermediate alkyl-palladium species would
be susceptible to protonolysis. In such a reaction, an
electrophilic palladium (or other metal) species would activate
the system either through direct metalation of indole or
through coordination to the olefin. Following C−C bond
B
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formation, protonative removal of the metal could regenerate
the electrophilic catalyst (Figure 2).
Table 1. Preparation of Ibogamine Analogues via
Electrophilic Palladation−Cyclization
a
Figure 2. Proposed mechanistic rationale for an electrophilic
cyclization. ML represents the metal (M) attached to one or more
ligands (L).
Unfortunately, a variety of Pd(II) salts under protic/acidic
conditions failed to effect cyclization (see Supporting
Information, Table S1). We also examined a large variety of
other electrophilic transition metal conditions (see Supporting
Information, Table S2), including platinum and ruthenium
catalysts effective for intramolecular indole−alkene hydro-
arylation reactions.17,18 Several gold-catalyzed conditions
reported for indole−alkene coupling were also attempted, as
well as the nonmetallic electrophilic reagent N-phenyl-
selenophthalimide.19−21 However, in all cases, none or only a
trace of the desired product was detected. A frequent problem
in many trials was the rapid reduction and precipitation of the
electrophilic metal species as the corresponding neutral metal
(e.g., palladium black). We suspect that reduction by the
tertiary amine of the substrate is a primary driver of these
difficulties. Furthermore, addition of a variety of oxidants did
not successfully prevent reduction and precipitation of the
metal in the case of palladium.
In contrast to these disappointing results, it was found that
the original conditions9−11 could be improved by a simple
modification. When the preformed palladium tetrafluoroborate
salt Pd(CH3CN)4(BF4)2 was used in place of a mixture of
PdCl2(CH3CN)2 and AgBF4, modest, but consistent, yields of
ibogamine were obtained following sodium borohydride
reduction of the resulting organopalladium intermediate
(Table 1, entry 1). This result indicates that silver is not
directly involved in electrophilic activation of the substrate and
serves only to exchange chloride for noncoordinating
tetrafluoroborate, thus generating a more active electrophile.
Indeed, a reagent system consisting of equimolar amounts of
Pd(CH3CN)4(BF4)2 and AgBF4 provided an identical yield to
the palladium salt alone, thus confirming the likely role of silver
as a simple halide scavenger. Our modified conditions were
applied with success to a variety of substrates (Table 1, entries
2−5). As expected, lower yields were obtained when the
a
b
Reactions run at 0.250 mmol scale. Isolated yields from
representative examples of two or more independent trials, NMR
yields in parentheses, trial-to-trial variation typically <5%. Run at
0.100 mmol scale. Run at 0.060 mmol scale.
c
d
heteroarene was more electron-poor, with both the fluoroin-
dole 3b and benzofuran 3d providing significantly reduced
yields. However, these conditions were not effective for the
formation of the eight-membered ring analogue when applied
to 3g (Table 1, entry 6). In all cases, the primary side products
were the hydrogenated starting materials (olefin reduced),
which were often observed in comparable yields to the desired
products. Presumably, these side products result from residual
starting material that is hydrogenated by liberated hydrogen
during the sodium borohydride quench. Accordingly, it was
found that extended reaction times reduced the amount of
hydrogenated byproduct but, surprisingly, did not increase
yields of the cyclized product. Using these conditions, an
attempt was also made to probe the viability of a protic
demetalation catalytic cycle (Figure 2). After treatment of 3a
with Pd(CH3CN)4(BF4)2 in the usual manner, tetrafluoroboric
acid diethyl ether complex was added in place of the normal
C
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NaBH4 treatment. Unfortunately, no conversion of the
intermediate organopalladium species to the product was
observed under these conditions, either at room temperature or
upon heating. Therefore, a strategy based on protonolysis to
regenerate an active Pd(II) catalytic species does not appear to
be feasible, and thus, we were unable to overcome the need for
stoichiometric palladium using this strategy.
Indole C−H Bond Functionalization: Bromination and
Reductive Heck Coupling. Encountering such difficulties
with the electrophilic activation approach and still desiring a
catalytic route to the iboga skeleton, an alternative strategy was
pursued employing traditional palladium chemistry. It was
found that substrate 3a could be selectively brominated at the
indole 2-position using trimethylphenylammonium tribromide
in ∼65% yield. This aryl bromide intermediate was then
cyclized by a reductive Heck reaction22 employing Pd(PPh3)4
as catalyst, with sodium formate as the hydride source (Table 2,
as bromination was selective for the indole 4-position, para to
the benzyloxy group. When benzofuran (3d) and benzothio-
phene (3f) substrates were used, no bromination was observed.
Finally, substrate 3g was successfully brominated, but no
cyclization occurred, only reduction of the aryl bromide back to
the starting material 3g. Therefore, although effective for the
synthesis of ibogamine itself, the reductive Heck procedure did
not provide a general solution for the synthesis of ibogamine
analogues varied at the aryl moiety.
Indole C−H Bond Functionalization: Low-Valent
Metal Insertion Approach. At this time, we became
interested in an alternative strategy employing a direct C−H
insertion mechanism. It was envisioned that oxidative addition
of a low-valent transition metal into the 2-position heteroaryl
C−H bond might provide a metal hydride species that could
then add directly to the olefin, followed by reductive
elimination to provide the cyclized product and regenerate
the catalyst (Figure 3). In particular, we were interested by a
Table 2. Preparation of Ibogamine Analogues via Reductive
Heck Reaction
entry
substrate
result
a
1
2
3
4
5
6
3a
3b
3c
3d
3f
4a, 42%
4b, 3%
bromination at 4-position
no bromination
Figure 3. Alternative strategy for iboga cyclization relying on direct C−
H insertion of a low-valent metal. ML represents the metal (M)
attached to one or more ligands (L).
no bromination
3g
no cyclization
a
∼65% yield for each individual step.
recent report of intermolecular hydroheteroarylation of
styrenes employing a nickel(0)/N-heterocyclic carbene
(NHC) catalyst system.23 The substrate scope of this work
included both electron-poor indoles (electron-withdrawing
group at the 3-position) and benzofuran, as well as a single
example demonstrating hydroheteroarylation of an aliphatic
olefin. Therefore, it was hoped that this Ni(0) catalyst system
might be employed intramolecularly to afford cyclization of the
iboga skeleton. Applying 20 mol % Ni(COD)2 and 24 mol %
IMes (1,3-bis(2,4,6-trimethylphenyl)-1,3-dihydro-2H-imidazol-
2-ylidene) in toluene at 130 °C to benzofuran substrate 3d,
good yields of the cyclized product 4d could be obtained. After
some optimization, it was found that heptane was a slightly
superior solvent for this transformation (Table 3, entry 1).
Interestingly, yields with the endo-epimer substrate 3e were not
as high (Table 3, entry 2). This disparity may result from a
difference in steric shielding of the tertiary amine by the ethyl
group between 3d and 3e, allowing for greater interference with
the catalytic species by the amine in endo-substrate 3e.
Alternatively, the steric bulk of the exo-ethyl group in 3d may
act to enrich the N-atom configuration in which the
heteroarylethyl substituent is constrained on the olefin side
and thus appropriately aligned for cyclization. Yields for these
transformations could not be further improved. Alternative
sources of Ni(0) or the use of phosphine ligands in place of
IMes strongly inhibited product formation. Likewise, use of the
alternative NHC ligand IPr did provide the desired products,
but in lower yield, while other NHCs provided only traces of
entry 1). Although initial trials with this reaction were low
yielding, some optimization identified DMSO as the ideal
solvent for this transformation, and with the optimized
conditions, yields of ∼65% were obtained with only trace
quantities of 3a observed (resulting from competing aryl
bromide reduction). Reduced catalyst loadings achieved
complete conversion but provided lower yields of product.
