Synthesis of substituted piperidines, decahydroquinolines and octahydroindolizines by radical rearrangement reactions of 2-alkylideneaziridines

Article abstract of DOI:10.1016/S0040-4020(02)00730-5

Rearrangement of a variety of 3-(2-methyleneaziridin-1-yl)propyl radicals, generated using Bu₃SnH/AIBN by homolytic cleavage of phenylselenide substituted 2-methyleneaziridines, produces 3-methylenepiperidines in yields ranging from 58 to 68%.

Full text of DOI:10.1016/S0040-4020(02)00730-5

Tetrahedron 58 (2002) 7165–7175
Synthesis of substituted piperidines, decahydroquinolines and
octahydroindolizines by radical rearrangement reactions of
2-alkylideneaziridines
*
´
Natacha Prevost and Michael Shipman
School of Chemistry, University of Exeter, Stocker Road, EX4 4QD Exeter, Devon, UK
Received 1 April 2002; accepted 23 April 2002
Abstract—Rearrangement of a variety of 3-(2-methyleneaziridin-1-yl)propyl radicals, generated using Bu3SnH/AIBN by homolytic
cleavage of phenylselenide substituted 2-methyleneaziridines, produces 3-methylenepiperidines in yields ranging from 58 to 68%. By
combining this radical rearrangement with an additional 5-exo-trig cyclisation, this method provides an octahydroindolizine with moderate
levels of diastereocontrol (d.r.¼4:1). This rearrangement works with related 2-isopropylideneaziridines, but cannot be successfully extended
to 4-(2-methyleneaziridin-1-yl)butyl radicals. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
In seeking to devise new synthetic methods using
2-methyleneaziridines, we became interested in exploring
their radical rearrangement chemistry. By analogy with the
work of Kilburn et al., who have demonstrated that radical
rearrangements of methylenecyclopropanes can be used to
construct a variety of carbocyclic ring systems,7 we
wondered whether heterocyclic systems might be accessible
by similar reactions involving 2-methyleneaziridines. The
basic strategy is outlined in Scheme 1. After generation
from a suitable precursor such as 2-methyleneaziridine 1,
the resulting alkyl radical within 2 might be expected to
cyclise onto the double bond via an exo manifold to generate
aziridinylcarbinyl radical 3. Further relief of ring strain from
this system by either C–N or C–C bond fission would lead
to aminyl radical 4 or carbon centred radical 5, respectively.
Earlier work by Stamm,8 Murphy,9 DeKimpe10 among
others11 has established that opening of simple aziridinyl-
carbinyl radicals is facile and usually results in the
formation of the aminyl radical by preferential opening of
the C–N bond. Thus, we anticipated that aminyl radical 4
would be produced, by an overall process which formally
can be considered as a ring expansion. Importantly, we
anticipated that by the incorporation of additional radical
acceptors into the substrates, further cyclisation reactions of
It is well established that relief of ring strain can provide a
powerful thermodynamic driving force for novel chemical
reactions. Our interest in developing new methods for
synthesis based upon this principle has led us to explore the
reactivity of 2-methyleneaziridines. This densely
functionalised heterocyclic system is calculated to possess
12–13 kcal mol21 (HF/6-31Gp level) more ring strain
energy than aziridine itself.1 It transpires that whilst first
prepared over 50 years ago,2 the chemistry of 2-methylene-
aziridines has not been extensively explored. Alper and
Hamel have shown that this heterocyclic system can be ring
expanded to the corresponding a-methylene-b-lactam by
palladium catalysed carbonylation.3 A variety of [2pþ2p]
and [3pþ2p] cycloaddition reactions of the exocyclic
double bond have been reported.4 Furthermore, several
reports concerning simple ring opening reactions of the
aziridine have been described.5 Recently, in our own
laboratories, we have developed multi-component reactions
of 2-methyleneaziridines involving aziridine ring opening
as the first step.6 This methodology has been used to make a
wide variety of ketones6c and amines, including the
hemlock alkaloid (S)-coniine in a very concise fashion.6b
Scheme 1.
Keywords: aziridines; radicals and radical reactions; strained compounds.
