Studies on difficult intramolecular hydroaminations in the context of four syntheses of alkaloid natural products

Article abstract of DOI:10.1021/jo4023149

Examples of intramolecular alkene hydroaminations forming six-membered ring systems are rare, especially for systems in which the double bond is disubstituted. Such cyclizations have important synthetic relevance. Herein we report a systematic study of these cyclizations using recently developed Cope-type hydroamination methodologies. Difficult intramolecular alkene hydroaminations were used as key steps in syntheses of 2-epi-pumiliotoxin C, coniine, N-norreticuline and desbromoarborescidine A. This effort required the development of optimized hydroamination conditions to improve the efficiency of the cyclizations. Collectively, our results show that Cope-type cyclizations can be achieved on a variety of challenging substrates and proceed under similar conditions for both N-H and N-substituted hydroxylamines.

Full text of DOI:10.1021/jo4023149

Article
pubs.acs.org/joc
Studies on Difficult Intramolecular Hydroaminations in the Context
of Four Syntheses of Alkaloid Natural Products
Isabelle Dion, Jean-Franco
Jennifer Y. Pfeiffer, Anne-Catherine Bedard, and Andre M. Beauchemin*
̧ is Vincent-Rocan, Lei Zhang, Pamela H. Cebrowski, Marie-Eve Lebrun,
́
́
Centre for Catalysis Research and Innovation, Department of Chemistry, University of Ottawa, 10 Marie-Curie, Ottawa, Ontario K1N
6N5, Canada
S
* Supporting Information
ABSTRACT: Examples of intramolecular alkene hydroami-
nations forming six-membered ring systems are rare, especially
for systems in which the double bond is disubstituted. Such
cyclizations have important synthetic relevance. Herein we
report a systematic study of these cyclizations using recently
developed Cope-type hydroamination methodologies. Difficult
intramolecular alkene hydroaminations were used as key steps
in syntheses of 2-epi-pumiliotoxin C, coniine, N-norreticuline
and desbromoarborescidine A. This effort required the
development of optimized hydroamination conditions to
improve the efficiency of the cyclizations. Collectively, our results show that Cope-type cyclizations can be achieved on a
variety of challenging substrates and proceed under similar conditions for both N-H and N-substituted hydroxylamines.
minor changes in substrate structure can dramatically change
the potential energy surface of intramolecular hydroaminations.
Changing the ring size can significantly impact the nature of the
transition state: for example, a syn-amino metalation event can
require an unfavorable boat conformation in six-membered ring
systems, in contrast to a favorable envelope conformation in five-
membered ring systems.9 Changing the alkene substitution
pattern also inherently impacts the stability and reactivity of
reaction intermediates: for example, 2° metal−alkyl intermedi-
ates are formed upon insertion onto internal alkenes, while 1°
metal−alkyl intermediates are formed from terminal alkenes.
Such considerations likely account for the limited number of
examples of intramolecular alkene hydroaminations forming
complex six-membered ring systems. Herein we report a
systematic study of such difficult cyclizations performed in the
context of alkaloid synthesis and describe improved conditions
that led to syntheses of 2-epi-pumiliotoxin C, coniine, N-
norreticuline, and desbromoarborescidine A.
INTRODUCTION
■
The development of broadly applicable intramolecular C−N
bond-forming reactions is of major importance, as nitrogen
heterocycles are omnipresent in both natural and synthetic
biologically active molecules. A variety of transformations have
thus been elaborated for the synthesis of nitrogen heterocycles.
Among those, the hydroamination of C−C π-bonds has
recently emerged as a versatile strategy.1 Intramolecular
hydroaminations can provide saturated or unsaturated nitro-
gen-containing heterocycles from simple precursors, and
stereoselective variants are emerging to access enantioenriched
products.2
Various approaches have been used to overcome the high
activation energy arising from a destabilizing interaction
between the electron-rich nitrogen atom and the C−C π-
bond.1 Catalytic methodologies requiring the use of Brønsted
or Lewis acids,3 strong bases,4 or transition-metal complexes
(actinides, lanthanides, early or late transition metals)5−7 have
resulted in the formation of a variety of heterocyclic ring
systems. Reactions of alkynes are generally quite versatile, but
cyclizations of alkene precursors are often limited to specific
ring systems. Even if alkene hydroamination is more
challenging than alkyne hydroamination, the formation of
five-membered ring systems is generally facile with terminal
alkenes.
Known for over 35 years,10,11 Cope-type hydroamination has
become a convenient approach for the formation of saturated
nitrogen heterocycles (Scheme 1).12 Cyclization of hydroxyl-
amines onto both alkenes and alkynes is possible under mild
conditions: reactions occur below room temperature in
favorable systems. This thermal hydroamination reactivity
occurs via a concerted, five-membered transition state (i.e.,
the reverse of a Cope elimination13) under neutral conditions
that are inherently compatible with a variety of functional
groups.14 The general features of Cope-type cyclizations of
In contrast, related cyclizations of internal alkenes or
homologues leading to six-membered ring systems are usually
challenging. To achieve such cyclizations, substrates benefiting
from a conformational bias (e.g., the Thorpe−Ingold effect) or
terminal alkenes are typically reported, thus suggesting limited
synthetic applicability in unbiased systems.8 Indeed, apparently
Received: October 16, 2013
Published: November 26, 2013
© 2013 American Chemical Society
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Scheme 1. General Trends of Intramolecular Cope-Type
Hydroaminations12
Scheme 3. Intermolecular Cope-Type Hydroamination in
the Presence of Alcoholic Solvents
reaction sequences to address the challenging issue of
thermoneutrality associated with (intermolecular) alkene
hydroamination.21 Indeed, reaction sequences in which a
second step follows a hydroamination event allow the
formation of more stable “hydroamination” products and thus
minimize the possible reversibility that could result in synthetic
limitations. The Cope-type hydroamination/Meisenheimer
rearrangement (CHMR) sequence (Scheme 4) was thus
alkenes are presented in Scheme 1, which also outlines some of
the limitations associated with this approach.12
As shown in Scheme 1, the formation of six-membered ring
systems and cyclizations on internal alkenes are also typically
more challenging Cope-type hydroaminations. Much synthetic
work has been performed to understand and demonstrate the
applicability of this reactivity. The scope of the reaction has
been broadened over the years, and while the cyclization of five-
membered rings remains the most encountered intramolecular
transformation, several challenging intramolecular Cope-type
cyclizations have been used to form complex nitrogen
heterocycles (Scheme 2).12,15 Recently, Krenske, Holmes, and
Houk have also provided a wealth of computational insight on
these cyclizations.16
Scheme 4. Cope-Type Hydroamination/Meisenheimer
Rearrangement Sequence
Scheme 2. Examples of Complex Heterocycles Synthesized
Using Intramolecular Cope-Type Hydroamination of
Alkenes17
developed, building on the propensity of the N-oxide
intermediate (formed via a Cope-type hydroamination) to
engage in a [2,3]-Meisenheimer rearrangement.22 This
sequence provides access to neutral hydroamination products
that are more stable than their N-oxide intermediates and also
obviates the need for a proton transfer step. Another attractive
feature of this approach is that it benefits from the improved
reactivity reported for N-substituted hydroxylamines in
cyclization reactions (N−Me vs N−H, Scheme 1).12 In
addition, N,N-disubstituted hydroxylamine reagents proved in
our hands to be more thermally stable than the parent N−H
primary hydroxylamines.
The scope of the Cope-type hydroamination methodologies
illustrated in Schemes 3 and 4 had been explored mostly in
intermolecular systems. Given that the majority of published
Cope-type cyclizations formed five-membered ring systems,12,15
we embarked on a systematic study to evaluate our two
methodologies in the context of difficult cyclizations forming
six-membered ring systems and compare them with established
Cope-type cyclization protocols. At the center of these efforts
was our desire to explore the reported beneficial effect of
nitrogen substitution (R = Me ≫ R = H; Scheme 1),12 since we
felt that this reactivity trend could be different in the presence of
alcohols as solvents. Herein we present our results in the
context of the syntheses of four alkaloids: 2-epi-pumiliotoxin C,
coniine, N-norreticuline, and desbromoarborescidine A.
Collectively, our results provide two different approaches and
improved reaction conditions to perform challenging intra-
molecular alkene hydroamination reactions.
Over the past few years, our group has reinvestigated Cope-
type hydroamination reactions.18 Our early efforts to develop
intermolecular reactions unveiled remarkable solvent effects:
alcoholic solvents are necessary for intermolecular alkene
hydroaminations to occur in high yields.19 We also provided
computational evidence for stabilization of the N-oxide
intermediate and for a solvent-assisted proton transfer process
leading to the hydroamination products (Scheme 3).19b In
subsequent studies, t-BuOH emerged as a superior solvent for
the thermolysis of primary N-alkylhydroxylamines.20 Under
these conditions, various substrates, substitution patterns,
electronic biases, and functional groups are well-tolerated.
The efficiency achievable under the conditions optimized for
intermolecular reactivity suggested that difficult cyclizations and
thus novel heterocyclic syntheses could be enabled under
improved conditions.
RESULTS AND DISCUSSION
■
In parallel to this work, a novel reaction sequence was
developed to overcome thermal instability associated with
primary N-alkylhydroxylamines. We were first drawn toward
Building on encouraging results obtained in intermolecular
Cope-type hydroamination reactions, we initiated synthetic
studies on the pumiliotoxin C system.23 Pumiliotoxin C is a
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potent toxin found in the skin secretions of the poison
Dendrobatidae frogs and is structurally characterized by a cis-
decahydroquinoline backbone with minimal substitution.24
This natural product and ring system has also been a popular
synthetic target, and several epimeric structures are also present
in the alkaloid literature.25 Our retrosynthetic analysis of
pumiliotoxin C, illustrated in Scheme 5, features a difficult
intramolecular alkene hydroamination step.
However, in agreement with the strong solvent effects observed
for intermolecular variants of the reaction (vide supra),19,20 we
explored the use of alcohols as solvents. Gratifyingly, the use of
an n-PrOH/H2O solvent mixture allowed the cyclization of
both epimers in yields of 37% (1α → 8α) and 9% (1β → 8β)
(Scheme 7). Since this reaction was performed on a 50:50
Scheme 7. Pumiliotoxin C System: Key Cope-Type
a
Hydroamination and Final Step
Scheme 5. Retrosynthetic Analysis of Pumiliotoxin C
Featuring an Alkene Hydroamination Reaction
It was speculated that pumiliotoxin C could be obtained via
an intramolecular Cope-type hydroamination to close the cis
junction of the decalin under kinetic control, followed by
reduction to provide the desired alkaloid. This approach could
be readily tested since it required a cyclization precursor of
moderate complexity (1). Substrate 1 was thus synthesized in
eight steps from 3,4-epoxy-1-cyclohexene (Scheme 6). First,
Scheme 6. Pumiliotoxin C System: Synthesis of the
a
Cyclization Precursor
a
Reagents and conditions: (a) n-PrOH/H2O, μW, 180 °C. (b) Zn,
AcOH.
mixture of epimers, this result indicates that the cyclization of
1α was quite efficient despite the forcing conditions (74% of
the theoretical yield). The epimeric products were separated
and then then independently subjected to Zn/AcOH reduction
conditions to effect cleavage of the N−O bond, providing 2-epi-
pumiliotoxin C (9, from 8α) and pumiliotoxin C (from 8β).
Comparison with literature data allowed unambiguous
assignation of each product, consequently allowing ration-
alization of the stereochemical outcome of the key hydro-
amination step.
The faster cyclization observed for epimer 1α under the
Cope-type hydroamination conditions suggests a more stable
transition state for the cyclization of 1α relative to 1β. This
observation is consistent with a boat conformation for the six-
membered ring system being formed in the Cope-type
hydroamination transition state. Indeed, in the cyclization of
1α the n-propyl substituent is in a pseudoequatorial position (R
= H, Figure 1), whereas for epimer 1β it must adopt a
disfavored pseudoaxial orientation.23 Support for this hypoth-
esis was recently provided in the computational work of
Krenske, Holmes, and Houk,16 which showed that cyclizations
of six-membered rings occur via a boat conformation. Indeed,
a
Reagents and conditions: (a) MeLi, CuCN, Et2O, −78 °C, 88%. (b)
MeC(OEt)3, o-O2NC6H4OH (cat.), 170 °C, 74%. (c) DIBAL,
CH2Cl2, −78 °C, 77% (95% brsm). (d) 1-Nitrobutane, KOt-Bu,
THF/t-BuOH (1:1), 0 °C to RT, 78%. (e) Ac2O, DMAP, Et2O, RT.
