Stereoselective synthesis of indoline, tetrahydroquinoline, and tetrahydrobenzazepine derivatives from o -bromophenyl N-tert-butylsulfinyl aldimines

Article abstract of DOI:10.1021/jo402759v

The diastereoselective addition of an allylic indium intermediate to chiral o-bromophenyl sulfinyl imine 4 proceeded with good levels of diastereoselectivity. The resulting homoallylic amine derivatives were transformed into lactams 7 and 12, which upon copper-mediated intramolecular N-arylation led to the formation of benzo-fused 1-azabicyclo[j.k.0]alkanes 8 and 13. Benzo-fused 2-allyl-substituted heterocycles 14 could also be prepared by means of a palladium-catalyzed N-arylation of the corresponding free amines. The synthesis of the alkaloid (-)-angustureine was easily accomplished from (S)-2-allyltetrahydroquinoline (14b).

Full text of DOI:10.1021/jo402759v

Article
pubs.acs.org/joc
Stereoselective Synthesis of Indoline, Tetrahydroquinoline, and
Tetrahydrobenzazepine Derivatives from o‑Bromophenyl N-tert-
Butylsulfinyl Aldimines
Juan Alberto Sirvent, Francisco Foubelo,* and Miguel Yus*
́ ́
Departamento de Química Organica, Facultad de Ciencias and Instituto de Síntesis Organica (ISO), Universidad de Alicante, Apdo.
99, 03080 Alicante, Spain
S
* Supporting Information
ABSTRACT: The diastereoselective addition of an allylic
indium intermediate to chiral o-bromophenyl sulfinyl imine 4
proceeded with good levels of diastereoselectivity. The
resulting homoallylic amine derivatives were transformed
into lactams 7 and 12, which upon copper-mediated
intramolecular N-arylation led to the formation of benzo-
fused 1-azabicyclo[j.k.0]alkanes 8 and 13. Benzo-fused 2-allyl-
substituted heterocycles 14 could also be prepared by means of
a palladium-catalyzed N-arylation of the corresponding free
amines. The synthesis of the alkaloid (−)-angustureine was
easily accomplished from (S)-2-allyltetrahydroquinoline (14b).
enzymes, ion channels, and G-protein-coupled receptors
(GPCRs).4 Different synthetic methodologies have been used
to access the benzo-fused 1-azabicyclo[j.k.0]alkanes I−VI in
either a racemic or enantioselective manner. For instance, the
Schmidt reaction involving benzocycloalkyl carbocations and
alkyl azides has been applied to the synthesis of heterocycles of
types I and III−V.5 The benzopyrrolizidine and -indolizidine
units (I and II, respectively) were also synthesized through
palladium(II)-catalyzed6 or copper-promoted7 oxidative tan-
dem cyclizations using N-acryloyl- or -benzoyl o-allyl aromatic
amines as substrates. The same types of heterocycles were
prepared by means of a general catalytic protocol of non-
carbonyl-stabilized rhodium carbenoid C−H insertions starting
from N-aziridinyl imines8 and also using a selenium-based
approach for a solid-phase synthesis.9 Tricycles with general
structures I and III were obtained under palladium catalysis
from chiral unsaturated amines by means of an intramolecular
N-arylation reaction followed by an intermolecular alkene
carboamination reaction.10 A recently reported methodology
involving regio- and stereoselective allylation and crotylation of
indoles with potassium organotrifluoroborate salts combined
with ring-closing metathesis allowed the synthesis in this case of
compounds of type II.11 Iridium-catalyzed enantioselective
hydrogenation of 2-substituted quinolines was used as the key
step in the stereoselective synthesis of heterocyclic compounds
of types III and IV.12 Enantioenriched benzo-fused indolizi-
dines and quinolizidines of types III and IV were also accessed
INTRODUCTION
■
Substituted benzo-fused 1-azabicyclo[j.k.0]alkanes with the
general structures I−VI (Figure 1) are embedded in numerous
natural products and other biologically active compounds.
Because of that, the rapid assembly of such molecules, in
addition to the search for new molecular scaffolds, represents a
constant challenge to synthetic organic and medicinal chemists.
Thus, the development of new methodologies to access to
these systems is of great interest. Related to the benzo-fused
pyrrolizidine I is, for instance, (−)-isatisine A (1), a complex
alkaloid isolated from the leaves of Isatis indigotica Fort,1 a
herbaceous plant species used in Chinese folk medicine. One
acetonide of (−)-isatisine A exhibits cytotoxicity against C8166
cells and anti-HIV activitiy. On the other hand, 14,15-
didehydro-10,11-dimethoxy-16-epivincamine (2),2 an alkaloid
isolated from Ervatamia officinalis, Ervatamia divaricata, and E.
divaricata Gouyahua plants of the Apocynaceae family, which
have been applied in China as folklore herbs for the treatment
of hypertension and sore throat, is an example of the benzo-
fused indolizidine II (Figure 1). Structurally related to
azabicycloalkane III is the pyridoacridine marine alkaloid
arnoamine C (3),3 isolated from ascidians of the genus
Cystodytes, which displays strong cytotoxic activity in different
cell lines at low concentration (Figure 1). In addition,
compounds bearing the 1-benzazepine moiety, a structural
motif common to heterocycles of types V and VI, have
achieved significant relevance as drugs, especially as anti-
depressants, for the treatment of neurodegenerative disorders,
and also in cardiovascular diseases. This class of compounds
exhibit biological activity toward different targets, such as
Received: December 12, 2013
Published: January 21, 2014
© 2014 American Chemical Society
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Figure 1. Basic structures of benzo-fused 1-azabicyclo[j.k.0]alkanes and representative natural products.
Scheme 1. Diastereoselective Synthesis of Amino Ester Derivatives 6
via a catalytic asymmetric hydrogenation cascade using
Hantzsch dihydropyridine as the hydride donor and catalytic
amounts of a chiral BINOL-based phosphoric acid13 as well as
through 7-endo-trig/ring contraction cascades involving pheno-
nium ions, but in this last case in a racemic form.14 Regarding
1-benzazepine derivatives V and VI, many methodologies to
synthesize these compounds are based on the expansion of
smaller rings involving cationic and radical intermediates.15
More recently, palladium-catalyzed C−C and C−N bond-
forming reactions have also been employed for the preparation
of these compounds.16 On the other hand, we have described
the stereoselective allylation of N-tert-butylsulfinyl aldimines17
and ketimines18 with allylindium species and the first one-pot
α-aminoallylation of aldehydes with chiral tert-butanesulfina-
mide, allyl bromides, and indium, which provides homoallylic
amines with high chemo- and stereoselectivity.19 It is worth
mentioning that N-tert-butylsulfinyl derivatives20 have found
high applicability in synthesis as electrophiles because both
enantiomers are accessible in large-scale processes21 and
because the chiral auxiliary is easily removed under acidic
conditions. In addition, practical processes for recycling the tert-
butanesulfinyl group upon deprotection of N-tert-butylsulfinyl
amines have also been reported.22 Being aware of the
importance of heterocycles having the general structures I−
VI with regard to biological activity and organic synthesis, we
decided to apply the indium-promoted diastereoselective
addition of allylic bromides to N-tert-butylsulfinyl aldimines
bearing an o-bromophenyl unit, in combination with an
intramolecular N-arylation, to develop new and flexible
synthetic pathways to target compounds of types I−VI.
RESULTS AND DISCUSSION
■
We have previously reported that the reaction of ethyl 2-
(bromomethyl)acrylate (5) with different chiral N-sulfinyl
aldimines in a saturated aqueous sodium bromide solution in
the presence of 4 equiv of indium at room temperature for 48 h
proceeds with high diastereoselectivity to afford the corre-
sponding amino ester derivatives, which could be easily
transformed into α-methylene-γ-butyrolactams.24 When we
applied these reaction conditions to chiral imines 4, amino
esters 6 were obtained in reasonable yields and diastereose-
lectivities (Scheme 1). The diastereomeric ratios for com-
pounds bearing the tert-butylsulfinyl unit were easily
determined by 1H NMR analysis of the crude reaction mixtures
through comparison of the integrals of the t-Bu and the N−H
groups for each diastereoisomer. On the other hand, the yields
given in Scheme 1 are isolated yields of the major
diastereomers after column chromatography purification. The
stereochemical pathway of the process is well-known:24 the
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Scheme 2. Synthesis of α-Methylene-γ-butyrolactams 7 from Amino Ester Derivatives 6
attack of the allylic indium intermediate occurs preferentially on
the Re face of these imines with the S configuration at the sulfur
atom.
Scheme 3. Synthesis of Tricyclic Compounds 8 from α-
Methylene-γ-butyrolactams 7
Amino ester derivatives 6 were converted into butyrolactams
7 upon removal of the tert-butylsulfinyl group by treatment first
with a 4 M HCl dioxane solution in methanol and then with
sodium methoxide in methanol to basic pH. Good to excellent
yields were achieved for compounds 7, and the corresponding
α-methylene-γ-butyrolactams were isolated in an almost
enantiopure form (Scheme 2).
Next, we carried out an intramolecular N-arylation in
compounds 7 under Ullmann-type reaction conditions. For a
model reaction, we optimized the cyclization of compound 7b
using a simple catalyst system developed by Buchwald and co-
workers: CuI, a diamine ligand, and K2CO3 as the base.25 All of
the reactions were performed at 100 °C in the presence of 2
equiv of K2CO3. Regarding the solvent, a higher conversion was
achieved using dioxane instead of toluene (Table 1, compare
Figure 1, respectively, and exhibit the S configuration at the
stereogenic center. The corresponding enantiomers could be
produced through the same synthetic pathway starting from the
chiral aldimines 4 with the R configuration at the sulfur atom.
In order to access compounds with pattern hydrocarbon
skeletons of types II, IV, and VI in Figure 1, we envisioned a
different protocol wherein the allylation of chiral tert-
butylsulfinyl imines 1 would be the first step of the synthesis.
The allylation of imines 4 under standard conditions developed
in our group (i.e., treatment with allyl bromide in the presence
of indium metal at 60 °C) produced the homoallylamine
derivatives 9 in excellent yields and diastereoselectivities
(Scheme 4).23 The same reaction products were prepared in
slightly lower yields and with almost identical diastereoselectiv-
ities by performing a one-pot α-aminoallylation of the
corresponding aldehydes with (S)-tert-butanesulfinamide and
allyl bromide in the presence of indium metal and titanium
tetraethoxide (Scheme 4).19 Column chromatography purifica-
tion allowed access to compounds 9 with high optical purity.
The attack of the allylindium here also took place on the Re
face of these imines with the S configuration at the sulfur atom.
Removal of the tert-butylsulfinyl unit in homoallylamine
derivatives 9 took place under acidic conditions, giving rise to
the free amines 10 in almost quantitative yields (Scheme 5).
Treatment of amines 10 under Shotten−Baumann reaction
conditions with acryloyl chloride at 0 °C in a two-phase solvent
system consisting of 4 M aqueous sodium hydroxide and
dichloromethane led to the formation of the target acrylamide
derivatives 11 in good yields (Scheme 5). It is found to be
important to perform the acylation at 0 °C because at higher
temperatures the 3-chloropropanamide derivative resulting
from conjugate addition of the chloride anion to the acrylamide
is formed in a significant amount. In addition, column
chromatography separation of acrylamides and 3-chloropropa-
namides is not an easy task. Although these undesired reaction
products do not interfere in the next step of the synthesis, this
Table 1. Optimization of the Intramolecular N-Arylation of
Compound 7b
conversion
a
entry
1
reaction conditions
(%)
CuI (5 mol %), DMEDA (10 mol %), K2CO3 (2 equiv),
PhMe, 110 °C, 20 h
28
2
3
CuI (5 mol %), DMEDA (10 mol %), K2CO3 (2 equiv),
50
1,4-dioxane, 100 °C, 20 h
CuI (8 mol %), DMEDA (16 mol %), K2CO3 (2 equiv),
1,4-dioxane, 100 °C, 20 h
100
a
Based on the disappearance of the starting compound 7b as
1
monitored by H NMR spectroscopy.
entries 1 and 2). In all cases, the copper(I) salt (CuI) and the
diamine [N,N′-dimethylethylenediamine (DMEDA)] were in a
1:2 molar ratio, and 8 mol % was the optimal loading of
copper(I) salt that led to complete conversion (Table 1, entry
3).