*
Corresponding author. Tel.: þ44-1392-263469; fax: þ44-1392-263464; e-mail: m.shipman@exeter.ac.uk
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00730-5

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7166
Scheme 2. Reagents and conditions: (i) 2,3-dibromopropene, K2CO3, THF,
reflux; (ii) NPSP, Bu3P, THF, 08C; (iii) NaNH2 (15 equiv.), NH3, 25 min.
aminyl radical 4 could be realised allowing more complex
heterocyclic systems to be assembled by this process.12 In
this paper, we describe in detail our work on such radical
rearrangement reactions.13
Scheme 4. Reagents and conditions: (i) K2CO3, 1,2-dichlorobenzene,
1608C; (ii) MsCl, Et3N, toluene, 08C!room temperature; (iii) (PhSe)2,
NaBH4, EtOH, reflux; (iv) NaNH2 (30 equiv.), NH3, 90 min.
(N-PSP) and tri-n-butylphosphine17 provided selenide 8,
which was transformed into 2-methyleneaziridine 9 by
treatment with excess sodium amide in liquid ammonia
according to the method originally described by Pollard and
Parcell.2 Attempts to purify 9 and the other 2-methylene-
aziridines used in this study by column chromatography or
distillation led to extensive degradation. In contrast, related
isopropylideneaziridine 17 (Scheme 4) could readily be
purified by silica gel chromatography. Fortuitously, 9 (and
the other 2-methyleneaziridines) were sufficiently pure that
they could be fully characterised and used in the subsequent
radical rearrangements without purification beyond a simple
aqueous work-up.
2. Results and discussion
2.1. Precursor synthesis
Whilst a wide variety of C–X bonds can be homolytically
cleaved to alkyl centred radicals,14 we felt that the selection
of the X grouping within 1 needed careful consideration
(Scheme 1). Since 2-methyleneaziridines are often made
under forcing reaction conditions {NaNH2/liq. NH3},2,15
traditional radical precursors such as alkyl bromides and
iodides could not be used. To circumvent these problems,
we chose the more heterolytically robust phenylselenide
group (X¼PhSe), which has been shown by Clive to be an
excellent precursor of carbon centred radicals.16 An
additional advantage of this group in synthetic terms, is
that it can be directly introduced from the corresponding
alcohol.17
Using the same three-step sequence of alkylation, selenation
and ring closure, 3-amino-3-phenylpropan-1-ol 1018 was
converted into 2-methyleneaziridine 13 via 11 and 12 in
good overall yield (Scheme 3). An additional substrate for
the radical chemistry, namely 2-isopropylideneaziridine 17,
was also made from amino alcohol 10. Alkenyl bromide 15,
bearing gem-dimethyl substitution, was made by ring
opening of 1,1-dibromo-2,2-dimethylcyclopropane 1419
with 10 in 1,2-dichlorobenzene at 1608C.20 Mesylation of
the hydroxyl group of 15 followed by displacement with
phenylselenide anion gave 16, which after further ring
closure gave 2-isopropylideneaziridine 17 (Scheme 4). The
two-step sequence used for the introduction of the phenyl
selenide group in this example appears to be as effective as
the direct N-PSP method which was not examined in this
With the selection of the radical progenitor made, the
synthesis of appropriate radical precursors was relatively
straightforward. The synthesis of 2-methyleneaziridine 9
was achieved in three steps from commercially available
3-aminopropanol 6 in good overall yield (Scheme 2).
Alkylation of 2,3-dibromopropene with a two-fold excess of
this inexpensive amino alcohol yielded 7 in 71% yield. We
have found that it is advantageous to use the electrophile as
the limiting reagent to suppress the formation of the
corresponding tertiary amine. Direct selenation of the
hydroxyl group of 7 using N-phenylselenophthalimide
Scheme 5. Reagents and conditions: (i) NH4OAc, AcOH, PhH, Dean–
Stark; (ii) NaBH(OAc)3, AcOH; (iii) LiAlH4, THF, 08C!reflux; (iv) 2,3-
dibromopropene, K2CO3, THF, reflux; (v) NPSP, Bu3P, THF, 08C;
(vi) NaNH2 (15 equiv.), NH3, 20 min.
Scheme 3. Reagents and conditions: (i) 2,3-dibromopropene, K2CO3, THF,
reflux; (ii) NPSP, Bu3P, THF, 08C; (iii) NaNH2 (15 equiv.), NH3, 10 min.

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7167
Scheme 8. Reagents and conditions: (i) Bu3SnH (slow addition), AIBN,
PhH (0.015 M), reflux.
amide gave 2-methyleneaziridine 29 which was again used
without further purification.