(f) K2CO3, Et2O, 35 °C, >99%, two steps. (g) Zn, AcOH, THF, RT,
70%. (h) NaBH3CN, HCl, MeOH, 95%.
cuprate-mediated opening of conjugated epoxide 2 provided
the allylic alcohol 3 necessary for the following Johnson
orthoester Claisen rearrangement.26,27 With the key diastereo-
meric relationship installed, reduction afforded aldehyde 5, and
installation of the complete carbon backbone was performed
using an approach based on the Henry reaction.28 Zinc
reduction of nitroalkene 6 afforded oxime 7,29 which was
reduced upon treatment with NaCNBH3 under acidic
conditions to afford two hydroxylamine epimers of the
cyclization precursor (1α and 1β).
The use of the Cope-type hydroamination conditions
previously reported by Oppolzer (benzene, 180 °C, sealed
tube) did not yield any of the desired cyclization product.14b
Figure 1. 2-epi-Pumiliotoxin C: Proposed boat Cope-type hydro-
amination TS.
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this allows the required planar orientation between the alkene
and hydroxylamine functionalities during the hydroamination
event.
These adapted protic reaction conditions allowed for a
difficult intramolecular Cope-type hydroamination of unprece-
dented complexity. In contrast, the attempted cyclization of
precursor 10 using the CHMR sequence did not provide any of
the desired product, even under forcing reaction conditions (eq
1). This failure to cyclize is consistent with steric destabilization
reduction/Wittig olefination provided alcohol 15 in 74% yield,
and the cis and trans isomers (Z:E = 7:1) were separated by
column chromatography over AgNO3-impregnated silica gel.33
A Mitsunobu reaction using BocNHOBoc was then performed
on 15 to introduce the hydroxylamine functionality,34 and
subsequent deprotection using TFA afforded cyclization
precursor 14.
Lacking a Thorpe−Ingold effect and possessing distal alkene
substitution, substrate 14 failed to cyclize under standard
literature conditions, and decomposition of the hydroxylamine
occurred upon heating.14 With the conditions developed for the
pumiliotoxin C system, the cyclization precursor was heated
using microwave irradiation at 140 °C in n-propanol/H2O.
Unfortunately, only an 11% yield of the desired product was
isolated (eq 2). Sodium cyanoborohydride was added to
associated with the nitrogen substituent being eclipsed with the
n-Pr side chain in the proposed tricyclic transition-state
structure (R = allyl, Figure 1). The only product that could
be isolated was nitroxide radical 11, which was likely formed via
reaction with adventitious oxygen at high temperature.30
Nitroxide 11 could be purified by silica gel chromatography
increase the yield of the cyclization, as a beneficial effect of this
additive has been observed in intermolecular Cope-type
hydroamination reactions.19a This additive allowed the
formation of coniine hydroxylamine (13) in 23% yield, a 2-
fold increase from the original microwave cyclization attempts.
In contrast to the previous system, coniine precursor 14 is a
terminal primary hydroxylamine, whereas the pumiliotoxin
precursors 1 are internal hydroxylamines (i.e., branching is
present on the carbon). As also observed in our intermolecular
alkene hydroamination work,19 terminal primary hydroxyl-
amines are more sensitive under thermolysis conditions.
Despite considerable experimentation, degradation and dime-
rization35 were the main outcomes when coniine precursor 14
was submitted to a variety of reaction conditions.
As discussed before, we speculated that reaction sequences of
N,N-dialkylhydroxylamines such as the CHMR cascade could
be useful for challenging cyclizations because of the increased
stability of hydroxylamine precursors and a more favorable
thermodynamic profile. The allylation of hydroxylamine 14 was
therefore accomplished using potassium carbonate and allyl
bromide in THF, affording the desired product 16 in 68% yield
(Scheme 10). With the allylated precursor in hand, the
cyclization was attempted under various conditions. No
significant solvent effect was gathered from the use of protic
1
and showed H and 13C NMR spectral data nearly identical to
those of hydroxylamine 10. However, an OH stretch was not
present in the IR spectrum, and nitroxide 11 was significantly
more polar (TLC analysis). Further support for the structure of
11 was acquired by electron paramagnetic resonance spectros-
copy (see the Supporting Information for the EPR spectrum).
Coniine was then selected for further development on the
basis of the general features of the intramolecular Cope-type
hydroamination reactivity of alkenes. It presented itself as the
ideal target for the optimization of a difficult six-membered-ring
cyclization, as the requisite precursor would combine all of the
known challenges to this reactivity (see Scheme 1): N−H
substitution, cyclization to form a six-membered ring system,
and the presence of an alkyl substituent at the distal position of
the alkene. In addition, it called for the synthesis of a simple
cyclization precursor, as shown in Scheme 8.31,32
Scheme 8. Retrosynthetic Analysis of Coniine Featuring an
Alkene Hydroamination Reaction
Scheme 10. Coniine: Optimized CHMR Sequence and Final
a
Step
Preparation of the coniine cyclization precursor was
accomplished in four steps (Scheme 9). A one-pot DIBAL
a
Scheme 9. Coniine: Formation of the Cyclization Precursor
a
a
Reagents and conditions: (a, b) DIBAL-H, toluene, −60 °C, 6 h; then
Reagents and conditions: (a) Allyl-Br, K2CO3, THF (0.25 M), RT, 4
n-PrPPh3Br, n-BuLi, THF, reflux, 1 h, 74% (Z:E = 7:1). (c)
BocNHOBoc, PPh3, DIAD, THF, 0 °C, 1 h, 83%. (d) TFA/
CH2Cl2, 30 min, quant.
h, 68%. (b) H2O (10 equiv), benzene (0.01 M), 150 °C, 16 h, sealed
tube, 42% (+15% SM). (c) Zn (dust), 10 M AcOH, 55 °C, 4 h. (d)
Ac2O, pyridine, RT, 16 h, 10%.
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Scheme 11. Retrosynthetic Analysis of N-Norreticuline Featuring an Alkene Hydroamination Reaction
solvents, as could be expected since no proton transfer step was
necessary. The highest yield was obtained in deoxygenated
nonpolar solvents such as benzene. The addition of water to the
system did not improve the reaction yield but helped prevent
degradation of the starting material. Diluted reactions proved
more efficient, as the main side reactions were dimerization and
deallylation of the cyclized product.36 Under improved
conditions, a modest but reliable 42% yield could be isolated,
along with 15% of unreacted starting material 16. With the
cyclized product in hand, the synthesis of coniine was
completed upon cleavage of N−O bond using zinc dust in a
solution of acetic acid.37 Because of the toxicity associated with
coniine, this reaction was only performed on a small scale, and
the product obtained was then quickly reacted with acetic
anhydride in pyridine to successfully afford the protected N-
acetyl-( )-coniine 18 in an unoptimized 10% yield over two
steps.38
Scheme 12. N-Norreticuline: Synthesis of the Cyclization
Precursors
a
The CHMR sequence was required for the synthesis of
coniine as it capitalized on more robust starting materials and
more stable hydroamination products. Given the success of this
challenging cyclization, we felt that more complex synthetic
targets were now within reach. We selected N-norreticuline for
further exploration of difficult cyclizations. Part of the family of
benzyltetrahydroisoquinolines, reticuline is an intermediate in
the biosynthetic pathway of morphinan, aporphine, proto-
berberine, and pavinan alkaloids.39 From an alkene hydro-
amination perspective,40 we speculated that such cyclization
would be slightly more facile because of favorable conforma-
tional effects and the activating effect of aromatic groups at the
distal alkene position.14b Retrosynthetic analysis of N-norreticu-
line (Scheme 11) called for the synthesis of two types of
cyclization precursors (22 and 23) required for comparison of
the two Cope-type hydroamination methodologies.
a
Reagents and conditions: (a) Br2, MeOH, 0 °C, 2 h, 76%. (b) PPh3,
CBr4, Zn (dust), CH2Cl2, RT, 1 h, quant. (c) n-BuLi, THF, −78 °C, 2
h, 80%. (d) PdCl2(PPh3)2, CuI, Et3N, RT, 24 h, 87%. (e) NH4OAc,
MeNO2, AcOH, 100 °C, 4 h, 82%. (f) SnCl2·H2O, EtOAc, RT, 10 h,
59%. (g) Lindlar catalyst, H2 (1 atm), EtOAc/1-hexene (1:1), 5 h,
87%. (h) NaCNBH3, pH ∼3, MeOH, RT, 1 h. (i) R = Me: 2-methallyl
chloride, DBU, DMF/THF (1:5), reflux, 2 h, 87%; R = H: K2CO3,
allyl-Br, THF, RT, 4 h, 50%.
Table 1. N- Norreticuline: Optimization of the Key
Cyclization
The synthesis of the cyclization precursors from aldehydes
24 and 25 is shown in Scheme 12. Bromination of protected
vanillin derivative 24 afforded the Sonogashira precursor 26 in
good yield.41 A Corey−Fuchs reaction sequence was performed
on protected iso-vanillin derivative 25, affording alkyne 27 in
80% yield.42 The two fragments were then combined using a
Sonogashira reaction to provide the disubstituted alkyne (not
shown).43 A modified Henry reaction sequence then proceeded
smoothly to provide nitroalkene 28, and tin-mediated reduction
afforded oxime 29.44 With the desired structural elements in
place, partial hydrogenation of the alkyne was effected with
Lindlar’s catalyst in the presence of a sacrificial alkene,
providing the cis-alkene (30, not shown) in 87% yield. The
oxime was then reduced with sodium cyanoborohydride to give
the somewhat labile hydroxylamine 22, which was rapidly
allylated or methallylated to provide the cyclization precursors
23a and 23b.
a
entry
substrate
R
conditions
yield (%)
27
1
2
3
4
5
22
H
H
A
A
B
B
B
b
22
51
23a
23b
23b
allyl
45
57
allyl
c
methallyl
54
a
Conditions A: n-PrOH (0.01 M), 120 °C, 16 h, sealed tube.
Conditions B: H2O (10 equiv), benzene (0.01 M), 120 °C, 18−24 h,
sealed tube. NaCNBH3 (1 equiv). 32% of the E isomer of the
b
c
starting material was also isolated.
(benzene, 120 °C, sealed tube) afforded <7% yield of the
desired product.14 However, in contrast to our previous results,
no desired product could be obtained under similar conditions
upon heating in n-PrOH/H2O. Thus, we performed the Cope-
type cyclizations on the free hydroxylamine 22 simply by
heating in n-PrOH:19a this provided lower yields than those
We then tested the key hydroamination step, and the results
are shown in Table 1. In agreement with our previous results,
the attempted cyclization of 22 under literature conditions
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obtained from the CHMR sequence, which is consistent with
the trends observed with coniine (Table 1, entries 1 and 2 vs
3−5). Interestingly, we again observed a beneficial effect using
NaCNBH3 as an additive (entry 1 vs 2).19a The CHMR
sequence afforded N-norreticuline precursor 21 in modest but
reliable yields (entries 3−5). The slightly higher yields observed
with methallyl substrate 23b can be attributed to the increased
stability of the methallyl substituent, which is less prone to
degradation and side reactions.45 Interestingly, with this
substrate the E isomer of the starting material was also
recovered in 32% yield after the reaction, confirming that the
intramolecular Cope-type hydroamination is reversible under
the reaction conditions.46 It should be noted that all of the
sequential reactions were performed at lower temperatures than
those used for the synthesis of coniine (120 vs 140 °C), which
supports the hypothesis that a slightly beneficial conformational
effect is present in the N-norreticuline system.
Bromination at the 2-position50,51 allowed the formation of the
heteroaryl halide necessary for the ensuing Sonogashira
reaction.52 Hydrogenation using Lindlar’s catalyst in the
presence of a sacrificial alkene afforded the cis-alkene needed
for the key step. However, this procedure proved to be scale-
sensitive, with little product formation occurring when the
reaction was performed on more than 500 mg. Thus, we opted
to perform partial hydrogenation of the alkyne using Rose-
nmund’s catalyst, and the desired alkene was obtained in 97%
yield.53 The ester reduction provided alcohol 37 in 77% yield.54
Oxidation under Parikh−Doering conditions afforded aldehyde
38.55 The hydroxylamine moiety was then incorporated via
reductive amination, and the desired hydroamination precursor
40 was produced in 61% yield over two steps. Deprotection of
the alcohol was also observed during the reduction step, thus
obviating the need for an additional deprotection step.
Hydroxylamine 40 was also derivatized to afford the allylated
and methallylated substrates in 48% and 38% yield, respectively.