Likewise, alternative formates (potassium and ammonium)
resulted in significantly reduced yields. Furthermore, it was
found that purification of the intermediate bromide was not
required. The crude bromination mixture could simply be
washed with aqueous ammonia in situ, concentrated, and used
directly in the cyclization step. This protocol provided an
overall yield of 42% over two steps, in agreement with the
yields obtained when the two steps were run independently.
The total synthesis of ibogamine was thus accomplished in
seven steps from pyridine (6.4% overall yield).
Pleased with the success of the reductive Heck reaction for
the efficient total synthesis of ibogamine, we attempted to apply
the same procedure to related substrates (Table 2, entries 2−
6). Unfortunately, these efforts met with poor results. With
electron-poor indole substrate 3b, only a very small quantity of
the desired product could be isolated, and the product mixture
was very complex, hindering purification. Further examination
revealed that both the bromination step and the cyclization step
(with pure bromide) were independently low yielding (<25%).
Difficulty was also encountered with electron-rich substrate 3c,
D
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Table 3. Preparation of Ibogamine Analogues via Ni-
Catalyzed C−H Activation
CONCLUSION
■
a
In closing, we examined the modular synthesis of the iboga
alkaloid core centered on a direct intramolecular cyclization.
This key C−H bond functionalization step proved unexpect-
edly difficult. Although there are a number of catalytic systems
that effect hydroarylation of unactivated alkenes, most of them
failed in the specific context of this cyclization. We propose that
the following structural features contribute to the difficulty of
this transformation: (1) the substitution of the indole in the 3-
position with an electron-donating group (that sterically
hinders indole metalation); (2) the isoquinuclidine’s basic
amine (that deactivates and reduces transition metal catalysts);
(3) the bicyclic nature of the isoquinuclidine (that prevents
oxidative cyclization); and (4) formation of a medium-sized
ring. Nevertheless, we have found a direct nickel-catalyzed
cyclization for the furan substrates that provides novel
oxaibogamine analogues and two palladium-based systems for
the formation of the seven-membered ring in iboga alkaloids.
Unfortunately, all three procedures suffer from significant
shortcomings, most notably low yields, high or stoichiometric
catalyst loading, and/or poor substrate scope. However, in
combination, the methods described do indeed provide
practical routes to several novel ibogamine analogues and
permit rapid access to a larger analogue library for a molecular
scaffold of high pharmacological interest. The difficulties
encountered in this work serve to highlight the challenges of
C−H bond functionalization methodology development within
the context of a complex substrate class and the shortcomings
of existing methodologies when applied to substrates with
interfering functional groups and multiple structural features.
a
b
Reactions run at 0.500 mmol scale. Isolated yields from
representative examples of two or more independent trials, NMR
yields in parentheses, trial-to-trial variation typically <5%. Run at
0.250 mmol scale with 10 mol % Ni(COD)2 and 10 mol % IMes in
toluene. Run at 0.250 mmol scale in toluene.
c
d
EXPERIMENTAL SECTION
■
product (see Supporting Information, Table S3). Furthermore,
reduction of the catalyst loading to 10 mol % resulted in
incomplete conversion. Other low-valent metals were also
completely ineffective for this transformation, with (COD)2Ir-
(BF4) and (COD)2Rh(BF4) showing no conversion of starting
material, both with and without IMes. Finally, the analogous
intermolecular reaction between 2b and 3-methylbenzofuran
was ineffective under these conditions, indicating that this
reaction benefits from intramolecular entropic enhancement.
Building on these results, application of similar conditions to
indole and benzothiophene substrates was attempted. Un-
fortunately, no conversion was observed in either case (Table 3,
entries 3 and 4). In the case of the indole substrate, it was
presumed that the reaction might be inhibited by competing
insertion into the more acidic N−H bond or by the higher
electron density of the heteroarene (compared to benzofuran).
Therefore, we felt that protection of the indole nitrogen could
remedy both of these potential difficulties by removing the
problematic N−H bond while decreasing the electron richness
of the heteroarene (with electron-withdrawing protecting
groups). Unfortunately, analogues of 3a protected at nitrogen
with a tosyl, triflyl, acetyl, or [2-(trimethylsilyl)ethoxy]methyl
group24 also failed in the cyclization. Similarly, an attempt to
use a pyridin-2-ylsulfonyl group on the indole nitrogen to
provide a directing effect also met with failure. Therefore, the
remarkable Ni-mediated transformation appears to be limited
to benzofuran substrates. A variety of alternative low-valent
metal catalyst systems were also screened on 3a and its N-
protected analogues, but no further effective conditions were
identified (see Supporting Information, Table S3).
General Considerations. Reagents and solvents (including
anhydrous solvents) were obtained from commercial sources and
were used without further purification unless otherwise stated. All
reactions were performed in flame-dried glassware under argon
atmosphere unless otherwise stated and monitored by TLC using
solvent mixtures appropriate to each reaction. Column chromatog-
raphy was performed on silica gel (40−63 μm). Nuclear magnetic
resonance spectra were recorded on 300, 400, or 500 MHz
instruments as indicated. Chemical shifts are reported as δ values in
parts per million referenced to CDCl3 (1H NMR = 7.26 and 13C NMR
= 77.16). Multiplicity is indicated as follows: s (singlet); d (doublet); t
(triplet); q (quartet); p (pentet); h (heptet); dd (doublet of doublets);
ddd (doublet of doublet of doublets); dt (doublet of triplets); td
(triplet of doublets); m (multiplet); br (broad). For those described
compounds containing a carbamate group, complex spectra with split
peaks are observed. This effect can be ascribed to the presence of
conformers about the carbamate group. As a result of these effects,
multiple peaks may correspond to the same proton group or carbon
atom. When possible, this is indicated by an “and” joining two peaks or
spectral regions. Furthermore, compounds containing fluorine are
subject to C−F coupling, resulting in splitting of some carbon peaks.
In these cases, peaks are listed as doublets, and the associated coupling
constants are indicated. Alternatively, certain carbon peaks overlap and
thus represent two carbons (indicated by (2C) designation). In all
cases the assignments of these complex peaks were determined by
COSY, HSQC, and/or DEPT-135 experiments. All carbon peaks are
rounded to one decimal place unless such rounding would cause two
close peaks to become identical. In these cases, two decimal places are
retained. High-resolution mass spectra (HRMS) were acquired on a
high-resolution sector-type double-focusing mass spectrometer (ion-
ization mode: FAB+). In calculated masses, the mass difference for loss
of one electron has been taken into account for positive ions.