Scheme 6. Reagents and conditions: (i) 2,3-dibromopropene, K2CO3, THF,
reflux; (ii) LiAlH4, THF, 08C!reflux; (iii) NPSP, Bu3P, THF, 08C; (iv)
NaNH2 (15 equiv.), NH3, 55 min.
2.2. Radical rearrangements
Initial efforts to optimise the radical rearrangement
chemistry were undertaken using phenyl substituted
2-methyleneaziridine 13 because we anticipated that the
products derived from this substrate would be substantially
less volatile and water soluble than those derived from the
unsubstituted 2-methyleneaziridine 9. Slow addition over
4.5 h of tri-n-butyltin hydride and AIBN in benzene via a
syringe pump to a refluxing solution of 13 in benzene
provided piperidine 30 in an optimised 68% yield
(Scheme 8). We have established that dilute reaction
conditions (final [13]¼0.015 M) and slow addition of the
Bu3SnH/AIBN mixture are necessary to obtain this yield.
From a practical standpoint, it is notable that whilst removal
of tin residues is often problematic in radical reactions, the
use of an acid/base extraction protocol in the work-up of 30
made the removal of the tin byproducts very straightforward
in this instance (see Section 3).
instance. Interestingly, more forcing conditions were
required for this ring closure than were needed to prepare
the analogous 2-methyleneaziridine 13 {NaNH2 (30 equiv.),
90 min cf. NaNH2 (15 equiv.), 10 min}.
b-Amino esters 19a and 19b were made from the
corresponding b-keto esters 18a21 and 18b21 by enamine
formation and subsequent reduction using sodium tri-
acetoxyborohydride according to a known method.22
Reduction with lithium aluminium hydride followed by
N-alkylation with 2,3-dibromopropene gave amino alcohols
20a and 20b, respectively. Selenation and final ring closure
yielded 2-methyleneaziridines 21a and 21b (Scheme 5).
b-Amino ester 22, made from 1,2-cyclohexanedicarboxylic
anhydride in three steps,23 was transformed into methylene-
aziridine 25 via 23 and 24 in good overall yield using similar
chemistry to that described above (Scheme 6).
The structure of piperidine 30 was unambiguously estab-
lished using standard spectroscopic techniques. Key struc-
tural elements were identified as indicated below. The
molecular formula (C12H15N) was established by high-
resolution mass spectrometry. The exocyclic double bond
bearing two hydrogens was identified by 1H NMR
spectroscopy (d 4.81 and 4.77). The presence of an NH
group was established by IR spectroscopy (3288 cm21) and
1H NMR spectroscopy (d 1.85, bs). The presence of CH and
CH2 groups adjacent to nitrogen was apparent by 13C NMR
spectroscopy (d 61.5 and 53.6, respectively). 1H NMR
spectroscopy revealed that this methylene CH2 was isolated
from other hydrogens as it possessed only geminal coupling
(J¼12.6 Hz). Finally, the presence of two additional
methylene carbons (d 36.2, 33.5) and the connectivity
between all the ring carbons was established using
correlation spectroscopy.
Finally, to explore the corresponding 6-exo radical cyclisa-
tion, we prepared homologous methyleneaziridine 29. To
our surprise, the synthesis of this compound was more
problematic than initially anticipated. Attempted selenation
of alcohol 27, made by alkylation of 2,3-dibromopropene
with 4-aminobutanol 26, led to complex mixtures from
which selenide 28 could not be isolated (cf. 7!8, Scheme
2). Speculating that intramolecular ring closure leading to
pyrrolidine formation might be competing with the desired
intermolecular substitution reaction, we decided to render
the NH non-nucleophilic prior to selenation. After Boc
protection of 27, selenation using N-PSP and tri-n-butyl-
phosphine proceeded uneventfully, yielding 28 after
removal of the Boc group using trifluoroacetic acid
(Scheme 7). Subsequent ring closure of 28 using sodium
These optimised reaction conditions were used to study the
radical rearrangements of the other 2-alkylideneaziridines
(9, 17, 21a, 21b, 25, 29). Reaction of 2-methyleneaziridine
9 with Bu3SnH/AIBN under these conditions provided
3-methylenepiperidine 31 in 58% yield after in situ Boc
Scheme 7. Reagents and conditions: (i) 2,3-dibromopropene, K2CO3, THF,
reflux; (ii) (Boc)2O, Et3N, DMAP, CH2Cl2; (iii) NPSP, Bu3P, THF, 08C;
(iv) TFA, CH2Cl2; (v) NaNH2 (15 equiv.), NH3, 45 min.