As for the previous syntheses, the key cyclization step was
attempted on the free hydroxylamine and on its allyl and
methallyl derivatives (Table 2). In these experiments, we again
observed a beneficial effect of using NaCNBH3 as an
additive.19a Indeed, the attempted cyclization in n-PrOH led
only to degradation of the starting material (entry 1), while a
modest 40% yield was obtained in the presence of NaCNBH3
(entry 2). Significantly higher yields were obtained using a
combination of two changes. First, we performed the reaction
using tertiary alcohols as solvents, in agreement with our recent
observation that decomposition of linear, primary hydroxyl-
amines is minimized when the heating is performed in t-
BuOH.20 Heating was also performed using microwave
irradiation, which provided increased yields of the Cope-type
hydroamination product over the sealed-tube conditions both
in the presence and in the absence of NaCNBH3 (entries 3 and
4 vs 5 and 6). Gratifyingly, the desired product 42 was obtained
in 87% yield with the use of t-BuOH as the solvent, NaCNBH3
as the additive, and microwave irradiation. The use of
structurally similar t-amyl alcohol provided similar results
under microwave irradiation (entry 6 vs 8). The CHMR
sequence also afforded the desired cyclization products reliably
but in modest yields. The methallyl substrate 41b provided the
cyclized product 43b in 53% yield, while the allyl substrate 41a
provided the cyclized product 43a in 64% yield. Again, we
believe this is due to the increased steric hindrance associated
with the methallyl substituent, which prevents the Meisen-
heimer rearrangement from occurring easily. This result is in
contrast to what was observed in the synthesis of N-
The synthesis of N-norreticuline was completed by reduction
of the N−O bond followed by partial deprotection of the
phenols (Scheme 13).47 This provided the desired product in a
total of 11 steps and 11% yield.48
a
Scheme 13. N-Norreticuline: Final Steps
a
Reagents and conditions: (a) Zn (dust), AcOH/H2O, RT, 5 h, 78%.
(b) BCl3, CH2Cl2, −10 °C to RT, > 99%.
Finally, a similar study leading toward the synthesis of
desbromoarborescidine A was undertaken. We selected this
simple bioactive natural product as a representative member of
the family of β-carboline alkaloids.49 The retrosynthetic analysis
is shown in Scheme 14. It was planned that the final cyclization
to give desbromoarborescidine A would come from a reductive
amination, while the key intramolecular hydroamination step
would allow the formation of the internal six-membered ring.
The alkene necessary for this reaction would be installed via a
palladium-catalyzed cross-coupling on a suitable brominated
indole.
The synthesis of the hydroamination precursors was
performed as shown in Scheme 15. The acid was first esterified
in acidified n-propanol, after which the indole was protected.
Scheme 14. Desbromoarborescidine A: Retrosynthetic Analysis
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a
Scheme 15. Desbromoarborescidine A: Synthesis of the Common Aldehyde
a
Reagents and conditions: (a) HCl (g), n-PrOH, reflux, 3 h, quant. (b) NBS, CH2Cl2, 0 °C, 2 h. (c) Boc2O, DMAP, CH2Cl2, RT, 0.5 h, 61% over
two steps. (d) Pd(PPh3)4, CuI, i-PrNH2, DME, 70 °C, 3.5 h, quant. (e) H2, Pd/BaSO4, quinoline, EtOH, RT, 7 h, 97%. (f) LiAlH4, THF, 0 °C, 20
min, 77%. (g) SO3·pyr, Et3N, DMSO, CH2Cl2, 0 °C, 1.5 h, 69%. (h) NH2OH·HCl, NaOAc, i-PrOH, RT, 1.5 h, 88%. (i) NaCNBH3, pH ∼3, MeOH,
RT, 1 h, 69%. (j) Allyl-Br, K2CO3, THF, RT, 6 h, 48%. (k) 2-Methallyl chloride, DBU, DMF/THF (1:5), reflux, 4 h, 38%
conditions, providing desbromoarborescidine A in a total of 13
steps and 8% overall yield.56,57
Table 2. Desbromoarborescidine A: Optimization of the
Hydroamination Step
a
CONCLUSION
■
This study allowed the comparison of novel methodologies in
the context of difficult intramolecular hydroaminations forming
six-membered ring systems. Cyclizations using Cope-type
hydroamination methodologies were achieved as key steps in
the syntheses of 2-epi-pumiliotoxin C, coniine, N-norreticuline,
and desbromoarborescidine A. Cyclizations of N−H hydroxyl-
amines in alcoholic solvents using NaCNBH3 as additive or
cyclizations of N-allyl (or N-methallyl) precursors using the
Cope-type hydroamination/Meisenheimer rearrangement
(CHMR) sequence proved to be reliable synthetic tools for
the difficult cyclizations leading to six-membered ring systems.
In addition, cyclization of both N−H hydroxylamine and N-
allyl (or N-methallyl) precursors occurred under similar
reaction conditions, suggesting that the important beneficial
effect of nitrogen substitution previously reported for intra-
molecular Cope-type hydroaminations depends on the reaction
conditions employed. Overall, these studies show that two
approaches can be utilized to minimize hydroxylamine
decomposition under thermolysis and consequently represent
intramolecular alkene hydroamination procedures of broad
applicability for the synthesis of alkaloid natural products.
entry
substrate
solvent
additive
yield (%)
1
2
40
40
40
40
40
40
40
40
41a
41b
n-PrOH
n-PrOH
t-BuOH
t-BuOH
−
0
40
48
77
70
87
44
80
64
53
NaCNBH3
3
−
4
NaCNBH3
−
NaCNBH3
b
5
t-BuOH
t-BuOH
c
6
7
t-AmOH
t-AmOH
C6H6
−
b
8
NaCNBH3
d
9
H2O
d
10
C6H6
H2O
a
Conditions: additive (1 equiv), solvent (0.01 M), 120 °C, 16 h, sealed
b
c
d
tube. μW irradiation, 4 h. μW irradiation, 16 h. 10 equiv.
norreticuline, where the methallylated substrate provided the
best results.
EXPERIMENTAL SECTION
■
In order to complete the total synthesis of desbromoarbor-
escidine A, the indole nitrogen was deprotected under acidic
conditions (Scheme 16). The N−O bond was then cleaved
using zinc dust, affording amino alcohol 43 in 73% yield for the
one-pot procedure. The primary alcohol was then activated
using SOCl2, and the cyclization was effected under basic
General Information. All of the reactions were performed in
flame-dried or oven-dried glass round-bottom flasks or 15−48 mL
sealed tubes under argon. Purification of the reaction products was
carried out by flash column chromatography using silica gel (40−63
μm). Analytical thin-layer chromatography (TLC) was performed on
aluminum sheets precoated with silica gel 60 F254, cut to size.
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a
Scheme 16. Desbromoarborescidine A: Final Steps
a
Reagents and conditions: (a) TFA, CH2Cl2, RT, 12 h; then H2O, Zn (dust), 16 h, 73%. (b) SOCl2, CH2Cl2, sealed tube, 40 °C, 3 h. (c) 2 M
NaOH, CH2Cl2, RT, 16 h, 55% over two steps.
Visualization was accomplished with UV light followed by dipping in a
potassium permanganate solution and/or heating, unless otherwise
noted. Microwave reactions were run in a Biotage microwave reactor
using appropriate glassware and monitoring the temperature with an
external sensor.
the light-beige solution, which took about 1 h. The solution was
cooled to −78 °C, and an ether solution (0.40 M, 40 mL) of 3,4-
epoxycyclohexene 2 (1.4 g, 14 mmol) was added via cannula. The
bright-yellow mixture was allowed to slowly warm to room
temperature over 5 h, and then the reaction was quenched with 130
mL of a saturated NH4Cl solution. After filtration through a Celite pad
and washing of the ether layer with a brine solution, the organic phase
was dried over sodium sulfate and carefully concentrated in vacuo
because of its volatility. The product was isolated as a colorless liquid
(1.38 g, 12.3 mmol, 88% yield) after column chromatography (30−
40% Et2O/hexanes). The product was sometimes even used without
purification directly in the next step. TLC: Rf 0.14 (20% EtOAc/
1H and 13C NMR spectra were recorded on 300 or 400 MHz and
75 or 100 MHz spectrometers, respectively, at ambient temperature.
Spectra are reported in parts per million using solvent as the internal
1
standard (CDCl3 at 7.26 ppm or C6D6 at 7.15 ppm for H NMR and
1
CDCl3 at 77.0 ppm or C6D6 at 128.1 ppm for 13C NMR). H NMR
data are reported as follows: multiplicity (ap = apparent, br = broad, s
= singlet, d = doublet, t = triplet, q = quartet, m = multiplet),
integration, coupling constant(s) in hertz. High-resolution mass
spectroscopy (HRMS) was performed on a mass spectrometer
(magnetic sector) with an electron beam of 70 eV. Infrared (IR)
spectra were obtained using neat thin films on a sodium chloride disk.
Melting points were determined using a melting point apparatus.
Materials. Dichloromethane, isopropanol, DME, and toluene were
dried by distillation over calcium hydride. Tetrahydrofuran and diethyl
ether were dried by distillation over sodium/benzophenone ketyl.
DMSO and DMF were dried over activated 3 Å molecular sieves.
Triethylamine was dried by distillation over calcium hydride, while
diisopropylamine and diethylamine were dried by distillation over
KOH pellets. Unless otherwise noted, all commercial materials were
used without further purification. Most of the procedures for
compounds 13−16 (coniine) and 19−31 (norreticuline) have been
reported previously.22
1
hexanes). The H and 13C NMR spectral data were found to be in
good agreement with those in the literature61 except that an extra peak
1
at 2.72 ppm (s, 1H) was found in the H NMR spectrum. The trans
stereochemistry was confirmed by comparing the obtained 13C NMR
data with those for the trans and cis stereoisomers reported in the
literature.62
( )-Ethyl 2-((1R*,6S*)-6-Methylcyclohex-2-enyl)acetate (4).
Prepared according to a literature procedure.27 A mixture of allylic
alcohol 3 (4.8 g, 42 mmol, 1.0 equiv), 2-nitrophenol (0.55 g, 3.9
mmol, 0.090 equiv), and triethyl orthoacetate (0.100 M, 434 mL) was
heated at 170 °C for a period of 6 h with a Dean−Stark apparatus. The
Dean−Stark trap was emptied every hour. After completion of the
reaction, the triethyl orthoacetate was then distilled through a Vigreux
column under vacuum at 65 °C. The distillate was purified by column
chromatography (3% ether/hexanes) to give a colorless liquid with a
flowery smell (5.7 g, 31 mmol, 74% yield). TLC: Rf 0.71 (20% EtOAc/
hexanes). 1H NMR (CDCl3, 300 MHz): δ 5.68 (ddd, J = 9.0, 5.1, and
3.4 Hz, 1H), 5.50 (ddd, J = 10.1, 4.2, and 2.1 Hz, 1H), 4.13 (q, J = 7.1
Hz, 2H), 2.49 (dd, J = 13.5 and 4.0 Hz, 1H), 2.24−2.10 (m, 2H),
2.02−1.96 (m, 2H), 1.72−1.61 (m, 1H), 1.49−1.27 (m, 2H), 1.24 (t, J
= 7.1 Hz, 3H), 0.97 (d, J = 6.4 Hz, 3H). 13C NMR (CDCl3, 75 MHz):
δ 173.1, 129.3, 127.4, 60.2, 39.4, 39.3, 33.0, 29.3, 24.2, 19.8, 14.2. IR
(film): 3021, 2958, 2926, 2873, 1736, 1459, 1370, 1342, 1270, 1246,
1187, 1152, 1036 cm−1. Exact mass calcd for C11H18O2 [M]+,
182.1307; not found. MS (CI-LRMS) m/z (relative intensity): 95
(100%), 94 (98%), 93 (92%), 79 (90%), 108 (87%), 139 (84%), 109
(76%), 137 (70%), 183 (44%), 182 (33%).
( )-2-((1S*,6R*)-6-Methylcyclohex-2-enyl)acetaldehyde (5).
Prepared according to a literature procedure.63 To a flame-dried flask
under an atmosphere of argon was added ester 4 (0.26 g, 1.4 mmol) in
dichloromethane (0.15 M, 9.3 mL). The mixture was cooled with an
ether/dry ice bath to below −78 °C. After a few minutes of stirring,
diisobutyl aluminum hydride (1.0 M in toluene, 1.4 mL, 1.0 equiv) was
added along the side of the flask. The reaction mixture was stirred for 1
h, and then the reaction was quenched with dry MeOH (1.4 mL) and
a saturated solution of Rochelle salt (5.6 mL). The mixture was diluted
with ether, removed from the ice bath, and stirred for 20 min. The
solution was filtered over Celite, which was further washed with ether.