When we applied the optimized conditions depicted in Table
1, entry 3, to enantioenriched butyrolactams 7, pyrroloindoline
(8a), -tetrahydroquinoline (8b), and -tetrahydrobenzazepine
(8c) derivatives were obtained, although in a modest yield in
the case of compound 8c (Scheme 3). These compounds
possess pattern hydrocarbon skeletons of types I, III, and V in
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Scheme 4. Diastereoselective Synthesis of Homoallylamine Derivatives 9
a
Obtained by one-pot aminoallylation of the corresponding aldehyde with (S)-tert-butanesulfinamide.
Scheme 5. Synthesis of Acrylamides 11 from Homoallylamine Derivatives 9
Scheme 6. Synthesis of Tricyclic Compounds 13 from Dihydropyridin-2-ones 12
side reaction could be an important drawback by affecting the
yield of the whole process.
-tetrahydroquinoline (13b) derivatives possess the pattern
hydrocarbon skeletons of types II and IV in Figure 1,
respectively, but through this synthetic strategy we could not
access a member of the type VI family, such as compound 13c.
Since the formation of the seven-membered ring through an
Ullmann-type intramolecular N-arylation from bromophenyl
dihydropyridin-2-one derivative 12c failed, we planned to
perform first an intramolecular N-arylation of the free amine
10c to synthesize the seven-membered ring of the benzazepine
unit and after that to form the lactam ring. In order to find out
the best reaction conditions for the intramolecular N-arylation,
we took homoallylamine derivative 10b as a model compound.
Ring-closing metathesis (RCM) of acrylamides 11 using a
Hoveyda−Grubbs second-generation ruthenium catalyst pro-
duced dihydropyridin-2-ones 12 in high yields in all cases
(Scheme 6). Compounds 12 were then treated under the
optimized conditions depicted in Table 1, entry 3 to perform an
intramolecular N-arylation, leading to the expected tricyclic
compounds 13a and 13b in excellent yields. However, the
reaction failed in the case of the pyridotetrahydrobenzazepine
derivative 13c, the starting lactam 12c being recovered at the
end of the reaction (Scheme 6). The pyridoindoline (13a) and
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As we expected, cyclization did not take place under the
Ullmann-type reaction conditions depicted in Table 1, entry 3,
which were found to be optimal for the lactam derivatives 7 and
12 (Table 2, entry 1). We were please to find that 100%
a little bit higher than for 13c (Scheme 8). Thus, starting from
common intermediate 10b, the overall yield was 52.3% for the
process 10b → 11b → 12b → 13b (lactam formation followed
by N-arylation), while the route 10b → 14b → 15b → 13b
(palladium-catalyzed N-arylation followed by formation of the
lactam) was carried out in 45.5% overall yield. The first strategy
seems to be superior, although benzazepine derivative 13c
could be prepared only by following the second route.
Compounds 8 and 13 are of interest not only because of
their basic molecular architectures but also because their α,β-
unsaturated lactam moieties allow further structural modifica-
tions, leading to more complex systems (Figure 2). In addition,
the double bond of the allylic moiety in compounds 14 can
participate in a number of further synthetically useful
transformations, including cross-metathesis, epoxidation, oxida-
tive cleavage, Heck-type reactions, cycloaddition, hydrobora-
tion, hydroformylation, hydrogenation, hydration, ozonolysis,
etc.27
For instance, the synthetic utility of (S)-2-allyltetrahydroqui-
noline (14b) was exemplified in the synthesis of the natural
alkaloid (−)-angustureine (18) isolated from Galipea officina-
lis,28 a Venezuelan shrubby tree used in folk medicine as a tonic
in dyspepsia, dysentery, and chronic diarrhea and also as an
antipyretic (Scheme 9).29 First, tetrahydroquinoline derivative
14b was treated with paraformaldehyde and NaBH3CN to give
2-allyl-N-methyltetrahydroquinoline (16) in 95% yield, and this
was followed by cross-metathesis with (Z)-hex-3-ene and final
in situ hydrogenation of the resulting olefin 17 (Scheme 9).
From compound 16 it was also possible to synthesize
dehydrohomocuspareine (19), a compound related to the
tetrahydroquinoline alkaloid cuspareine, by performing a Heck-
type reaction with 4-bromoveratrol (Scheme 9).
Table 2. Optimization of the Intramolecular N-Arylation of
Homoallylamine 10b
conversion
a
entry
1
reaction conditions
(%)
CuI (8 mol %), DMEDA (16 mol %), K2CO3 (2 equiv),
1,4-dioxane, 100 °C, 20 h
0
2
3
4
Pd(OAc)2 (5 mol %), ( )-BINAP (7.5 mol %), Cs2CO3
100
100
68
(2 equiv), PhMe, 110 °C, 15 h
Pd(OAc)2 (5 mol %), PPh3 (15 mol %), Cs2CO3 (2
equiv), PhMe, 110 °C, 21 h
Pd(OAc)2 (2 mol %), PPh3 (6 mol %), Cs2CO3 (2
equiv), PhMe, 110 °C, 24 h
a
1
Based on the disappearance of the starting 10b as monitored by H
NMR spectroscopy.
conversion was achieved under palladium catalysis using 5 mol
% Pd(OAc)2 and 7.5 mol % ( )-BINAP with 2 equiv of
Cs2CO3 as a base in toluene at 100 °C for 15 h (Table 2, entry
2).26 Total conversion was also achieved under very similar
reaction conditions but using 15 mol % PPh3 instead of the
more expensive ligand ( )-BINAP (Table 2, entry 3).
Unfortunately, decreasing the loading of Pd(OAc)2 from 5 to
2 mol % led to a lower conversion (Table 2, entry 4).
Bicyclic compounds 14 were obtained when homoallylamine
derivatives 10 were submitted to the reaction conditions shown
in Table 2, entry 3. Purification of the reaction products was
very easy by performing an acidic−basic workup. Concerning
the chemical efficiency of the cyclization in regard to the size of
the ring, 2-allylindoline (14a) was formed in lower yield than
the tetrahydroquinoline (14b) and tetrahydrobenzazepine
(14c) derivatives (Scheme 7).
Fortunately, pyridotetrahydrobenzazepine derivative 13c
could be prepared in two steps from tetrahydrobenzazepine
14c: initial N-acylation with acryloyl chloride in dichloro-
methane under anhydrous reaction conditions and subsequent
RCM of the resulting acrylamide 15c using the Hoveyda−
Grubbs second-generation ruthenium catalyst (Scheme 8). Just
for a comparative study regarding the effectiveness of the two
synthetic strategies to access compounds 13, pyridotetrahy-
droquinoline derivative 13b was also synthesized from 2-
allyltetrahydroquinoline (14b) in two steps, and the yields were
CONCLUSION
■
Benzo-fused 1-azabicyclo[j.k.0]alkanes 8 and 13 with the
general structures I−VI as well as 2-allylindoline, -tetrahy-
droquinoline, and -tetrahydrobenzazepine 14 were easily
accessible in high optical purity from imines derived from
aliphatic aldehydes with a 2-bromophenyl substituent and (S)-
tert-butanesulfinamide. The methodology presented here
comprised as key steps a diastereoselective addition of an
allylic indium intermediate to the chiral sulfinyl imine 4 and an
intramolecular N-arylation using either Ullmann-type reaction
conditions (for lactams 7 and 12) or a palladium-mediated
process (for free amines 10). The functionalized tricyclic
compounds 8 and 13 as well as 2-allyl-substituted heterocycles
14 could be used as building blocks for the synthesis of more
complex molecules. As an example, the natural alkaloid
(−)-angustureine (18) was synthesized starting from (S)-2-
allyltetrahydroquinoline (14b).
Scheme 7. Synthesis of 2-Allylindoline 14a, -tetrahydroquinoline 14b, and -tetrahydrobenzazepine 14c from Homoallylamines
10
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Scheme 8. Synthesis of Tricyclic Compounds 13b and 13c from 14b and 14c
Figure 2. Potential applications of compounds 8, 13, and 14 in synthesis.
Scheme 9. Synthesis of (−)-Angustureine (18) from (S)-2-Allyltetrahydroquinoline (14b)
of-flight (TOF) analyzer, and the samples were ionized by ESI
EXPERIMENTAL SECTION
■
techniques and introduced through an ultrahigh-pressure liquid
General Remarks. (SS)-tert-Butanesulfinamide and its enantiomer
were a gift of Medalchemy (>99% ee by chiral HPLC on a Chiracel AS
column, 90:10 n-hexane/i-PrOH, 1.2 mL/min, λ = 222 nm). TLC was
performed on silica gel 60 F254 using aluminum plates and visualized
with phosphomolybdic acid (PMA) stain. Flash chromatography was
carried out on hand-packed columns of silica gel 60 (230−400 mesh).
Melting points are uncorrected. Optical rotations were measured using
a polarimeter with a thermally jacketed 5 cm cell at approximately 20
°C, and concentrations (c) are given in g/100 mL. Infrared analyses
were performed with a spectrophotometer equipped with an ATR
component; wavenumbers are given in cm−1. Low-resolution mass
spectra were obtained using electron impact (EI) mode at 70 eV;
fragment ions are reported in m/z with relative intensities (%) in
parentheses. High-resolution mass spectrometry (HRMS) was also
carried out in EI mode at 70 eV on an apparatus equipped with a time-
1
chromatograph. H NMR spectra were recorded at 300 or 400 MHz
using CDCl3 as the solvent and TMS (0.00 ppm) as an internal
standard. The data are reported in the form chemical shift
(multiplicity, coupling constant(s) in Hz, integration). The multi-
plicities are denoted as follows: s = singlet, d = doublet, t = triplet, q =
quadruplet, h = heptet, m = multiplet or unresolved, br = broad signal.
13C NMR spectra were recorded with 1H decoupling at 100 MHz and
referenced to CDCl3 at 77.16 ppm. DEPT-135 experiments were
performed to assign CH, CH2, and CH3. Compounds 4a,10 4b,10 and
4c23 were prepared from the corresponding o-bromophenyl aldehydes
and (SS)-tert-butanesulfinamide in THF in the presence of 2 equiv of
titanium tetraethoxide.
General Procedure for the Synthesis of Amino Ester
Derivatives 6. A mixture of the corresponding aldimine 4 (0.5
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mmol), ethyl 2-(bromomethyl)acrylate (5) (0.128 g, 0.65 mmol), and
indium powder (0.226 g, 2.0 mmol) in a saturated aqueous NaBr
solution (5 mL) was stirred for 48 h at 23 °C. Then the resulting
mixture was hydrolyzed with water (10 mL), extracted with EtOAc (3
× 10 mL), dried over anhydrous MgSO4, and evaporated (15 Torr).
The resulting residue was purified by column chromatography (silica
gel, hexane/EtOAc) to yield the pure product 6. Yields and physical
and spectroscopic data follow.
General Procedure for the Synthesis of α-Methylene-γ-
butyrolactams 7. To a solution of the corresponding amino ester 6
(0.2 mmol) in MeOH (1 mL) was added a 4 M HCl dioxane solution
(0.5 mL) at 0 °C. After 2 h of stirring at the same temperature, a 2 M
NaOMe MeOH solution (2 mL) was added, and the resulting mixture
was stirred for 1 h at 0 °C. After that, it was hydrolyzed with water (10
mL), extracted with EtOAc (3 × 10 mL), dried over anhydrous
MgSO4, and evaporated (15 Torr). The resulting residue was purified
by column chromatography (silica gel, hexane/EtOAc) to yield the
pure product 7. Yields and physical and spectroscopic data follow.