2-(5-Fluoro-1H-indol-3-yl)ethanol (S1a). Compound S1a was
prepared using the modified Fischer indole synthesis protocol
E
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described by Campos.25 4-Fluorophenylhydrazine hydrochloride (8.13
g, 50.0 mmol) was dissolved in a mixture of DMAc (70 mL) and 4%
m/m aqueous H2SO4 (70 mL) and heated to 100 °C. 2,3-
Dihydrofuran (3.78 mL, 50.0 mmol) was then added dropwise over
2 min, and the brown solution was stirred for 3 h at 100 °C. After
cooling to room temperature, the mixture was extracted with EtOAc
(3 × 50 mL, then 25 mL), and the combined organics were washed
with H2O (3 × 50 mL), dried over Na2SO4, and concentrated to give a
yellow-orange oil. This was purified by column chromatography (1:1
hexanes:EtOAc) to yield alcohol S1a as an orange-red oil (5.57 g,
62%). Spectral and physical properties were in agreement with those
previously reported.26
mmol), and the resulting mixture was stirred for 1 h. At this time, the
reaction mixture was filtered through a silica plug, washing the plug
with additional CH2Cl2 (225 mL). The filtrate was concentrated to
afford a yellow oil that was further purified by column chromatography
(hexanes, two column volumes → 8:2 hexanes:Et2O, three column
volumes) to yield the pure bromide S2b as a pale-yellow oil that slowly
1
crystallized to an off-white solid (3.78 g, 64%). Mp 65−67 °C; H
NMR (500 MHz, CDCl3) δ 8.29 (br s, 1H), 7.48 (d, J = 7.1 Hz, 2H),
7.44−7.39 (m, 2H), 7.39−7.34 (m, 1H), 7.22 (d, J = 8.0 Hz, 1H),
7.08−7.02 (m, 2H), 6.74 (d, J = 7.7 Hz, 1H), 5.21 (s, 2H), 3.64 (t, J =
7.7 Hz, 2H), 3.33 (t, J = 7.7 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ
145.6, 137.1, 128.8, 128.6, 128.3, 128.0, 127.0, 122.0, 120.2, 114.1,
111.6, 103.4, 70.4, 33.1, 29.7; HRMS (FAB+) m/z [M]+ calcd for
C17H17NO79Br+ 330.0488, found 330.0483.
2-(7-(Benzyloxy)-1H-indol-3-yl)ethanol (S1b). Glyoxylate ester
S3 (5.64 g, 18.2 mmol, see below for preparation) was carefully added
to a suspension of LiAlH4 (2.08 g, 54.7 mmol) in anhydrous THF (90
mL) at room temperature, and the resulting yellowish-gray mixture
was refluxed for 5 h. After cooling in ice, the reaction was quenched by
the successive addition of H2O (2.1 mL), 15% aqueous NaOH (2.1
mL), and H2O again (6.3 mL). The resulting mixture was stirred
vigorously until the aluminum salts were white and loose and then
filtered, washing the filter cake with Et2O (3 × 50 mL). The combined
filtrate and washings were concentrated to afford alcohol S1b as a
cloudy pale-brown oil that slowly crystallized to an off-white solid
3-(2-Bromoethyl)benzofuran (S2c). To a solution of alcohol S1c
(4.76 g, 29.35 mmol) and carbon tetrabromide (14.60 g, 44.03 mmol)
in anhydrous CH2Cl2 (60 mL) at room temperature was carefully
added triphenylphosphine (11.55 g, 44.03 mmol), and the resulting
dark orange-brown mixture was left to stir for 30 min. At this time, the
reaction mixture was filtered through a silica plug, washing the plug
with additional CH2Cl2 (150 mL). The filtrate was concentrated to
afford a yellow oil which was redissolved in CH2Cl2 (50 mL) and
washed through a second silica plug, again washing the plug with
additional CH2Cl2 (150 mL). The yellow oil obtained on
concentration of the filtrate was then purified by column
chromatography (hexanes, two column volumes → 20:1 hexanes:Et2O,
three column volumes) to yield pure bromide S2c as a pale-yellow oil
(6.35 g, 96%). Spectral and physical properties were in agreement with
those previously reported.27
3-(2-Bromoethyl)benzo[b]thiophene (S2d). To a solution of
alcohol S1d (895 mg, 5.02 mmol) and carbon tetrabromide (2.50 g,
7.53 mmol) in anhydrous CH2Cl2 (10 mL) at room temperature was
carefully added triphenylphosphine (1.98 g, 7.53 mmol), and the
resulting dark red-brown mixture was stirred for 15 min. The reaction
mixture was then concentrated and purified directly by column
chromatography (6:1 hexanes:EtOAc) to yield pure bromide S2d as an
orange oil after thorough drying under high vacuum to remove
bromoform impurity (1.14 g, 94%). Spectral and physical properties
were in agreement with those previously reported.31
3-(3-Bromopropyl)-1H-indole (S2e). Alcohol S1e (3-(1H-indol-
3-yl)propan-1-ol) was prepared starting from phenylhydrazine hydro-
chloride (2.17 g, 15.0 mmol) using a modified Fischer indole synthesis
protocol as previously described.25 The crude alcohol was obtained as
an orange oil containing solvent and other impurities (2.44 g). The
whole of this material was dissolved in anhydrous CH2Cl2 (30 mL)
along with carbon tetrabromide (6.93 g, 20.90 mmol), and
triphenylphosphine (5.82 g, 20.90 mmol) was carefully added at
room temperature. After stirring for 30 min, the reaction mixture was
concentrated and purified directly by column chromatography (6:1
hexanes:EtOAc) to yield pure bromide S2e as a pale-yellow oil (1.81 g,
51% for two steps). Spectral and physical properties were in agreement
with those previously reported.32
Methyl 2-(7-(Benzyloxy)-1H-indol-3-yl)-2-oxoacetate (S3).
To a solution of 7-benzyloxyindole (4.91 g, 22.0 mmol) in anhydrous
THF (65 mL) at 0 °C was added oxalyl chloride (2.49 mL, 28.6
mmol) dropwise over 5 min, and the resulting yellow-orange solution
was stirred at 0 °C for 4 h. The reaction mixture was then
concentrated in vacuo to yield the crude acyl chloride intermediate as a
yellow-brown solid. To this material was added anhydrous MeOH (40
mL); the mixture was cooled in ice; and one neck of the flask was
opened under a strong flow of argon to remove any evolved HCl gas
as Et3N (3.99 mL, 28.6 mmol) was added dropwise over 3 min. The
yellow mixture was then sealed again and refluxed for 2 h and then
cooled to 0 °C, and the solids were collected by filtration, washing at
the filter with several small portions of ice-cold MeOH. Glyoxylate
ester S3 was thus obtained as yellow ochre crystals (5.67 g, 83%). Mp
175−178 °C; 1H NMR (400 MHz, CDCl3) δ 9.09 (br s, 1H), 8.41 (d,
J = 3.3 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.49−7.44 (m, 2H), 7.44−
7.34 (m, 3H), 7.25 (t, J = 8.0 Hz, 1H), 6.86 (d, J = 7.7 Hz, 1H), 5.21
(s, 2H), 3.94 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 177.9, 163.3,
1
(4.86 g, 100%). Mp 70−72 °C; H NMR (400 MHz, CDCl3) δ 8.36
(br s, 1H), 7.49 (dd, J = 7.7, 1.1 Hz, 2H), 7.45−7.35 (m, 3H), 7.26 (d,
J = 8.0 Hz, 1H), 7.05 (t, J = 7.9 Hz, 1H), 7.02 (d, J = 2.3 Hz, 1H), 6.75
(d, J = 7.7 Hz, 1H), 5.21 (s, 2H), 3.89 (br s, 2H), 3.02 (t, J = 6.4 Hz,
2H), 1.59 (br s, 1H); 13C NMR (101 MHz, CDCl3) δ 145.6, 137.2,
129.1, 128.8, 128.3, 128.0, 127.8, 122.3, 120.0, 112.8, 112.0, 103.4,
+
70.4, 62.8, 29.0; HRMS (FAB+) m/z [M]+ calcd for C17H18NO2
268.1332, found 268.1334.