Scheme 9. Reagents and conditions: (i) Bu3SnH (slow addition), AIBN,
PhH (0.015 M), reflux; (ii) (Boc)2O, Et3N.

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7168
protection to reduce the volatility and water solubility of the
product (Scheme 9). However, attempts to extend this
chemistry to a larger ring size proved entirely unsuccessful.
Under identical conditions, 29 produced no trace of azepane
1
32. Analysis of the crude reaction mixture by H NMR
spectroscopy indicated that the methyleneaziridine ring was
largely intact, and that the integration for one methylene
triplet (d 2.88, ascribed to –CH2SePh in 29) was
significantly reduced relative the methyleneaziridine
signals. Direct observation of the anticipated new methyl
triplet was not possible because of the presence of Bu3Sn–
signals in this region of the spectrum. On the basis of this
evidence, we tentatively suggest that the major product from
this reaction is the reduction product, N-butyl-2-methyl-
eneaziridine. Unfortunately, repeated attempts to isolate and
fully characterise this compound by chromatography were
unsuccessful.
Scheme 13. Reagents and conditions: (i) Bu3SnH (slow addition), AIBN,
PhH (0.015 M), reflux.
chromatography on neutral alumina (Scheme 13). More
careful analysis by 1H NMR and GC–MS suggests that both
of the possible diastereoisomers were produced in the
reaction. A diastereomeric ratio (d.r.¼4:1) was obtained by
integration of the two resolved methyl doublets {d 1.02
(major) and 1.15 (minor)} in the 1H NMR spectrum
(CDCl3) prior to chromatography. We believe the modest
isolated yield of octahydroindolizine 37 is largely a
reflection of its polarity and volatility, and not the efficiency
of this reaction sequence. We were unable to isolate and
separately characterise the minor diastereomer from this
reaction.
Greater success was achieved in the rearrangement of
2-methyleneaziridine 21a. This substrate was transformed
into 6-alkylpiperidine 33 in 67% yield using the same
Bu3SnH/AIBN method (Scheme 10). Furthermore,
2-methyleneaziridine 25 was rearranged to the decahydro-
quinoline skeleton which was again conveniently isolated
after in situ N-Boc protection (Scheme 11). The ring
junction stereochemistry within 34 was assigned as cis on
the basis of strong nOe enhancements observed between
H-4a and H-8a {H-8a (5.8%) from H-4a; and of H-4a (9.2%)
from H-8a}. Furthermore, reaction of isopropylidene-
aziridine 17 with Bu3SnH/AIBN then Boc2O gave
piperidine 35 in 62% yield (Scheme 12).
The assignment of the bicyclic structure of 37 was relatively
straightforward by NMR spectroscopy (in C6D6). In
addition to the expected signals for the 3-methylenepiper-
idine system, it was apparent that the monosubstituted olefin
present in 21b was no longer present, and had been replaced
by an additional methine carbon adjacent to nitrogen (d
53.5) whose hydrogen was coupled to a methyl doublet (d
1
We have examined whether the presumed aminyl radical
generated in this rearrangement chemistry will participate in
additional radical cyclisations.12 Treatment of 21b with
Bu3SnH/AIBN resulted in the isolation of octahydroindol-
izine 37 in 39% yield as a single diastereomer after careful
1.00) in the H NMR spectrum. All other data including
1H–13C and 1H–1H correlation spectra were consistent with
the octahydroindolizine skeleton. Unfortunately, we have
been unable to unambiguously establish the relative
stereochemistry within 37. 1H NMR experiments (nOe
and NOESY) failed to provide any useful information
concerning the relative stereochemistry. Furthermore,
attempts to grow single crystals of the corresponding
hydrochloride salt for X-ray diffraction studies were
unsuccessful.
The chemical yields of these radical rearrangements are
generally good, especially bearing in mind that the
2-methylenaziridine precursors were not purified (vide
supra). We speculate that the reactions proceed via
aziridinylcarbinyl radical 3, formed by 5-exo-trig cyclisa-
tion of the initially formed alkyl radical, which then
undergoes C–N bond cleavage to 4 to relieve the ring
strain associated with the 1-azabicyclo[3.1.0]hexane ring
system (Scheme 1). We have been unable to detect enamine
products derived from the alternative ring fission (i.e. 5).
