Studies concerning the electrophilic amino-alkene cyclisation for the synthesis of bicyclic amines

Article abstract of DOI:10.1039/b819610a

The bromination of a series of cyclohexenyl substituted secondary amines 1a-i has been investigated using Br₂, PHT and NBS. In the case of Br₂ and NBS the secondary amines preferentially undergo N-bromination. In contrast, PHT cleanly affords the products of alkene dibromination. In the case of Br₂ the N-bromo species then give the products of alkene dibromination, albeit less efficiently. On subsequent treatment with K₂CO₃ these dibromides form the corresponding hexahydroindoles 2a-h and octahydroquinoline 2i. The presence of an N-substituent bearing a stereogenic centre (1h and 1i) was studied and the products 2h and 2i were isolated with no diastereoselectivity. When NBS was used a novel cyclisation, forming bromo-substituted octahydroindoles 9a,b and d, was observed. In relation to this sequence it was shown that these products were not intermediates in the former Br₂/PHT processes and that the reaction only proceeded in the presence of the succinimide by-product of N-bromination.

Full text of DOI:10.1039/b819610a

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Studies concerning the electrophilic amino-alkene cyclisation for the
synthesis of bicyclic amines†
Johannes E. M. N. Klein, Helge Mu¨ller-Bunz and Paul Evans*
Received 4th November 2008, Accepted 4th December 2008
First published as an Advance Article on the web 23rd January 2009
DOI: 10.1039/b819610a
The bromination of a series of cyclohexenyl substituted secondary amines 1a-i has been investigated
using Br2, PHT and NBS. In the case of Br2 and NBS the secondary amines preferentially undergo
N-bromination. In contrast, PHT cleanly affords the products of alkene dibromination. In the case of
Br2 the N-bromo species then give the products of alkene dibromination, albeit less efficiently. On
subsequent treatment with K2CO3 these dibromides form the corresponding hexahydroindoles 2a-h and
octahydroquinoline 2i. The presence of an N-substituent bearing a stereogenic centre (1h and 1i) was
studied and the products 2h and 2i were isolated with no diastereoselectivity. When NBS was used a
novel cyclisation, forming bromo-substituted octahydroindoles 9a,b and d, was observed. In relation to
this sequence it was shown that these products were not intermediates in the former Br2/PHT processes
and that the reaction only proceeded in the presence of the succinimide by-product of N-bromination.
formation proceeds via initial alkene dibromination followed by
Introduction
a regioselective base mediated elimination and SN2¢ cyclisation
sequence4 affording the products 2 of formal C–H activation.‡
Mechanistically, although this seems reasonable, it does not
adequately account for the reported observation that when R
represents a-methylbenzyl the bicyclic product 2 is isolated in
high diastereomeric excess (>95% d.e).3 Since the stereogenic
centre is, in this instance, remote from the double bond it would
appear remarkable that this group would dictate and control the
stereofacial sense of the intermolecular bromonium ion formation
required for the generation of 2 as a single diastereoisomer.
One possible alternative mechanistic explanation for this reported
diastereocontrol is that the secondary amine is directly involved in
the activation of the trisubstituted alkene by initial N-bromination
to form 5. In turn it may be speculated that this N-bromo species 5
might react with the alkene in an intramolecular sense via a polar
transition state of the type 6 or 7. In relation to this suggestion
numerous examples do exist concerning the formation of N-halo
There have been several recent reports concerning the reaction of
amines with alkenes not possessing electron-withdrawing groups
in the presence of various catalysts and mediators. In these ex-
amples alkene functionalisation affords alkyl amino compounds.1
However, arguably a more synthetically useful reaction is the halo-
amino functionalisation of alkenes since in this instance both
alkenyl carbon atoms become functionalised, thereby enabling
further derivatisation. Several examples of this class of reaction
have been reported using various substrates and halogen sources.2
In relation to this general reaction type an efficient sequence
caught our attention in which the cyclic alkene 1 undergoes
a 2-step intramolecular conversion into 2 following its initial
reaction with acid washed bromine and subsequent treatment
with K2CO3 (Scheme 1).3 The authors speculate that this trans-
Centre for Synthesis and Chemical Biology, School of Chemistry and Chem-
ical Biology, University College Dublin, Dublin 4, Ireland. E-mail: paul.
evans@ucd.ie
† Electronic supplementary information (ESI) available: General pro-
cedures for the preparation of secondary amines 1a–1f, procedures
for the synthesis of amines 1g–1i, experimental details for the X-ray
crystallography and X-ray structures of compounds 2a, 1b·HBr and S6.
CCDC reference numbers 707945–707951. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/b819610a
‡ Substituted cyclopentenyl and cyclohexenyl systems were not employed
in this study, consequently it is not possible to state unequivocally whether
this process is SN2¢ rather than SN2, although the pathway followed is
crucial since the different modes of substitution lead to diastereoisomeric
products when R contains a stereogenic centre.4 The direct SN2 displace-
ment of 3 appears to be precluded based on stereoelectronic arguments.
Scheme 1 The bromo-amino cyclisation of alkenyl secondary amines 1.
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Scheme 2 Synthesis of hexahydroindoles 2a–g (X = Br, or H).
compounds from electron rich amines.5–8 Typically such species
possess limited stability and their reactivity and stability has been
investigated both from a theoretical and practical standpoint. For
example, their treatment with base leads to dehydrohalogenation
and formation of an imine.5 A synthetic application of this
sequence has been used in order to achieve a-amino function-
alisation as applied to the synthesis of perhydrohistrionicotoxin.6
Additionally, several reports indicate that this general class of
compound may effectively act as halogenating agents (i.e. 6)7 and
the possibility that 5 might, alternatively, act as an electrophilic
source of nitrogen was also considered.8 Examples involving the
bromination, or chlorination of double bonds in the presence of
basic amino functionality (i.e. non-protected) are scarce.9
also indicating a pathway involving N-bromination followed by
elimination and subsequent hydrolysis of the so-formed imine.
Although this evidence combined to suggest that mechanisms
involving species such as 6 or 7 may indeed operate, another
possibility is that the N-bromo species 5 releases molecular
bromine, which over time leads to the formation of the dibromide
(of the type 3). Additional secondary amines 1b (Entry 2, Method
A), 1e (Entry 5, Method A) provided the corresponding hexahy-
droindoles 2b and 2e in similarly reasonable yields following their
respective treatment with bromine and subsequently K2CO3.
While the use of a conventional protecting group to obviate
the apparently rapid N-halogenation pathway and achieve clean
bromination would only serve to add steps to a synthesis, the
use of hydrotribromide was attempted. In this instance it was felt
that protonation (i.e. temporary protection) of the amine would
effectively prevent N-bromination, ultimately leading to a cleaner
process.10 Additionally, ammonium ion formation would preclude
the direct intermediacy of N-bromo species 5 in the reaction mech-
anism. In the presence of the commercially available pyrrolidone
hydrotribromide (PHT)11 smooth alkenyl dibromination could be
carried out at room temperature in dichloromethane. For example,
1a was converted into the dibromoammonium species 3a (as
its HBr salt), which was characterised by NMR spectroscopy
and mass spectrometry. The dibromide 3a was then successfully
subjected to the second cyclisation step as before. Thus, 2a was
isolated following purification by flash column chromatography
in 85% yield (Scheme 2, Entry 1). Notably, following this modified
reaction procedure (Method B) significantly cleaner reactions were
observed for all the secondary amine substrates studied (1b–g) and
the hexahydroindole adducts (2b–g) were isolated in consistently
higher yields than the sequence effected using molecular bromine
(Method A). In the case of 2f, no products of electrophilic aromatic
substitution were detected.
Results and discussion
Intrigued by the possibility that the functionalisation of this type
of alkene (Scheme 1) might proceed via initial N-bromination
followed by intramolecular bromonium ion formation (6), or
direct cyclisation (7) our first approaches focussed on the use
of the N-benzylamine derivative 1a § following the previou◦sly
described procedure.3 Exposure of 1a to Br2 (1.2 equiv.) at -78 C
for 0.5 hours in dichloromethane, followed by treatment of the
material thus obtained with K2CO3 (3 equiv.) in acetone at 50 ◦C,
gave N-benzyl hexahydroindole 2a reproducibly in 50–61% yield
(see Scheme 2, Entry 1, Method A).
Although the desired product 2a was obtained, several experi-
mental observations gave further insight into the possible pathway
of this reaction. Crude proton NMR spectroscopy after the initial
treatment of 1a with 1.0 equivalent of bromine (CDCl3, rt, after
5 minutes) indicated significant preservation of the double bond
(ca. 50%), which was attributed to the competitive formation of an
N-bromoammonium compound of type 5a (see also Scheme 5).¶
Furthermore, the formation of benzaldehyde was observed,
With this information in hand we then investigated the di-
astereoselective cyclisation of a-methylbenzylamine containing
substrates ( )-1h and (+)-1i (Scheme 3).§ In both cases, using
either molecular bromine or the modified PHT conditions, the
§ For the synthesis of secondary amines 1a–g and the X-ray crystallo-
graphic structure of 2a see ESI.†
¶ Treatment of 1a with 0.5 equiv., 1 equiv. and 2 equiv. of Br2 indicated
that complete alkenyl bromination only occurred using 2 equivalents of
Br2, while the use of sub-stoichiometric or stoichiometric amounts resulted
in selective, initial N-bromination leading to 5a. Evidence for this was
indicated by a significant shift of the benzylic proton signal observed by
NMR spectroscopy. Compound 5a was also prepared using NBS and
although it proved to be unstable, proton NMR spectra were comparable
(Scheme 5).