The organic layer was dried with sodium sulfate, filtered, and
concentrated in vacuo. Purification by column chromatography (16%
ether/hexanes) gave the aldehyde as a light-yellow oil (0.15 g, 1.1
mmol, 77% yield, 95% brsm). TLC: Rf 0.38 (8% ether/hexanes). The
aldehyde was then used for the following reaction.
3,4-Epoxycyclohexene (2). Prepared according to a literature
procedure.58 To a stirring mixture of 1,3-cyclohexadiene (12.7 g, 15.1
mL, 159 mmol) and anhydrous sodium carbonate (86 g, 635 mmol,
4.0 equiv) in dichloromethane (0.900 M, 174 mL) at −1 °C was added
dropwise a commercially available 32% solution of peracetic acid (12.6
g, 35.1 mL, 167 mmol, 1.05 equiv) in dilute acetic acid that had been
pretreated with a small amount of sodium acetate. The mixture was
stirred at room temperature until a negative peroxide test was obtained
with starch−iodide paper. By TLC, the reaction looked done after 3 h.
The solid salts were removed by filtration and were washed well with
additional solvent. Distillation through a Vigreux column permitted
the separation of the solvent from the subsequent collection of the
product in an ice-cold collecting flask as a light-yellow liquid (7.7 g, 80
1
mmol, 50%). TLC: Rf 0.57 (20% EtOAc/hexanes). The H NMR
spectral data were found to be in good agreement with those in the
literature.59
( )-(1S*,4S*)-4-Methylcyclohex-2-enol (3). Prepared according
to a literature procedure26 using copper cyanide azeotroped with dry
toluene (2 mL of toluene for each 100 mg of copper cyanide) before
use in the reaction.60 The salt content of the starting methyllithium ether
solution was said to be very important. A common ion effect seems to cause
the cyanocuprate to be quite insoluble, to the extent that the reaction may
not take place at all in some instances when the solutions are not salt-free.
The amount of organocuprate could be lowered to 2 equiv without affecting
the yield. Copper cyanide (3.8 g, 42 mmol, 3.0 equiv) was gently flame-
dried under vacuum in the reaction flask. It was then suspended in
dried ether (0.070 M, 210 mL) under an inert atmosphere before
being cooled to −40 °C. An equimolar amount of freshly titrated
methyllithium solution (28 mL, 42 mmol, 3.0 equiv, 1.5 M in diethyl
ether) was slowly added. The suspension was then stirred at the same
temperature until no copper cyanide remained visible at the bottom of
( )-1-((1S*,6R*)-6-Methylcyclohex-2-enyl)-3-nitrohexan-2-
ol. Prepared according to a modified literature procedure28 but can
also be prepared in an aqueous medium.64 To a flame-dried flask was
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added aldehyde 5 (0.40 g, 2.9 mmol), nitrobutane (0.36 g, 3.5 mmol,
1.5 equiv) in a 1:1 mixture of THF (1.9 M, 1.5 mL), and tert-butanol
(1.9 M, 1.5 mL). The reaction mixture was cooled to 0 °C, and
potassium tert-butoxide (0.32 g, 2.9 mmol, 1.0 equiv) was added. The
ice bath was removed after 15 min, and the mixture was stirred at
room temperature for 2 h. The reaction was quenched with a saturated
solution of ammonium chloride, and the mixture was extracted with
ether. The combined organic layers were dried with sodium sulfate,
filtered, and concentrated in vacuo. Purification by column
chromatography (16% ether/hexanes) gave the product as a light-
yellow oil (0.546 g, 2.26 mmol, 78% yield; mixture of diaster-
eoisomers). TLC: Rf 0.11 (8% ether/hexanes). 1H NMR (CDCl3, 300
MHz): δ 5.78−5.66 (m, 1H), 5.66−5.48 (m, 1H), 4.44 (ddd, J = 14.9,
7.9, and 3.6 Hz, 1H), 4.23−4.10 (m, 1H), 2.42 (dd, J = 18.4 and 4.3
Hz, 1H), 2.21−2.04 (m, 1H), 2.04−1.92 (m, 2H), 1.83−1.59 (m, 3H),
1.54 (t, J = 6.2 Hz, 1H), 1.48−1.23 (m, 4H), 1.03−0.88 (m, 6H). 13C
NMR (CDCl3, 75 MHz): δ 129.7, 128.7, 128.1, 127.7, 92.6, 92.1, 71.0,
69.8, 39.4, 38.3, 37.6, 37.4, 33.0, 31.8, 30.3, 29.5, 29.4, 28.2, 24.2, 23.4,
19.8, 19.7, 19.3, 13.5, 13.5. IR (film): 3447, 2964, 2922, 2877, 1546,
1455, 1375, 1356 cm−1. HRMS (EI) m/z (relative intensity): 237.9917
(11.8%), 236.9803 (62.2%), 218.9570 (23.6%), 215.0195 (35.5%),
214.9851 (34.8%), 158.9971 (28.6%), 138.1005 (21.1%), 137.0224
(93.1%), 109. 0996 (47.3%), 95.0855 (75.6%).
( )-(3S*,4R*)-4-Methyl-3-((Z)-3-nitrohex-2-enyl)cyclohex-1-
ene (6). Prepared according to a literature procedure.28b A solution of
the nitroalcohol (0.16 g, 0.67 mmol) and acetic anhydride (0.075 g,
0.069 mL, 0.73 mmol, 1.1 equiv) in ether (0.15 M, 4.4 mL) was cooled
to 0 °C and stirred for a few minutes. DMAP (0.016 g, 0.13 mmol,
0.20 equiv) was added, and the reaction mixture was allowed to stir at
room temperature for 2 h. The mixture was diluted with ether, and the
reaction was quenched with water. The organic layer was washed
sequentially with a saturated solution of sodium bicarbonate and then
ammonium chloride. The aqueous layers were back-extracted with
ether. The combined organic layers were dried with sodium sulfate,
filtered, and concentrated in vacuo. The crude material was used
directly for the next reaction.
To the crude nitroacetate was added t-BuOH (0.14 M, 4.8 mL) at
room temperature followed by potassium carbonate (0.11 g, 0.80
mmol, 1.2 equiv). The reaction mixture was warmed to 35 °C and
stirred at that temperature overnight under an argon atmosphere. The
reaction was quenched with water, and the mixture was extracted with
ether. The combined organic layers were dried with sodium sulfate,
filtered, and concentrated in vacuo. The crude material was purified by
flash chromatography (4% ether/hexanes) to afford 6 as a yellow oil
(0.15 g, 0.67 mmol, >99% yield). TLC: Rf 0.26 (4% ether/hexanes).
1H NMR (CDCl3, 300 MHz): δ 7.12 (dd, J = 8.8 and 6.7 Hz, 1H),
5.76 (ap dq, J = 10.1 and 2.3 Hz, 1H), 5.45 (ap dq, J = 10.0 and 2.1
Hz, 1H), 2.66−2.50 (m, 2H), 2.48−2.32 (m, 1H), 2.31−2.18 (m, 1H),
2.09−1.90 (m, 3H), 1.76−1.62 (m, 1H), 1.61−1.46 (m, 2H), 1.45−
1.21 (m, 2H), 1.00 (d, J = 6.3 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H). 13C
NMR (CDCl3, 75 MHz): δ 152.3, 135.1, 128.9, 128.6, 42.1, 32.8, 32.2,
29.7, 28.3, 24.4, 21.2, 20.0, 13.7. IR (film): 3021, 2964, 2926, 2842,
1664, 1520, 1459, 1432, 1379, 1337, 1105, 847, 729 cm−1. HRMS
(EI): exact mass calcd for C13H21NO2 [M]+, 223.1572; found,
223.1581.
mixture was filtered over Celite, and the aqueous layer was extracted
with ethyl acetate. The combined organic layers were dried with
sodium sulfate, filtered, and concentrated in vacuo. The crude material
was purified by flash chromatrography (20% ether/hexanes) to afford
7 as a clear oil (0.237 g, 1.13 mmol, 70% yield). TLC: Rf 0.37 and 0.31
(20% EtOAc/hexanes) because of the two oxime stereoisomers.
1
Characterization was done on the mixture of stereoisomers. H NMR
(CDCl3, 300 MHz): δ 8.50 (br s, 1H), 5.75−5.66 (m, 1H), 5.60 (ddd,
J = 10.1, 4.0, and 1.9 Hz, 0.6 H), 5.54 (ddd, J = 10.1, 4.2, and 2.1 Hz,
0.4H), 2.44−2.06 (m, 4H), 2.01−1.95 (m, 2H), 1.81−1.60 (m, 3H),
1.60−1.38 (m, 4H), 1.38−1.17 (m, 1H), 0.99−0.91 (m, 6H). 13C
NMR (CDCl3, 75 MHz): δ 162.1, 162.1, 130.2, 130.0, 127.3, 127.2,
42.4, 41.9, 36.2, 32.2, 32.1, 30.8, 30.0, 29.8, 29.7, 29.6, 29.1, 24.5, 24.5,
24.3, 20.0, 19.6, 19.1, 14.4, 13.9. IR (film): 3231, 3100, 3019, 2959,
2924, 2872, 2842, 1652, 1455, 1435, 1376, 955 cm−1. HRMS (EI):
exact mass calcd for C13H23NO [M]+, 209.1780; found, 209.1793.
(
)-N-Hydroxy-1-((1S*,6R*)-6-methylcyclohex-2-enyl)-
hexan-3-amine (1). Prepared according to a literature procedure14a
and worked up using a known method.65 To a solution of oxime 7
(0.053 g, 0.26 mmol) in MeOH (0.078 M, 3.3 mL) was added a crystal
of methyl orange (just enough to render a yellow color to the
solution). Sodium cyanoborohydride (0.018 g, 0.28 mmol, 1.1 equiv)
was then added under an inert atmosphere. The yellow solution was
stirred at room temperature, and a HCl/MeOH (1:5) solution was
added dropwise so as to keep the solution pink. After the solution had
stayed pink for 30 min, the reaction was analyzed by TLC and judged
to be complete. The mixture was neutralized with a 25% aqueous
NaOH solution and then poured into brine. The suspension was
extracted with dichloromethane. The combined organic extracts were
dried over sodium sulfate, filtered, and concentrated in vacuo.
Purification by flash chromatography (60% ether/hexanes) gave a
colorless oil (0.051 g, 0.24 mmol, 95% yield). TLC: Rf 0.08 (20%
EtOAc/hexanes). Characterization was performed on a mixture of
1
stereoisomers. H NMR (CDCl3, 500 MHz): δ 6.45 (br s, 2H), 5.66
(ddd, J = 10.0, 5.9, and 3.5 Hz, 1H), 5.56−5.52 (m, 1H), 2.81−2.77
(m, 1H), 1.98−1.97 (m, 2H), 1.74−1.58 (m, 2H), 1.57−1.45 (m, 3H),
1.45−1.21 (m, 7H), 0.95 (d, J = 6.6 Hz, 3H), 0.91 (t, J = 6.7 Hz, 3H).
13C NMR (CDCl3, 126 MHz): δ 130.5, 130.5, 126.8, 126.8, 61.7, 61.7,
42.4, 42.4, 33.7, 33.4, 32.4, 32.3, 29.8, 29.8, 29.6, 29.6, 28.0, 27.9, 24.4,
24.4, 20.0, 19.1, 19.0, 14.3. IR (film): 3256, 3020, 2959, 2929, 2868,
1652, 1458, 1431, 1378, 686 cm−1. HRMS (EI): exact mass calcd for
C13H25NO [M]+, 211.1936; found, 211.1919.