2-(Benzofuran-3-yl)ethanol (S1c). A solution of ester S4 (6.21 g,
30.4 mmol, see below for preparation) in anhydrous THF (25 mL)
was added dropwise to a suspension of LiAlH4 (3.00 g, 79.0 mmol) in
anhydrous THF (80 mL) over 10 min, and the resulting mixture was
then refluxed for 1 h. After cooling to room temperature the reaction
was quenched by the successive addition of H2O (3 mL), 15% aqueous
NaOH (3 mL), and H2O again (9 mL). The resulting mixture was
stirred vigorously until the aluminum salts were white and loose and
then filtered, washing the filter cake with Et2O (2 × 30 mL, then 2 ×
50 mL). The combined filtrate and washings were concentrated to
yield the pure alcohol S1c as a yellow oil (4.81 g, 98%). Spectral and
physical properties were in agreement with those previously
reported.27
2-(Benzo[b]thiophen-3-yl)ethanol (S1d). Compound S1d was
prepared via LiAlH4 reduction of benzo[b]thiophene-3-acetic acid as
previously described.28 The crude product was obtained as an orange
oil of sufficient purity for the next step (895 mg, 97%). Spectral and
physical properties were in agreement with those previously
reported.29
3-(2-Bromoethyl)-5-fluoro-1H-indole (S2a). To a solution of
alcohol S1a (5.51 g, 30.75 mmol) and carbon tetrabromide (14.28 g,
43.05 mmol) in anhydrous CH3CN (160 mL) at 0 °C was added
triphenylphosphine (10.49 g, 39.98 mmol) in five equal portions over
10 min, and the resulting mixture was stirred for 20 min at 0 °C. At
this time, the reaction mixture was concentrated, and the resulting
dark-orange oil was dissolved in CH2Cl2 and washed through a silica
plug, washing with CH2Cl2 until all product had passed through. The
eluate was then concentrated and washed through a second silica plug,
starting with 2:1 hexanes/CH2Cl2 until most of the upper bromoform
impurity had been eluted and then with CH2Cl2 to finish elution of the
product. The collected eluate-containing product was again con-
centrated and purified by column chromatography (6:1 hexanes:E-
tOAc) to yield pure bromide S2a as a yellow oil which slowly solidified
to a waxy yellow-brown solid (4.97 g, 67%). Spectral and physical
properties were in agreement with those previously reported.30
7-(Benzyloxy)-3-(2-bromoethyl)-1H-indole (S2b). To a sol-
ution of alcohol S1b (4.81 g, 18.0 mmol) and carbon tetrabromide
(8.95 g, 27.0 mmol) in anhydrous CH2Cl2 (36 mL) at room
temperature was carefully added triphenylphosphine (7.08 g, 27.0
F
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145.4, 136.6, 135.7, 128.9, 128.6, 128.1, 127.8, 126.8, 124.4, 115.4,
organics were washed with H2O (250 mL), saturated aqueous
NaHCO3 (250 mL), and H2O again (50 mL), dried over Na2SO4,
and concentrated to provide a cloudy, pale-yellow oil. This was washed
through a short silica column with 7:3 hexanes:EtOAc, and the eluate
was concentrated to yield pure exo-isoquinuclidine 2a as a pale-yellow
oil (10.12 g, 59%). The spectral data were in agreement with the
epimer incorrectly assigned to the endo configuration by Krow and in
agreement with the data reported by Hodgson.12,13
endo-Methyl 7-Ethyl-2-azabicyclo[2.2.2]oct-5-ene-2-carbox-
ylate (2b). To a suspension of endo-tosylhydrazone 2b (3.50 g, 9.27
mmol) in MeOH (41 mL) was added a solution of sodium
cyanoborohydride (833 mg, 13.26 mmol) and ZnCl2 (904 mg, 6.63
mmol) in MeOH (28 mL), and the resulting mixture was refluxed for
3 h. The reaction was then quenched with 1% aqueous NaOH (200
mL) and extracted with cyclohexane (3 × 50 mL). The combined
organics were washed with H2O (50 mL) and brine (50 mL), dried
over Na2SO4, and concentrated to provide a clear, colorless oil. This
was washed through a short silica column with 1:1 hexanes:EtOAc,
and the eluate was concentrated to yield pure endo-isoquinuclidine 2b
as a colorless oil (1.11 g, 61%). The spectral data were in agreement
with the epimer incorrectly assigned to the exo configuration by
Krow.13
General Procedure for Preparation of N-Arylalkylisoquinu-
clidines (3a−g). To a solution of exo- or endo-isoquinuclidine 2a or
2b (1 equiv) in anhydrous CH2Cl2 (0.125 M, based on 2) at 0 °C was
added iodotrimethylsilane (4 equiv), and the resulting mixture was
stirred for 10 min at 0 °C and then at room temperature until TLC
indicated that no 2 remained (typically ∼1 h). The reaction mixture
was then concentrated to yield the deprotected isoquinuclidine
hydroiodide salt in quantitative yield. To this material was added the
appropriate bromoalkylheteroarene S2a−e (1 equiv) and NaHCO3 (4
equiv), followed by anhydrous CH3CN (0.208 M, based on 2), and
the resulting mixture was refluxed until TLC indicated the
disappearance of the bromide (typically 2−4 days). The reaction
was then diluted with H2O, made strongly basic with aqueous NaOH,
and extracted with CHCl3 (3×). The combined organics were washed
with H2O, dried over Na2SO4, and concentrated to provide the crude
product, which was purified by column chromatography with an
appropriate solvent mixture (as described below for each compound).
exo-2-(2-(1H-Indol-3-yl)ethyl)-7-ethyl-2-azabicyclo[2.2.2]-
oct-5-ene (3a). The product 3a was prepared using commercially
available 3-(2-bromoethyl)-1H-indole and purified by column
chromatography (8:2 hexanes:EtOAc + 2% Et3N). It was obtained
as a viscous yellow oil (4.82 g, 84%). Spectral and physical properties
were in agreement with those previously reported.12
115.0, 106.0, 70.7, 52.9; HRMS (FAB+) m/z [M + H]+ calcd for
+
C18H16NO4 310.1074, found 310.1079.