(R)-5-(2-Bromobenzyl)-3-methylenepyrrolidin-2-one (7a). The
general procedure was followed using amino ester derivative 6a (129
mg, 0.31 mmol). Purification by column chromatography (hexane/
AcOEt, 1:1) yielded 7a (62 mg, 75%) as a colorless oil. [α]2D3 −60 (c
0.85, CH2Cl2); Rf 0.57 (AcOEt); IR ν (film) 3210, 1694, 1658, 1439
cm−1; δH 7.58 (dd, J = 7.9, 1.2 Hz, 1H), 7.28 (dd, J = 7.3, 1.3 Hz, 1H),
7.21 (dd, J = 7.6, 2.0 Hz, 1H), 7.13 (ddd, J = 7.9, 7.2, 2.0 Hz, 1H), 6.42
(br s, 1H), 6.01 (t, J = 2.7 Hz, 1H), 5.37 (t, J = 2.3 Hz, 1H), 4.08−3.99
(m, 1H), 3.04 (dd, J = 13.5, 5.8 Hz, 1H), 2.99 (ddt, J = 17.1, 7.8, 2.6
Hz, 1H), 2.86 (dd, J = 13.5, 8.0 Hz, 1H), 2.61 (ddt, J = 17.1, 4.0, 2.6
Hz, 1H); δC 170.2 (C), 138.9 (C), 136.7 (C), 133.4 (CH), 131.5
(CH), 128.9 (CH), 127.9 (CH), 124.8 (C), 116.7 (CH2), 50.8 (CH),
43.5 (CH2), 32.9 (CH2); LRMS (EI) m/z (%) 267 ([M(81Br)]+, 1),
96 (100), 53 (14); HRMS (ESI) calcd for C12H1379BrNO ([M + H]+)
266.0181, found 266.0192.
(S)-5-(2-Bromophenylethyl)-3-methylenepyrrolidin-2-one (7b).
The general procedure was followed using amino ester derivative 6b
(202 mg, 0.47 mmol). Purification by column chromatography
(hexane/AcOEt, 1:1) yielded 7b (124 mg, 94%) as a colorless oil.
[α]2D3 −25 (c 0.91, CH2Cl2); Rf 0.46 (AcOEt); IR ν (film) 3203, 1693,
1658, 1299, 1022, 924 cm−1; δH 7.53 (d, J = 7.8 Hz, 1H), 7.42 (br s,
1H), 7.26−7.21 (m, 1H), 7.12−7.03 (m, 1H), 5.99 (q, J = 2.4 Hz,
1H), 5.36 (t, J = 2.3 Hz, 1H), 3.77−3.66 (m, 1H), 3.02 (ddt, J = 17.1,
7.8, 2.5 Hz, 1H), 2.80 (t, J = 8.0 Hz, 2H), 2.54 (ddt, J = 17.2, 4.3, 2.7
Hz, 1H), 1.92−1.79 (m, 2H); δC 170.9 (C), 140.4 (C), 139.5 (C),
133.0 (CH), 130.5 (CH), 128.1 (CH), 127.8 (CH), 124.4 (C), 116.2
(CH2), 51.0 (CH), 37.5 (CH2), 33.1 (CH2), 32.4 (CH2); LRMS (EI)
m/z (%) 200 ([M − Br]+, 81), 201 (14), 97 (10), 96 (100), 53 (15);
HRMS (ESI) calcd for C13H1579BrNO ([M + H]+) 280.0337, found
280.0333.
(S)-5-(3-Bromophenylpropyl)-3-methylenepyrrolidin-2-one (7c).
The general procedure was followed using amino ester derivative 6c
(115 mg, 0.26 mmol). Purification by column chromatography
(hexane/AcOEt, 1:1) yielded 7c (71 mg, 93%) as a white solid. Mp
59−61 °C (hexane/CH2Cl2); [α]2D3 −17 (c 0.91, CH2Cl2); Rf 0.51
(AcOEt); IR ν (KBr) 3199, 1694, 1658, 1439, 1291, 749 cm−1; δH 7.53
(dd, J = 8.0, 0.9 Hz, 1H), 7.25−7.18 (m, 2H), 7.06 (ddd, J = 8.0, 6.9,
2.2 Hz, 1H), 6.94 (br s, 1H), 5.97 (t, J = 2.8 Hz, 1H), 5.34 (s, 1H),
3.73−3.64 (m, 1H), 2.98 (dd, J = 17.1, 7.8 Hz, 1H), 2.76 (t, J = 7.5 Hz,
2H), 2.45 (ddt, J = 17.1, 4.3, 2.7 Hz, 1H), 1.73−1.50 (m, 4H); δC
170.6 (C), 141.1 (C), 139.4 (C), 133.0 (CH), 130.5 (CH), 127.9
(CH), 127.6 (CH), 124.5 (C), 116.2 (CH2), 51.2 (CH), 37.0 (CH2),
36.0 (CH2), 33.2 (CH2), 26.0 (CH2); LRMS (EI) m/z (%) 295
([M(81Br)]+, 1), 214 (59), 171 (5), 169 (5), 96 (100), 53 (12);
HRMS (EI) calcd for C14H1681BrNO 295.0395, found 295.0390.
General Procedure for the Synthesis of Tricyclic Com-
pounds 8 from α-Methylene-γ-butyrolactams 7. A mixture of the
corresponding α-methylene-γ-butyrolactam 7 (0.3 mmol), CuI (4.6
mg, 0.024 mmol), K2CO3 (83 mg, 0.6 mmol), and N,N′-
dimethylethylenediamine (5.6 mg, 7 μL, 0.048 mmol) in dry dioxane
(0.75 mL) was stirred at 100 °C under Ar for 20 h in a high-pressure
tube. Then the resulting mixture was cooled to room temperature,
hydrolyzed with H2O (5 mL), extracted with AcOEt (3 × 10 mL),
dried over anhydrous MgSO4, and evaporated (15 Torr). The resulting
residue was purified by column chromatography (silica gel, hexane/
EtOAc) to yield the pure product 8. Yields and physical and
spectroscopic data follow.
(4R,SS)-Ethyl N-(tert-Butylsulfinyl)-4-amino-5-(2-bromophenyl)-2-
methylenepentanoate (6a). The general procedure was followed
using imine 4a (302 mg, 1 mmol). Purification by column
chromatography (hexane/AcOEt, 2:1) yielded 6a (272 mg, 65%) as
a colorless oil. [α]2D3 +2 (c 1.01, CH2Cl2); Rf 0.45 (AcOEt); IR ν (film)
3220, 1714, 1472, 1045 cm−1; δH 7.52 (dd, J = 8.0, 0.9 Hz, 1H), 7.25
(d, J = 7.6, 2.2 Hz, 1H), 7.22 (d, J = 7.6, 1.2 Hz, 1H), 7.07 (ddd, J =
8.0, 6.9, 2.3 Hz, 1H), 6.35 (d, J = 1.3 Hz, 1H), 5.74 (d, J = 1.1 Hz,
1H), 4.22 (q, J = 7.1 Hz, 2H), 3.89−3.78 (m, 1H), 3.60 (br d, J = 7.0
Hz, 1H), 2.96 (dd, J = 13.8, 5.7 Hz, 1H), 2.89 (dd, J = 13.8, 8.8 Hz,
1H), 2.83 (dd, J = 14.0, 7.1 Hz, 1H), 2.64 (ddd, J = 14.1, 5.8, 0.6 Hz,
1H), 1.31 (t, J = 7.1 Hz, 3H), 1.04 (s, 9H); δC 167.4 (C), 138.2 (C),
137.0 (C), 133.0 (CH), 132.0 (CH), 128.9 (CH2), 128.3 (CH), 127.4
(CH), 125.2 (C), 61.2 (CH2), 56.7 (CH), 56.0 (C), 42.2 (CH2), 38.9
(CH2), 22.6 (CH3), 14.3 (CH3); LRMS (EI) m/z (%) 361 ([M(81Br)
− C4H8]+, 2), 281 (16), 270 (21), 268 (18), 262 (15), 247 (73), 245
(70), 208 (14), 207 (62), 191 (15), 190 (100), 184 (40), 182 (38),
174 (89), 172 (18), 171 (43), 169 (45), 166 (27), 144 (22), 143 (15),
142 (96), 129 (11), 128 (35), 118 (31), 117 (24), 116 (21), 115 (25),
112 (11), 100 (37), 96 (19), 91 (37), 90 (33), 89 (31), 87 (20), 69
(33), 63 (10), 59 (10); HRMS (EI) calcd for C14H1881BrNO3S ([M −
C4H8]+) 361.0170, found 361.0161.
(4S,SS)-Ethyl N-(tert-Butylsulfinyl)-4-amino-6-(2-bromophenyl)-2-
methylenehexanoate (6b). The general procedure was followed using
imine 4b (316 mg, 1 mmol). Purification by column chromatography
(hexane/AcOEt, 2:1) yielded 6b (324 mg, 75%) as a colorless oil.
[α]2D3 +40 (c 1.01, CH2Cl2); Rf 0.66 (AcOEt); IR ν (film) 3276, 1714,
1471, 1370, 1046 cm−1; δH 7.52 (dd, J = 8.0, 0.8 Hz, 1H), 7.19−7.26
(m, 2H), 7.06 (ddd, J = 8.1, 6.7, 2.4 Hz, 1H), 6.32 (d, J = 1.3 Hz, 1H),
5.72 (d, J = 1.0 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.71 (br d, J = 6.4
Hz, 1H), 3.45−3.61 (m, 1H), 2.91 (ddd, J = 13.5, 11.1, 5.0 Hz, 1H),
2.69−2.78 (m, 2H), 2.65 (dd, J = 14.2, 5.6 Hz, 1H), 1.84 (ddd, J =
13.9, 10.8, 5.4 Hz, 1H), 1.66−1.77 (m, 1H), 1.30 (t, J = 7.1 Hz, 3H),
1.25 (s, 9H); δC 167.5 (C), 141.2 (C), 137.1 (C), 132.9 (CH), 130.4
(CH), 128.6 (CH2), 127.8 (CH), 127.7 (CH), 124.4 (C), 61.2 (CH2),
56.1 (C), 55.5 (CH), 38.7 (CH2), 35.9 (CH2), 32.6 (CH2), 22.9
(CH3), 14.27 (CH3); LRMS (EI) m/z (%) 375 ([M(81Br) − C4H8]+,
2), 294 (13), 261 (81), 260 (10), 259 (78), 197 (57), 195 (57), 191
(13), 171 (100), 170 (10), 169 (100), 142 (11), 132 (43), 130 (11),
117 (53), 116 (12), 115 (28), 104 (10), 103 (11), 91 (14), 90 (20), 89
(13), 87 (25), 77 (16), 69 (13); HRMS (ESI) calcd for
C19H2979BrNO3S ([M + H]+) 430.1052, found 430.1054.
(4S,SS)-Ethyl N-(tert-Butylsulfinyl)-4-amino-7-(2-bromophenyl)-2-
methyleneheptanoate (6c). The general procedure was followed
using imine 4c (304 mg, 0.92 mmol). Purification by column
chromatography (hexane/AcOEt, 2:1) yielded 6c (306 mg, 74%) as a
colorless oil. [α]2D3 +39 (c 1.01, CH2Cl2); Rf 0.67 (AcOEt); IR ν (film)
3228, 2978, 1712, 1174, 1049, 751 cm−1; δH 7.52 (dd, J = 7.9, 1.1 Hz,
1H), 7.24−7.16 (m, 2H), 7.05 (ddd, J = 8.0, 6.9, 2.3 Hz, 1H), 6.30 (d,
J = 1.3 Hz, 1H), 5.69 (d, J = 1.1 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H),
3.60 (d, J = 5.9 Hz, 1H), 3.54−3.42 (m, 1H), 2.72 (t, J = 7.6 Hz, 2H),
2.61 (br d, J = 6.2 Hz, 2H), 1.82−1.48 (m, 4H), 1.31 (t, J = 7.1 Hz,
3H), 1.19 (s, 9H); δC 167.6 (C), 141.5 (C), 137.2 (C), 132.9 (CH),
130.4 (CH), 128.5 (CH2), 127.7 (CH), 127.5 (CH), 124.5 (C), 61.2
(CH2), 55.9 (C), 55.2 (CH), 38.3 (CH2), 36.1 (CH2), 35.1 (CH2),
25.9 (CH2), 22.9 (CH3), 14.3 (CH3); LRMS (EI) m/z (%) 389
([M(81Br) − C4H8]+, 4), 275 (35), 273 (36), 211 (43), 209 (48), 207
(10), 187 (10), 174 (11), 171 (22), 169 (24), 146 (11), 132 (11), 131
(100), 130 (16), 115 (23), 104 (19), 103 (11), 91 (21), 90 (12), 87
(18), 77 (12), 69 (13); HRMS (EI) calcd for C16H2281BrNO3S ([M −
C4H8]+) 387.0504, found 387.0490.