( )-N-Hydroxy-(2R*,4aS*,5R*,8aR*)-decahydro-5-methyl-2-
propylquinoline [( )-N-Hydroxy-2-epi-pumiliotoxin C (8α)]
and ( )-N-Hydroxy-(2S*,4aS*,5R*,8aR*)-decahydro-5-methyl-
2-propylquinoline [( )-N-Hydroxypumiliotoxin C (8β)]. Because
of facile oxidation of the hydroxylamine, great care was taken to eliminate
traces of oxygen from the reaction mixture. n-PrOH and H2O were
distilled under argon prior to use. To a pressure vessel equipped with a
magnetic stir bar was added hydroxylamine 1 (0.0955 g, 0.452 mmol),
which was then dissolved in a mixture of n-PrOH (0.15 M, 3.0 mL)
and H2O (0.081 mL, 4.5 mmol, 10 equiv) under argon. The solution
was degassed at 0 °C by bubbling argon for 10 min. The pressure
vessel was capped and it was heated in the microwave at 180 °C for 5
h. After the mixture was cooled to room temperature, more H2O was
added, and the mixture was extracted with EtOAc. The combined
organic extracts were dried over sodium sulfate, filtered, and
concentrated in vacuo. Purification by column chromatography (10−
60% Et2O/hexanes) gave N-hydroxy-2-epi-pumiliotoxin C (0.036 g,
0.17 mmol, 37% yield) with 20% Et2O/hexanes as the eluent and N-
hydroxypumiliotoxin C (0.0089 g, 0.042 mmol, 9.3% yield) with 8%
Et2O/hexanes as the eluent, both as white solids. The unreacted
starting hydroxylamine was also found with 60% Et2O/hexanes as the
eluent (0.0389 g, 0.184 mmol, 41% yield) as one stereoisomer.
Data for 8α. TLC: Rf 0.29 (20% EtOAc/hexanes). 1H NMR
(CDCl3, 300 MHz): δ 3.47 (d, J = 9.9 Hz, 1H), 2.75 (t, J = 9.3 Hz,
1H), 2.10−1.10 (m, 17H), 1.04 (d, J = 7.0 Hz, 3H), 0.91 (t, J = 7.1 Hz,
3H). 13C NMR (CDCl3, 75 MHz): δ 61.5, 58.6, 42.0, 35.5, 33.4, 30.4,
27.1, 24.5, 19.9, 19.0, 18.0, 14.5, 14.3. IR (film): 3127, 2955, 2933,
(
)-1-((1R*,6S*)-6-Methylcyclohex-2-enyl)hexan-3-one
Oxime (7). Prepared according to a literature procedure.29 A round-
bottom flask was charged with a stir bar, and zinc dust (1.04 g, 15.9
mmol, 9.90 equiv) was added. The flask was flame-dried under argon.
1,2-Dibromoethane (0.035 mL) was added in THF (0.5 mL), and the
solution was flamed to boiling three times. Chlorotrimethylsilane
(0.032 mL) was added, and the reaction mixture was stirred for
approximately 5 min at room temperature. Once the zinc was
successfully activated, half of the THF (0.95 M, 17 mL) was added,
and the mixture was cooled to 0 °C. A 4 M solution of acetic acid (8.0
mL, 31.9 mmol, 19.8 equiv) was added, and the reaction mixture was
stirred for a few more minutes. Nitroalkene 6 (0.359 g, 1.61 mmol)
was diluted with the rest of the THF and then added by cannula into
the reaction mixture, which was stirred for 5 min. The reaction was
quenched slowly with a saturated solution of sodium bicarbonate. The
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2863, 1464, 1371 cm−1. HRMS (EI): exact mass calcd for C13H25NO
[M]+, 211.1936; found, 211.1952.
(0.044 g, 0.72 mmol). Argon was bubbled in the solution for 10 min.
The tube was sealed and heated at 140 °C for 16 h, after which the
reaction mixture was cooled to room temperature, dissolved in EtOAc,
and then washed twice with brine. The organic extract was then dried
on Na2SO4 and concentrated in vacuo to give a residue. The crude
mixture was purified by silica gel column chromatography (80%
EtOAc in hexanes) to yield the desired compound as a colorless oil
Data for 8β. TLC: Rf 0.58 (20% EtOAc/hexanes). 1H NMR
(CDCl3, 300 MHz): δ 2.73 (br s, 1H), 2.47 (t, J = 10.0 Hz, 1H), 2.37
(d, J = 14.2 Hz, 1H), 2.05−1.58 (m, 6H), 1.57−1.17 (m, 9H), 1.08−
0.94 (m, 1H), 0.92 (t, J = 7.2 Hz, 3H), 0.81 (d, J = 6.5 Hz, 3H). 13C
NMR (CDCl3, 75 MHz): δ 69.0, 67.3, 44.7, 35.9, 35.2, 29.0, 28.5, 26.3,
25.9, 20.8, 19.9, 18.9, 14.4. IR (film): 3412, 3356, 2963, 2952, 2928,
2872, 2859, 2823, 1454, 1443 cm−1. HRMS (EI): exact mass calcd for
C13H25NO [M]+, 211.1936; found, 211.1936.
1
(0.023 g, 23%). TLC: Rf 0.26 (80% EtOAc/hexanes). H NMR (300
MHz, CDCl3): δ 3.32 (ap d, J = 11.3 Hz, 1H), 2.49 (ap t, J = 13.0 Hz,
1H), 2.29−2.22 (m, 1H), 1.96−1.82 (m, 2H), 1.74−1.54 (m, 3H),
1.44−1.10 (m, 5H), 0.92 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 67.5, 59.7, 35.5, 30.9, 25.8, 23.8, 18.9, 14.4. IR (film): 3203,
2937, 2860, 1447, 1040 cm−1. HRMS (EI): exact mass calcd for
C8H17NO [M]+, 143.1310 (100%), 144.13437 (9%); found, 144.1342.
1-(Allyloxy)-2-propylpiperidine (17). In a sealed tube equipped
with a magnetic stir bar, hydroxylamine 16 (0.050 g, 0.27 mmol) was
dissolved in benzene (2.7 mL). Argon was bubbled in the solution for
10 min. The tube was sealed and heated at 150 °C for 16 h. The
reaction mixture was cooled to room temperature and then directly
purified by flash chromatography on silica gel with a gradient of 1% to
10% diethyl ether in hexanes to yield the desired compound as a
( )-(2R*,4aS*,5R*,8aR*)-Decahydro-5-methyl-2-propylqui-
noline [( )-2-epi-Pumiliotoxin C (9)]. Prepared according to a
literature procedure.37 N-Hydroxy-epi-pumiliotoxin C (0.0145 g,
0.0687 mmol) was dissolved in a 10 M AcOH aqueous solution
(0.040 M, 1.7 mL). The mixture was heated to 55 °C, and then zinc
dust (0.045 g, 0.69 mmol, 10 equiv) was added with vigorous stirring.
After 4 h, TLC analysis revealed complete consumption of the starting
material. The reaction mixture was cooled, diluted with 13 mL of H2O,
and basicified to pH 14 by addition of 6 M KOH. The solution was
extracted with CHCl3. The combined organic extracts were dried over
sodium sulfate, filtered, and concentrated in vacuo. Purification by
column chromatography (0−100% EtOAc/CHCl3) gave 2-epi-
pumiliotoxin C as the free base as a white solid (0.013 g, 0.067
mmol, 72% yield) with 20−100% EtOAc/CHCl3 as the eluent. TLC:
1
yellow oil (0.021 g, 42%). TLC: Rf 0.78 (50% EtOAc/hexanes). H
NMR (300 MHz, CDCl3): δ 5.97−5.89 (tdd, J = 16.5, 10.4, and 6.1
Hz, 1H), 5.27 (dd, J = 15.8 and 1.5 Hz, 1H), 5.16 (ap d, J = 10.3 Hz,
1H), 4.25−4.15 (m, 2H), 3.36 (d, J = 9.9 Hz, 1H), 2.41 (ap t, J = 10.4
Hz, 1H), 2.31 (ap t, J = 6.4 Hz, 1H), 1.87−1.78 (m, 2H), 1.71−1.68
(m, 1H), 1.61−1.53 (m, 2H), 1.42−1.36 (m, 1H), 1.34−1.27 (m, 2H),
1.25−1.14 (m, 2H), 0.91 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 134.6, 117.9, 74.4, 67.3, 57.4, 35.7, 31.2, 26.2, 24.3, 19.1,
14.9. IR (film): 3085, 2936, 2859, 2828, 1648, 1443, 1036, 995, 921
cm−1. HRMS (EI): exact mass calcd for C11H21NO [M]+, 183.1623;
found, 183.1621.
N-Hydroxy-1-(3-isopropoxy-4-methoxybenzyl)-1,2,3,4-tetra-
hydro-7-isopropoxy-6-methoxyisoquinoline (20). In an oven-
dried sealed tube equipped with a magnetic stir bar, the primary
hydroxylamine (crude, 0.14 mmol) and NaCNBH3 (0.0085 g, 0.14
mmol) were dissolved in n-PrOH (14 mL). The reaction mixture was
purged with argon for 15 min through a septum. The septum was
quickly replaced by a Teflon screw cap, and the reaction vessel was
sealed. The reaction mixture was heated at 120 °C for 16 h, cooled,
transferred to a separate round-bottomed flask, and rinsed three times
with additional n-PrOH, and the solvent was evaporated. The crude
residue was purified by silica column chromatography with an eluent
of 50% EtOAc in hexanes, affording a yellow oil (0.029 g, 51%). TLC:
Rf 0.72 (70% EtOAc/hexanes). 1H NMR (400 MHz, C6D6): δ 6.94 (d,
J = 2.0 Hz, 1H), 6.81 (dd, J = 8.1 and 1.9 Hz, 1H), 6.63 (s, 1H), 6.61
(d, J = 8.2 Hz, 1H), 6.38 (s, 1H), 4.37−4.31 (m, 2H), 4.27−4.20 (m,
1H), 3.39 (s, 3H), 3.38 (s, 3H), 3.34−3.28 (m, 2H), 3.15−3.06 (m,
2H), 2.78 (ddd, J = 12.2, 5.6, and 5.6 Hz, 1H), 2.67 (ddd, J = 16.4, 6.1,
and 6.1 Hz, 1H), 1.20 (d, J = 6.0 Hz, 3H), 1.20 (d, J = 6.0 Hz, 3H),
1.19 (d, J = 6.0 Hz, 3H), 1.17 (d, J = 6.1 Hz, 3H). 13C NMR (100
MHz, C6D6): δ 150.1, 150.0, 148.0, 146.3, 132.8, 129.5, 122.81, 118.9,
116.4, 113.0, 112.6, 71.5, 71.3, 68.7, 55.7, 55.5, 51.9, 26.6, 22.4, 22.4,
22.3, 22.1. IR (film): 2979, 2934, 2842, 1607, 1512, 1445, 1261, 1235,
1109, 1033, 934, 858, 813, 771 cm−1. HRMS (EI): exact mass calcd for
C13H18NO3 [M − 3-isopropoxy-4-methoxybenzyl]+, 236.1287; found,
236.1268.
1
Rf 0.06 (10% MeOH/EtOAc). H NMR (CDCl3, 300 MHz): δ 3.12
(dt, J = 10.2 and 4.1 Hz, 1H), 2.86−2.73 (m, 1H), 2.28 (br s, 1H),
1.91−1.63 (m, 4H), 1.62−1.46 (m, 4H), 1.46−1.22 (m, 6H), 1.20−
1.03 (m, 2H), 0.98 (d, J = 7.2 Hz, 3H), 0.89 (t, J = 7.0 Hz, 3H). 13C
NMR (CDCl3, 75 MHz): δ 50.0, 49.5, 41.7, 38.2, 32.5, 31.2, 28.1, 25.1,
1
20.4, 19.3, 19.2, 14.2. The H and 13C NMR spectral data were found
to be in good agreement with those in the literature.66
( )-2-epi-Pumiliotoxin C Hydrochloride Salt (9·HCl). The free
amine was converted into its hydrochloride salt by bubbling dry HCl
1
gas for 25 min in a MeOH solution. H NMR (CDCl3, 500 MHz): δ
9.44−9.25 (br m, 1H), 9.23−9.02 (br m, 1H), 3.64−3.53 (m, 1H),
3.27−3.10 (m, 1H), 2.06−1.14 (m, 16H), 1.02 (d, J = 7.0 Hz, 3H),
0.93 (t, J = 7.3 Hz, 3H). 13C NMR (CDCl3, 75 MHz): δ 51.3, 51.2,
38.3, 34.1, 31.9, 29.6, 26.9, 23.8, 23.2, 19.6, 18.9, 18.8, 13.8.