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Scheme 3 Investigation of diastereoselective approaches to hexahydroindole 2h and octahydroquinoline 2i.
corresponding hexahydroindole 2h and octahydroquinoline 2i
were formed in moderate to good yield. However, using either
Br2 or PHT it was immediately evident from inspection of the
crude proton NMR spectra that these reactions did not proceed in
a diastereoselective fashion. Furthermore, in both cases, using
either reaction conditions, formation of an approximately 1:1
mixture of diastereoisomers was evident. In the case of the racemic
hexahydroindole 2h, in our hands, the diastereoisomers proved
only partially separable by flash column chromatography. The
slightly faster moving diastereoisomer was separated in a small
amount and its spectroscopic data proved equivalent to that
reported.3a This material crystallised as its HCl salt and an X-
ray structure was obtained, thereby demonstrating its relative
stereochemistry (Fig. 1).12 Using Br2 (2.2 equiv.) the identity of
the intermediate dibromide 3h was subsequently investigated. Cru-
cially, 2.2 equivalents of Br2 were required for complete conversion
and after work-up we assume that degradation of any N-bromo
species occurs (see also above and the footnote¶). Although the
proton NMR spectrum was not helpful, splitting, attributed to
the presence of two diastereomeric species (S*,S*,R*)-3h and
(R*,R*,R*)-3h, was detected in the carbon NMR spectrum. The
homologated a-methylbenzylamine (+)-1i was also prepared for
comparison and although the cyclisation proved to be slower than
in the previous case, octahydroquinoline 2i successfully formed as
a mixture of two diastereoisomers.
In this instance the diastereoisomers proved to be readily separa-
ble by flash column chromatography enabling their complete spec-
troscopic characterisation in this enantiopure series. The slower
moving diastereoisomer proved to be crystalline as its HCl salt
(Fig. 1) and the relative stereochemistry of both diastereoisomers
was thus deduced.13 As observed for 2h, spectroscopic data for
the faster moving diastereoisomer (R,R)-2i matched that reported
previously.3a
Clearly based on these results no difference in diastereoselec-
tivity was observed between the different methods for bromi-
nation, which serves to suggest that, in our hands at least, this
reaction does not proceed via the type of discrete intramolecular
intermediate proposed in Scheme 1, which might be able to
Fig.
1
X-ray crystallographic structures of (R*,R*)-2h·HCl12 and
(S,R)-2i·HCl13 (thermal ellipsoids drawn at the 15% probability level).
Note that for 2h·HCl the co-crystallised H2O is not shown for clarity.
efficiently relay stereochemical information from the chiral centre
attached to the amine to the alkene. It seems likely, therefore,
that the diastereomeric mixture of dibromides 3h and 3i generate
a diastereomeric mixture of 8 which then undergoes cyclisation
to 2h and 2i. Evidence for the intermediacy of 8 was observed
on storage of the intermediate dibromide 3h in CDCl3; within
48 hours a characteristic alkenyl signal in its 1H-NMR spectrum
developed, which was assigned to allylic bromide 8 (5.70 ppm).
Nevertheless, we decided to further investigate the formation
of N-bromoamino species of the type 5 and attempted to study
the reaction and hoped for cyclisation of benzylamine 1a using
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Scheme 4 NBS mediated cyclisation of cyclohexenyl amines 1a, 1b and 1d.
N-bromosuccinimide (NBS). Potentially the type of tertiary
amine product 9 of this reaction might be formed according to
hypothetical transition states 6, or 7 (Scheme 1). Regioselective
base mediated elimination of such a species might then be expected
to generate the final unsaturated products 2. Treatment of 1a
with 1 equivalent of NBS in dichloromethane resulted in the
rapid consumption of the starting material and the formation
of a significantly less-polar compound. If the reaction period
was prolonged and the temperature raised to 40 ◦C the bicyclic
adduct 9a was indeed obtained (32%) following purification by
flash column chromatography (Scheme 4). Identical results were
observed for alternative starting materials 1b and 1d. Even though
the yields for this process were low the adducts formed as single
diastereoisomers and the relative stereochemistry was elucidated
by X-ray crystallography after formation of 9a·HCl (Fig. 2).14
Scheme 5 Selective N-halogenation of amino alkenes 1a and 1b.
tion proved not to be possible since one of these diastereoisomers
proved to decompose to several unidentified products.
Since these results suggested the involvement of an N-bromo
species in the formation of 9 we attempted the cyclisation of N-
bromo compound 5a (after the removal of succinimide) under
reflux conditions as before. This, however, did not lead to forma-
tion of the cyclised product. In contrast, when 5a was prepared
in diethyl ether and the solvent was changed to dichloromethane
without the prior removal of succinimide by filtration, cyclisation
to 9a was observed in comparable yield (27%). This observation
serves to suggest that either, under these conditions NBS is
reformed reversibly, or that protonation15 of the N-bromo species
5a is a crucial process in the intramolecular formation of 9a.
The corresponding N-chloro species proved to be more stable
than their bromine counterparts and 10a and 10b were isolated in
good yield and fully characterised spectroscopically. Contrasting
reactivity was also observed for 10a; this species did not form
bicycle 11a under conditions identical to those that proved suc-
cessful for the bromide 9a. Instead 10a was recovered unchanged,
an observation that again reflects the enhanced stability of the
N-chloro series.
N-Benzyl bicyclic adducts 2a and 2g were subjected to standard
catalytic hydrogenation under acidic conditions, leading to both
debenzylation and hydrogenation of the double bond. The sec-
ondary amino compounds were then converted into their toluene
sulfonamides 12a and 12g to simplify purification (Scheme 6). A
drastic difference was observed in terms of the diastereoselectivity
for the alkenyl reduction process: whilst 2a gave 12a as a single
diastereoisomer 2g gave 12g as a mixture of diastereoisomers
(ca. 1:1).16
Fig. 2 X-ray crystallographic structure of 9a·HCl (thermal ellipsoids
drawn at the 50% probability level).14
Although the X-ray structure of 9a indicated that the only anti-
periplanar hydrogen–bromine relationship would give rise to 2a,
treatment with K2CO3 in acetone at 50 ◦C (comparable to the
second step in the conversion of 1 to 2) did not lead to elimination,
which served to indicate that 9 cannot be a direct intermediate in
this cyclisation process.
During attempts to further optimise this reaction we realised
that on altering the solvent from dichloromethane to diethyl
ether cyclisation was not observed. The sole product from this
reaction was the N-bromo compound 5a that could be isolated
on filtration (Scheme 5). However, this species proved to be
only moderately stable and over time underwent decomposition
forming the hydrobromide salt of 1a. When 5a was prepared using
1.2 equivalents of bromine, limited stability was also observed (see
discussion above).
The relative stereochemistry of 12a was uncovered by X-ray
crystallography (Fig. 3)17 which provides relevant information
for previous studies concerning this compound in which the
relative stereochemistry was not definitively assigned.18 Similarly,
the hydrogenation of 9a was investigated in order to remove the
benzyl group and although this process proceeded in only low
yield (23%) the expected product 13 was obtained with the tertiary
bromide intact.
Generally, 9a,b and d proved to be stable enough to enable
characterisation but, in the amino form, were found to decompose
over time. We finally attempted to investigate the corresponding
cyclisation using 1h, hoping to observe a stereoselective process.
However, in this instance we believe that, again, a mixture of
adducts was formed in low yield although complete characterisa-
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Scheme 6 Debenzylation of bicycles 2a, 2g and 9a.
Varian 3100 FT-IR spectrometer. High Resolution Mass Spectra
(HRMS) were recorded using a Waters Corp, Micromass LCT,
Electrospray Ionization (ESI) spectrometer. Melting points were
determined in an open capillary on a Gallenkamp melting point
apparatus and are uncorrected. The amine-hydrochloride salts
were prepared as follows: the amine was dissolved in Et2O/pentane
(ca. 25 mg/ml) and HCl gas (generated from solid NH4Cl by
dropwise addition of conc. H2SO4) was bubbled through the
solution via a Teflon cannula. The resultant precipitate was filtered,
dried under vacuum and the hydrochloride salts were recrystallised
from a suitable solvent. For the syntheses of secondary amines 1a-i
see ESI.†
Fig. 3 X-ray crystallographic structure of 12a (thermal ellipsoids drawn
at the 50% probability level).17
Conclusion
In summary, while the results discussed served to demonstrate
that the amino alkenes employed in this study show a strong
tendency to form N-halo species more rapidly than reaction at
the alkene (when treated with Br2 or NBS), we cannot confirm the
direct involvement of such species in the cyclisation step leading
to hexahydroindoles. As such it seems that this N-halogenation
process may be viewed as a side reaction rather than a productive
element of the overall reaction pathway. The diastereoselective
formation of hexahydroindoles and octahydroquinolines has been
investigated following the claim that high diastereoselectivity may
be achieved.3 However, using an a-methylbenzyl substituent as a
directing group we were unable to reproduce the reported results,
suggesting that this work should be viewed with caution. In
relation to this sequence we have demonstrated that PHT may
be used to brominate a double bond in the presence of an amine
featuring temporary protection through protonation, and in doing
so have improved the overall yield for the aminocyclisation proce-
dure. Finally, differences in the diastereoselectivity of the catalytic
hydrogenation of hexahydroindoles and octahydroquinolines were
noticed.