Ethyl 2-(Benzofuran-3-yl)acetate (S4). Compound S4 was
prepared by a slight modification of the literature procedure.33
A
solution of benzofuran-3(2H)-one (5.00 g, 37.3 mmol) and
(carbethoxymethylene)triphenylphosphorane (14.28 g, 41.0 mmol)
in anhydrous toluene (125 mL) was refluxed for 87 h and then
concentrated in vacuo. On standing, copious crystals formed in the
dark-brown liquid. The mixture was diluted with 10:1 hexanes:EtOAc
and the crystalline mass crushed thoroughly. The supernatant was then
decanted, leaving behind as much of the solids as possible. The
residual crystalline solids were washed 3× with 10:1 hexanes:EtOAc,
removing and saving the supernatant each time. The combined washes
were then purified directly by column chromatography (10:1
hexanes:EtOAc, large fractions collected) to yield the pure ester S4
as an orange oil (6.30 g, 83%). Spectral and physical properties were in
agreement with those previously reported.34
exo-Methyl 7-(1-(2-Tosylhydrazono)ethyl)-2-azabicyclo-
[2.2.2]oct-5-ene-2-carboxylate (1a) and endo-Methyl 7-(1-(2-
Tosylhydrazono)ethyl)-2-azabicyclo[2.2.2]oct-5-ene-2-carbox-
ylate (1b). Exo-tosylhydrazone 1a and endo-tosylhydrazone 1b were
prepared by the method of Krow.13 However, in contrast to the
previous report, crystalline products were obtained for both stereo-
isomers. Further, the stereochemistry of 1a and 1b has been revised
from the initial report13 as confirmed by 2D NMR experiments and by
the reduction of 1a to exo product 2a, the structure of which has been
previously assigned by Hodgson using X-ray crystallography.12 Also,
isoquinuclidine 2a was converted to ibogamine, further confirming the
exo stereochemistry of the 7-ethyl group. For clarification, the
preparation of 1a and 1b is described as follows. A mixture of exo/
endo-methyl 7-acetyl-2-azabicyclo[2.2.2]oct-5-ene-2-carboxylate35
(60:40 exo:endo ratio, 34.93 g, 167 mmol) and p-toluenesulfonhy-
drazide (31.10 g, 167 mmol) in anhydrous THF (136 mL) was heated
at 50 °C for 15 h, at which time a white precipitate had formed. The
reaction mixture was cooled to room temperature, and the white
precipitate was collected by filtration, washing 3× at the filter with ice-
cold MeOH, to provide pure endo-tosylhydrazone 1b as a fine white
powder (19.55 g, 31%). The filtrate and washings were combined and
concentrated to a tan solid, which was recrystallized from MeOH to
obtain the pure exo-tosylhydrazone 1a as white plates (33.14 g, 53%).
1a. The exo-tosylhydrazone was prepared by separation of the exo/
endo mixture as described above. The spectral data were in agreement
with the epimer incorrectly assigned to the endo configuration by
Krow.13 Mp 162−166 °C (inaccurate due to trapped MeOH); H
1
NMR (400 MHz, CDCl3) (spectrum complicated by conformers) δ
7.85 and 7.79 (d, J = 8.3 Hz, 2H), 7.35−7.28 (m, 3H), 6.46−6.37 (m,
2H), 4.74−4.68 and 4.61−4.57 (m, 1H), 3.52 and 3.34 (s, 3H), 3.02
and 2.94 (dd, J = 9.8, 2.2 Hz, 1H), 2.87 and 2.78 (dt, J = 9.8, 2.6 Hz,
1H), 2.73−2.67 (m, 1H), 2.48−2.37 (m, 1H), 2.44 (s, 3H), 2.30 and
2.09 (ddd, J = 13.1, 4.4, 2.4 Hz, 1H), 1.89 and 1.80 (s, 3H), 1.42−1.26
(m, 1H).
endo-7-Ethyl-2-(2-(5-fluoro-1H-indol-3-yl)ethyl)-2-
azabicyclo[2.2.2]oct-5-ene (3b). The product 3b was purified by
column chromatography (1:1 hexanes:EtOAc + 2% Et3N) and
obtained as a tan solid (450 mg, 60%). Mp 140−143 °C; H NMR
1
(400 MHz, CDCl3) δ 7.91 (br s, 1H), 7.26−7.20 (m, 2H), 7.05 (d, J =
2.2 Hz, 1H), 6.92 (td, J = 9.0, 2.5 Hz, 1H), 6.38 (t, J = 6.9 Hz, 1H),
6.18−6.11 (m, 1H), 3.41−3.36 (m, 1H), 3.03 (dd, J = 9.7, 1.8 Hz,
1H), 2.95−2.76 (m, 3H), 2.61−2.46 (m, 2H), 2.10 (dt, J = 9.7, 2.7 Hz,
1H), 2.07−1.98 (m, 1H), 1.79 (ddd, J = 12.1, 9.2, 2.8 Hz, 1H), 1.24−
1.11 (m, 1H), 1.07−0.94 (m, 1H), 0.86 (t, J = 7.3 Hz, 3H), 0.82−0.74
(m, 1H); 13C NMR (101 MHz, CDCl3) (spectrum complicated by
C−F coupling) δ 157.8 (d, JC−F = 235 Hz), 133.8, 132.9, 130.2, 128.1
1b. The endo-tosylhydrazone was prepared by separation of the exo/
endo mixture as described above. The spectral data were in agreement
with the epimer incorrectly assigned to the exo configuration by
Krow.13 Mp 181−184 °C; H NMR (400 MHz, CDCl3) (spectrum
1
complicated by conformers) δ 7.81 (t, J = 7.4 Hz, 2H), 7.32 (d, J = 8.0
Hz, 2H), 7.12 (s, 1H), 6.19 (q, J = 7.5 Hz, 1H), 6.02 (dd, J = 12.0, 5.6
Hz, 1H), 4.87 and 4.77 (d, J = 4.3 Hz, 1H), 3.69 and 3.66 (s, 3H), 3.23
(d, J = 10.1 Hz, 1H), 3.01−2.85 (m, 2H), 2.74 (br s, 1H), 2.45 and
2.44 (s, 3H), 1.87−1.66 (m, 1H), 1.71 and 1.69 (s, 3H), 1.59−1.47
(m, 1H).
(d, JC−F = 9.1 Hz), 123.5, 115.1 (d, JC−F = 5.1 Hz), 111.7 (d, JC−F
=
10.1 Hz), 110.3 (d, JC−F = 26.2 Hz), 103.9 (d, JC−F = 20.2 Hz), 58.9,
57.3, 54.5, 40.6, 31.6, 30.8, 28.8, 24.6, 11.7; HRMS (FAB+) m/z [M +
+
H]+ calcd for C19H24FN2 299.1919; found 299.1928.
exo-2-(2-(7-(Benzyloxy)-1H-indol-3-yl)ethyl)-7-ethyl-2-
azabicyclo[2.2.2]oct-5-ene (3c). The product 3c was purified by
column chromatography (9:1 hexanes:EtOAc, three column volumes
→ 9:1 hexanes:EtOAc + 2% Et3N, five column volumes) and obtained
as a viscous yellow oil (70.3 mg, 36%). 1H NMR (500 MHz, CDCl3) δ
8.18 (br s, 1H), 7.48 (d, J = 7.1 Hz, 2H), 7.44−7.38 (m, 2H), 7.38−
7.33 (m, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.04−6.98 (m, 2H), 6.71 (d, J
= 7.7 Hz, 1H), 6.38−6.28 (m, 2H), 5.20 (s, 2H), 3.28 (s, 1H), 3.12 (d,
J = 8.3 Hz, 1H), 2.93−2.75 (m, 3H), 2.58−2.48 (m, 1H), 2.45 (s, 1H),
exo-Methyl 7-Ethyl-2-azabicyclo[2.2.2]oct-5-ene-2-carboxy-
late (2a). exo-Tosylhydrazone 1a (33.02 g, 87.5 mmol), sodium
cyanoborohydride (21.99 g, 350 mmol), and p-toluenesulfonic acid
monohydrate (1.40 g, 7.36 mmol) were combined in anhydrous THF
(250 mL) and refluxed for 21 h. At this time, additional p-TsOH·H2O
(0.35 g, 1.84 mmol) was added, and reflux was continued for an
additional 4 h. The reaction mixture was then diluted with H2O (250
mL) and extracted with cyclohexane (3 × 100 mL). The combined
G
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1.98 (d, J = 9.1 Hz, 1H), 1.69−1.53 (m, 2H), 1.53−1.45 (m, 1H),
1.35−1.28 (m, 1H), 0.98−0.94 (m, 1H), 0.92 (t, J = 7.4 Hz, 3H); 13C
NMR (126 MHz, CDCl3) δ 145.5, 137.4, 132.9 (2C), 129.3, 128.7,
128.2, 127.9, 126.9, 121.2, 119.5, 115.7, 112.2, 103.1, 70.3, 59.2, 56.4,
56.1, 41.3, 31.8, 29.9, 27.3, 24.7, 12.7; HRMS (FAB+) m/z [M + H]+
calcd for C26H31N2O+ 387.2431, found 387.2439.