(S)-2-Methylene-9,9a-dihydro-1H-pyrrolo[1,2-a]indol-3(2H)-one
(8a).30 The general procedure was followed using lactam 7a (42 mg,
0.16 mmol). Purification by column chromatography (hexane/AcOEt,
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3:1) yielded 8a (15 mg, 52%) as a white solid. Mp 76−78 °C (hexane/
CH2Cl2); [α]2D3 +285 (c 1.09, CH2Cl2); Rf 0.24 (hexane/AcOEt: 3/1);
IR ν (KBr) 1686, 1657, 1602, 1480, 1410, 757 cm−1; δH 7.68 (d, J =
7.8 Hz, 1H), 7.26−7.19 (m, 2H), 7.07 (t, J = 7.5 Hz, 1H), 6.07 (dd, J =
3.4, 1.6 Hz, 1H), 5.42 (dd, J = 2.9, 1.4 Hz, 1H), 4.65−4.55 (m, 1H),
3.21 (dd, 15.7, 8.2 Hz, 1H), 3.24−3.14 (m, 2H), 2.90 (dd, J = 15.4,
10.7 Hz, 1H), 2.78−2.68 (m, 1H); δC 164.4 (C), 143.7 (C), 139.7
(C), 134.1 (C), 128.0 (CH), 125.4 (CH), 124.8 (CH), 117.1 (CH2),
115.2 (CH), 60.2 (CH), 36.3 (CH2), 34.2 (CH2); LRMS (EI) m/z
(%) 185 (M+, 100), 186 (14), 184 (18), 157 (16), 156 (32), 117 (42),
90 (14), 89 (16), 68 (14); HRMS (ESI) calcd for C12H12NO ([M +
H]+) 186.0919, found 186.0915.
(S)-2-Methylene-3,3a,4,5-tetrahydropyrrolo[1,2-a]quinolin-1(2H)-
one (8b). The general procedure was followed using lactam 7b (89
mg, 0.318 mmol). Purification by column chromatography (hexane/
AcOEt, 4:1) yielded 8b (34 mg, 54%) as a white solid. Mp 88−92 °C
(hexane/CH2Cl2); [α]D23 +150 (c 1.11, CH2Cl2); Rf 0.33 (hexane/
AcOEt, 3:1); IR ν (KBr) 3062, 2843, 1681, 1655, 1390, 905, 745
cm−1; δH 8.71 (d, J = 8.3 Hz, 1H), 7.23 (t, J = 7.8 Hz, 1H), 7.14 (d, J =
7.5 Hz, 1H), 7.05 (td, J = 7.5, 1.1 Hz, 1H), 6.10 (t, J = 2.8 Hz, 1H),
5.40 (t, J = 2.4 Hz, 1H), 3.93−3.84 (m, 1H), 3.06 (ddt, J = 16.8, 7.6,
2.1 Hz, 1H), 3.01−2.94 (m, 1H), 2.93−2.85 (m, 1H), 2.49 (ddt, J =
16.9, 6.3, 3.1 Hz, 1H), 2.23−2.16 (m, 1H), 1.75 (ddd, J = 25.0, 12.7,
5.6 Hz, 1H); δC 166.3 (C), 139.6 (C), 136.8 (C), 129.3 (CH), 126.9
(CH), 126.3 (C), 124.1 (CH), 120.0 (CH), 116.5 (CH2), 54.7 (CH),
31.4 (CH2), 29.6 (CH2), 27.7 (CH2); LRMS (EI) m/z (%) 199 (M+,
100), 200 (14), 198 (43), 170 (39), 131 (24), 130 (26); HRMS (EI)
calcd for C13H13NO 199.0997, found 199.0983.
(S)-2-Methylene-2,3,3a,4,5,6-hexahydro-1H-benzo[f ]pyrrolo[1,2-
a]azepin-1-one (8c). The general procedure was followed using
lactam 7c (67 mg, 0.228 mmol). Purification by column chromatog-
raphy (hexane/AcOEt, 3:1) yielded 8c (13 mg, 27%) as a white solid.
Mp 101−103 °C (hexane/CH2Cl2); [α]2D3 −31 (c 1.03, CH2Cl2); Rf
0.17 (hexane/AcOEt, 3:1); IR ν (KBr) 2931, 1689, 1659, 1494, 1402
cm−1; δH 7.35 (dd, J = 7.5, 1.1 Hz, 1H), 7.29−7.14 (m, 3H), 6.13 (t, J
= 2.8 Hz, 1H), 5.45 (ddd, J = 2.6, 1.7, 0.7 Hz, 1H), 3.63−3.53 (m,
1H), 3.16 (ddt, J = 16.7, 8.7, 3.3 Hz, 1H), 2.83−2.66 (m, 2H), 2.51
(ddd, J = 16.8, 3.6, 1.8 Hz, 1H), 2.08−1.94 (m, 2H), 1.74−1.55 (m,
1H), 1.54−1.36 (m, 1H); δC 167.5 (C), 139.4 (C), 139.3 (C), 138.7
(C), 130.3 (CH), 127.4 (CH), 127.2 (CH), 127.1 (CH), 117.0 (CH2),
58.3 (CH), 39.5 (CH2), 35.2 (CH2), 33.8 (CH2), 25.8 (CH2); LRMS
(EI) m/z (%) 213 (M+, 100), 214 (15), 212 (45), 198 (14), 185 (11),
184 (33), 156 (15), 145 (10), 144 (18), 117 (23), 68 (10); HRMS
(EI) calcd for C14H16NO 214.1232, found 214.1223.
(3S,SS)-1-(2-Bromophenyl)-N-(tert-butylsulfinyl)hex-5-en-3-amine
(9b).23 The general procedure was followed using imine 4b (221 mg,
0.70 mmol). Purification by column chromatography (hexane/AcOEt,
3:1) yielded 9b (202 mg, 81%) as a colorless oil. [α]2D3 +43 (c 0.95,
CH2Cl2); Rf 0.34 (hexane/AcOEt, 1:1); IR ν (film) 3215, 1471, 1439,
1052, 1022, 749 cm−1; δH 7.52 (d, J = 7.9 Hz, 1H), 7.19−7.26 (m,
2H), 7.03−7.09 (m, 1H), 5.75−5.87 (m, 1H), 5.15−5.22 (m, 2H),
3.37−3.46 (m, 1H), 3.33 (br d, J = 6.6 Hz, 1H), 2.89 (ddd, J = 13.5,
11.1, 5.1 Hz, 1H), 2.73 (ddd, J = 13.5, 11.1, 5.7 Hz, 1H), 2.39−2.55
(m, 2H), 1.70−1.91 (m, 2H), 1.25 (s, 9H); δC 141.3 (ArC), 134.0
(CH), 133.0 (CH), 130.4 (CH), 127.9 (CH), 127.7 (CH), 124.5
(ArC), 119.4 (CH2), 56.1 (C), 55.1 (CH), 40.7 (CH2), 35.5 (CH2),
32.7 (CH2), 22.9 (CH3); LRMS (EI) m/z (%) 261 (29), 259 (29),
222 (46), 197 (37), 195 (37), 172 (16), 171 (97), 169 (100), 132
(39), 118 (23), 117 (49), 115 (10), 104 (12), 103 (14), 102 (15), 91
(24), 90 (28), 89 (17), 77 (26), 70 (21).
(4S,SS)-7-(2-Bromophenyl)-N-(tert-butylsulfinyl)hept-1-en-4-
amine (9c).23 The general procedure was followed using imine 4c
(300 mg, 0.91 mmol). Purification by column chromatography
(hexane/AcOEt, 3:1) yielded 9c (318 mg, 94%) as a colorless oil.
[α]2D3 +40 (c 1.06, CH2Cl2); Rf 0.44 (hexane/AcOEt, 1:1); IR ν (film)
3217, 1471, 913, 750 cm−1; δH 7.50−7.56 (m, 1H), 7.16−7.26 (m,
2H), 7.01−7.10 (m, 1H), 5.70−5.86 (m, 1H), 5.11−5.20 (m, 2H),
3.31−3.41 (m, 1H), 3.22 (br d, J = 6.0 Hz, 1H), 2.72 (t, J = 7.6 Hz,
2H), 2.38−2.46 (m, 1H), 2.27−2.37 (m, 1H), 1.51−1.78 (m, 4H),
1.20 (s, 9H); δC 141.5 (C), 134.2 (CH), 132.9 (CH), 130.4 (CH),
127.7 (CH), 127.5 (CH), 124.5 (C), 119.1 (CH2), 55.9 (C), 54.7
(CH), 40.5 (CH2), 36.2 (CH2), 34.7 (CH2), 25.9 (CH2), 22.8 (CH3);
LRMS (EI) m/z (%) 317 (20), 315 (19), 275 (11), 273 (11), 224
(10), 211 (29), 209 (30), 171 (25), 169 (25), 146 (12), 132 (11), 131
(100), 130 (18), 118 (24), 115 (16), 104 (29), 103 (18), 102 (15), 91
(40), 90 (21), 89 (16), 77 (25), 70 (14), 56 (15), 55 (10).
General Procedure for the Synthesis of Homoallylamine
Derivatives 9 from 2-Bromophenyl Aldehydes. A mixture of
indium powder (173 mg, 1.50 mmol), (S)-tert-butanesulfinamide (121
mg, 1.00 mmol), the corresponding 2-bromophenyl aldehyde (1.15
mmol), and Ti(OEt)4 (456 mg, 0.450 mL, 2.00 mmol) in THF (2
mL) was stirred under Ar for 1 h at 23 °C. At this time, allyl bromide
(166 mg, 0.132 mL, 1.5 mmol) was added, and the reaction mixture
was heated for 5 h at 60 °C. The mixture was allowed to cool to room
temperature, quenched with brine (2 mL), and diluted with EtOAc.
The resulting suspension was filtered through a short pad of Celite and
concentrated in vacuo (15 Torr). The residue was purified by column
chromatography (silica gel, hexane/AcOEt) to yield the product 9.
Yields follow.
General Procedure for the Synthesis of Homoallylamine
Derivatives 9 from Imines 4. A mixture of the corresponding N-
tert-butylsulfinyl imine 4 (1.0 mmol), allyl bromide (166 mg, 0.132
mL, 1.5 mmol), and indium (144 mg, 1.25 mmol) in dry THF (3 mL)
was stirred for 6 h at 60 °C. Then the resulting mixture was hydrolyzed
with H2O (5 mL), and the solution was extracted with AcOEt (3 × 5
mL). The combined organic phases were washed with brine (3 × 10
mL), dried with anhydrous MgSO4, and evaporated (15 Torr). The
residue was purified by column chromatography (silica gel, hexane/
AcOEt) to yield the product 9. Yields and physical and spectroscopic
data follow.
(2R,SS)-1-(2-Bromophenyl)-N-(tert-butylsulfinyl)pent-4-en-2-
amine (9a).23 The general procedure was followed using imine 4a
(453 mg, 1.5 mmol). Purification by column chromatography
(hexane/AcOEt, 3:1) yielded 9a (378 mg, 73%) as a yellow solid.