General procedure for the amino cyclisation using molecular
bromine, Method A3a,b
The appropriate secondary amine was dissolved in anhydrous
dichloromethane (10 ml/mmol) under an atmosphere of N2.
The solution was cooled to -78 ◦C before Br2 (1.2 equiv.) was
added as a solution in anhydrous dichloromethane (1 ml/mmol)
over a period of 15 min. The solution was stirred for a further
15 min at low temperature. Solvent was removed under reduced
pressure and the residue suspended in acetone (10 ml/mmol)
and K2CO3 (3 equiv.) was added. The suspension was heated to
50 ◦C for 72 h before the solvent was removed under reduced
pressure and the residue partitioned between H2O (10 ml/mmol)
and dichloromethane (20 ml/mmol). The aqueous layer was
further extracted with dichloromethane (2 ¥ 10 ml/mmol) and
the combined organic extracts dried over Na2SO4. After filtration
the solvent was removed under reduced pressure and the crude
products were purified by column chromatography as indicated
below.
General procedure for the amino cyclisation using pyrrolidone
hydrotribromide, (PHT), Method B
Experimental
Reactions with anhydrous solvents were carried out under an at-
mosphere of N2. Glassware was either dried in an oven or by heat-
gun before use, assembled hot and cooled to room temperature
under a stream of N2. Anhydrous dichloromethane (CH2Cl2) was
distilled from CaH2 prior to use. Reagents were purchased from
Acros, or Aldrich, and used without further purification. Thin
layer chromatography (TLC) was carried out on Merck silica gel
aluminum sheets (60 F254). UV light and a KMnO4 solution were
The secondary amine was dissolved in dichloromethane
(10 ml/mmol) under air. To the solution was added PHT (1 equiv.)
in one portion. The solution was stirred for a total of 15 min
and the solvent subsequently removed under reduced pressure.
The residue was dissolved in acetone (10 ml/mmol) and K2CO3
(3 equiv.) was added in one portion. The suspension was heated to
50 ◦C for 67–70 h before the solvent was removed under reduced
pressure and the residue partitioned between H2O (10 ml/mmol)
and dichloromethane (20 ml/mmol). The aqueous layer was re-
extracted with dichloromethane (2 ¥ 10 ml/mmol). The combined
organic layers were dried over Na2SO4 and the solvent removed
under reduced pressure. The crude products were purified by
column chromatography as indicated below.
˚
used as visualising agents. Merck silica gel (60 A, 0.040–0.063 mm)
was used for flash column chromatography. Proton NMR spectra
were recorded on a Varian 300 MHz, 400 MHz, 500 MHz
or 600 MHz spectrometer and calibrated using the residual
non-deuterated solvent signal. IR spectra were recorded on a
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1-Benzyl-2,3,5,6,7,7a-hexahydro-1H-indole (2a)
1H) 2.39 (s, 6H) 2.27 (s, 3H) 2.23–2.36 (m, 2H) 2.11–2.22 (m, 2H)
2.03–2.10 (m, 2H) 1.82–1.91 (m, 1H) 1.45–1.60 (m, 1H) 1.16–1.26
(m, 1H); 13C-NMR (100.5 MHz, CDCl3) d (ppm) 141.3 (C) 137.6
(C) 136.0 (C) 132.8 (C) 128.9 (CH) 117.8 (CH) 65.4 (CH) 52.0
(CH2) 51.8 (CH2) 28.2 (CH2) 27.9 (CH2) 25.2 (CH2) 20.9 (CH3)
20.6 (CH2) 20.3 (CH3); IR (neat) 3441, 3004, 2923, 2836, 2782,
2716, 1689, 1613, 1580 cm-1; HRMS (ES+): calcd. for [C18H26N]+
256.2065; found 256.2072.
The title compound was purified by column chromatography
(EtOAc-cyclohexane; 1:12) which gave 2a as a yellow oil [Method
A: 62%; Method B: 85%]. The purified product solidified upon
storage in the fridge to give X-ray quality crystals (see ESI†). M.pt.
◦
1
28–30 C; Rf = 0.45 (EtOAc); H-NMR (500 MHz, CDCl3) d
(ppm) 7.33 (d, J = 7.5 Hz, 2H) 7.29 (t, J = 7.5 Hz, 2H) 7.22 (t,
J = 7.5 Hz, 1H) 5.43 (bs, 1H) 4.06 (d, J = 13.0 Hz, 1H) 3.22 (d,
J = 13.0 Hz, 1H) 2.92–2.97 (m, 1H) 2.57–2.63 (m, 1H) 2.32–2.38
(m, 2H) 2.02–2.13 (m, 4H) 1.81–1.88 (m, 1H) 1.43–1.54 (m, 1H)
1.54 (q, J = 12.0 Hz, 1H); 13C-NMR (125.6 MHz, CDCl3) d (ppm)
140.3 (C) 138.9 (C) 129.1 (CH) 128.1 (CH) 126.8 (CH) 118.5 (CH)
64.4 (CH) 58.8 (CH2) 52.0 (CH2) 28.1 (CH2) 27.9 (CH2) 25.1 (CH2)
20.5 (CH2); IR (neat) 3377, 3030, 2927, 2851, 2785, 2723, 2348,
1651, 1609 cm-1; HRMS (ES+) calcd. for [C15H20N]+ 214.1596;
found 214.1586.
1-(2-Bromo-4,5-dimethoxybenzyl)-2,3,5,6,7,7a-hexahydro-1H-
indole (2e)
Purification by flash column chromatography (EtOAc-
cyclohexane; 1:12) gave 2e as a light tan solid [Method A:
63%; Method B: 77%]. M.pt. 84–86 ◦C; Rf = 0.40 (EtOAc);
1H-NMR (500 MHz, CDCl3) d (ppm) 7.03 (s, 1H) 6.99 (s, 1H)
5.44 (bs, 1H) 3.99 (d, J = 13.5 Hz, 1H) 3.86 (s, 3H) 3.85 (s, 3H)
3.40 (d, J = 13.5 Hz, 1H) 3.00–3.05 (m, 1H) 2.67–2.73 (m, 1H)
2.35–2.43 (m, 2H) 2.19 (q, J = 9.0 Hz, 1H) 2.07–2.13 (m, 1H)
2.02–2.07 (m, 2H) 1.82–1.88 (m, 1H) 1.44–1.55 (m, 1H) 1.13–1.23
(m, 1H); 13C-NMR (125.6 MHz, CDCl3) d (ppm) 148.4 (C) 148.3
(C) 140.3 (C) 130.4 (C) 118.5 (CH) 115.2 (CH) 114.0 (C) 113.6
(CH) 64.7 (CH) 57.6 (CH2) 56.1 (CH3) 56.0 (CH3) 52.3 (CH2)
28.1 (CH2) 28.0 (CH2) 25.0 (CH2) 20.4 (CH2); IR (CH2Cl2) 3376,
3000, 2932, 2936, 2796, 1648, 1603, 1506 cm-1; HRMS (ES+):
calcd. for [C17H23NO2Br]+ 352.0912; found 352.0918.
1-(4-Methoxybenzyl)-2,3,5,6,7,7a-hexahydro-1H-indole (2b)
The title compound was purified by flash column chromatography
(EtOAc-cyclohexane; 1:7) to give 2b as a clear oil [Method A:
53%; Method B: 88%]. Rf = 0.30 (EtOAc); 1H-NMR (500 MHz,
CDCl3) d (ppm) 7.24 (d, J = 8.5 Hz, 2H) 6.83 (d, J = 8.5 Hz,
2H) 5.42 (bs, 1H) 3.99 (d, J = 12.7 Hz, 1H) 3.79 (s, 3H) 3.17 (d,
J = 12.7 Hz, 1H) 2.90–2.95 (m, 1H) 2.54–2.60 (m, 1H) 2.31–2.37
(m, 2H) 2.02–2.13 (m, 4H) 1.81–1.87 (m, 1H) 1.42–1.53 (m, 1H)
1.12–1.21 (m, 1H); 13C-NMR (125.6 MHz, CDCl3) d (ppm) 158.6
(C) 140.4 (C) 131.0 (C) 130.2 (CH) 118.5 (CH) 113.5 (CH) 64.3
(CH) 58.1 (CH2) 55.2 (CH3) 51.9 (CH2) 28.1 (CH2) 27.9 (CH2)
25.1 (CH2) 20.5 (CH2); IR (neat) 3061, 2998, 2930, 2834, 2780,
2718, 2542, 2483, 2278, 2065, 1995, 1882, 1756, 1692, 1612, 1586,
1513 cm-1; HRMS (ES+): calcd. for [C16H22NO]+ 244.1701; found
244.1693.