exo-2-(2-(Benzofuran-3-yl)ethyl)-7-ethyl-2-azabicyclo[2.2.2]-
oct-5-ene (3d). The product 3d was purified by column
chromatography (19:1 hexanes:EtOAc) and obtained as an orange-
brown oil (940 mg, 46%). 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J =
7.3 Hz, 1H), 7.49 (s, 1H), 7.47−7.41 (m, 1H), 7.30−7.25 (m, 1H),
7.22 (td, J = 7.4, 1.1 Hz, 1H), 6.38−6.27 (m, 2H), 3.22 (d, J = 5.1 Hz,
1H), 3.09 (dd, J = 9.1, 2.1 Hz, 1H), 2.87−2.66 (m, 3H), 2.57−2.48
(m, 1H), 2.44 (br s, 1H), 1.94 (dt, J = 9.0, 2.4 Hz, 1H), 1.64−1.42 (m,
3H), 1.35−1.24 (m, 1H), 0.95−0.90 (m, 1H), 0.87 (t, J = 7.4 Hz, 3H);
13C NMR (126 MHz, CDCl3) δ 155.3, 141.7, 133.1, 132.8, 128.6,
of the substrate 3a−g (0.250 mmol) in anhydrous CH3CN (9.0 mL)
resulting in a color change (ranging from orange to deep-red
depending on the substrate). The reaction mixture was stirred for 2
h at room temperature and then warmed to 70 °C and stirred for a
further 16 h. At this time, the reaction was cooled to 0 °C, and
anhydrous MeOH (2.25 mL) was added followed by NaBH4 (30.3 mg,
0.800 mmol), causing the immediate precipitation of palladium black.
The resulting black mixture was stirred for 20 min at 0 °C, then
diluted with Et2O (50 mL), and filtered through Celite, and the filter
cake was washed with additional Et2O (4 × 10 mL). The combined
filtrate and washings were concentrated to afford the crude product.
The NMR yield was then determined using mesitylene (10 μL) as an
internal standard, and the product was purified by column
chromatography with an appropriate solvent mixture (as described
below for each compound).
rac-Ibogamine (4a). The product 4a was purified by column
chromatography (9:1 hexanes:EtOAc + 2% Et3N) and obtained as a
colorless oil that slowly crystallized to a waxy white solid (20.3 mg,
29%). Spectral and physical properties were in agreement with those
previously reported.12 1H NMR (500 MHz, CDCl3) δ 7.61 (br s, 1H),
7.51−7.46 (m, 1H), 7.28−7.24 (m, 1H), 7.15−7.07 (m, 2H), 3.44−
3.33 (m, 2H), 3.21−3.12 (m, 1H), 3.09 (dt, J = 9.2, 2.0 Hz, 1H), 3.00
(d, J = 9.1 Hz, 1H), 2.93 (ddd, J = 11.6, 4.0, 1.7 Hz, 1H), 2.88 (s, 1H),
2.75−2.64 (m, 1H), 2.11−2.01 (m, 1H), 1.89−1.78 (m, 2H), 1.66
(ddd, J = 13.2, 6.7, 3.5 Hz, 1H), 1.61−1.53 (m, 2H), 1.53−1.44 (m,
1H), 1.27−1.17 (m, 1H), 0.92 (t, J = 7.2 Hz, 3H); 13C NMR (126
MHz, CDCl3) δ 142.0, 134.8, 129.9, 121.1, 119.3, 118.1, 110.2, 109.4,
57.7, 54.3, 50.1, 42.1, 41.6, 34.3, 32.3, 28.0, 26.7, 20.8, 12.1.
124.1, 122.2, 119.7, 119.1, 111.5, 57.9, 56.3, 56.2, 41.3, 31.8, 29.9, 27.4,
23.0, 12.6; HRMS (FAB+) m/z [M + H]+ calcd for C19H24NO+
282.1853; found 282.1862.
endo-2-(2-(Benzofuran-3-yl)ethyl)-7-ethyl-2-azabicyclo-
[2.2.2]oct-5-ene (3e). The product 3e was purified by column
chromatography (15:1 hexanes:EtOAc + 2% Et3N, three column
volumes → 9:1 hexanes:EtOAc + 2% Et3N, three column volumes)
and obtained as a pale-yellow oil (422 mg, 60%). 1H NMR (500 MHz,
CDCl3) δ 7.55 (d, J = 7.3 Hz, 1H), 7.45 (s, 1H), 7.45 (d, J = 5.8 Hz,
1H), 7.30−7.25 (m, 1H), 7.25−7.20 (m, 1H), 6.39 (t, J = 7.3 Hz, 1H),
6.17−6.11 (m, 1H), 3.41−3.34 (m, 1H), 3.03 (dd, J = 9.6, 1.8 Hz,
1H), 2.91−2.74 (m, 3H), 2.59−2.53 (m, 1H), 2.53−2.47 (m, 1H),
2.07 (dt, J = 9.6, 2.7 Hz, 1H), 2.05−1.98 (m, 1H), 1.78 (ddd, J = 12.1,
9.2, 2.8 Hz, 1H), 1.23−1.13 (m, 1H), 1.06−0.96 (m, 1H), 0.86 (t, J =
7.4 Hz, 3H), 0.82−0.76 (m, 1H); 13C NMR (75 MHz, CDCl3) δ
155.3, 141.5, 133.7, 130.2, 128.5, 124.2, 122.3, 119.8, 118.9, 111.5,
57.9, 57.4, 54.5, 40.9, 31.6, 30.7, 28.8, 23.2, 11.8; HRMS (FAB+) m/z
[M + H]+ calcd for C19H24NO+ 282.1853, found 282.1864.
endo-2-(2-(Benzo[b]thiophen-3-yl)ethyl)-7-ethyl-2-azabicy-
clo[2.2.2]oct-5-ene (3f). The product 3f was purified by column
chromatography (9:1 hexanes:EtOAc, three column volumes → 9:1
hexanes:EtOAc + 2% Et3N, three column volumes) and obtained as a
yellow oil (150 mg, 40%). 1H NMR (500 MHz, CDCl3) δ 7.84 (d, J =
7.8 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.41−7.36 (m, 1H), 7.36−7.30
(m, 1H), 7.13 (s, 1H), 6.40 (t, J = 7.2 Hz, 1H), 6.17−6.12 (m, 1H),
3.44−3.39 (m, 1H), 3.08−2.97 (m, 3H), 2.97−2.88 (m, 1H), 2.66−
2.57 (m, 1H), 2.55−2.49 (m, 1H), 2.11 (dt, J = 9.7, 2.7 Hz, 1H),
2.09−2.01 (m, 1H), 1.80 (ddd, J = 12.1, 9.2, 2.8 Hz, 1H), 1.24−1.14
(m, 1H), 1.07−0.96 (m, 1H), 0.86 (t, J = 7.4 Hz, 3H), 0.83−0.77 (m,
1H); 13C NMR (101 MHz, CDCl3) δ 140.5, 139.2, 135.1, 133.8,
130.2, 124.2, 124.0, 123.0, 121.8, 121.7, 58.0, 57.5, 54.4, 40.6, 31.6,
30.7, 28.8, 27.9, 11.7; HRMS (FAB+) m/z [M + H]+ calcd for
C19H24NS+ 298.1624, found 298.1625.
rac-12-Fluoro-4-epi-ibogamine (4b). The product 4b was
purified by column chromatography (7:3 hexanes:EtOAc + 2%
Et3N) and obtained as an amorphous off-white solid (8.3 mg, 11%).