Mp 42−45 °C (hexane/CH2Cl2); [α]2D3 +9 (c 1.08, CH2Cl2); Rf 0.32
(hexane/AcOEt, 1:1); IR ν (KBr) 3216, 1736, 1472, 1045, 1024, 912,
749 cm−1; δH 7.53 (d, J = 8.5 Hz, 1H), 7.21−7.25 (m, 2H), 7.03−7.11
(m, 1H), 5.79−5.93 (m, 1H), 5.18−5.25 (m, 2H), 3.63−3.72 (m, 1H),
3.34 (br d, J = 6.9 Hz, 1H), 2.95 (dd, J = 7.2, 5.5 Hz, 2H), 2.48 (t, J =
6.7 Hz, 2H), 1.06 (s, 9H); δC 138.3 (C), 133.9 (CH), 133.0 (CH),
132.0 (CH), 128.3 (CH), 127.4 (CH), 125.2 (C), 119.5 (CH2), 56.2
(CH), 56.0 (C), 41.8 (CH2), 40.7 (CH2), 22.6 (CH3); LRMS (EI) m/
z (%) 247 (3), 245 (3), 208 (9), 184 (8), 182 (8), 171 (11), 169 (11),
118 (100), 91 (11), 90 (11), 89 (10).
(2R,SS)-1-(2-Bromophenyl)-N-(tert-butylsulfinyl)pent-4-en-2-
amine (9a).23 The general procedure was followed using (2-
bromophenyl)acetaldehyde (995 mg, 5.0 mmol). Purification by
column chromatography (hexane/AcOEt, 3:1) yielded 9a (1.07 g,
62%) as a yellow solid.
(3S,SS)-1-(2-Bromophenyl)-N-(tert-butylsulfinyl)hex-5-en-3-amine
(9b).23 The general procedure was followed using 3-(2-bromophenyl)-
propanal (782 mg, 3.67 mmol). Purification by column chromatog-
raphy (hexane/AcOEt, 3:1) yielded 9b (1.04 g, 80%) as a colorless oil.
(4S,SS)-7-(2-Bromophenyl)-N-(tert-butylsulfinyl)hept-1-en-4-
amine (9c).23 The general procedure was followed using 4-(2-
bromophenyl)butanal (1.16 g, 5.11 mmol). Purification by column
chromatography (hexane/AcOEt, 3:1) yielded 9c (1.51 g, 80%) as a
colorless oil.
General Procedure for the Synthesis of Homoallylamines 10
from Homoallylamine Derivatives 9. To a solution of the
corresponding homoallylamine derivative 9 (0.5 mmol) in dry THF
(1 mL) at 0 °C was added HCl (6 M solution, 0.25 mL, 1.5 mmol).
The reaction mixture was stirred at room temperature for 1 h, and
then cooled to 0 °C. NaOH (4 M solution, 1 mL, 4 mmol) was added,
and the mixture was diluted with AcOEt (10 mL). The aqueous phase
was extracted with AcOEt (2 × 10 mL), and then the organic phases
were washed with H2O (10 mL), dried with anhydrous MgSO4, and
evaporated (15 Torr) to yield the free amine 10. Yields and physical
and spectroscopic data follow.
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(R)-1-(2-Bromophenyl)pent-4-en-2-amine (10a). The general
procedure was followed using sulfinamide 9a (688 mg, 2.0 mmol).
Removal of the solvents at low pressure yielded 10a (475 mg, 97%) as
a yellow oil. [α]D23 −10 (c 1.11, CH2Cl2); Rf 0.41 (CH2Cl2/MeOH,
9:1); IR ν (film) 2923, 2856, 1470, 1438 cm−1; δH 7.55 (d, J = 7.8 Hz,
1H), 7.26−7.22 (m, 2H), 7.12−7.05 (m, 1H), 5.84 (dddd, J = 16.8,
10.2, 7.9, 6.4 Hz, 1H), 5.20−5.08 (m, 2H), 3.19 (tt, J = 8.2, 4.9 Hz,
1H), 2.95 (dd, J = 13.4, 5.0 Hz, 1H), 2.64 (dd, J = 13.4, 8.4 Hz, 1H),
2.31 (dddt, J = 13.8, 6.3, 4.7, 1.4 Hz, 1H), 2.18−2.05 (m, 1H), 1.47 (br
s, 2H); δC 139.1 (C), 135.6 (CH), 133.1 (CH), 131.7 (CH), 128.1
(CH), 127.4 (CH), 125.0 (C), 117.9 (CH2), 50.6 (CH), 44.3 (CH2),
42.1 (CH2); LRMS (EI) m/z (%) 200 ([M(81Br) − C3H5]+, 22), 198
(22), 119 (16), 118 (11), 91 (11), 70 (100); HRMS (ESI) calcd for
LRMS (EI) m/z (%) 295 ([M(81Br)]+, 2), 254 (29), 252 (29), 214
(10), 200 (33), 198 (34), 124 (100), 91 (10), 90 (11), 89 (10), 70
(53), 55 (46); HRMS (ESI) calcd for C14H1779BrNO ([M + H]+)
294.0494, found 294.0485.
(S)-N-Acryloyl-1-(2-bromophenyl)hex-5-en-3-amine (11b). The
general procedure was followed using sulfinamide 9b (179 mg, 0.50
mmol). Purification by column chromatography (hexane/AcOEt, 3:1)
yielded 11b (230 mg, 84%) as a white solid. Mp 50−53 °C (hexane/
CH2Cl2); [α]2D3 +17 (c 1.05, CH2Cl2); Rf 0.56 (hexane/AcOEt, 1:1);
IR ν (KBr) 3271, 1654, 1626, 1543, 1438 cm−1; δH 7.51 (d, J = 7.8 Hz,
1H), 7.25−7.20 (m, 2H), 7.10−7.00 (m, 1H), 6.29 (dd, J = 17.0, 1.6
Hz, 1H), 6.11 (dd, J = 17.0, 10.1 Hz, 1H), 5.88−5.71 (m, 1H), 5.64
(dd, J = 10.1, 1.6 Hz, 1H), 5.59 (br d, J = 8.8 Hz, 1H), 5.15−5.04 (m,
2H), 4.19 (m, 1H), 2.88−2.67 (m, 2H), 2.42−2.22 (m, 2H), 1.87
(dddd, J = 10.4, 6.2, 5.5, 3.7 Hz, 1H), 1.79−1.62 (m, 1H); δC 165.3
(C), 141.0 (C), 134.1 (CH), 132.9 (CH), 131.2 (CH), 130.6 (CH),
127.9 (CH), 127.7 (CH), 126.5 (CH2), 124.3 (C), 118.3 (CH2), 48.7
(CH), 39.3 (CH2), 34.8 (CH2), 33.0 (CH2); LRMS (EI) m/z (%) 309
([M(81Br)] +, 2), 307 (2), 269 (11), 268 (85), 267 (12), 266 (86), 215
(10), 214 (97), 213 (11), 212 (100), 197 (24), 195 (25), 171 (43),
169 (45), 132 (16), 125 (13), 116 (12), 115 (11), 90 (14), 89 (10), 84
(10), 77 (13), 72 (28), 7 (16), 55 (69); HRMS (ESI) calcd for
C15H1979BrNO ([M + H]+) 308.0650, found 308.0638.
(S)-N-Acryloyl-7-(2-bromophenyl)hept-1-en-4-amine (11c). The
general procedure was followed using sulfinamide 9c (155 mg, 0.42
mmol). Purification by column chromatography (hexane/AcOEt, 3:1)
yielded 11c (111 mg, 83%) as a white solid. Mp 73−75 °C (hexane/
CH2Cl2); [α]2D3 −2.5 (c 1.02, CH2Cl2); Rf 0.57 (hexane/AcOEt, 1:1);
IR ν (KBr) 3273, 2941, 1653, 1625, 1545, 748 cm−1; δH 7.51 (d, J =
8.0 Hz, 1H), 7.23−7.16 (m, 2H), 7.04 (ddd, J = 8.0, 6.4, 2.7 Hz, 1H),
6.26 (dd, J = 16.9, 1.6 Hz, 1H), 6.07 (dd, J = 16.9, 10.2 Hz, 1H), 5.85−
5.68 (m, 1H), 5.62 (dd, J = 10.2, 1.6 Hz, 1H), 5.45 (br d, J = 9.0 Hz,
1H), 5.13−5.02 (m, 2H), 4.22−4.07 (m, 1H), 2.82−2.65 (m, 2H),
2.37−2.16 (m, 2H), 1.75−1.39 (m, 4H); δC 165.2 (C), 141.5 (C),
134.2 (CH), 132.9 (CH), 131.2 (CH), 130.5 (CH), 127.7 (CH),
127.5 (CH), 126.4 (CH2), 124.5 (C), 118.2 (CH2), 48.5 (CH), 39.2
(CH2), 36.0 (CH2), 34.1 (CH2), 26.4 (CH2); LRMS (EI) m/z (%)
323 ([M(81Br)]+, 1), 282 (32), 280 (32), 228 (77), 226 (79), 211
(40), 209 (41), 171 (20), 169 (15), 152 (13), 130 (19), 129 (11), 124
(10), 91 (11), 90 (12), 72 (52), 70 (26), 56 (13), 55 (100); HRMS
(ESI) calcd for C16H2179BrNO ([M + H]+) 322.0807, found 322.0811.
General Procedure for the Synthesis of Pyridine-2-ones 12
from Acrylamides 11. A mixture of the corresponding acrylamide 11
(0.75 mmol) and Hoveyda−Grubbs ruthenium catalyst (19 mg,
0.0225 mmol) in dry CH2Cl2 (7.5 mL) was stirred at 40 °C under Ar
for 3 h. Then the solvent was evaporated (15 Torr), and the resulting
residue was purified by column chromatography (silica gel, hexane/
AcOEt) to yield the product 12. Yields and physical and spectroscopic
data follow.
C11H 79BrN ([M + H]+) 240.0388, found 240.0379.
15
(S)-1-(2-Bromophenyl)hex-5-en-3-amine (10b). The general pro-
cedure was followed using sulfinamide 9b (573 mg, 1.50 mmol).
Removal of the solvents at low pressure yielded 10b (380 mg, 100%)
as a colorless oil. [α]D23 −7 (c 1.16, CH2Cl2); Rf 0.37 (CH2Cl2/MeOH,
9:1); IR ν (film) 2917, 1470, 1438, 1022, 913, 747 cm−1; δH 7.52 (d, J
= 7.8 Hz, 1H), 7.24−7.21 (m, 2H), 7.11−7.00 (m, 1H), 5.89−5.73 (m,
1H), 5.16−5.11 (m, 1H), 5.10−5.08 (m, 1H), 2.93−2.71 (m, 3H),
2.36−2.25 (m, 1H), 2.12−1.97 (m, 1H), 1.75 (dddd, J = 13.5, 10.8,
5.9, 5.0 Hz, 1H), 1.66−1.53 (m, 1H), 1.46 (br d, J = 0.8 Hz, 2H); δC
141.7 (C), 135.7 (CH), 132.9 (CH), 130.4 (CH), 127.7 (CH), 127.6
(CH), 124.5 (C), 117.7 (CH2), 50.5 (CH), 42.7 (CH2), 38.0 (CH2),
33.1 (CH2); LRMS (EI) m/z (%) 214 ([M(81Br) − C3H5]+, 98), 213
(12), 212 (100), 197 (8), 195 (8), 171 (77), 169 (78), 90 (13), 70
(19); HRMS (ESI) calcd for C12H1779BrN ([M + H]+) 254.0544,
found 254.0537.
(S)-7-(2-Bromophenyl)hept-1-en-4-amine (10c). The general
procedure was followed using sulfinamide 9c (502 mg, 1.35 mmol).