1-(Furan-2-ylmethyl)-2,3,5,6,7,7a-hexahydro-1H-indole (2f)3a
Compound 2f was purified by column chromatography (EtOAc-
cyclohexane; 1:19) to give a yellow oil [Method A: 65%;3 Method
B: 74%]. Rf = 0.60 (EtOAc); 1H-NMR (400 MHz, CDCl3) d (ppm)
7.35–7.36 (m, 1H) 6.30 (dd, J = 2.0 Hz, J = 3.0 Hz, 1H) 6.19 (d,
J = 3.0 Hz, 1H) 5.41 (bs, 1H) 3.94 (d, J = 14.0 Hz, 1H) 3.46
(d, J = 14.0 Hz, 1H) 3.01–3.06 (m, 1H) 2.53–2.60 (m, 1H) 2.34–
2.42 (m, 2H) 2.21–2.28 (m, 1H) 1.99–2.10 (m, 3H) 1.80–1.87 (m,
1H) 1.40–1.52 (m, 1H) 1.10–1.20 (m, 1H); 13C-NMR (100.5 MHz,
CDCl3) d (ppm) 152.4 (C) 141.8 (CH) 140.0 (C) 118.6 (CH) 110.0
(CH) 108.0 (CH) 63.5 (CH) 51.9 (CH2) 49.8 (CH2) 27.9 (CH2) 27.7
(CH2) 25.0 (CH2) 20.5 (CH2); IR (neat) 3437, 3114, 3062, 2922,
2858, 2788, 2660, 1642, 1599, 1504 cm-1; HRMS (ES+): calcd. for
[C13H18NO]+ 204.1388; found 204.1380.
1-(2-Methoxybenzyl)-2,3,5,6,7,7a-hexahydro-1H-indole (2c)
Purification by column chromatography (EtOAc-cyclohexane;
1:7) gave the title compound 2c as a clear yellow oil [Method B:
1
88% yield]. Rf = 0.40 (EtOAc); H-NMR (400 MHz, CDCl3) d
(ppm) 7.36 (dd, J = 1.5 Hz, J = 7.5 Hz, 1H) 7.22 (dt, J = 1.5 Hz,
J = 8.0 Hz, 1H) 6.91 (t, J = 7.5 Hz, 1H) 6.81 (d, J = 8.0, 1H)
5.42 (bs, 1H) 4.04 (d, J = 13.5 Hz, 1H) 3.83 (s, 3H) 3.40 (d, J =
13.5 Hz, 1H) 3.03–3.08 (m, 1H) 2.62–2.69 (m, 1H) 2.34–2.40 (m,
2H) 2.12–2.22 (m, 2H) 2.03–2.08 (m, 2H) 1.83–1.90 (m, 1H) 1.44–
1.56 (m, 1H) 1.14–1.24 (m, 1H); 13C-NMR (100.5 MHz, CDCl3)
d (ppm) 157.6 (C) 140.6 (C) 130.8 (CH) 127.9 (CH) 127.1 (C)
120.2 (CH) 118.4 (CH) 110.3 (CH) 64.2 (CH) 55.3 (CH3) 52.0
(CH2) 51.8 (CH2) 28.1 (CH2) 28.0 (CH2) 25.2 (CH2) 20.6 (CH2);
IR (neat) 3441, 3000. 2930 2857, 2835, 2789, 2721, 1690, 1601,
1589 cm-1; HRMS (ES+): calcd. for [C16H22NO]+ 244.1701; found
244.1700.
1-Benzyl-1,2,3,4,6,7,8,8a-octahydroquinoline (2g)
The title compound was isolated following purification by flash
column chromatography (EtOAc-cyclohexane; 2:23) as a clear
1
oil [Method B: 62%]. Rf = 0.30 (EtOAc); H-NMR (400 MHz,
CDCl3) d (ppm) 7.27–7.33 (m, 4H) 7.19–7.24 (m, 1H) 5.51 (bs,
1H) 4.16 (d, J = 13.5 Hz, 1H) 3.11 (d, J = 13.5 Hz, 1H)
2.82–2.88 (m, 1H) 2.7–2.76 (m, 1H) 2.19–2.32 (m, 2H) 1.90–
2.12 (m, 4H) 1.73–1.83 (m, 1H) 1.42–1.60 (m, 4H); 13C-NMR
(100.5 MHz, CDCl3) d (ppm) 139.6 (C) 136.8 (C) 129.2 (CH)
128.1 (CH) 126.7 (CH) 122.6 (CH) 61.0 (CH) 58.3 (CH2) 53.3
(CH2) 34.5 (CH2) 29.6 (CH2) 26.3 (CH2) 25.5 (CH2) 21.6 (CH2); IR
(neat) 3084, 3061, 3026, 2931, 2856, 2836, 2784, 2746, 2724, 2651,
1602 cm-1; HRMS (ES+): calcd. for [C16H22N]+ 228.1752; found
228.1743.
1-(2,4,6-Trimethylbenzyl)-2,3,5,6,7,7a-hexahydro-1H-indole (2d)
The title compound was purified by flash column chromatography
(EtOAc-cyclohexane; 1:19) to give 2d as a white solid [Method B:
85%]. M.pt. 35–37 ◦C; Rf = 0.55 (EtOAc); 1H-NMR (400 MHz,
CDCl3) d (ppm) 6.83 (s, 2H) 5.40 (bs, 1H) 3.91 (d, J = 12.5 Hz,
1H) 3.33 (d, J = 12.5 Hz, 1H) 2.81–2.81 (m, 1H) 2.59–2.66 (m,
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1-(1-Phenylethyl)-2,3,5,6,7,7a-hexahydro-1H-indole (2h)
2837, 2795, 2750, 2717, 1947, 1875, 1805, 1710, 1672, 1601 cm-1;
HRMS (ES+): calcd for [C17H24N]+ 242.1909; found 242.1903.
(S)-1-((R)-1-Phenylethyl)-1,2,3,4,6,7,8,8a-octahydroquinoline (2i):
[a]D = +248 (c 0.2, CHCl3); Rf = 0.20 (EtOAc); 1H-NMR
(400 MHz, CDCl3) d (ppm) 7.33 (t, J = 7.5 Hz, 2H) 7.23–7.28
(m, 3H) 5.47 (bs, 1H) 4.41 (q, J = 7.0 Hz, 1H) 3.10–3.16 (m, 1H)
2.66–2.73 (m, 1H) 2.45–2.53 (m, 1H) 2.12–2.19 (m, 1H) 1.98–2.10
(m, 1H) 1.84–1.95 (m, 2H) 1.73–1.84 (m, 2H) 1.61–1.68 (m, 1H)
1.34–1.58 (m, 3H) 1.47 (d, J = 7.0 Hz, 3H); 13C-NMR (100.5 MHz,
CDCl3) d (ppm) 139.4 (C) 137.1 (C) 128.6 (CH) 127.7 (CH) 126.8
(CH) 122.7 (CH) 58.0 (CH) 55.0 (CH) 46.2 (CH2) 34.6 (CH2) 29.3
(CH2) 26.9 (CH2) 25.5 (CH2) 21.7 (CH2) 19.4 (CH3); IR (neat)
3059, 3028, 2928, 2855, 2800, 2762, 2718, 1944, 1871, 1802, 1740,
1671, 1601; HRMS (ES+): calcd for [C17H24N]+ 242.1909; found
242.1899.
Following the general procedures 2h was prepared albeit after
5 d for the second, K2CO3, operation [Method A: 51%; Method
B: 67% as a 1:1 mixture of diastereoisomers (determined by
1H-NMR spectroscopy of crude reaction products)]. The two
diastereoisomers proved to be very difficult to separate by flash
column chromatography. However, partial purification proved
to be possible (EtOAc-cHex; 2:23) enabling characterisation of
both diastereoisomers. The relative stereochemistry of the faster
moving diastereoisomer was determined by X-ray crystallography
after formation of the hydrochloride salt. X-ray quality crystals
were obtained by slow evaporation from EtOAc. (R*)-1-((R*)-1-
Phenylethyl)-2,3,5,6,7,7a-hexahydro-1H-indole (2h):3a viscous oil;
1
Rf = 0.20 (EtOAc); H-NMR (400 MHz, CDCl3) d (ppm) 7.37
(d, J = 7.5 Hz, 2H) 7.28 (t, J = 7.5 Hz, 2H) 7.21 (t, J = 7.5 Hz,
1H) 5.39 (bs, 1H) 3.64 (q, J = 6.5 Hz, 1H) 3.02–3.07 (m, 1H)
2.68–2.74 (m, 1H) 2.31–2.42 (m, 3H) 1.94 (bs, 2H) 1.57–1.66 (m,
1H) 1.39 (d, J = 6.5 Hz, 3H) 1.23–1.38 (m, 2H) 0.83 (q, J =
12.0 Hz, 1H); 13C-NMR (100.5 MHz, CDCl3) d (ppm) 145.6 (C)
141.0 (C) 128.0 (CH) 127.7 (CH) 126.7 (CH) 118.5 (CH) 63.7
(CH) 62.1 (CH) 48.5 (CH2) 29.6 (CH2) 27.7 (CH2) 25.0 (CH2)
20.9 (CH2) 18.6 (CH3); IR (neat) 3061, 3026, 2971, 2930, 2836,
2783, 2727, 2666, 1945, 1874, 1806, 1749, 1600 cm-1; HRMS
(ES+): calcd for [C16H22N]+ 228.1752; found 228.1741. (S*)-1-
((R*)-1-Phenylethyl)-2,3,5,6,7,7a-hexahydro-1H-indole (2h): Rf =
0.20 (EtOAc); 1H-NMR (400 MHz, CDCl3) d (ppm) 7.19–7.38 (m,
5H) 5.38 (bs, 1H) 4.06 (q, J = 7.0 Hz, 1H) 2.96–3.06 (m, 1H) 2.45–
2.54 (m, 1H) 2.26–2.34 (m, 2H) 2.16–2.26 (m, 2H) 1.97–2.06 (m,
2H) 1.80–1.88 (m, 1H) 1.53 (d, J = 7.0 Hz, 3H) 1.40–1.50 (m, 1H)
1.13–1.23 (m, 1H); 13C-NMR (100.5 MHz, CDCl3) d (ppm) 140.3
(C) 139.5 (C) 128.5 (CH) 127.6 (CH) 126.9 (CH) 118.5 (CH) 60.1
(CH) 57.7 (CH) 44.9 (CH2) 28.5 (CH2) 27.5 (CH2) 25.2 (CH2) 20.6
(CH2) 19.8 (CH3); IR (neat) 3083, 3060, 3026, 2972, 2931, 2858,
2836, 2783, 2727, 2666 cm-1; HRMS (ES+): calcd for [C16H22N]+
228.1752; found 228.1745. Data obtained from mixture of both
diastereiosmers.