( )-(2S*,4aS*,5R*,8aR*)-Decahydro-5-methyl-2-propylqui-
noline [( )-Pumiliotoxin C]. Prepared according to the same
literature procedure as described previously for 2-epi-pumiliotoxin C.23
Purification by column chromatography (0−50% EtOAc/CHCl3) gave
pumiliotoxin C as the free base as a white solid (0.0035 g, 0.018 mmol,
92% yield) with 0−20% EtOAc/CHCl3 as the eluent. TLC: Rf 0.12
(10% MeOH/EtOAc). 1H NMR (CDCl3, 300 MHz): δ 2.90−2.85 (m,
1H), 2.62−2.49 (m, 1H), 2.03−1.03 (m, 17H), 0.90 (t, J = 7.1 Hz,
3H), 0.84 (d, J = 6.6 Hz, 3H). The 1H NMR spectral data were found
to be in good agreement with reported literature data.67
N-Allyl-N-oxyl-1-((1S,6R)-6-methylcyclohex-2-enyl)hexan-3-
amine (11). A solution of N-allylhydroxylamine (0.0276 g, 0.110
mmol, 1.0 equiv) in C6D6 (1 mL, 0.1 M) in a sealed tube was degassed
by bubbling of argon for 15 min. The mixture was then heated to 150
°C for 9 h. The solvent was evaporated, and purification by column
chromatography (20−100% Et2O/hexanes) gave a colorless oil as the
major product (0.011 g, 0.044 mmol, 40% yield; mixture of
diastereoisomers). TLC: Rf 0.14 (20% EtOAc/hexanes). 1H NMR
(CDCl3, 300 MHz): δ 5.92 (tdd, J = 16.3, 10.2, and 6.1 Hz, 1H), 5.67
(ddd, J = 9.4, 5.8, and 3.4 Hz, 1H), 5.54 (ddd, J = 10.0, 4.5, and 2.8
Hz, 1H), 5.18 (ddd, J = 17.2, 3.1, and 1.6 Hz, 1H), 5.08 (dd, J = 10.2
and 1.0 Hz, 1H), 3.24 (ap d, J = 6.2 Hz, 2H), 2.59−2.48 (m, 1H),
2.04−1.94 (m, 2H), 1.77−1.14 (m, 12H), 0.97−0.85 (m, 6H) (the 1H
NMR spectrum was contaminated with Et2O signals since further
evaporation led to the appearance of new peaks). 13C NMR (CDCl3,
75 MHz): δ 135.5, 130.6, 130.6, 127.0, 126.9, 117.2, 56.8, 56.7, 49.1,
42.4, 42.4, 35.4, 35.2, 32.4, 32.3, 29.9, 29.2, 29.0, 24.5, 20.1, 18.9, 18.7,
14.3. IR (film): 3081, 3020, 2955, 2925, 2872, 1735, 1640, 1458, 990,
914 cm−1.
(Z)-N-(2-(3-Isopropoxy-4-methoxystyryl)-4-isopropoxy-5-
methoxyphenethyl)-N-hydroxyprop-2-en-1-amine (23a). To a
flame-dried round-bottom flask equipped with a magnetic stir bar was
added (Z)-2-[2-(3-isopropoxy-4-methoxystyryl)-4-isopropoxy-5-me-
thoxyphenyl]-N-hydroxyethanamine (0.042 g, 0.10 mmol), which
was dissolved in acetonitrile (0.5 mL). Potassium carbonate (0.042 g,
0.30 mmol) and distilled allyl bromide (0.026 mL, 0.30 mmol) were
subsequently added, and the solution was purged with argon. The
reaction mixture was stirred overnight under argon, diluted with ethyl
acetate, filtered (rinsing with ethyl acetate), and concentrated. The
resulting crude oil was purified by silica gel chromatography (50%
EtOAc/hexanes), which yielded a colorless oil (0.023 g, 50%). TLC: Rf
N-Hydroxyconiine (13). To a sealed tube equipped with a
magnetic stir bar were added (Z)-N-hydroxyoct-5-en-1-amine (0.10 g,
0.72 mmol) in n-propanol (60 mL) and sodium cyanoborohydride
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0.51 (50% EtOAc/CH2Cl2). The unpurified oil was used directly in
the next step due to instability.
(100 MHz, acetone-d6): δ 170.4, 149.7, 137.4, 129.7, 125.6, 123.9,
119.6, 117.9, 116.0, 111.4, 86.0, 67.1, 31.9, 28.4, 22.8, 10.7. IR (film):
2974, 2937, 1738, 1449, 1353, 1318, 1155, 745 cm−1. HRMS (EI):
exact mass calcd for C18H22N1O4Br [M]+, 395.0732; found, 395.0721.
tert-Butyldimethyl(pent-4-ynyl-1-oxy)silane. Prepared follow-
ing procedures developed by Snider.69 To a dry flask under an argon
atmosphere was added distilled CH2Cl2 (5.00 mL) followed by 4-
pentyn-1-ol (0.330 mL, 3.57 mmol) and distilled triethylamine (0.696
mL, 17.9 mmol). The solution was cooled to 0 °C and tert-
butyldimethylsilyl chloride (0.645 g, 4.28 mmol) dissolved in 1.00 mL
of distilled CH2Cl2 was added to the reaction flask slowly. The
solution was warmed to room temperature. The solution gradually
turned from yellow to pink over the course of 24 h. The reaction was
quenched with a few drops of water, and the reaction mixture was
extracted with CH2Cl2 (10 mL) and water (10 mL). The aqueous
phase was extracted with 1:1 EtOAc/hexanes (2 × 10 mL). The
combined organic phases were dried over Na2SO4, filtered, and
concentrated in vacuo to afford the crude product as a light-yellow oil.
The crude material was purified by flash silica gel chromatography with
hexanes to yield the product as a clear colorless oil (0.544 g, 78%).
TLC: Rf 0.90 (1:9 EtOAc/hexanes). The NMR data were in
accordance with literature values.68
1-(3-Isopropoxy-4-methoxybenzyl)-1,2,3,4-tetrahydro-7-
isopropoxy-6-methoxyisoquinoline-N-(2-allyloxide) (21a). In
an oven-dried sealed tube equipped with a magnetic stir bar, (Z)-N-
(2-(3-isopropoxy-4-methoxystyryl)-4-isopropoxy-5-methoxypheneth-
yl)-N-hydroxyprop-2-en-1-amine (0.014 g, 0.031 mmol) was dissolved
in benzene (3.0 mL). Distilled water (0.005 mL, 0.3 mmol) was added,
and the reaction mixture was purged with argon for 15 min through a
septum. The septum was quickly replaced by a Teflon screw cap, and
the reaction vessel was sealed. The reaction mixture was heated at 120
°C for 16 h, cooled, transferred to a separate round-bottom flask, and
rinsed three times with additional benzene, and the solvent was
evaporated. The crude residue was purified by silica column
chromatography (10−40% EtOAc/hexanes), affording a clear, color-
1
less oil (0.0063 g, 45%). TLC: Rf 0.80 (30% EtOAc/hexanes). H
NMR (500 MHz, C6D6): δ 6.97 (d, J = 1.9 Hz, 1H), 6.83 (dd, J = 8.2
and 2.0 Hz, 1H), 6.61 (d, J = 8.2 Hz, 1H), 6.59 (s, 1H), 6.40 (s, 1H),
5.97 (tdd, J = 16.3, 10.5, and 5.9 Hz, 1H), 5.20 (dd, J = 17.3 and 1.7
Hz, 1H), 5.03 (dd, J = 10.4 and 1.8 Hz, 1H), 4.50 (t, J = 6.1 Hz, 1H),
4.39−4.32 (m, 1H), 4.31−4.28 (m, 2H), 4.26−4.18 (m, 1H), 3.39 (s,
3H), 3.38 (s, 3H), 3.32−3.27 (m, 2H), 3.20 (ddd, J = 12.0, 5.3, and 5.3
Hz, 1H), 3.06 (dd, J = 14.1 and 6.6 Hz, 1H), 2.95−2.89 (m, 1H), 2.54
(ddd, J = 16.0, 5.1, and 5.1 Hz, 1H), 1.21 (d, J = 6.1 Hz, 3H), 1.20 (d,
J = 6.3 Hz, 3H), 1.19 (d, J = 6.5 Hz, 3H), 1.17 (d, J = 6.1 Hz, 3H). 13C
NMR (C6D6, 75 MHz): δ 150.1, 149.9, 147.9, 146.3, 135.4, 133.0,
129.6, 126.9, 122.8, 118.9, 117.0, 116.6, 112.8, 112.6, 73.6, 71.4, 71.2,
66.8, 55.6, 55.5, 48.5, 41.0, 26.2, 22.4, 22.4, 22.3, 22.3. IR (film): 2975,
2926, 2830, 1614, 1566, 1512, 1265, 1219, 1139, 1105, 1033, 991, 919,
843 cm−1. Exact mass calcd for C27H37NO5 [M + H], 455.2672; not
found. LRMS (electrospray): found 455.6.
Propyl 2-(1H-Indol-3-yl)acetate (32a). Prepared following a
procedure developed by Jackson.50 Indole-3-acetic acid (6.00 g, 34.3
mmol) was dissolved in 170 mL of n-propanol (distilled over CaH2) in
a dry three-neck flask. HCl gas generated in situ with NaCl and H2SO4
was bubbled through the mixture for ca. 20 min until saturation,
whereupon the mixture was refluxed at 110 °C for 2.5 h, at which
point TLC indicated reaction completion. The solvent was evaporated
in vacuo and extracted with ether and sat. NaHCO3. The organic
phase was washed with water and then brine, dried over Na2SO4, and
concentrated in vacuo to afford the crude product as a red-brown oil.
The crude product was purified over a short silica gel column with 3:7
EtOAc/hexanes to yield the product (7.44 g, >99%) as a beige solid.
TLC: Rf 0.30 (3:7 EtOAc/hexanes). The NMR data are in accordance
with literature values.68
tert-Butyl 2-(5-(tert-Butyldimethylsilyloxy)pent-1-ynyl)-3-(2-
oxo-2-propoxyethyl)-1H-indole-1-carboxylate (35). Prepared
following a procedure adapted from Baran’s original report.52 tert-
Butyl 2-bromo-3-(2-oxo-2-propoxyethyl)-1H-indole-1-carboxylate
(3.00 g, 7.57 mmol) and tert-butyldimethyl(pent-4-ynyloxy)silane
(2.25 g, 11.4 mmol) were dissolved in degassed DME (30.0 mL,
distilled over CaH2) in a dry round-bottom flask charged with argon.
Tetrakis(triphenylphosphine)palladium (2.60 g, 2.27 mmol) was
added to the solution, and the solution was degassed again with
argon. CuI (1.00 g, 5.30 mmol) was subsequently added to the
mixture, which was degassed. Degassed isopropylamine (6.45 mL, 75.7
mmol, distilled over NaOH) was added to the mixture, which was
again degassed with argon. The reaction flask was equipped with a dry
condenser, and the contents were heated to 70 °C for 3.5 h. TLC
indicated that the reaction was complete. The brown reaction mixture
was cooled to room temperature, added to saturated NaHCO3 (15
mL), and extracted with EtOAc (2 × 25 mL). The combined organics
were dried over Na2SO4, filtered, and concentrated to yield the crude
product as a brown oil. Silica gel column chromatography using 0.3%
acetone in toluene afforded the product with trace impurities (3.89 g,
1
100%) as a brown oil. TLC: Rf 0.32 (0.3% acetone in toluene). H
NMR (400 MHz, CDCl3): δ 8.17 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 7.8
Hz, 1H), 7.36−7.21 (m, 2H), 4.03 (t, J = 6.6 Hz, 2H), 3.89−3.80 (m,
4H), 2.65 (t, J = 7.1 Hz, 2H), 1.92−1.81 (m, 2H), 1.69 (s, 9H), 1.67−
1.55 (m, 2H), 0.97−0.84 (m, 12H), 0.09 (s, 6H). 13C NMR (100
MHz, acetone-d6): δ 170.7, 150.1, 136.3, 129.6, 126.2, 123.8, 121.6,
120.9, 120.1, 116.2, 100.5, 84.6, 72.7, 66.8, 62.2, 32.6, 31.4, 28.3, 26.3,
22.7, 18.8, 16.9, 10.6, −5.1. IR (film): 2953, 2930, 2854, 1729, 1455,
1360, 1326, 1254, 1147, 832, 740 cm−1. HRMS (EI): exact mass calcd
for C29H43N1O5Si [M]+, 513.2911; found, 513.2899.