Removal of the solvents at low pressure yielded 10c (357 mg, 99%) as
a colorless oil. [α]D23 −4 (c 1.01, CH2Cl2); Rf 0.34 (CH2Cl2/MeOH,
9:1); IR ν (film) 2925, 1470, 1437, 1022, 913 cm−1; δH 7.53−7.50 (m,
1H), 7.23−7.20 (m, 2H), 7.08−7.01 (m, 1H), 5.85−5.73 (m, 1H),
5.12−5.06 (m, 2H), 2.88−2.79 (m, 1H), 2.79−2.67 (m, 2H), 2.30−
2.20 (m, 1H), 2.06−1.94 (m, 1H), 1.79−1.58 (m, 2H), 1.57−1.34 (m,
4H); δC 141.8 (C), 135.8 (CH), 132.9 (CH), 130.4 (CH), 127.6
(CH), 127.5 (CH), 124.5 (C), 117.5 (CH2), 50.5 (CH), 42.6 (CH2),
37.3 (CH2), 36.3 (CH2), 26.7 (CH2); LRMS (EI) m/z (%) 214
([M(81Br) − C3H5]+, 99), 227 (12), 226 (100), 169 (11), 130 (39),
129 (12), 104 (14), 70 (23), 56 (12); HRMS (ESI) calcd for C13H
79BrN ([M + H]+) 268.0701, found 268.0691.
19
General Procedure for the Synthesis of Acrylamides 11 from
Homoallylamine Derivatives 9. To a solution of the corresponding
homoallylamine derivative 9 (0.5 mmol) in dry THF (1 mL) at 0 °C
was added HCl (6 M solution, 0.25 mL, 1.5 mmol). The reaction
mixture was stirred at room temperature for 1 h and then cooled to 0
°C. NaOH (4 M solution, 1 mL, 4 mmol) was added, and after 5 min,
CH2Cl2 (1.5 mL) and acryloyl chloride (54 mg, 51 μL, 0.6 mmol)
were also added. The resulting reaction mixture was stirred for 30 min
at room temperature and then diluted with AcOEt (15 mL). The
aqueous phase was extracted with AcOEt (2 × 15 mL), and then the
organic phases were washed with H2O (10 mL), dried with anhydrous
MgSO4, and evaporated (15 Torr). The residue was purified by
column chromatography (silica gel, hexane/AcOEt) to yield the
product 11. Yields and physical and spectroscopic data follow.
(R)-N-Acryloyl-1-(2-bromophenyl)pent-4-en-2-amine (11a). The
general procedure was followed using sulfinamide 9a (473 mg, 1.38
mmol). Purification by column chromatography (hexane/AcOEt, 3:1)
yielded 11a (281 mg, 69%) as a white solid. Mp 81−83 °C (hexane/
CH2Cl2); [α]2D3 −18 (c 1.04, CH2Cl2); Rf 0.56 (hexane/AcOEt, 1:1);
IR ν (KBr) 3215, 1471, 1439, 1052, 1022, 749 cm−1; δH 7.52 (dd, J =
7.9, 1.0 Hz, 1H), 7.29−7.19 (m, 2H), 7.06 (ddd, J = 8.0, 6.9, 2.2 Hz,
1H), 6.19 (dd, J = 17.0, 1.6 Hz, 1H), 6.02 (dd, J = 17.0, 10.1 Hz, 1H),
5.92−5.73 (m, 1H), 5.76 (br d, J = 6.7 Hz, 1H), 5.57 (dd, J = 10.1, 1.6
Hz, 1H), 5.17−5.07 (m, 2H), 4.47−4.33 (m, 1H), 2.99 (d, J = 7.2 Hz,
1H), 2.45−2.26 (m, 2H); δC 165.2 (C), 137.9 (C), 134.2 (CH), 132.9
(CH), 131.3 (CH), 131.1 (CH), 128.3 (CH), 127.7 (CH), 126.3
(CH2), 125.0 (C), 118.4 (CH2), 49.9 (CH), 39.9 (CH2), 38.8 (CH2);
(R)-6-(2-Bromobenzyl)-5,6-dihydropyridin-2(1H)-one (12a). The
general procedure was followed using acrylamide 11a (221 mg, 0.75
mmol). Purification by column chromatography (hexane/AcOEt, 3:2)
yielded 12a (164 mg, 82%) as a white solid. Mp 69−72 °C (hexane/
CH2Cl2); [α]2D3 −13 (c 1.02, CH2Cl2); Rf 0.47 (AcOEt); IR ν (KBr)
3220, 1672, 1609, 1470, 1426 cm−1; δH 7.57 (dd, J = 8.0, 1.2 Hz, 1H),
7.28 (td, J = 7.4, 1.2 Hz, 1H), 7.21 (dd, J = 7.6, 1.7 Hz, 1H), 7.14 (td, J
= 7.9, 1.8 Hz, 1H), 6.61 (ddd, J = 9.9, 4.9, 3.5 Hz, 1H), 5.94 (ddd, J =
9.9, 3.6, 2.0 Hz, 1H), 5.68 (br s, 1H), 4.00−3.91 (m, 1H), 3.06 (dd, J =
13.5, 6.0 Hz, 1H), 2.95 (dd, J = 13.5, 8.2 Hz, 1H), 2.45 (dt, J = 17.7,
5.3 Hz, 1H), 2.28 (dddd, J = 17.7, 9.5, 3.4, 2.3 Hz, 1H); δC 166.3 (C),
140.4 (CH), 136.3 (C), 133.5 (CH), 131.6 (CH), 129.0 (CH), 127.9
(CH), 124.9 (C), 124.7 (CH), 50.5 (CH), 41.7 (CH2), 29.6 (CH2);
LRMS (EI) m/z (%) 171 ([M(81Br) − C5H6NO]+, 3), 169 (3), 97
(6), 96 (100), 95 (12), 78 (12), 68 (10); HRMS (ESI) calcd for
C12H1379BrNO ([M + H]+) 266.0181, found 266.0177.
(S)-6-(2-Bromophenethyl)-5,6-dihydropyridin-2(1H)-one (12b).
The general procedure was followed using acrylamide 11b (90 mg,
0.29 mmol). Purification by column chromatography (hexane/AcOEt,
3:2) yielded 12b (61 mg, 75%) as a white solid. Mp 80−83 °C
(hexane/CH2Cl2); [α]D23 +26 (c 0.70, CH2Cl2); Rf 0.38 (AcOEt); IR ν
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(KBr) 3220, 1672, 1610, 1470, 1422 cm−1; δH 7.53 (d, J = 7.8 Hz,
1H), 7.24 (d, J = 4.1 Hz, 2H), 7.08 (dt, J = 8.0, 4.4 Hz, 1H), 6.61 (ddd,
J = 9.9, 5.2, 3.3 Hz, 1H), 6.44 (br s, 1H), 5.93 (ddd, J = 9.9, 3.5, 2.1
Hz, 1H), 3.72−3.60 (m, 1H), 2.81 (ddd, J = 9.1, 6.9, 2.4 Hz, 2H), 2.46
(tt, J = 9.7, 4.9 Hz, 1H), 2.31−2.18 (m, 1H), 1.97−1.80 (m, 2H); δC
166.6 (C), 140.6 (CH), 140.3 (C), 133.0 (CH), 130.4 (CH), 128.1
(CH), 127.8 (CH), 124.6 (CH), 124.4 (C), 50.6 (CH), 35.6 (CH2),
32.1 (CH2), 29.8 (CH2); LRMS (EI) m/z (%) 200 ([M − Br]+, 54),
132 (10), 96 (100), 78 (10), 68 (11); HRMS (ESI) calcd for
C13H1579BrNO ([M + H]+) 280.0337, found 280.0330.
(S)-6-[3-(2-Bromophenyl)propyl]-5,6-dihydropyridin-2(1H)-one
(12c). The general procedure was followed using acrylamide 11c (129
mg, 0.40 mmol). Purification by column chromatography (hexane/
AcOEt, 3:2) yielded 12c (96 mg, 81%) as a colorless oil. [α]2D3 +33 (c
0.77, CH2Cl2); Rf 0.47 (AcOEt); IR ν (film) 3221, 2933, 1672, 1610,
749 cm−1; δH 7.52 (dd, J = 8.0, 1.0 Hz, 1H), 7.26−7.18 (m, 2H), 7.06
(ddd, J = 7.9, 7.1, 2.1 Hz, 1H), 6.59 (ddd, J = 9.9, 5.3, 3.1 Hz, 1H),
6.04 (br s, 1H), 5.93−5.87 (m, 1H), 3.67−3.58 (m, 1H), 2.80−2.72
(m, 2H), 2.40 (dt, J = 17.7, 5.4 Hz, 1H), 2.20−2.10 (m, 1H), 1.74−
1.55 (m, 4H); δC 166.6 (C), 141.0 (C), 140.7 (CH), 133.0 (CH),
130.4 (CH), 127.9 (CH), 127.6 (CH), 124.6 (CH), 124.4 (C), 50.9
(CH), 35.9 (CH2), 35.0 (CH2), 29.9 (CH2), 25.8 (CH2); LRMS (EI)
m/z (%) 294 ([M(81Br)]+ − 1, 2), 292 (2), 267 (5), 265 (5), 214
(26), 96 (100); HRMS (ESI) calcd for C14H1779BrNO ([M + H]+)
294.0473, found 294.0482.
General Procedure for the Synthesis of Tricyclic Com-
pounds 13 from Pyridine-2-ones 12. A mixture of the
corresponding pyridine-2-one 12 (0.3 mmol), CuI (4.6 mg, 0.024
mmol), K2CO3 (83 mg, 0.6 mmol), and N,N′-dimethylethylenedi-
amine (5.6 mg, 7 μL, 0.048 mmol) in dry dioxane (0.75 mL) was
stirred at 100 °C under Ar for 20 h in a high-pressure tube. Then the
resulting mixture was cooled to room temperature, hydrolyzed with
H2O (5 mL), extracted with AcOEt (3 × 10 mL), dried over
anhydrous MgSO4, and evaporated (15 Torr). The resulting residue
was purified by column chromatography (silica gel, hexane/EtOAc) to
yield the pure product 13. Yields and physical and spectroscopic data
follow.
(R)-9a,10-Dihydropyrido[1,2-a]indol-6(9H)-one (13a). The gen-
eral procedure was followed using pyridine-2-one 12a (112 mg, 0.42
mmol). Purification by column chromatography (hexane/AcOEt, 3:1)
yielded 13a (70 mg, 90%) as a white solid. Mp 93−96 °C (hexane/
CH2Cl2); [α]2D3 +89 (c 1.00, CH2Cl2); Rf 0.41 (hexane/AcOEt, 1:1);
IR ν (KBr) 1650, 1587, 1478, 1416 cm−1; δH 8.22 (d, J = 7.9 Hz, 1H),
7.26−7.19 (m, 2H), 7.03 (t, J = 7.5 Hz, 1H), 6.68 (ddd, J = 9.8, 6.4,
2.0 Hz, 1H), 6.10 (dd, J = 9.9, 3.0 Hz, 1H), 4.26−4.16 (m, 1H), 3.29
(dd, J = 15.5, 8.3 Hz, 1H), 2.88 (dd, J = 15.5, 10.9 Hz, 1H), 2.70 (dt, J
= 17.63, 5.18 Hz, 1H), 2.45−2.34 (m, 1H); δC 162.3 (C), 142.4 (C),
139.1 (CH), 129.7 (C), 127.8 (CH), 126.8 (CH), 124.6 (CH), 123.7
(CH), 116.1 (CH), 57.8 (CH), 36.0 (CH2), 31.1 (CH2); LRMS (EI)
m/z (%) 185 (M+, 100), 186 (13), 156 (16), 118 (97), 117 (56), 90
(26), 89 (28), 68 (61), 63 (10); HRMS (ESI) calcd for C12H12NO
([M + H]+) 186.0919, found 186.0912.