2R*-((1R*,2S*)-1,2-Dibromocyclohexyl)-N-(1-phenylethyl)-
ethylamine and 2R*-((1S*,2R*)-1,2-dibromocyclohexyl)-N-(1-
phenylethyl)ethylamine (3h)
2-Cyclohex-1-enyl-N-(1-phenylethyl)ethylamine 1h (230 mg,
1.0 mmol, 1 equiv.) was dissolved in anhydrous CH2Cl2 (30 ml)
and NaHCO3 (168 mg, 2.0 mmol, 2 equiv.) added. The mixture
was cooled to -78 ◦C. Br2 (113 ml, 2.2 mmol, 2.2 equiv.) was added
as a solution in anhydrous CH2Cl2 (10 ml) in a dropwise fashion.
◦
The mixture was stirred for 10 min at -78 C and subsequently
slowly warmed to room temperature (approx. 1 h). The mixture
was poured into a saturated Na2SO3 solution (20 ml) and was
extracted with CH2Cl2 (3 ¥ 40 ml). The combined organic layers
were dried over MgSO4, filtered and the solvent removed under
reduced pressure. The crude material was directly subjected to flash
column chromatography (EtOAc-cyclohexane; 1:9 to 3:7) and the
title compound (162 mg, 42%) was isolated as a clear oil. Rf =
1
0.25 (EtOAc); H-NMR (400 MHz, CDCl3) d (ppm) 7.31–7.34
(m, 4H) 7.21–7.25 (m, 1H) 4.52–4.57 (bs/m, 1H) 3.82 (bq, J =
6.5 Hz, 1H) 2.74–2.87 (m, 2H) 2.45–2.55 (m, 1H) 2.08–2.29 (m,
2H) 1.90–2.04 (m, 2H) 1.76–1.89 (m, 3H) 1.70 (bs, 1H) 1.50–1.65
(m, 2H) 1.37 (d, J = 6.5 Hz, 3H); 13C-NMR (100.5 MHz, CDCl3)
d (ppm) 145.35 (C) 145.3 (C) 128.45 (CH) 128.4 (CH) 126.9 (CH)
126.5 (CH) 126.45 (CH) 74.25 (C) 74.2 (C) 59.5 (CH) 59.4 (CH)
58.3 (CH) 58.2 (CH) 45.1 (CH2, broad) 43.35 (CH2) 43.3 (CH2)
35.85 (CH2) 35.8 (CH2) 31.75 (CH2) 31.7 (CH2) 24.4 (CH3) 24.3
(CH3) 22.05 (CH2) 22.0 (CH2) 20.4 (CH2) 20.35 (CH2).
(S)- and (R)-1-((R)-1-Phenylethyl)-1,2,3,4,6,7,8,8a-
octahydroquinoline (2i)
Following the general procedure apart from conducting the
second, cyclisation, step for 8 d. The two diastereoisomers were
separated by flash column chromatography (EtOAc-cHex; 1:19)
to give the title compounds as clear oils [Method A: 45%;
(R,R)-2i: 24%, (S,R)-2i: 21%; Method B: 65%; (R,R)-2i: 32%,
(S,R)-2i: 33%]. The relative stereochemistry was determined for
the slower moving (S,R)-diastereoisomer by X-ray crystallogra-
phy after formation of the hydrochloride salt and recrystalli-
sation from CH2Cl2. (R)-1-((R)-1-phenylethyl)-1,2,3,4,6,7,8,8a-
octahydroquinoline (2i):3a [a]D = -46.1 (c 0.2, CHCl3); Rf = 0.40
(EtOAc); 1H-NMR (400 MHz, CDCl3) d (ppm) 7.46 (d, J =
7.5 Hz, 2H) 7.29 (t, J = 7.5 Hz, 2H) 7.19 (t, J = 7.5 Hz, 1H)
5.48 (bs, 1H) 4.39 (q, J = 7.0 Hz, 1H) 3.04–3.10 (m, 1H) 2.43–
2.51 (m, 1H) 2.13–2.25 (m, 3H) 1.91–2.10 (m, 3H) 1.78–1.86 (m,
1H) 1.44–1.60 (m, 3H) 1.29–1.38 (m, 1H) 1.28 (d, J = 7.0 Hz,
3H); 13C-NMR (100.5 MHz, CDCl3) d (ppm) 144.7 (C) 137.7 (C)
127.9 (CH) 127.8 (CH) 126.1 (CH) 121.6 (CH) 57.6 (CH) 53.8
(CH) 45.1 (CH2) 34.7 (CH2) 29.0 (CH2) 26.7 (CH2) 25.5 (CH2)
21.7 (CH2) 7.7 (CH3); IR (neat) 3085, 3059, 3028, 2929, 2855,
N-Benzyl-[2-((1R*,2S*)-1,2-dibromocyclohexyl)ethyl]amine (3a)
N-Benzyl-2-cyclohex-1-enylethylamine 1a (215 mg, 1.0 mmol,
1 equiv.) was dissolved in anhydrous CH2Cl2 (30 ml) under
an atmosphere of N2, NaHCO3 (168 mg, 2.0 mmol, 2 equiv.)
added in one portion and the solution cooled to -78 ◦C. Br2
(113 ml, 2.2 mmol, 2.2 equiv.) was added dropwise as a solution in
anhydrous CH2Cl2 (10 ml). The mixture was stirred for 10 min. The
cooling bath was then removed and the mixture slowly warmed
to room temperature before pouring into a saturated Na2S2O3
solution (20 ml). Extraction with CH2Cl2 (2 ¥ 25 ml), drying of
the combined organic layers over Na2SO4, filtration and solvent
removal under reduced pressure afforded the crude product.
Immediate purification by flash column chromatography (EtOAc-
cHex; 1:9) gave 3a as a clear oil (48 mg, 13%). Note: the product
992 | Org. Biomol. Chem., 2009, 7, 986–995
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thus obtained was observed to undergo slow decomposition. Rf =
(300 MHz, CDCl3) d (ppm) 7.05 (s, 1H) 6.98 (s, 1H) 3.91 (d, J =
14.0 Hz, 1H) 3.85 (s, 3H) 3.84 (s, 3H) 3.47 (d, J = 14.0 Hz, 1H)
2.96–3.03 (m, 2H) 2.52–2.60 (m, 1H) 2.35–2.45 (m, 1H) 2.15–2.24
(m, 1H) 1.99–2.11 (m, 2H) 1.80–1.91 (m, 1H) 1.47–1.73 (m, 4H)
1.34–1.43 (m, 1H); 13C-NMR (75 MHz, CDCl3) d (ppm) 148.4
(C) 148.3 (C) 130.7 (C) 115.4 (CH) 113.4 (C) 113.1 (CH) 69.7
(CH) 69.2 (C) 56.6 (CH2) 56.1 (CH3) 56.0 (CH3) 50.8 (CH2) 40.6
(CH2) 38.8 (CH2) 23.9 (CH2) 23.1 (CH2) 20.4 (CH2); IR (neat)
3080, 2933, 2838, 2256, 1681, 1603 cm-1; HRMS (ES+): calcd. for
[C17H24N79Br2O2]+ 432.0174; found 432.0159.
1
0.25 (EtOAc); H-NMR (500 MHz, CDCl3) d (ppm) 7.25–7.39
(m, 5H) 4.64 (bs, 1H) 3.86 (s, 2H) 2.96–3.05 (m, 2H) 2.54–2.61
(m, 1H) 2.20–2.24 (m, 2H) 1.98–2.10 (m, 2H) 1.81–1.94 (m, 3H)
1.75 (bs, 1H) 1.57–1.70 (m, 2H); 13C-NMR (125 MHz, CDCl3)
d (ppm) 140.1 (C) 128.4 (CH) 128.1 (CH) 127.0 (CH) 74.3 (C)
59.5 (CH) 54.0 (CH2) 45.1 (CH2) 44.9 (CH2) 35.9 (CH2) 31.8
(CH2) 22.1 (CH2) 20.4 (CH2); IR (neat) 3323, 3030, 2935, 2856,
1652, 1611 cm-1; HRMS (ES+): calcd for [C15H22N79Br2]+ 374.0119;
found 374.0107.