(Z)-tert-Butyl 2-(5-(tert-Butyldimethylsilyloxy)pent-1-enyl)-
3-(2-oxo-2-propoxyethyl)-1H-indole-1-carboxylate (36). Pre-
pared following modified versions of procedures developed by
Carreira.53 tert-Butyl 2-(5-(tert-butyldimethylsilyloxy)pent-1-ynyl)-3-
(2-oxo-2-propoxyethyl)-1H-indole-1-carboxylate (0.329 g, 0.641
mmol) was dissolved in freshly distilled 1:1 EtOAc/1-hexene (64
mL) in a dry flask under argon. Pd/C (10% w/w) (0.110 g, 30 wt %)
was added to the solution, and hydrogen was bubbled through the
solvent. The mixture was stirred vigorously for 45 min, whereupon
proton NMR indicated that the reaction was complete. The mixture
was filtered through Celite and washed with EtOAc (2 × 10 mL). The
solution was concentrated in vacuo to afford the product as a clear
light-yellow oil (0.320 g, 97%) with no further purification. TLC: Rf
0.68 (1:9 EtOAc/hexanes). 1H NMR (100 MHz, CDCl3): δ 8.14 (d, J
= 8.3 Hz, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.35−7.18 (m, 2H), 6.45 (d, J
= 11.3 Hz, 1H), 5.84 (dt, J = 7.4 and 11.3 Hz, 1H), 4.03 (t, J = 6.8 Hz,
2H), 3.60 (s, 2H), 3.53 (t, J = 6.6 Hz, 2H), 2.12−1.97 (m, 2H), 1.72−
1.50 (m, 13H), 0.88 (t, J = 7.4 Hz, 3H), 0.80 (s, 9H), −0.03 (s, 6H).
tert-Butyl 2-Bromo-3-(2-oxo-2-propoxyethyl)-1H-indole-1-
carboxylate (34). Prepared following a procedure adapted from
reports by Feldman.51 In a dry round-bottom flask flushed with argon
was added propyl 2-(1H-indol-3-yl)acetate (7.44 g, 34.3 mmol)
followed by distilled CH2Cl2 (35 mL). The dissolved solution was
cooled to 0 °C, and freshly recrystallized N-bromosuccinimide (6.12 g,
34.3 mmol) was added in three portions, upon which the color of the
solution turned deep purple. The mixture was maintained at 0 °C and
stirred for 2 h. TLC indicated reaction completion. The mixture was
concentrated in vacuo to yield the crude material as a purple oil, which
was filtered through silica gel and concentrated to afford a yellow oil
(7.66 g, 25.9 mmol, 86%). The yellow oil was dissolved in distilled
CH2Cl2 (225 mL). DMAP (5.00 g, 41.2 mmol) was added, followed
by Boc2O (8.95 g, 41.2 mmol). The solution was stirred at room
temperature for 30 min, at which point TLC indicated reaction
completion. The mixture was added to 30 mL of CH2Cl2, and the
resulting mixture was extracted with 30 mL of water (2×). The organic
phase was dried over Na2SO4, filtered, and concentrated in vacuo to
afford the crude product as a yellow solid. The crude material was
purified over silica gel chromatography with 1:9 EtOAc/hexanes to
yield the product (8.2 g, 61% over two steps) as a yellow oil. TLC: Rf
1
0.24 (1:9 EtOAc/hexanes). H NMR (300 MHz, acetone-d6): δ 8.10
(d, J = 8.2 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.33−7.27 (m, 1H), 7.23
(td, J = 1.3 and 1.1 Hz, 1H), 4.04 (t, J = 6.6 Hz, 2H), 3.81 (s, 2H),
1.71 (s, 9H), 1.68−1.54 (m, 2H), 0.88 (t, J = 7.4 Hz, 3H). 13C NMR
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13C NMR (100 MHz, CDCl3): δ 171.2, 150.3, 136.1, 133.9, 133.4,
to pH 8 with 3 M NaOH. The solution was dropped in brine and
extracted three times with CH2Cl2. The combined organic phases were
dried over MgSO4, filtered, and concentrated. The crude product was
purified by flash chromatography (10% MeOH/CH2Cl2) to afford a
colorless oil (0.310 g, 69%). TLC: Rf 0.39 (10% MeOH/CH2Cl2). 1H
NMR (400 MHz, CDCl3): δ 8.11 (d, J = 8.2 Hz, 1H), 7.56 (d, J = 7.5
Hz, 1H), 7.31−7.22 (m, 2H), 6.47 (d, J = 11.2 Hz, 1H), 5.88−5.81
(m, 1H), 3.58 (t, J = 6.3 Hz, 2H), 3.19 (t, J = 7.1 Hz, 2H), 2.87 (t, J =
6.0 Hz, 2H), 2.19−2.10 (m, 2H), 1.68−1.63 (m, 11H). 13C NMR (100
MHz, CDCl3): δ 150.4, 135.9, 133.6, 132.8, 129.6, 124.2, 122.6, 121.6,
118.7, 116.9, 115.6, 83.9, 62.3, 52.9, 31.9, 28.2, 25.9, 22.3. IR (film):
3340, 2979, 2926, 2850, 1729, 1463, 1371, 1330 cm−1. HRMS m/z
(relative intensity): 322.2878 (31.5%), 215.0222 (25.5%), 214.0172
(24.9%), 168.0329 (27.5%), 167.0255 (20.5%), 57.0709 (100%),
41.0511 (30.6%).
129.7, 124.1, 122.5, 121.4, 118.7, 115.7, 115.6, 83.7, 62.6, 62.1, 60.4,
32.4, 28.3, 25.8, 25.7, 21.1, 18.2, 14.2, 5.3. IR (film): 2930, 2857, 1731,
1459, 1359, 1137, 1117, 837, 775, 745 cm−1. HRMS (EI): exact mass
calcd for C29H45N1O5Si [M]+, 515.3067; found, 515.3015.
(Z)-tert-Butyl 2-(5-(tert-Butyldimethylsilyloxy)pent-1-enyl)-
3-(2-hydroxyethyl)-1H-indole-1-carboxylate (37). Prepared fol-
lowing a procedure adapted from Iwabuchi’s original report.54 (Z)-tert-
Butyl 2-(5-(tert-butyldimethylsilyloxy)pent-1-enyl)-3-(2-oxo-2-propox-
yethyl)-1H-indole-1-carboxylate (0.35 g, 0.68 mmol) was dissolved in
distilled THF (1.5 mL). The solution was cooled to 0 °C, and LiAlH4
(0.031 g, 0.81 mmol) was added. The solution was stirred at 0 °C for
15 min. TLC indicated completion of the reaction. Water was added,
and the solution was stirred at room temperature for 10 min. Filtration
over Celite followed by concentration afforded the crude product,
which was purified by flash chromatography (25% EtOAc/Hexane) to
afford the desired product as a colorless oil (0.240 g, 77%). TLC: Rf
0.30 (1:4 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.15 (d, J
= 8.2 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.28−7.24 (m, 2H), 6.46 (d, J
= 11.3 Hz, 1H), 5.82 (d, J = 11.2 Hz, 1H), 3.84 (t, J = 6.8 Hz, 2H),
3.55 (t, J = 6.5 Hz, 2H), 2.89 (t, J = 6.8 Hz, 2H), 2.08 (d, J = 7.3 Hz,
2H), 1.70−1.53 (m, 12H), 0.80 (s, 9H), −0.03 (s, 6H). 13C NMR
(100 MHz, CDCl3): δ 150.4, 136.2, 134.0, 133.5, 129.8, 124.2, 122.6,
121.5, 118.8, 115.9, 115.7, 83.8, 62.7, 62.2, 32.5, 28.4, 28.3, 26.0, 25.8,
18.3, −5.2. IR (film): 2930, 2857, 1732, 1456, 1360, 837, 774, 744
cm−1. HRMS (EI): exact mass calcd for C26H41N1O4Si [M]+,
459.2805; found, 459.2844.
(Z)-tert-Butyl 2-(5-(tert-Butyldimethylsilyloxy)pent-1-enyl)-
3-(2-oxoethyl)-1H-indole-1-carboxylate (38). Prepared following
a procedure adapted from Mukai’s original report.55b (Z)-tert-Butyl 2-
(5-(tert-butyldimethylsilyloxy)pent-1-enyl)-3-(2-hydroxyethyl)-1H-in-
dole-1-carboxylate (0.503 g, 1.09 mmol) was dissolved in distilled
CH2Cl2 (5.50 mL). DMSO (0.230 mL, 3.28 mmol) and Et3N (0.420
mL, 3.28 mmol) were added, and the solution was cooled to 0 °C.
Pyridine−sulfur trioxide complex (0.522 g, 3.28 mmol) was added, and
the solution was stirred at 0 °C for 2 h. TLC indicated completion of
the reaction. A saturated solution of NH4Cl was added, and the layers
were separated. The aqueous phase was extracted three times with
CH2Cl2. The organic layers were combined, dried over MgSO4, and
concentrated to afford the crude product, which was purified by flash
chromatography (5% EtOAc/Hexane) to afford the desired product
(0.343 g, 69%) as a colorless oil. TLC: Rf 0.56 (1:10 EtOAc/hexanes).
1H NMR (300 MHz, CDCl3): δ 9.69 (t, J = 2.2 Hz, 1H), 8.18 (d, J =
8.3 Hz, 1H), 7.41−7.36 (m, 1H), 7.34−7.31 (m, 1H), 7.28−7.23 (m,
1H), 6.45 (d, J = 11.2 Hz, 1H) 5.87 (dt, J = 11.3 and 7.4 Hz, 1H), 3.64
(d, J = 2.2 Hz, 2H), 3.55 (t, J = 6.4 Hz, 2H), 2.06 (qd, J = 7.5 and 1.6
Hz, 2H), 1.67 (s, 9H), 1.64−1.55 (m, 2H), 0.80 (s, 9H), −0.02 (s,
6H). 13C NMR (100 MHz, CDCl3): δ 199.2, 150.1, 135.9, 134.4,
134.3, 129.4, 124.5, 122.8, 120.9, 118.4, 115.7, 110.5, 84.0, 62.3, 40.0,
32.2, 28.2, 25.8, 25.7, 18.1, −5.4. IR (film): 3447, 2956, 1730, 1472,
1453 cm−1. HRMS (EI): exact mass calcd for C21H31NO2Si [M − Boc
+ H]+, 357.2124; found, 357.2143.
(Z)-tert-Butyl 3-(2-(Hydroxyamino)ethyl)-2-(5-hydroxypent-
1-enyl)-1H-indole-1-carboxylate (40). Prepared following a
procedure adapted from Fuchs’ original report.70 (Z)-tert-Butyl 2-(5-
(tert-butyldimethylsilyloxy)pent-1-enyl)-3-(2-oxoethyl)-1H-indole-1-
carboxylate (0.42 g, 0.92 mmol) was dissolved in i-PrOH (3.00 mL).
Sodium acetate (0.226 g, 2.76 mmol) was added, followed by
hydroxylamine hydrochloride salt (0.0700 g, 1.01 mmol). The solution
was stirred at room temperature for 1.5 h. TLC indicated completion
of the reaction. A saturated solution of NaHCO3 was added, followed
by water. The layers were separated, and the aqueous phase was
extracted three times with EtOAc. The organic layers were combined,
dried over MgSO4, and concentrated to afford a crude oxime as a
yellow oil (0.385 g, 88%). To a solution of this oxime (0.591 g, 1.25
mmol) in MeOH (6.5 mL) was added a pinch of methyl orange
followed by HCl (20% in MeOH) until a pink color was obtained.
NaBH3CN (0.0950 g, 1.50 mmol) was added, followed by the HCl
solution until the pink color was persistent (pH ∼3). The solution was
then stirred at room temperature for 1 h. The reaction was quenched
(Z)-tert-Butyl 3-(2-(Allyl(hydroxy)amino)ethyl)-2-(5-hydroxy-
pent-1-enyl)-1H-indole-1-carboxylate (41a). (Z)-tert-Butyl 3-(2-
(hydroxyamino)ethyl)-2-(5-hydroxypent-1-enyl)-1H-indole-1-carboxy-
late (0.15 g, 0.42 mmol) was dissolved in THF (2.1 mL). K2CO3
(0.175 g, 1.26 mmol) was added, followed by allyl bromide (0.110 mL,
1.26 mmol). The suspension was then stirred at room temperature for
6 h. TLC analysis indicated completion of the reaction. The solution
was concentrated in vacuo to afford the crude product, which was
purified by flash chromatography (10% MeOH/CH2Cl2) to afford the
title product (0.080 g, 48%) as a colorless oil. TLC: Rf 0.61 (10%
1
MeOH/CH2Cl2). H NMR (400 MHz, C6D6): δ 8.51 (d, J = 8.2 Hz,
1H), 7.71 (d, J = 7.4 Hz, 1H) 7.30−7.26 (m, 1H), 7.22−7.19 (m, 1H),
6.46 (d, J = 11.2 Hz, 1H), 6.09−5.99 (m, 1H), 5.71−5.64 (m, 1H),
5.15−5.06 (m, 2H), 3.38−3.34 (m, 4H), 3.16−3.13 (m, 2H), 3.02−
2.98 (m, 2H), 2.18−2.12 (m, 2H), 1.54−1.47 (m, 2H), 1.40 (s, 9H).