However, we cannot discount the formation of trace
amounts of these materials as they might be expected to
be chemically rather labile. The observation that 2-iso-
propylideneaziridine 17 undergoes rearrangement to 35
indicates that the C–N bond fission step (i.e. 3!4) is facile
and occurs even when the intermediate is a more stable,
tertiary centred radical.
Scheme 10. Reagents and conditions: (i) Bu3SnH (slow addition), AIBN,
PhH (0.015 M), reflux.
Scheme 11. Reagents and conditions: (i) Bu3SnH (slow addition), AIBN,
PhH (0.015 M), reflux; (ii) (Boc)2O, Et3N.
Indirect evidence for the production of the aminyl radical
in these rearrangements is provided by the fact that
Scheme 12. Reagents and conditions: (i) Bu3SnH (slow addition), AIBN,
PhH (0.015 M), reflux; (ii) (Boc)2O, Et3N.

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7169
2-methyleneaziridine 21b undergoes a tandem cyclisation to
octahydroindolizine 37 presumably via aminyl radical 36
(Scheme 13). Whilst the relative stereochemistry within 37
is unknown, the level of diastereocontrol observed in this
reaction (d.r.¼4:1) is appreciably higher than that observed
by Bowman, who observed essentially no stereocontrol in a
related 5-exo radical cyclisation of a piperidinyl radical.24
By analogy with work on 5-exo ring closures of cyclohexyl
radicals,25 it is tempting to speculate that the methyl group
within the major diastereomer is located trans to the ring
junction hydrogen.
combined aqueous layers was adjusted to pH 12
(CAUTION) using saturated K2CO3 solution, then extracted
with EtOAc (4£20–40 mL). The combined organic layers
were dried (MgSO4) and evaporated under reduced pressure
to give the b-amino ester which were characterised and used
without further purification.
3.2.1. 3-Amino-5-phenyl-pentanoic acid ethyl ester (19a).
3-Oxo-5-phenyl-pentanoic acid ethyl ester 18a21 (6.32 g,
28.7 mmol) and NH4OAc (22.1 g, 287 mmol) in benzene
(287 mL) and AcOH (58 mL) were refluxed for 5 days, then
worked up according to General method A. The resulting
b-enamino ester was reduced with NaBH4 (2.64 g,
69.8 mmol) in glacial AcOH (80 mL), to give after work-
up, 19a (3.38 g, 53% over two steps) as a colourless oil. IR
(film) 3365, 2924, 1731, 1618, 1444, 1163 cm21; 1H NMR
(300 MHz, CDCl3) d 7.35–7.10 (5H, m), 4.15 (2H, q,
J¼7.1 Hz), 3.26–3.18 (1H, m), 2.80–2.58 (2H, m), 2.49
(1H, dd, J¼15.6, 4.0 Hz), 2.30 (1H, dd, J¼15.6, 8.7 Hz),
1.88–1.48 (4H, m), 1.26 (3H, t, J¼7.1 Hz); 13C NMR
(100 MHz, CDCl3) d 172.4 (s), 141.8 (s), 128.5 (d), 128.3
(d), 125.9 (d), 60.3 (t), 48.0 (d), 42.8 (t), 39.3 (t), 32.4 (t),
14.2 (q); MS (EI) m/z 221 (Mþ), 204, 91.
The failure of homologue 29 to rearrange to azepane 32 via
a 6-exo-trig cyclisation is perhaps unsurprising. In studying
the rearrangement of the related (methylenecyclopropyl)-
butyl radicals, Kilburn observed only small amounts of
products derived from 6-exo cyclisations. The major
products they observed were simple reduction of the
(methylenecyclopropyl)butyl radical, and competitive
7-endo-trig cyclisation of this radical.26
In conclusion, our studies have demonstrated for the first
time that 2-methyleneaziridines and related structures can
participate in radical rearrangements. This chemistry
provides a novel entry into a variety of functionalised
heterocyclic systems incorporating a piperidine nucleus.
Efforts to use these and related rearrangements in synthesis
are ongoing in our laboratories.
3.2.2. 3-Amino-hept-6-enoic acid ethyl ester (19b).