N-Benzyl-N-chloro-2-cyclohex-1-enylethylamine (10a)
General procedure for the synthesis of bromooctahydroindoles 9
N-Benzyl-2-cyclohex-1-enylethylamine 1a (215 mg, 1.0 mmol,
1 equiv.) was dissolved in CH2Cl2 (5 ml) and the solution cooled
to 0 ◦C. Solid NCS (134 mg, 1.0 mmol, 1 equiv.) was added in
one portion and the mixture stirred for 15 min. The solvent was
removed under reduced pressure and the residue suspended in
pentane (5 ml) and filtered through a sintered funnel. The solid
was washed with pentane (2 ¥ 5 ml) and the combined filtrate
concentrated under reduced pressure. The crude product was
immediately subjected to column chromatography (pentane-Et2O;
9:1) to give 10a (183 mg, 73%) as a clear oil. Rf = 0.70 (EtOAc);
1H-NMR (300 MHz, CDCl3) d (ppm) 7.30–7.42 (m, 5H) 5.48 (bs,
1H) 4.14 (s, 2H) 3.08 (t, J = 7.5 Hz, 2H) 2.38 (t, J = 7.5 Hz,
2H) 1.98–2.07 (m, 2H) 1.89–1.98 (m, 2H) 1.53–1.70 (m, 4H); 13C-
NMR (75 MHz, CDCl3) d (ppm) 137.1 (C) 134.8 (C) 129.1 (CH)
128.3 (CH) 127.7 (CH) 122.6 (CH) 68.1 (CH2) 61.9 (CH2) 36.2
(CH2) 28.8 (CH2) 25.2 (CH2) 22.9 (CH2) 22.4 (CH2); IR (neat)
3040, 2918, 2847, 2665, 1659, 1604 cm-1; HRMS (ES+): calcd. for
[C15H2135ClN]+ 250.1363; found 250.1351.
The secondary cyclohex-1-enyl-amine
1
was dissolved ◦in
dichloromethane (5 ml/mmol). The solution was cooled to 0 C
and solid NBS (1 equiv.) was added in one portion. The mixture
was stirred at 0 ◦C for 30 min, then warmed to room temperature
over a period of 30 min and subsequently heated to reflux for 1 h.
The volatiles were removed under reduced pressure and the residue
suspended in pentane (5 ml/mmol), filtered through a sintered
funnel, washed with pentane (2 ¥ 5 ml/mmol) and the combined
filtrates concentrated in vacuo. Flash column chromatography
(EtOAc-cyclohexane; 1:19) gave the products as indicated below.
(3aS*,7aR)-1-Benzyl-3a-bromooctahydroindole (9a)
The title compound 9a (32%) was isolated as a viscous colourless
oil. X-ray crystals of the corresponding HCl salt were formed
from CH2Cl2. Rf = 0.60 (EtOAc-cyclohexane; 1:4); 1H-NMR
(500 MHz, CDCl3) d (ppm) 7.28–7.33 (m, 4H) 7.21–7.26 (m, 1H)
4.05 (d, J = 13.5 Hz, 1H) 3.22 (d, J = 13.5 Hz, 1H) 2.92–2.98 (m,
1H) 2.86–2.89 (m, 1H) 2.33–2.42 (m, 2H) 2.08–2.18 (m, 2H) 1.95–
2.01 (m, 1H) 1.84–1.91 (m, 1H) 1.75–1.81 (m, 1H) 1.58–1.69 (m,
2H) 1.51–1.58 (m, 1H) 1.37–1.43 (m, 1H); 13C-NMR (125 MHz,
CDCl3) d (ppm) 139.5 (C) 128.4 (CH) 128.2 (CH) 126.8 (CH) 69.4
(CH) 68.8 (C) 57.6 (CH2) 50.6 (CH2) 40.9 (CH2) 38.7 (CH2) 23.6
(CH2) 23.1 (CH2) 19.8 (CH2); IR (neat) 3108, 3085, 3063, 3028,
2933, 2879, 2858, 2803, 1655, 1606, 1586, 1561 cm-1; HRMS (ES+):
calcd. for [C15H21N79Br]+ 294.0857; found 294.0865.
N-Chloro-2-cyclohex-1-enyl-N-(4-methoxybenzyl)ethylamine
(10b)
As above, 2-cyclohex-1-enyl-N-(4-methoxybenzyl)ethylamine 1b
(245 mg, 1.0 mmol, 1 equiv.) was dissolved in CH2Cl2 (5 ml)
cooled to 0 ◦C and solid NCS (134 mg, 1.0 mmol, 1 equiv.)
added. After stirring for 15 min the solvent was removed and the
residue suspended in pentane (10 ml). After filtration the resultant
solid was washed with pentane (2 ¥ 10 ml) and the combined
filtrate concentrated under reduced pressure. The crude product
was purified by flash column chromatography (pentane-Et2O; 9:1)
which gave 10b (260 mg, 93%) as a clear oil. Rf = 0.75 (EtOAc);
1H-NMR (300 MHz, CDCl3) d (ppm) 7.25 (d, J = 8.5 Hz, 2H)
6.86 (d, J = 8.5 Hz, 2H) 5.43 (bs, 1H) 4.04 (s, 2H) 3.79 (s, 3H)
3.00 (t, J = 7.5 Hz, 2H) 2.32 (t, J = 7.5 Hz, 2H) 1.93–2.02 (m,
2H) 1.85–1.93 (m, 2H), 1.48–1.62 (m, 4H); 13C-NMR (75 MHz,
CDCl3) d (ppm) 159.2 (C) 134.9 (C) 130.4 (CH) 129.2 (C) 122.5
(CH) 113.6 (CH) 67.5 (CH2) 61.5 (CH2) 55.2 (CH3) 36.2 (CH2)
28.5 (CH2) 25.2 (CH2) 22.9 (CH2) 22.3 (CH2); IR (neat) 3036,
2998, 2927, 2835, 1668, 1613, 1586, 1514 cm-1; HRMS (ES+):
calcd. for [C16H2335ClNO]+ 280.1468; found 280.1458.
(3aS*,7aR*)-3a-Bromo-1-(4-methoxybenzyl)octahydroindole (9b)
The title compound 9b (32%) was isolated as a viscous colourless
oil. Rf = 0.50 (EtOAc-cyclohexane; 1:4); H-NMR (300 MHz,
1
CDCl3) d (ppm) 7.21 (d, J = 8.5 Hz, 2H) 6.84 (d, J = 8.5 Hz, 2H)
3.96 (d, J = 13.0 Hz, 1H) 3.78 (s, 3H) 3.17 (d, J = 13.0 Hz, 1H)
2.89–2.96 (m, 1H) 2.82–2.87 (m, 1H) 2.29–2.43 (m, 2H) 2.04–2.18
(m, 2H) 1.93–2.02 (m, 1H) 1.74–1.87 (m, 2H) 1.48–1.69 (m, 3H)
1.32–1.46 (m, 1H); 13C-NMR (75 MHz, CDCl3) d (ppm) 158.5 (C)
131.4 (C) 129.5 (CH) 113.6 (CH) 69.3 (CH) 68.9 (C) 56.9 (CH2)
55.2 (CH3) 50.4 (CH2) 40.9 (CH2) 38.7 (CH2) 23.6 (CH2) 23.1
(CH2) 19.8 (CH2); IR (neat) 3061, 3031, 2996, 2933, 2858, 2833,
2806, 2727, 2685, 1668, 1612, 1586, 1512 cm-1; HRMS (ES+):
calcd. for [C16H23N79BrO]+ 324.0963; found 324.0974.
2-Cyclohex-1-enyl-N-(4-methoxybenzyl)ethylammonium bromide
(1b·HBr)
(3aS*,7aR*)-3a-Bromo-1-(2-bromo-4,5-dimethoxybenzyl)-
octahydroindole (9d)
2-Cyclohex-1-enyl-N-(4-methoxybenzyl)ethylamine 1b (245 mg,
1 mmol, 1 equiv.) was dissolved in Et2O (5 ml) and the solution
cooled to 0 ◦C. To the solution was added solid NBS (178 mg,
According to the procedure described 9d (32%) was obtained as
1
a viscous colourless oil. Rf = 0.40 (EtOAc-cHex; 1:4); H-NMR
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1 mmol, 1 equiv.) in one portion. The suspension was stirred for
30 min at room temperature before the solid was removed by
filtration, which was washed with pentane (2 ¥ 5 ml). The filtrate
was immediately concentrated under reduced pressure to give N-
bromo-2-cyclohex-1-enyl-N-(4-methoxybenzyl)ethylamine 5b as a
clear oil (324 mg, 100%). This N-halogenated species was directly
subjected to NMR analysis. Due to the instability of the compound
into H2O (10 ml) and the aqueous layer was acidified using 1 M
HCl (pH ~ 2). The aqueous layer was extracted with CH2Cl2
(2 ¥ 10 ml) and the combined organic layers were washed with
brine (10 ml), dried over MgSO4, filtered and the solvent removed
under reduced pressure. The crude material was subjected to
flash column chromatography (EtOAc-cyclohexane; 1:19) which
gave 12a (103 mg, 74%) as a colourless solid. X-ray quality
crystal◦s were obtained by slow evaporation from EtOH. M.pt.