1H NMR (400 MHz, CDCl3) δ 7.73 (br s, 1H), 7.15 (dd, J = 8.7, 4.4
Hz, 1H), 7.10 (dd, J = 9.8, 2.4 Hz, 1H), 6.84 (td, J = 9.1, 2.5 Hz, 1H),
3.44−3.23 (m, 3H), 3.20−3.09 (m, 2H), 3.05 (dd, J = 11.6, 5.3 Hz,
1H), 2.89 (s, 1H), 2.63−2.51 (m, 1H), 2.09−1.94 (m, 3H), 1.90 (s,
1H), 1.70−1.61 (m, 1H), 1.38 (p, J = 7.2 Hz, 2H), 1.13−1.03 (m,
1H), 0.93 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3)
(spectrum complicated by C−F coupling) δ 158.1 (d, JC−F = 235 Hz),
144.0, 130.9, 130.2 (d, JC−F = 10.1 Hz), 110.9 (d, JC−F = 10.1 Hz),
110.5 (d, JC−F = 5.1 Hz), 109.2 (d, JC−F = 26.3 Hz), 103.0 (d, JC−F
=
24.2 Hz), 57.3, 54.7, 49.7, 42.0, 35.1, 34.4, 31.7, 28.5, 26.3, 20.3, 12.2;
HRMS (FAB+) m/z [M + H]+ calcd for C19H24FN2+ 299.1919, found
299.1924.
rac-14-(Benzyloxy)ibogamine (4c). The reaction was run on a
0.100 mmol scale. The product 4c was purified by column
chromatography (20:1 hexanes:EtOAc + 2% Et3N) and obtained as
a pale-yellow glass (8.8 mg, 23%). 1H NMR (400 MHz, CDCl3) δ 7.87
(br s, 1H), 7.51−7.45 (m, 2H), 7.44−7.33 (m, 3H), 7.11 (d, J = 7.9
Hz, 1H), 6.99 (t, J = 7.8 Hz, 1H), 6.67 (d, J = 7.7 Hz, 1H), 5.19 (s,
2H), 3.42−3.31 (m, 2H), 3.20−3.05 (m, 2H), 3.01−2.88 (m, 2H),
2.85 (s, 1H), 2.69−2.60 (m, 1H), 2.03 (t, J = 12.4 Hz, 1H), 1.87−1.75
(m, 2H), 1.65 (dd, J = 13.1, 3.1 Hz, 1H), 1.60−1.39 (m, 3H), 1.25−
1.17 (m, 1H), 0.90 (t, J = 7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3)
δ 144.9, 141.8, 137.4, 131.3, 128.7, 128.2, 128.0, 125.0, 119.6, 111.3,
109.9, 102.7, 70.4, 57.7, 54.4, 50.2, 42.1, 41.6, 34.4, 32.3, 28.0, 26.7,
21.0, 12.1; HRMS (FAB+) m/z [M + H]+ calcd for C26H31N2O+
387.2431, found 387.2438.
exo-2-(3-(1H-Indol-3-yl)propyl)-7-ethyl-2-azabicyclo[2.2.2]-
oct-5-ene (3g). The product 3g was purified by column
chromatography (15% EtOAc in hexanes + 2% Et3N, three column
volumes → 20% EtOAc in hexanes + 2% Et3N) and obtained as a
viscous pale-yellow oil (86 mg, 58%). 1H NMR (400 MHz, CDCl3) δ
7.88 (bs s, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H),
7.21−7.15 (m, 1H), 7.13−7.08 (m, 1H), 6.99−6.96 (m, 1H), 6.34−
6.23 (m, 2H), 3.19−3.16 (m, 1H), 3.05 (dd, J = 9.1, 2.3 Hz, 1H),
2.88−2.71 (m, 2H), 2.51 (dt, J = 11.8, 7.4 Hz, 1H), 2.43−2.37 (m,
1H), 2.30−2.21 (m, 1H), 1.87−1.69 (m, 3H), 1.68−1.53 (m, 2H),
1.51−1.42 (m, 1H), 1.34−1.24 (m, 1H), 0.96−0.88 (m, 1H), 0.92 (t, J
= 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 136.5, 132.9 (2C),
127.8, 121.9, 121.3, 119.20, 119.16, 117.2, 111.1, 58.1, 56.4, 55.9, 41.5,
31.8, 30.0, 29.0, 27.4, 22.8, 12.7. HRMS (FAB+) m/z [M + H]+ calcd
rac-16-Oxaibogamine (4d). The product was not isolated due to
low yield. NMR yield was calculated as 11% in two independent trials.
For spectral data, see the Ni-catalyzed preparation below.
rac-16-Thia-4-epi-ibogamine (4f). The reaction was run on a
0.060 mmol scale. The product 4f was purified by column
chromatography (9:1 hexanes:EtOAc + 2% Et3N, 4 column volumes
→ 8:2 hexanes:EtOAc + 2% Et3N, 2 column volumes) and obtained as
+
for C20H27N2 295.2169, found 295.2182.
1
a pale-yellow oil (6.0 mg, 34%). H NMR (500 MHz, CDCl3) δ 7.74
General Procedure for Preparation of Iboga Alkaloids by
Pd(CH3CN)4(BF4)2-Mediated Cyclization of N-Arylalkylisoqui-
nuclidines (4a−f). In a glovebox, a Schlenk flask was charged with
Pd(CH3CN)4(BF4)2 (144 mg, 0.325 mmol). It was then sealed and
removed from the glovebox, and anhydrous CH3CN (3.5 mL) was
added to form a yellow solution. To this solution was added a solution
(d, J = 7.9 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H),
7.26 (t, J = 7.6 Hz, 1H), 3.46−3.30 (m, 3H), 3.28−3.18 (m, 1H),
3.18−3.09 (m, 2H), 2.92 (s, 1H), 2.82 (d, J = 14.7 Hz, 1H), 2.13 (t, J
= 12.5 Hz, 1H), 2.02−1.90 (m, 3H), 1.75 (dd, J = 13.4, 6.6 Hz, 1H),
1.46−1.36 (m, 2H), 1.11−1.00 (m, 1H), 0.94 (t, J = 7.4 Hz, 3H); 13C
H
DOI: 10.1021/jo5018102
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The Journal of Organic Chemistry
Article
NMR (126 MHz, CDCl3) δ 145.3, 141.6, 138.2, 131.0, 124.0, 123.5,
122.2, 120.9, 57.7, 54.6, 50.7, 42.2, 35.6, 35.2, 31.6, 28.0, 26.5, 23.5,
12.2; HRMS (FAB+) m/z [M + H]+ calcd for C19H24NS+ 298.1624,
found 298.1620.