corresponding homoallylamine 10 (0.5 mmol), Cs2CO3 (326 mg, 1.0
mmol), PPh3 (20 mg, 0.075 mmol), and Pd(OAc)2 (5.6 mg, 0.025
mmol) in dry toluene (5 mL) was stirred at 110 °C under Ar for 21 h
in a high-pressure tube. Then the resulting mixture was cooled to
room temperature, hydrolyzed with 3 M HCl (5 mL, 15 mmol), and
diluted with AcOEt (10 mL). The organic phase was extracted with 3
M HCl (4 × 10 mL), and then all of the aqueous phases were
basicified with NaOH to pH 13 and extracted with AcOEt (4 × 15
mL). The resulting organic phase was dried over anhydrous MgSO4
and evaporated (15 Torr). The residue was purified by column
chromatography (silica gel, hexane/EtOAc) to yield the pure product
14. Yields and physical and spectroscopic data follow.
(R)-2-Allylindoline (14a). The general procedure was followed
using homoallylamine 10a (96 mg, 0.40 mmol). Purification by
column chromatography (hexane/AcOEt, 10:1) yielded 14a (43 mg,
68%) as a yellow oil. [α]D23 +14 (c 0.75, CH2Cl2); Rf 0.43 (hexane/
AcOEt, 10:1); IR ν (film) 3375, 2926, 1608, 1484, 1466, 1246, 914,
744 cm−1; δH 7.07 (d, J = 7.3 Hz, 1H), 7.00 (t, J = 7.6 Hz, 1H), 6.68
(td, J = 7.4, 1.0 Hz, 1H), 6.60 (d, J = 7.7 Hz, 1H), 5.90−5.75 (m, 1H),
5.17−5.06 (m, 2H), 3.89 (dtd, J = 8.7, 7.2, 6.0 Hz, 1H), 3.14 (dd, J =
15.6, 8.7 Hz, 1H), 2.73 (dd, J = 15.6, 7.1 Hz, 1H), 2.36−2.28 (m, 2H);
δC 150.7 (C), 135.3 (CH), 128.6 (C), 127.4 (CH), 124.9 (CH), 118.7
(CH), 117.6 (CH2), 109.3 (CH), 58.8 (CH), 41.1 (CH2), 35.8
(CH2); LRMS (EI) m/z (%) 159 (M+, 12), 118 (100), 117 (17), 91
(14); HRMS (ESI) calcd for C11H 14N ([M + H]+) 160.1126, found
160.1126.
(S)-2-Allyl-1,2,3,4-tetrahydroquinoline (14b). The general proce-
dure was followed using homoallylamine 10b (127 mg, 0.50 mmol).
Purification by column chromatography (hexane/AcOEt, 10:1)
yielded 14b (77 mg, 89%) as a yellow oil. [α]2D3 +48 (c 1.07,
CH2Cl2); Rf 0.55 (hexane/AcOEt, 9:1); IR ν (film) 3398, 2921, 1483,
1309, 913 cm−1; δH 6.97−6.91 (m, 2H), 6.59 (td, J = 7.4, 1.1 Hz, 1H),
6.47−6.43 (m, 1H), 5.88−5.76 (m, 1H), 5.19−5.12 (m, 2H), 3.84 (br
s, 1H), 3.28 (dddd, J = 9.8, 8.0, 5.0, 2.9 Hz, 1H), 2.87−2.68 (m, 2H),
2.36−2.28 (m, 1H), 2.21−2.12 (m, 1H), 1.95 (dddd, J = 12.5, 5.7, 3.7,
3.0 Hz, 1H), 1.63 (dddd, J = 12.8, 11.2, 9.8, 5.5 Hz, 1H); δC 144.61
(C), 135.1 (CH), 129.3 (CH), 126.8 (CH), 121.3 (C), 118.0 (CH2),
117.1 (CH), 114.2 (CH), 50.6 (CH), 41.3 (CH2), 28.3 (CH2), 26.5
(CH2); LRMS (EI) m/z (%) 173 (M+, 16), 133 (12), 132 (100), 130
(17), 117 (17); HRMS (ESI) calcd for C12H16N ([M + H]+)
174.1283, found 174.1280.
(S)-2-Allyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine (14c). The gen-
eral procedure was followed using homoallylamine 10c (134 mg, 0.50
mmol). Purification by column chromatography (hexane/AcOEt,
10:1) yielded 14c (79 mg, 84%) as a yellow oil. [α]2D3 −19 (c 1.07,
CH2Cl2); Rf 0.61 (hexane/AcOEt, 9:1); IR ν (film) 3341, 2924, 1476,
1258, 737 cm−1; δH 7.11−6.99 (m, 2H), 6.83 (td, J = 7.4, 1.2 Hz, 1H),
6.70 (dd, J = 7.7, 1.1 Hz, 1H), 5.83 (dddd, J = 16.2, 11.0, 8.8, 5.3 Hz,
1H), 5.27−5.12 (m, 2H), 3.70 (br s, 1H), 2.86−2.64 (m, 3H), 2.40−
2.13 (m, 2H), 2.02−1.81 (m, 2H), 1.66−1.42 (m, 2H); δC 148.9 (C),
135.9 (CH), 134.2 (C), 130.6 (CH), 126.7 (CH), 121.2 (CH), 119.9
(CH), 118.4 (CH2), 57.0 (CH), 42.1 (CH2), 38.1 (CH2), 35.6 (CH2),
26.4 (CH2); LRMS (EI) m/z (%) 187 (M+, 9), 147 (11), 146 (100),
131 (12), 130 (13), 118 (18); HRMS (ESI) calcd for C13H 18N ([M +
H]+) 188.1439, found 188.1433.
(S)-4,4a,5,6-Tetrahydro-1H-pyrido[1,2-a]quinolin-1-one (13b).
The general procedure was followed using pyridine-2-one 12b (49
mg, 0.175 mmol). Purification by column chromatography (hexane/
AcOEt, 3:1) yielded 13b (29 mg, 83%) as a white solid. Mp 58−60 °C
(hexane/CH2Cl2); [α]D23 +83 (c 0.81, CH2Cl2); Rf 0.44 (hexane/
AcOEt, 1:1); IR ν (KBr) 3045, 2942, 1665, 1488, 1397, 1316 cm−1; δH
8.06 (dd, J = 8.3, 0.8 Hz, 1H), 7.22−7.16 (m, 1H), 7.10−7.06 (m,
1H), 6.99 (td, J = 7.4, 1.2 Hz, 1H), 6.70−6.65 (m, 1H), 6.08 (ddd, J =
9.7, 2.2, 1.4 Hz, 1H), 4.00−3.92 (m, 1H), 2.82−2.68 (m, 2H), 2.49−
2.36 (m, 2H), 2.05 (dq, J = 13.7, 4.6 Hz, 1H), 1.84 (dtd, J = 13.1, 10.1,
4.9 Hz, 1H); δC 164.63 (C), 140.27 (CH), 136.91 (C), 130.20 (C),
128.27 (CH), 126.98 (CH), 126.34 (CH), 124.06 (CH), 123.61
(CH), 56.48 (CH), 31.66 (CH2), 29.77 (CH2), 27.63 (CH2); LRMS
(EI) m/z (%) 199 (M+, 100), 200 (15), 170 (12), 132 (87), 131 (74),
130 (97), 103 (10), 77 (14), 68 (12); HRMS (ESI) calcd for C13H
14NO ([M + H]+) 200.1075, found 200.1066.
General Procedure for the Synthesis of Acrylamides 15 from
Heterocycles 14. To a solution of the corresponding heterocycle 14
(1.25 mmol) and Et3N (171 mg, 0.24 mL, 1.7 mmol) in dry CH2Cl2
(3 mL) was added dropwise acryloyl chloride (159 g, 0.15 mL, 1.76
mmol) at 0 °C. The reaction mixture was stirred at room temperature
for 2 h, hydrolyzed with H2O (5 mL), and diluted with AcOEt (15
mL). The aqueous phase was extracted with AcOEt (3 × 10 mL), and
then the organic phases were dried with anhydrous MgSO4 and
evaporated (15 Torr). The residue was purified by column
chromatography (silica gel, hexane/AcOEt) to yield the product 15.
Yields and physical and spectroscopic data follow.
(S)-N-Acryloyl-2-allyl-1,2,3,4-tetrahydroquinoline (15b). The gen-
eral procedure was followed using heterocycle 14b (77 mg, 0.44
mmol). Purification by column chromatography (hexane/AcOEt,
10:1) yielded 15b (63 mg, 63%) as a colorless oil. [α]2D3 −389 (c 1.03,
General Procedure for the Synthesis of 2-Allyl Benzo-Fused
Heterocycles 14 from Homoallylamines 10. A mixture of the
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CH2Cl2); Rf 0.30 (hexane/AcOEt, 6:1); IR ν (film) 2947, 1651, 1651,
1614, 1489, 1404, 1323, 1241, 914, 750 cm−1; δH 7.22−7.13 (m, 3H),
7.02 (d, J = 7.1 Hz, 1H), 6.42 (s, 1H), 6.41 (d, J = 0.8 Hz, 1H), 5.81−
5.69 (m, 1H), 5.65−5.59 (m, 1H), 5.00 (s, J = 1.1 Hz, 1H), 4.98−4.94
(m, 1H), 4.93−4.84 (m, 1H), 2.66 (dt, J = 15.1, 5.4 Hz, 1H), 2.56
(ddd, J = 15.2, 10.1, 5.5 Hz, 1H), 2.42−2.25 (m, 2H), 2.20−2.11 (m,
1H), 1.54 (dddd, J = 12.8, 10.1, 6.9, 5.6 Hz, 1H); δC 165.4 (C), 137.2
(C), 134.4 (CH), 129.8 (CH), 127.8 (CH), 127.7 (CH2), 126.4
(CH), 126.3 (CH), 125.9 (CH), 117.4 (CH2), 51.7 (CH), 38.9
(CH2), 29.7 (CH2), 25.7 (CH2); LRMS (EI) m/z (%) 186 ([M −
[α]2D3 −9 (c 1.27, CH2Cl2); Rf 0.72 (hexane/AcOEt, 9:1); IR ν (film)
2929, 1602, 1497, 1332, 1213, 911 cm−1; δH 7.08 (t, J = 7.8 Hz, 1H),
6.97 (d, J = 7.3 Hz, 1H), 6.59 (td, J = 7.3, 1.1 Hz, 1H), 6.53 (d, J = 8.2
Hz, 1H), 5.79 (dddd, J = 16.8, 10.3, 8.1, 6.4 Hz, 1H), 5.12−5.03 (m,
2H), 3.37−3.27 (m, 1H), 2.93 (s, 3H), 2.89−2.74 (m, 1H), 2.70−2.60
(m, 1H), 2.47−2.36 (m, 1H), 2.21−2.08 (m, 1H), 1.97−1.79 (m, 2H);
δC 145.3 (C), 135.6 (CH), 128.8 (CH), 127.2 (CH), 121.9 (C), 117.2
(CH2), 115.6 (CH), 110.6 (CH), 58.8 (CH), 38.0 (CH3), 36.0 (CH2),
24.4 (CH2), 23.5 (CH2); LRMS (EI) m/z (%) 187 (M+, 12), 147
(11), 146 (100), 144 (11), 131 (17), 130 (15); HRMS (ESI) calcd for
C13H18N ([M + H]+) 188.1439, found 188.1445.
+
C3H5] , 46), 133 (11), 132 (100), 130 (10), 55 (16); HRMS (ESI)
calcd for C15H18NO ([M + H]+) 228.1388, found 228.1383.
(S)-N-Acryloyl-2-allyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine
(15c). The general procedure was followed using homoallylamine 14c
(180 mg, 0.96 mmol). Purification by column chromatography
(hexane/AcOEt, 10:1) yielded 15c (122 mg, 52%) as a yellow oil.