3-Oxo-hept-6-enoic acid ethyl ester 18b21 (2.00 g,
11.8 mmol) and NH4OAc (9.04 g, 117 mmol) in benzene
(117 mL) and AcOH (23 mL) were refluxed for 3 days, then
worked up according to General method A. The resulting
b-enamino ester was reduced with NaBH4 (1.10 g,
29.1 mmol) in glacial AcOH (32 mL), to give after work-
up, 19b (1.03 g, 51% over two steps) as a colourless oil. IR
3. Experimental
3.1. General
(film) 3370, 2980, 1721, 1639, 1178 cm21 1H NMR
;
(400 MHz, CDCl3) d 5.83–5.70 (1H, m), 5.05–4.90 (2H,
m), 4.14 (2H, q, J¼7.2 Hz), 3.21–3.15 (1H, m), 2.43 (1H,
dd, J¼15.7, 4.1 Hz), 2.29 (1H, dd, J¼15.7, 8.8 Hz), 2.20–
1.98 (4H, m), 1.55–1.38 (2H, m), 1.28 (3H, t, J¼7.2 Hz);
13C NMR (100 MHz, CDCl3) d 172.4 (s), 138.0 (d), 114.9
(t), 60.3 (t), 47.8 (d), 42.5 (t), 36.6 (t), 30.3 (t), 14.2 (q); MS
(CI) m/z 172 (MHþ), 158; HRMS (ESþ): calcd for
C9H18NO2 172.1337; found 172.1336.
All experiments were performed under an inert atmosphere
in oven-dried glassware. Tetrahydrofuran (THF) was
distilled from sodium/benzophenone immediately prior to
use. All other solvents and reagents were purified by
standard protocols. Petroleum ether refers to that boiling in
the 40–608C. Chromatography was performed on Fisher
Matrex 60 silica gel unless otherwise stated. Other general
details have been reported previously.5c
3.3. General method B: two step reduction/alkylation
sequence for the preparation of 20a,b
3.2. General method A: synthesis of b-amino esters
(19a,b)22
To a stirred slurry of lithium aluminium hydride
(2.8 M equiv.) in dry THF at 08C was added 19a,b
(1.0 M equiv.) in THF dropwise. The solution was heated
to reflux for 3 h, then cooled to 08C and water (2–4 mL)
added (CAUTION). The precipitated salts were filtered off
and washed with THF. The filtrate was dried (MgSO4) then
the solvent removed in vacuo. To the resulting g-amino
alcohol in THF was added 2,3-dibromopropene
(0.4 M equiv.) and K2CO3 (0.8–0.9 M equiv.) and the
mixture heated at reflux for 2 days. On cooling to room
temperature, the mixture was filtered and the precipitate
washed with diethyl ether. The filtrate was washed with
10% sodium hydroxide (2£10 mL) and the aqueous layer
re-extracted with diethyl ether (3£20 mL). The combined
organic extracts were washed with water (2£10 mL), dried
(MgSO4) and the solvent removed under reduced pressure.
Purification by column chromatography gave 20a,b as
detailed below.
The b-keto ester (1 M equiv.) and ammonium acetate
(10 M equiv.) in benzene and acetic acid were heated
under reflux for 3–5 days using a Dean–Stark apparatus to
collect water. On cooling, the benzene was removed under
reduced pressure. The residue was diluted with EtOAc,
washed with saturated NaHCO3 solution to neutralise the
acetic acid (CAUTION), then the organic layer dried
(MgSO4). The resulting b-enamino ester, contaminated
with unreacted b-keto ester, was used without further
purification. To a stirred solution of glacial acetic acid was
added NaBH4 (2.4–2.5 M equiv.) portionwise whilst the