50–52 C (EtOH); Rf = 0.25 (EtOAc-cyclohexane; 1:9); 1H-NMR
(500 MHz, CDCl3) d (ppm) 7.71 (d, J = 8.0 Hz, 2H) 7.30 (d,
J = 8.0 Hz, 2H) 3.48–3.56 (m, 2H) 3.18 (q, J = 9.0 Hz, 1H)
2.42 (s, 3H) 1.76–1.92 (m, 3H) 1.49–1.65 (m, 5H) 1.29–1.41 (m,
2H) 1.17–1.27 (m, 1H); 13C-NMR (125.6 MHz, CDCl3) d (ppm)
142.9 (C) 135.3 (C) 129.5 (CH) 127.2 (CH) 59.5 (CH) 47.2 (CH2)
37.7 (CH) 29.8 (CH2) 27.6 (CH2) 26.2 (CH2) 23.1 (CH2) 21.4
(CH3) 21.3 (CH2); IR (CH2Cl2) 3625, 3549, 3064, 3029, 2929,
2859, 1922, 1813, 1598, 1339, 1161 cm-1; HRMS (ES+): calcd. for
[C15H22NO2S]+ 280.1371; found 280.1368.
1
1
only a H-NMR spectrum was obtained. H-NMR (300 MHz,
CDCl3) d (ppm) 7.25 (d, J = 8.5 Hz, 2H) 6.86 (d, J = 8.5 Hz,
2H) 5.43 (bs, 1H) 4.05 (s, 2H) 3.78 (s, 3H) 2.98 (t, J = 7.0 Hz,
2H) 2.32 (t, J = 7.0 Hz, 2H) 1.93–2.01 (m, 2H) 1.85–1.93 (m, 2H)
1.48–1.64 (m, 4H). A crystalline solid formed from CDCl3 which
was subjected to X-ray analysis and was identified as 1b·HBr (yield
◦
1
not determined). M.pt. 148 C (decomp.); H-NMR (300 MHz,
CDCl3) d (ppm) 9.11 (bs, 2H) 7.53 (d, J = 8.5 Hz, 2H) 6.91 (d,
J = 8.5 Hz, 2H) 5.49 (bs, 1H) 4.04 (s, 2H) 3.76 (s, 3H) 2.88 (t,
J = 8.0 Hz, 2H) 2.47 (t, J = 8.0 Hz, 2H) 1.92–2.01 (m, 2H) 1.77–
1.85 (m, 2H) 1.47–1.62 (m, 4H); 13C-NMR (75 MHz, CDCl3) d
(ppm) 160.5 (C) 132.1 (C) 132.0 (CH) 125.3 (CH) 121.6 (C) 114.5
(CH) 55.2 (CH3) 50.0 (CH2) 44.1 (CH2) 33.9 (CH2) 28.0 (CH2) 25.2
(CH2) 22.6 (CH2) 22.0 (CH2); IR (CH2Cl2) 3433, 2929, 2795, 2700,
2396, 1613, 1516 cm-1; Anal. Calcd. for C16H24BrNO: C (58.90) H
(7.41) N (4.29) Br (24.49), Found: C (58.61) H (7.20) N (4.26) Br
(24.37).
(4aR*,8aR*)- and (4aS*,8aR*)-1-(Toluene-4-sulfonyl)-
decahydroquinoline (12g)
As above, a mixture of 1-benzyl-1,2,3,4,6,7,8,8a-octahydroquino-
line 2g (70 mg, 0.31 mmol, 1 equiv.), Pd/C (10% Pd on carbon,
w/w, 33 mg, 0.031 mmol, 0.1 equiv.) in glacial acetic acid (6 ml) was
stirred under an atmosphere of H2 (1 atm.) at room temperature for
24 h. The crude amine was dissolved in CH2Cl2 (6 ml) and TsCl
(65 mg, 0.34 mmol, 1.1 equiv.) and K2CO3 (428 mg, 3.1 mmol,
10 equiv.) were added. The suspension was stirred for 14 h at room
temperature. Work up as above gave the crude product which
was subjected to column chromatography (cyclohexane-EtOAc;
19:1) to give 12g (44 mg, 48%—approximately a 1:1 mixture of
cis and trans diastereoisomers) as a clear oil. Rf = 0.30 (EtOAc-
cyclohexane; 1:9); 1H-NMR (400 MHz, CDCl3) d (ppm) 7.64–7.73
(m, 4H) 7.22–7.31 (m, 4H) 4.03–4.12 (m, 1H) 3.92–4.02 (m, 1H)
3.65–3.73 (m, 1H) 2.91 (t, J = 13.0 Hz, 1H) 2.69–2.79 (m, 1H)
2.42–2.50 (m, 1H) 2.41 (s, 6H) 2.21–2.29 (m, 1H) 1.48–1.80 (m,
14H) 1.07–1.47 (m, 9H) 0.87–1.02 (m, 2H); 13C-NMR (100.5 MHz,
CDCl3) d (ppm) 142.8 (C) 142.6 (C) 139.0 (C) 137.9 (C) 129.6 (CH)
129.5 (CH) 127.1 (CH) 126.9 (CH) 65.1 (CH) 55.3 (CH) 48.6
(CH2) 41.1 (CH) 40.3 (CH2) 35.0 (CH) 33.5 (CH2) 31.8 (CH2) 31.7
(CH2) 31.6 (CH2) 26.0 (CH2) 25.6 (CH2) 25.5 (CH2) 25.4 (CH2)
25.3 (CH2) 24.0 (CH2) 23.5 (CH2) 21.5 (CH3, 2x) 20.0 (CH2); IR
(neat) 3064, 3028, 2927, 2855, 1920, 1689, 1656, 1599, 1337, 1323,
1169, 1152 cm-1; HRMS (ES+): calcd. for [C16H24NO2S]+ 294.1528;
found 294.1541.
N-Benzyl-2-((1R*,2S*)-1,2-dibromocyclohexyl)ethylammonium
bromide (3a·HBr)
N-Benzyl-2-cyclohex-1-enylethylamine 1a (46 mg, 0.21 mmol,
1 equiv.) was dissolved in CDCl3 (2 ml). PHT (106 mg, 0.21 mmol,
1 equiv.) was added in one portion and the mixture stirred for
15 min. Complete conversion was observed by NMR spectroscopy
and the title compound was characterized as its HBr salt. 1H-NMR
(600 MHz, CDCl3) d (ppm) 9.74 (bs, 2H) 7.57–7.59 (m, 2H) 7.32–
7.38 (m, 3H) 4.38 (s, 1H) 4.16 (t, J = 5.5 Hz, 2H) 3.15–3.27 (m, 2H)
2.53–2.63 (m, 2H) 2.40–2.46 (m, 1H) 1.98–2.02 (m, 1H) 1.89–1.94
(m, 1H) 1.82–1.86 (m, 1H) 1.70–1.78 (m, 2H) 1.59–1.65 (m, 1H)
1.48–1.55 (m, 1H); 13C-NMR (150 MHz, CDCl3) d (ppm) 130.2
(CH) 129.9 (C) 129.4 (CH) 129.0 (CH) 71.3 (C) 58.4 (CH) 50.5
(CH2) 42.6 (CH2) 39.7 (CH2) 35.5 (CH2) 31.5 (CH2) 21.8 (CH2)
20.3 (CH2); HRMS (ES+): calcd. for [C15H22N79Br2]+ 374.0119;
found 374.0104.
(3aR*,7aR*)-1-(Toluene-4-sulfonyl)octahydroindole (12a)18
1-Benzyl-2,3,5,6,7,7a-hexahydro-1H-indole
2a
(107
mg,
0.5 mmol, 1 equiv.) was dissolved in glacial acetic acid (10 ml)
and the solution degassed for 30 min with a steady stream of N2.
Pd/C (10% Pd on carbon, w/w, 53 mg, 0.05 mmol, 0.1 equiv.) was
added and the flask purged with H2 and subsequently equipped
with a H2 balloon. The reaction mixture was stirred for 24 h at
room temperature. Filtration through celite and washing with
glacial acetic acid (2 ¥ 10 ml) followed by concentration of
the combined filtrates under reduced pressure gave the crude
secondary amine. The residue was dissolved in CH2Cl2 (10 ml)
and K2CO3 (691◦mg, 5 mmol, 10 equiv.) added. The suspension
was cooled to 0 C before TsCl (95 mg, 0.5 mmol, 1 equiv.) was
added in one portion. The mixture was stirred at 0 ◦C for 1 h
followed by 6 h at room temperature. The mixture was poured
(3aS*,7aR*)-3a-Bromo-1-(toluene-4-sulfonyl)octahydroindole (13)
As above, rac-(3aS,7aR)-1-benzyl-3a-bromooctahydro-1H-indole
9a (200 mg, 0.68 mmol, 1 equiv.) and Pd/C (10% Pd on carbon,
w/w, 72 mg, 0.068 mmol, 0.1 equiv.) in glacial acetic acid (13 ml)
was stirred under H2 (1 atm.) for 13.5 h at room temperature.