[α]2D3 −179 (c 1.09, CH2Cl2); Rf 0.28 (hexane/AcOEt, 6:1); IR ν
(film) 2928, 1653, 1490, 1405, 1254 cm−1; δH 7.31−7.18 (m, 3H),
7.02 (d, J = 6.8 Hz, 1H), 6.36 (dd, J = 16.8, 2.1 Hz, 1H), 5.94 (dd, J =
16.8, 10.3 Hz, 1H), 5.74 (ddt, J = 17.1, 10.3, 6.8 Hz, 1H), 5.48 (dd, J =
10.3, 2.1 Hz, 1H), 5.06−4.93 (m, 3H), 2.81−2.72 (m, 1H), 2.65 (dt, J
= 14.2, 4.5 Hz, 1H), 2.15−2.03 (m, 1H), 1.99−1.86 (m, 2H), 1.84−
1.72 (m, 1H), 1.65−1.51 (m, 2H); δC 165.3 (C), 140.4 (C), 138.3
(C), 135.2 (CH), 130.4 (CH), 129.8 (CH), 129.1 (CH), 128.4 (CH),
127.5 (CH2), 126.8 (CH), 117.0 (CH2), 51.3 (CH), 36.1 (CH2), 33.3
(CH2), 31.1 (CH2), 21.2 (CH2); LRMS (EI) m/z (%) 241 (M+, 3),
201 (10), 200 (66), 147 (13), 146 (100), 55 (14); HRMS (ESI) calcd
for C16H20NO ([M + H]+) 242.1545, found 242.1544.
General Procedure for the Synthesis of Tricyclic Com-
pounds 13 from Acrylamides 15. A mixture of the corresponding
acrylamide 15 (0.50 mmol) and Hoveyda−Grubbs ruthenium catalyst
(12.6 mg, 0.015 mmol) in dry CH2Cl2 (5 mL) was stirred under Ar at
40 °C for 3 h. Then the solvent was evaporated (15 Torr), and the
resulting residue was purified by column chromatography (silica gel,
hexane/AcOEt) to yield products 13. Yields and physical and
spectroscopic data follow.
Synthesis of (−)-Angustureine (18) from (S)-2-Allyl-N-
methyl-1,2,3,4-tetrahydroquinoline (16). A mixture of 2-allyl-N-
methyltetrahydroquinoline 16 (93 mg, 0.50 mmol), cis-3-hexene (86
mg, 0.127 mL, 1.0 mmol), and Hoveyda−Grubbs ruthenium catalyst
(12.7 mg, 0.015 mmol) in dry CH2Cl2 (6 mL) was stirred under Ar at
40 °C for 3 h, and then the solvent was evaporated (15 Torr). The
resulting residue was dissolved in MeOH (9 mL), and 10% Pd/C (27
mg, 0.015 mmol) was added. The resulting reaction mixture was
stirred for 12 h at 23 °C under H2 (1 atm) and then filtered through
Celite and evaporated (15 Torr). The resulting residue was purified by
column chromatography (silica gel, hexane/AcOEt, 20:1) to yield 59
mg (0.27 mmol, 54%) of pure (−)-angustureine (18).31 Physical and
spectroscopic data follow: colorless oil; [α]2D3 −6.8 (c 1.00, CH2Cl2);
Rf 0.18 (hexane/AcOEt, 20:1); IR ν (film) 2926, 1602, 1498, 741
cm−1; δH 7.06 (t, J = 7.7 Hz, 1H), 6.95 (d, J = 7.3 Hz, 1H), 6.57 (td, J
= 7.3, 1.0 Hz, 1H), 6.51 (d, J = 8.2 Hz, 1H), 3.21 (dq, J = 8.5, 4.2 Hz,
1H), 2.91 (s, 3H), 2.84−2.73 (m, 1H), 2.64 (dt, J = 16.2, 4.2 Hz, 1H),
1.92−1.83 (m, 2H), 1.64−1.53 (m, 1H), 1.45−1.20 (m, 8H), 0.89 (t, J
= 6.9 Hz, 3H); δC 145.5 (C), 128.7 (CH), 127.2 (CH), 122.0 (C),
115.3 (CH), 110.5 (CH), 59.1 (CH), 38.1 (CH3), 32.2 (CH2), 31.4
(CH2), 25.9 (CH2), 24.6 (CH2), 23.7 (CH2), 22.8 (CH2), 14.2
(CH3); LRMS (EI) m/z (%) 217 (M+, 14), 147 (11), 147 (11), 146
(100), 144 (8).
Synthesis of (S,E)-2-[3-(3,4-Dimethoxyphenyl)allyl]-1-meth-
yl-1,2,3,4-tetrahydroquinoline (19). A mixture of 2-allyl-N-
methyltetrahydroquinoline 16 (51 mg, 0.27 mmol), 4-bromoveratrol
(148 mg, 0.100 mL, 0.68 mmol), K2CO3 (75 mg, 0.54 mmol), and
Pd(PPh3)4 (15.6 mg, 0.0135 mmol) in dry dioxane (1 mL) was stirred
at 100 °C under Ar for 24 h in a high-pressure tube. Then the resulting
mixture was cooled to room temperature, diluted with AcOEt (10
mL), filtered through a short pad of Celite, and concentrated in vacuo
(15 Torr). The residue was purified by column chromatography (silica
gel, hexane/AcOEt, 17:1) to yield 35 mg (0.11 mmol, 40%) of pure
compound 19. Physical and spectroscopic data follow: yellow oil; [α]D23
−29 (c 1.10, CH2Cl2); Rf 0.53 (hexane/AcOEt, 3:1); IR ν (film) 2931,
1601, 1511, 1498, 1260 cm−1; δH 7.09 (t, J = 7.7 Hz, 1H), 6.99 (d, J =
7.1 Hz, 1H), 6.90−6.85 (m, 2H), 6.81 (d, J = 8.8 Hz, 1H), 6.61 (t, J =
7.3 Hz, 1H), 6.55 (d, J = 8.1 Hz, 1H), 6.36 (d, J = 15.7 Hz, 1H), 6.05
(ddd, J = 15.0, 8.0, 6.8 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.41 (td, J
= 8.4, 4.3 Hz, 1H), 2.97 (s, 3H), 2.93−2.81 (m, 1H), 2.73−2.63 (m,
1H), 2.59−2.49 (m, 1H), 2.29 (dt, J = 14.0, 8.6 Hz, 1H), 2.02−1.86
(m, 2H); δC 149.2 (C), 148.6 (C), 145.3 (C), 132.0 (CH), 130.8 (C),
128.9 (CH), 127.3 (CH), 125.3 (CH), 121.9 (C), 119.0 (CH), 115.7
(CH), 111.3 (CH), 110.6 (CH), 108.7 (CH), 59.2 (CH3), 56.1
(CH3), 56.0 (CH3), 38.1 (CH), 35.2 (CH2), 24.7 (CH2), 23.6 (CH2);
LRMS (EI) m/z (%) 323 (M+, 39), 203 (10), 172 (25), 147 (12), 146
(100), 144 (19), 131 (16), 130 (15), 120 (29), 91 (10); HRMS (ESI)
calcd for C21H26NO2 ([M + H]+) 324.1964, found 324.1974.
(S)-4,4a,5,6-Tetrahydro-1H-pyrido[1,2-a]quinolin-1-one (13b).
The general procedure was followed using acrylamide 15b (58 mg,
0.25 mmol). Purification by column chromatography (hexane/AcOEt,
3:1) yielded 13b (42 mg, 83%) as a white solid.
(S)-4a,5,6,7-Tetrahydrobenzo[f ]pyrido[1,2-a]azepin-1(4H)-one
(13c). The general procedure was followed using homoallylamine 15c
(87 mg, 0.36 mmol). Purification by column chromatography
(hexane/AcOEt, 10:1) yielded 13c (60 mg, 79%) as a white solid.
Mp 130−132 °C (hexane/CH2Cl2); [α]2D3 −118 (c 1.03, CH2Cl2); Rf
0.30 (hexane/AcOEt, 1:2); IR ν (KBr) 1657, 1614, 1595, 1434, 1426
cm−1; δH 7.28−7.17 (m, 4H), 6.59 (dddd, J = 9.8, 6.2, 2.4, 1.3 Hz,
1H), 6.06 (ddd, J = 9.9, 3.0, 0.6 Hz, 1H), 3.63−3.54 (m, 1H), 2.92
(ddt, J = 18.0, 7.2, 2.7 Hz, 1H), 2.80 (ddd, J = 14.2, 11.9, 2.3 Hz, 1H),
2.69 (ddd, J = 14.2, 6.2, 2.2 Hz, 1H), 2.34−2.16 (m, 2H), 2.08−1.95
(m, 1H), 1.68−1.58 (m, 1H), 1.58−1.41 (m, 1H); δC 163.0 (C), 142.0
(C), 139.7 (C), 138.6 (CH), 130.1 (CH), 128.5 (CH), 127.7 (CH),
127.1 (CH), 125.0 (CH), 57.9 (CH), 34.9 (CH2), 33.8 (CH2), 31.0
(CH2), 26.1 (CH2); LRMS (EI) m/z (%) 213 (M+, 85), 214 (13), 212
(25), 196 (10), 184 (11), 146 (21), 145 (100), 144 (28), 130 (17),
118 (30), 117 (46), 115 (10), 91 (11), 90 (18), 89 (15), 68 (15);
HRMS (ESI) calcd for C14H16NO ([M + H]+) 214.1232, found
214.1225.
Synthesis of (S)-2-Allyl-N-methyl-1,2,3,4-tetrahydroquino-
line (16). A mixture of 2-allyltetrahydroquinoline 14b (123 mg,
0.71 mmol), paraformaldehyde (95 mg, 3.2 mmol), NaBH3CN (133
mg, 2.1 mmol), and acetic acid (126 mg, 0.120 mL, 2.1 mmol) in
acetonitrile (6 mL) was stirred at 23 °C for 16 h. Then the resulting
mixture was hydrolyzed with 3 M HCl (5 mL, 15 mmol) and diluted
with AcOEt (10 mL). The organic phase was extracted with 3 M HCl
(4 × 10 mL), and then all of the aqueous phases were basicified with
NaOH to pH 13 and extracted with AcOEt (4 × 15 mL). The
resulting organic phase was dried over anhydrous MgSO4 and
evaporated (15 Torr) to give 126 mg (0.67 mmol, 95%) of pure
compound 16. Physical and spectroscopic data follow: Yellow wax;
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H, 13C NMR, and DEPT spectra for all of the
reported compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: foubelo@ua.es.
■
1366
dx.doi.org/10.1021/jo402759v | J. Org. Chem. 2014, 79, 1356−1367

The Journal of Organic Chemistry
Article
(21) (a) Weix, D. J.; Ellman, J. A. Org. Lett. 2003, 5, 1317. (b) Weix,
D. J.; Ellman, J. A. Org. Synth. 2005, 82, 157.
(22) (a) Wakayama, M.; Ellman, J. A. J. Org. Chem. 2009, 74, 2646.
*E-mail: yus@ua.es.
Notes
The authors declare no competing financial interest.
(b) Aggarwal, V. K.; Barbero, N.; McGarrigle, E. M.; Mickle, G.;
Navas, R.; Suar
2009, 50, 3482.
́
ez, J. R.; Unthank, M. G.; Yar, M. Tetrahedron Lett.
ACKNOWLEDGMENTS
■
(23) Sirvent, J. A.; Foubelo, F.; Yus, M. Eur. J. Org. Chem. 2013, 2461.
(24) Dema, H. K.; Foubelo, F.; Yus, M. Heterocycles 2011, 82, 1411.
(25) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 7421.
(26) Liu, M.; Li, J.; Xiao, X.; Xie, Y.; Shi, Y. Chem. Commun. 2013,
49, 1404.
(27) Carreira, E. M.; Kvaerno, L. Classics in Stereoselective Synthesis;
Wiley-VCH: Weinheim, Germany, 2009; pp 153−185.
(28) (a) Jacquemond-Collet, I.; Hannedouche, S.; Fabre, N.;
We thank the Spanish Ministerio de Ciencia e Innovacion
(Grants CTQ2007-65218, Consolider Ingenio 2010-CSD-
2007-00006, and CTQ2011-24165), the Generalitat Valenciana
(Grant PROMETEO/2009/039 and FEDER), and the
University of Alicante for generous and continuous financial
support.
́
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