temperature was maintained between 15 and 208C. After
30 min, hydrogen evolution had ceased. The b-enamino
ester prepared above was added in one portion and the
mixture stirred for 3 h at room temperature. The acetic acid
was removed in vacuo at 508C, then the residue dissolved in
EtOAc and washed several times with water. The pH of the

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7170
3.3.1. 3-[N-(2-Bromo-2-propenyl)-amino]-5-phenylpen-
tan-1-ol (20a). Using General method B, 19a (3.09 g,
14.0 mmol) in THF (20 mL) was reacted with LiAlH4
(1.50 g, 39.5 mmol) in THF (45 mL) to give after work-up,
the corresponding alcohol which was further reacted with
2,3-dibromopropene (0.59 mL, 5.71 mmol), K2CO3 (1.71 g,
12.4 mmol) in THF (25 mL). Final work-up and purification
by column chromatography (40!50% EtOAc in petroleum
ether containing 1% Et3N) gave 20a (1.34 g, 79%) as a
yellow oil. IR (film) 3318, 2924, 2847, 1623, 1444,
EtOAc in petroleum ether containing 0.5% triethylamine)
gave 7 (3.30 g, 71%) as a pale yellow oil. IR (film) 3298,
2929, 2858, 1623, 1065 cm21; 1H NMR (400 MHz, CDCl3)
d 5.75 (1H, s), 5.53 (1H, s), 3.74 (2H, t, J¼5.5 Hz), 3.42
(2H, s), 3.00 (2H, bs), 2.75 (2H, t, J¼5.7 Hz), 1.68 (2H,
pentet, J¼5.8 Hz); 13C NMR (100 MHz, CDCl3) d 132.7
(s), 118.2 (t), 63.3 (t), 57.2 (t), 47.1 (t), 31.0 (t); MS (CI) m/z
196 (MHþ: 81Br), 194 (MHþ: 79Br), 116; HRMS (CI): calcd
for C6H13NBrO 194.0180; found 194.0181. Anal. calcd for
C6H12NBrO: C, 37.13; H, 6.23; N, 7.22%. Found C, 37.37;
H, 6.63; N, 7.07%.
1060 cm21 1H NMR (400 MHz, CDCl3) d 7.31–7.25
;
(2H, m), 7.21–7.15 (3H, m), 5.72 (1H, s), 5.53 (1H, s),
3.95–3.88 (1H, m), 3.80–3.74 (1H, m), 3.53 (1H, d,
J¼14.6 Hz), 3.43 (1H, d, J¼14.6 Hz), 3.10–2.70 (2H,
bs), 2.88–2.81 (1H, m), 2.73–2.58 (2H, m), 1.95–1.71
(3H, m), 1.63–1.53 (1H, m); 13C NMR (100 MHz, CDCl3)
d 141.6 (s), 132.5 (s), 128.5 (d), 128.2 (d), 126.0 (d),
118.3 (t), 61.7 (t), 56.0 (d), 54.6 (t), 35.4 (t), 33.8 (t), 32.2
(t); MS (CI) m/z 300 (MHþ: 81Br), 298 (MHþ: 79Br), 220;
HRMS (ESþ): calcd for C14H21BrNO 298.0806; found
298.0808.
3.4.2. 3-[N-(2-Bromo-2-propenyl)amino]-3-phenylpro-
pan-1-ol (11). Compound 1018 (1.50 g, 9.93 mmol) was
treated with K2CO3 (1.35 g, 9.77 mmol) and 2,3-dibromo-
propene (0.91 g, 4.55 mmol) in THF (20 mL) for 3 days
according to General method C. Work-up and chromato-
graphy (60!70% EtOAc in petroleum ether containing
0.5% triethylamine) gave 11 (1.11 g, 90%) as a pale yellow
oil. IR (film) 3324, 2929, 1623, 1449, 1070 cm21; 1H NMR
(400 MHz, CDCl3) d 7.37–7.25 (5H, m), 5.67 (1H, s), 5.54
(1H, s), 3.85 (1H, dd, J¼8.6, 4.6 Hz), 3.80–3.75 (2H, m),
3.35 (1H, d, J¼14.7 Hz), 3.22 (1H, d, J¼14.7 Hz), 2.93 (2H,
m), 2.03–1.91 (1H, m), 1.90–1.82 (1H, m); 13C NMR
(100 MHz, CDCl3) d 142.4 (s), 132.5 (s), 128.7 (d), 127.5
(d), 126.8 (d), 118.4 (t), 61.8 (t), 61.1 (d), 54.9 (t), 39.2 (t);
MS (CI) m/z 272 (MHþ: 81Br), 270 (MHþ: 79Br), 192;
HRMS (ESþ): calcd for C12H17BrNO 270.0493; found
270.0491.