13C NMR (100 MHz, CDCl3): δ 150.4, 136.7, 134.3, 133.6, 132.7,
130.2, 124.4, 122.8, 121.9, 119.2, 118.3, 117.7, 116.0, 83.0, 63.8, 61.9,
58.8, 32.3, 27.8, 26.2, 23.1. IR (film) 3382, 2983, 2937, 2854, 1728,
1457, 1369 cm−1. HRMS (EI): exact mass calcd for C20H26NO3 [M −
N(C3H5)OH + H]+, 328.1907; found, 328.1815.
(Z)-tert-Butyl 3-(2-(Hydroxy(2-methallyl)amino)ethyl)-2-(5-
hydroxypent-1-enyl)-1H-indole-1-carboxylate (41b). (Z)-tert-
Butyl 3-(2-(hydroxyamino)ethyl)-2-(5-hydroxypent-1-enyl)-1H-in-
dole-1-carboxylate (0.15 g, 0.42 mmol) was dissolved in THF (2.1
mL) and DMF (0.040 mL). DBU was added (0.070 mL, 0.46 mmol),
followed by 3-chloro-2-methylpropene (0.125 mL, 1.26 mmol). The
solution was heated at reflux for 4 h, diluted with EtOAc, and extracted
five times with a 1:1 solution of brine and water. The combined
organic phases were dried over MgSO4 and concentrated to afford the
crude product, which was purified by flash chromatography (50%
EtOAc/hexane) to afford the desired product (0.065 g, 38%) as a
yellow oil. TLC: Rf 0.45 (60% EtOAC, hexane). 1H NMR (400 MHz,
C6D6): δ 8.50 (d, J = 8.2 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.29 (t, J =
7.4 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 6.45 (d, J = 11.2 Hz, 1H), 5.70−
5.63 (m, 1H), 4.95 (s, 1H), 4.85 (s, 1H), 3.38−3.34 (m, 2H), 3.28 (br
s, 2H), 3.15−3.12 (m, 2H), 3.00−2.97 (m, 2H), 2.16−2.10 (m, 2H),
1.76 (s, 3H), 1.54−1.47 (m, 2H), 1.40 (s, 9H). 13C NMR (100 MHz,
CDCl3): δ 150.4, 141.5, 136.7, 133.6, 132.7, 130.2, 124.4, 122.8, 121.9,
119.1, 117.7, 116.0, 114.5, 83.1, 67.1, 61.9, 58.5, 32.3, 27.8, 26.2, 22.8,
21.3. IR (film) 3386, 2979, 2936, 2865, 1729, 1458, 1370 cm−1. HRMS
(EI): exact mass calcd for C20H26NO3 [M − N(C4H )OH + H]+,
7
328.1907; found, 328.1815.
tert-Butyl 2-Hydroxy-1-(4-hydroxybutyl)-3,4-dihydro-1H-
pyrido[3,4-b]indole-9(2H)-carboxylate (42). To a solution of
(Z)-tert-butyl 3-(2-(hydroxyamino)ethyl)-2-(5-hydroxypent-1-enyl)-
1H-indole-1-carboxylate (0.110 g, 0.31 mmol) in t-BuOH (20 mL)
was added NaBH3CN (0.02 g, 0.31 mmol). Argon was bubbled
through the solution until saturation (15 min). The reaction mixture
was stirred for 4 or 16 h in a sealed tube at 120 °C in an oil bath or in a
microwave reactor. The solution was concentrated and purified by
flash chromatography (5% MeOH in CH2Cl2) to yield the product as
a colorless oil (0.096 g, 87%). TLC: Rf 0.5 (10% MeOH in CH2Cl2).
1H NMR (400 MHz, C6D6): δ 8.34 (d, J = 8.2 Hz, 1H), 7.38 (d, J =
7.6 Hz, 1H), 7.32, (ddd, J = 8.4, 7.2, and 1.3 Hz, 1H), 7.25−7.21 (m,
2H), 4.92 (dd, J = 10.3 and 2.1 Hz, 1H), 3.50 (td, J = 6.3 and 2.8 Hz,
12746
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Article
2H), 3.28−3.22 (m, 1H), 3.11−3.00 (m, 2H), 2.27−2.23 (m, 1H),
2.08−2.00 (m, 2H), 1.93−1.74 (m, 2H), 1.65−1.50 (m, 2H), 1.40−
1.25 (br m, 10 H). 13C NMR (100 MHz, CDCl3): δ 150.2, 135.9,
135.4, 129.2, 123.9, 122.6, 118.0, 115.7, 113.3, 83.8, 64.2, 62.7, 46.1,
34.4, 32.3, 28.3, 23.0, 16.3. IR (film) 3333, 2922, 2850, 1728, 1455,
1368 cm−1. HRMS (EI): exact mass calcd for C20H28N2O4 [M]+,
360.2049; found, 360.2050.
CH2Cl2. The combined organic layers were washed twice with water,
dried over MgSO4, and condensed to afford a brown oil. The oil was
purified by column chromatography to afford the product as a white
solid. TLC: Rf 0.33 (5:1:94 MeOH/NH4OH/CH2Cl2). 1H NMR (300
MHz, CDCl3): δ 7.72 (br s, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.32 (d, J =
7.3 Hz, 1H), 7.12 (dt, J = 14.5 and 7.1 Hz, 2H), 3.27 (d, J = 10.3 Hz,
1H), 3.12−3.00 (m, 3H), 2.77−2.63 (m, 2H), 2.41 (td, J = 10.7 and
3.6 Hz, 1H), 2.09 (d, J = 12.5 Hz, 1H), 1.92 (d, J = 12.4 Hz, 1H),
1.73−1.79 (m, 2H), 1.48−1.64 (m, 2H). HRMS (EI): exact mass calcd
for C15H18N2 [M]+, 226.1470; found, 226.1467. The NMR data were
in accordance with literature values.57c,71
tert-Butyl 2-(Allyloxy)-1-(4-hydroxybutyl)-3,4-dihydro-1H-
pyrido[3,4-b]indole-9(2H)-carboxylate (43a). (Z)-tert-Butyl-3-(2-
(allyl(hydroxy)amino)ethyl)-2-(5-hydroxypent-1-enyl)-1H-indole-1-
carboxylate (0.073 g, 0.18 mmol) was dissolved in benzene (18 mL).
Distilled water (0.034 μL) was added, and argon was bubbled through
the solution for 15 min. The solution was stirred for 16 h in a sealed
tube at 120 °C, concentrated, and purified by flash chromatography
(5% MeOH/CH2Cl2) to afford the desired product (0.047 g, 64%) as
ASSOCIATED CONTENT
* Supporting Information
■
S
NMR spectra of all new compounds and EPR spectrum of 11.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
a colorless oil. TLC: Rf 0.71 (10% MeOH/CH2Cl2). H NMR (400
MHz, C6D6): δ: 8.33 (d, J = 8.3 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H),
7.34−7.30 (m, 1H), 7.25−7.21 (m, 1H), 6.03−5.93 (m, 1H), 5.18 (dq,
J = 17.3 and 1.6 Hz, 1H), 5.02 (ddt, J = 10.4, 2.0, and 1.1 Hz, 1H),
4.97 (d, J = 10.5 Hz, 1H), 4.25 (dq, J = 6.0 and 1.3 Hz, 2H), 3.48 (t, J
= 6.4 Hz, 2H), 3.38−3.33 (m, 1H), 3.11−2.95 (m, 2H), 2.26−2.21 (m,
1H), 2.07−1.98 (m, 1H), 1.97−1.88 (m, 1H), 1.84−1.75 (m, 1H),
1.60−1.52 (m, 2H), 1.36 (s, 9H), 1.30−1.20 (m, 1H). 13C NMR (100
MHz, CDCl3): δ 150.9, 137.3, 136.8, 136.0, 130.5, 124.4, 123.3, 118.7,
117.5, 116.7, 114.7, 83.5, 73.7, 62.9, 62.6, 44.6, 35.4, 33.4, 28.3, 24.1,
17.7. IR (film) 3405, 2972, 2935, 2865, 1728, 1456, 1372 cm−1. HRMS
AUTHOR INFORMATION
Corresponding Author
*E-mail: andre.beauchemin@uottawa.ca.
■
Notes
The authors declare no competing financial interest.
(EI): exact mass calcd for C23H32N2O [M]+, 400.2362; found,
ACKNOWLEDGMENTS
4
■
400.2382.
Financial support from the University of Ottawa, the Canadian
Foundation for Innovation, the Ontario Ministry of Research
and Innovation (Ontario Research Fund and Early Researcher
Award to A.M.B.), NSERC (Discovery Grant, Discovery
Accelerator Supplement, CRD, and CREATE Grants to
A.M.B.), the Canadian Society for Chemistry, AstraZeneca
Canada, Boehringer Ingelheim (Canada) Ltd., and Merck
Frosst Canada is gratefully acknowledged. Scholarships to I.D.
(NSERC CGS-M and PGS D), M.-E.L. (OGS and NSERC),
and J.Y.P. (FQRNT) are also acknowledged. We also thank Dr.
Belinda Heyne and Prof. Juan C. Scaiano for assistance with the
acquisition of the EPR spectrum of compound 11.
tert-Butyl 1-(4-Hydroxybutyl)-2-(2-methallyloxy)-3,4-dihy-
dro-1H-pyrido[3,4-b]indole-9(2H)-carboxylate (43b). (Z)-tert-
Butyl 3-(2-(hydroxy(2-methallyl)amino)ethyl)-2-(5-hydroxypent-1-
enyl)-1H-indole-1-carboxylate (0.054 g, 0.13 mmol) was dissolved in
benzene (13 mL). Distilled water (0.020 mL) was added, and argon
was bubbled through the solution for 15 min. The solution was stirred
for 16 h in a sealed tube at 120 °C, concentrated, and purified by flash
chromatography (60% EtOAC/hexane) to afford the desired product
(0.029 g, 53%) as a colorless oil. TLC: Rf 0.7 (60% EtOAC/hexane).
1H NMR (300 MHz, C6D6): δ 8.29 (d, J = 8.1 Hz, 1H), 7.35 (d, J =
7.8 Hz, 1H), 7.29−7.25 (m, 1H), 7.20−7.15 (m, 1H), 4.99 (s, 1H),
4.92 (d, J = 10.5 Hz, 1H), 4.80 (s, 1H), 4.17 (s, 2H), 3.44 (t, J = 6.5
Hz, 2H), 3.35−3.29 (m, 1H), 3.08−2.88 (m, 2H), 2.22−2.16 (m, 1H),
2.02−1.83 (m, 2H), 1.78−1.70 (m, 1H), 1.64 (s, 3H), 1.54−1.47 (m,
2H), 1.32 (s, 9H), 1.21−1.10 (m, 1H). 13C NMR (100 MHz, CDCl3):
δ 151.0, 143.0, 137.3, 136.8, 130.5, 124.4, 123.3, 118.7, 116.7, 114.7,
113.4, 83.5, 76.8, 62.9, 62.6, 44.5, 35.4, 33.4, 28.3, 24.1, 20.4, 17.7. IR
(film): 3431, 2983, 2926, 2850, 1727, 1456, 1372 cm−1. HRMS (EI):
exact mass calcd for C24H34N2O4 [M]+, 414.2519; found, 414.2502.
1-(4-Hydroxybutyl)-3,4-dihydro-1H-pyrido[3,4-b]indole (43).
To a solution of tert-butyl 2-hydroxy-1-(4-hydroxybutyl)-3,4-dihydro-
1H-pyrido[3,4-b]indole-9(2H)-carboxylate (0.055 g, 0.19 mmol) in
CH2Cl2 (1 mL) was added TFA (1 mL) dropwise. The solution was
allowed to stir at room temperature for 12 h, and water (1 mL) was
added, followed by zinc dust (0.124 g, 1.9 mmol). The solution was
stirred overnight, and 6 M NaOH was added until pH 10 was reached.
The solution was filtered through Celite with hot methanol. The
resulting solution was extracted three times with CH2Cl2 and a
saturated NaCl solution. The organic layers were combined, dried over
MgSO4, and condensed to afford the crude product as a yellow oil
(0.035 g, 73%). The product was used without further purification for
the next step.
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