The crude amine was dissolved in CH2Cl2 (7 ml) and treated
with triethylamine (105 ml, 0.75 mmol, 1.1 equiv.) and TsCl
(129 mg, 0.68 mmol, 1 equiv.). After work up as detailed above the
crude product was purified by column chromatography (EtOAc-
cyclohexane; 1:19). Thus, the title compound (55 mg, 23%) was
obtained as a white gum. Rf = 0.25 (EtOAc-cyclohexane; 1:4);
994 | Org. Biomol. Chem., 2009, 7, 986–995
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1H-NMR (500 MHz, CDCl3) d (ppm) 7.75 (d, J = 8.0 Hz, 2H)
7.30 (d, J = 8.0 Hz, 2H) 3.84 (dd, J = 6.5, 10.0 Hz, 1H) 3.65
(dt, J = 2.0, 9.5 Hz, 1H) 3.47 (dt, J = 7.5, 9.5 Hz, 1H) 2.43–
2.49 (m, 1H) 2.41 (s, 3H) 2.36–2.41 (m, 1H) 2.20–2.30 (m, 2H)
2.04 (dd, J = 7.0, 14.0 Hz, 1H) 1.67–1.75 (m, 1H) 1.49–1.60 (m,
2H) 1.28–1.39 (m, 2H); 13C-NMR (125.6 MHz, CDCl3) d (ppm)
143.2 (C) 134.7 (C) 129.4 (CH) 127.7 (CH) 71.4 (C) 68.4 (CH)
46.2 (CH2) 39.5 (CH2) 37.8 (CH2) 33.7 (CH2) 23.7 (CH2) 22.8
(CH2) 21.5 (CH3); IR (CH2Cl2) 3030, 2940, 2890, 2863, 1642, 1599,
1343, 1160, 667 cm-1; HRMS (ES+): calcd. for [C15H2179BrNO2S]+
358.0476; found 358.0473.
5 B. R. Cho, S. K. Namgoong and T. R. Kim, J. Chem. Soc., Perkin Trans.
2, 1987, 853.
6 E. J. Corey, J. F. Arnett and G. N. Widinger, J. Am. Chem. Soc., 1975,
97, 430.
7 (a) For examples see: P. L. Southwick and V. L. Walsh, J. Am. Chem.
Soc., 1955, 77, 405; (b) G. Berti and A. Marsili, Tetrahedron, 1966,
22, 2977; (c) N. G. Ramesh, E. H. Heijne, A. J. H. Klunder and B.
Zwanenburg, Tetrahedron, 2002, 58, 1361.
8 (a) E. Erdik and M. Ay, Chem. Rev., 1989, 89, 1947; (b) H. Wack, A. E.
Taggi, A. M. Hafez, W. J. Drury, III and T. Lectka, J. Am. Chem. Soc.,
2001, 123, 1531; (c) S. P. Bew, D. L. Hughes, N. J. Palmer, V. Savic,
K. M. Soapi and M. A. Wilson, Chem. Commun., 2006, 4338; (d) A. C.
Smith and R. M. Williams, Angew. Chem., Int. Ed., 2008, 47, 1736.
9 D. St, C. Black and J. E. Doyle, Aus. J. Chem., 1978, 31, 2247.
10 Y. Yokoyama, T. Yamaguchi, M. Sato, E. Kobayashi and Y. Murakami,
Chem. Pharm. Bull., 2006, 54, 1715.
11 (a) D. V. C. Awang and S. Wolfe, Can. J. Chem., 1969, 47, 706; (b) W. E.
Daniels, M. E. Chiddix and S. A. Glickman, J. Org. Chem., 1963, 28,
573.
Acknowledgements
We thank Dr Dilip Rai for high resolution mass spectra and Dr.
Yannick Ortin for assistance with NMR spectra.
12 Compound 2h·HCl; Molecular formula: C16H22ClN·H2O; Formula
weight: 281.81 gmol-1; Crystal ◦system: Monoclinic; Unit cell dimen-
◦
˚
˚
sions: a = 10.3845(9) A, a = 90 ; b = 14.8703(13) A, b = 107.902(2) ;
◦
3
˚
˚
c = 10.5114(9) A, g = 90 ; Volume: 1544.6(2) A ; Temperature: 293(2)
K; Space group: P21/n; Number of formula units in unit cell (Z): 4;
Reflections collected: 26250; Independent reflections: 3029 [R(int) =
0.0178]; Final R indices [I>2sigma(I)]: R1 = 0.0501, wR2 = 0.1499; R
indices (all data): R1 = 0.0533, wR2 = 0.1540.
References
1 T. M. Mu¨ller, K. C. Hultzsch, M. Yus, F. Foubelo and M. Tasa, Chem.
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2 (a) For examples see: D. E. Horning and J. M. Muchowski,
Can. J. Chem., 1974, 52, 1321; (b) F. Diaba, E. Ricou and J. Bonjoch,
Org. Lett., 2007, 9, 2633; (c) K. C. Majumdar, U. K. Kundu, U. Das,
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K. C. Jang, J. H. Kim and K. H. Park, Chem. Commun., 1999, 251;
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and Y. Kita, Chem. Commun., 2006, 832; (g) R. R. Gataullin, N. A.
Likhacheva and I. B. Abdrakhmanov, Russ. J. Org. Chem., 2007, 43,
409; (h) M. C. Marcotullio, V. Campagna, S. Sternativo, F. Costantino
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Pu and B. Wang, Tetrahedron Lett., 2007, 48, 7444; (j) A. Lei, X. Lu
and G. Liu, Tetrahedron Lett., 2004, 45, 1785; (k) M. R. Manzoni, T. P.
Zabawa, D. Kasi and S. R. Chemler, Organometallics, 2004, 23, 5618;
13 Compound 2i·HCl; Molecular formula: C17H24NCl; Formula weight:
277.82 gmol-1; Crystal system: Monoclinic; Unit cell dimensions: a =
◦
◦
◦
˚
˚
˚
16.115(2) A, a = 90 ; b = 10.4898(13) A, b = 121.095(3) ; c =
3
˚
10.9685(14) A, g = 90 ; Volume: 1587.7(4) A ; Temperature: 293(2) K;
Space group: C2; Number of formula units in unit cell (Z): 4; Reflections
collected: 4287; Independent reflections: 1664 [R(int) = 0.0327]; Final
R indices [I>2sigma(I)]: R1 = 0.0432, wR2 = 0.1006; R indices (all
data): R1 = 0.0517, wR2 = 0.1045; Flack parameter: -0.02(10).
14 Compound 9a·HCl; Molecular formula: C15H21NClBr; Formula
weight: 330.69 gmol-1; Crystal ◦system: Monoclinic; Unit cell dimen-
◦
˚
˚
sions: a = 26.387(5) A, a = 90 ; b = 6.8937(12) A, b = 122.455(3) ;
◦
3
˚
˚
c = 19.161(3) A, g = 90 ; Volume: 2941.0(9) A ; Temperature: 100(2)
K; Space group: C2/c; Number of formula units in unit cell (Z): 8;
Reflections collected: 28702; Independent reflections: 3626 [R(int) =
0.0271]; Final R indices [I>2sigma(I)]: R1 = 0.0267, wR2 = 0.0686; R
indices (all data): R1 = 0.0297, wR2 = 0.0700.
˚
(l) M. Hemmerling, A. Sjo¨holm and P. Somfai, Tetrahedron: Asymm.,
1999, 10, 4091; (m) J. Cossy, L. Tresnard and D. G. Pardo, Tetrahedron
Lett., 1999, 40, 1125; (n) H. Senboku, Y. Kajizuka, H. Hasegawa, H.
Fujita, H. Suginome, K. Orito and M. Tokuda, Tetrahedron Lett., 1999,
55, 6465; (o) E. J. Corey, C. -P. Chen and G. A. Reichard, Tetrahedron
Lett., 1989, 30, 5547; (p) R. Askani, T. Andermann and K. M.
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15 M. Noack, S. Kalsow and R. Go¨ttlich, Synlett, 2004, 1110.
16 P. Wipf and J.-L. Methot, Org. Lett., 2000, 2, 4213.
17 Compound 12a; Molecular formula: C15H21NO2S; Formula weight:
279.39 gmol-1; Crystal system: Orthorhombic; Unit ◦cell dimensions:
◦
˚
˚
a = 6.237(2) A, a = 90 ; b = 12.419(4) A, b = 90 ; c = 17.923(6)
◦
3
˚
˚
A, g = 90 ; Volume: 1388.2(8) A ; Temperature: 100(2) K; Space
group: P212121; Number of formula units in unit cell (Z): 4; Reflections
collected: 5752; Independent reflections: 1710 [R(int) = 0.0877]; Final
R indices [I>2sigma(I)]: R1 = 0.0554, wR2 = 0.1326; R indices (all
data): R1 = 0.0640, wR2 = 0.1371.
3 (a) Z. Shao, J. Chen, Y. Tu, L. Li and H. Zhang, Chem. Commun., 2003,
1918; (b) Z. Shao, F. Peng, B. Zhu, Y. Tu and H. Zhang, Chin. J. Chem.,
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L. Li and H. Zhang, Synth. Commun., 2004, 34, 2031.
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Lett., 2007, 9, 4427; (b) U. M. Rai and A. Hassner, Heterocycles, 1990,
30, 817.
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 986–995 | 995
©