(20 × 20 cm plate, 1 mm silica layer, 80:1 hexanes:EtOAc + 2% Et3N)
to provide a second portion of pure product as a viscous, nearly
colorless oil (83.8 mg). The overall yield of pure product 4d was 104
mg (74%). 1H NMR (500 MHz, CDCl3) δ 7.43−7.39 (m, 1H), 7.39−
7.35 (m, 1H), 7.24−7.18 (m, 2H), 3.47−3.39 (m, 1H), 3.28−3.13 (m,
3H), 3.02−2.92 (m, 2H), 2.82 (s, 1H), 2.54 (d, J = 15.7 Hz, 1H), 2.05
(t, J = 12.4 Hz, 1H), 1.90−1.77 (m, 2H), 1.66 (ddd, J = 13.3, 6.4, 3.1
Hz, 1H), 1.62−1.43 (m, 3H), 1.25−1.17 (m, 1H), 0.92 (t, J = 7.2 Hz,
3H); 13C NMR (126 MHz, CDCl3) δ 160.0, 153.7, 130.9, 123.3,
122.1, 118.7, 111.6, 110.6, 57.3, 53.3, 49.7, 41.5, 41.1, 33.0, 32.3, 27.5,
26.5, 19.5, 11.9; HRMS (FAB+) m/z [M]+ calcd for C19H23NO+
281.1775, found 281.1772.
rac-16-Oxa-4-epi-ibogamine (4e). The crude reaction mixture
was purified directly by column chromatography (9:1 hexanes:EtOAc
+ 2% Et3N) to yield a viscous, orange-brown oil contaminated with a
coeluting impurity. The NMR yield of product contained in this
material (42%) was determined using mesitylene (10 μL) as an
internal standard, and it was then further purified by preparative TLC
(20 × 20 cm plate, 1 mm silica layer, Et2O + 1% Et3N) to provide the
pure product 4e as a viscous, pale-yellow oil (53.3 mg, 38%). 1H NMR
(500 MHz, CDCl3) δ 7.43−7.39 (m, 1H), 7.38−7.34 (m, 1H), 7.24−
7.18 (m, 2H), 3.44 (ddd, J = 13.8, 4.7, 2.3 Hz, 1H), 3.38−3.29 (m,
2H), 3.25 (ddd, J = 17.0, 12.3, 4.7 Hz, 1H), 3.12−3.02 (m, 2H), 2.88
(s, 1H), 2.57−2.49 (m, 1H), 2.09−1.94 (m, 3H), 1.92−1.85 (m, 1H),
1.62 (ddd, J = 13.3, 6.0, 3.7 Hz, 1H), 1.47−1.34 (m, 2H), 1.18−1.09
(m, 1H), 0.95 (t, J = 7.4 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ
160.7, 153.4, 130.7, 123.3, 122.2, 118.6, 112.1, 110.7, 56.5, 53.5, 49.1,
41.9, 34.3, 34.1, 31.6, 28.5, 26.4, 18.9, 12.3; HRMS (FAB+) m/z [M +
H]+ calcd for C19H24NO+ 282.1853, found 282.1859.
General Procedure for the Preparation of Iboga Alkaloids
by Reductive Heck Reaction (4a,b). To a solution of the substrate
(3a or 3b) (0.100 mmol) in anhydrous CH2Cl2 (0.90 mL) was added
a solution of trimethylphenylammonium tribromide (41.4 mg, 0.110
mmol) in anhydrous CH2Cl2 (0.50 mL) dropwise at room
temperature over 20 min. The resulting dark-red solution was stirred
until TLC showed no starting material (∼10 min) and then quenched
with H2O (2.0 mL) and basified with saturated NH4OH (0.25 mL),
and the aqueous layer was removed. The remaining organic layer was
then washed with H2O (1.0 mL) and concentrated in vacuo to provide
the crude bromide as a viscous brown oil (Note: If desired, the
bromide intermediate may be purified by column chromatography: 9:1
hexanes:EtOAc + 2% Et3N for bromide from 3a; 8:2 hexanes:EtOAc +
2% Et3N for bromide from 3b). To the crude bromide was added
tetrakis(triphenylphosphine)palladium(0) (11.6 mg, 0.010 mmol) and
sodium formate (27.2 mg, 0.400 mmol, powdered and dried with
gentle heating under vacuum before use), followed by anhydrous
DMSO (0.40 mL), and the resulting mixture was heated to 130 °C for
1 h (gas evolution occurs). The reaction was then diluted with H2O (1
mL) and extracted with CH2Cl2 (3 × 1 mL) (Note: On a larger scale,
the use of Et2O is recommended to avoid excessive DMSO in the
organic extracts). The combined organics were dried over Na2SO4 and
concentrated to afford the crude product. The NMR yield was then
determined using mesitylene (10 μL) as an internal standard, and the
product was purified by column chromatography with an appropriate
solvent mixture (as described below for each compound).
Ethyltrichlorosilane-Treated Silica Gel. Deactivated silica was
prepared as follows. To a suspension of silica gel (40−63 μm, 50 g) in
CH2Cl2 (200 mL) was added ethyltrichlorosilane (4.0 mL) (gas
evolution occurs), and the resulting mixture was stirred for 15 min. At
this time the treated silica was collected by filtration, washed with
CH2Cl2 (2 × 100 mL) and MeOH (3 × 100 mL), and dried in vacuo
with gentle warming. Treated TLC plates were prepared in the same
manner. However, these were UV opaque and thus were developed in
an iodine chamber.
rac-Ibogamine (4a). The reaction was run on a 0.100 mmol scale.
The product 4a was purified by column chromatography (9:1
hexanes:EtOAc + 2% Et3N) and obtained as a colorless oil that
slowly crystallized to a waxy white solid (11.9 mg, 42%). Spectral and
physical properties were in agreement with those previously reported12
and with those of the material obtained from the electrophilic Pd
procedure (see above).
rac-12-Fluoro-4-epi-ibogamine (4b). The reaction was run on a
0.500 mmol scale. The product 4b was purified by repeated column
chromatography on both silica (8:2 hexanes:EtOAc + 2% Et3N, two
column volumes → 7:3 hexanes:EtOAc + 2% Et3N, two column
volumes → 6:4 hexanes:EtOAc + 2% Et3N, until product eluted) and
ethyltrichlorosilane-treated silica (see below for preparation) (column
1 = 20:1 → 10:1 → 5:1 CH2Cl2:MeOH; column 2 = 20:1
CH2Cl2:MeOH, three column volumes → 20:1 CH2Cl2:MeOH +
2% Et3N) and obtained as an amorphous off-white solid (5.1 mg, 3%).
Spectral and physical properties were in agreement with those of the
material obtained from the electrophilic Pd procedure (see above).
General Procedure for Preparation of Oxaibogamine
Analogues by Ni(0) C−H Insertion (4d,e). In a glovebox, a vial
was charged with Ni(COD)2 (27.5 mg, 0.100 mmol) and 1,3-bis(2,4,6-
trimethylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene (IMes, 36.5 mg,
0.120 mmol) followed by anhydrous heptane (1.0 mL), and the
resulting black solution was stirred at room temperature for 15 min.
To this mixture was then added a solution of the benzofuran substrate
(3d or 3e) (141 mg, 0.500 mmol) in anhydorus heptane (1.5 mL),
and the reaction vessel was sealed, removed from the glovebox, and
heated at 130 °C for 3 h. After cooling to room temperature the
reaction mixture was purified directly by a combination of column
chromatography and preparative TLC as described below for each
substrate.
ASSOCIATED CONTENT
■
S
* Supporting Information
Supplemental schemes outlining the synthesis of starting
materials, tables of attempted cyclization conditions, 1H
NMR for all compounds, and 13C NMR for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sames@chem.columbia.edu.
Notes
The authors declare no competing financial interest.
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