3.3.2. 3-[N-(2-Bromo-2-propenyl)-amino]-hept-6-en-1-ol
(20b). Using General method B, 19b (0.50 g, 2.92 mmol) in
THF (5 mL) was reacted with LiAlH4 (313 mg, 8.25 mmol)
in THF (10 mL) to give after work-up the corresponding
alcohol which was further reacted with 2,3-dibromopropene
(0.121 mL, 1.17 mmol), K2CO3 (335 mg, 2.42 mmol) in
THF (15 mL). Final work-up and purification by column
chromatography (30!40% EtOAc in petroleum ether
containing 1% Et3N) gave 20b (262 mg, 90%) as a yellow
oil. IR (film) 3329, 3073, 2929, 1634, 1454, 1070,
3.4.3. 4-[N-(2-Bromo-2-propenyl)-amino]-butan-1-ol
(27). Compound 26 (2.00 g, 22.4 mmol) was treated with
K2CO3 (3.05 g, 22.1 mmol) and 2,3-dibromopropene
(2.24 g, 11.2 mmol) in THF (45 mL) for 2 days according
to General method C. Work-up and chromatography
(160:40:1; EtOAc–petroleum ether–Et3N!190:10:1;
EtOAc:MeOH:Et3N) gave 27 (1.76 g, 75%) as a yellow
oil. IR (film) 3339, 2934, 2842, 1618, 1444, 1060 cm21; 1H
NMR (400 MHz, CDCl3) d 5.75 (1H, s), 5.55 (1H, s), 3.58
(2H, t, J¼5.3 Hz), 3.43 (2H, s), 3.00 (2H, bs), 2.58 (2H, t,
J¼6.1 Hz), 1.68–1.55 (4H, m); 13C NMR (100 MHz,
CDCl3) d 132.6 (s), 118.3 (t), 62.5 (t), 57.0 (t), 47.4 (t),
31.8 (t), 27.7 (t); MS (CI) m/z 210 (MHþ: 81Br), 208 (MHþ:
79Br), 130; HRMS (ESþ): calcd for C7H15BrNO 208.0337;
found 208.0338.
1
906 cm21; H NMR (400 MHz, CDCl3) d 5.84–5.75 (2H,
m), 5.53 (1H, s), 5.05–4.95 (2H, m), 3.85 (1H, ddd, J¼10.7,
7.3, 3.3 Hz), 3.75 (1H, ddd, J¼10.7, 7.2, 3.5 Hz), 3.56 (1H,
d, J¼14.7 Hz), 3.44 (1H, d, J¼14.7 Hz), 3.20–2.80 (2H,
bs), 2.86–2.78 (1H, m), 2.18–2.02 (2H, m), 1.82–1.75 (1H,
m), 1.72–1.62 (1H, m), 1.60–1.48 (2H, m); 13C NMR
(100 MHz, CDCl3) d 137.9 (d), 132.6 (s), 118.1 (t), 115.1
(t), 61.6 (t), 55.9 (d), 54.6 (t), 33.7 (t), 32.8 (t), 30.1 (t); MS
(CI) m/z 250 (MHþ: 81Br), 248 (MHþ: 79Br) 168; HRMS
(ESþ): calcd for C10H19BrNO 248.0650; found 248.0648.
3.4. General method C: N-alkylation of amino alcohol
To a stirred solution of the amino alcohol (2–2.2 M equiv.)
in THF was added potassium carbonate (2–2.2 M equiv.)
and 2,3-dibromopropene (1.0 M equiv.) dropwise. The
resultant mixture was heated under reflux for 2–3 days.
On cooling, the solution was filtered and the precipitate
washed with diethyl ether. The filtrate was washed with
10% sodium hydroxide (2£10 mL) then the aqueous
layer re-extracted with diethyl ether (3£20 mL). The
combined organic extracts were washed with water
(2£10 mL), dried (MgSO4), the solvent removed in vacuo
to give the crude product which was purified by column
chromatography.
3.4.4. (1R p,2S p)-2-[N-(2-Bromo-2-propenyl)-amino]-
cyclohexane-1-carboxylic acid methyl ester (38). Com-
pound 2223 (0.45 g, 2.86 mmol) was treated with K2CO3
(0.39 g, 2.82 mmol) and 2,3-dibromopropene (0.28 g,
1.43 mmol) in THF (15 mL) for 2 days according to
General method C. Work-up and chromatography
(10!20% EtOAc in petroleum ether) gave 38 (0.40 g,
100%) as a pale yellow oil. IR (film) 3344, 2934, 2858,
1726, 1173 cm21; 1H NMR (400 MHz, CDCl3) d 5.80 (1H,
s), 5.52 (1H, s), 3.68 (3H, s), 3.47 (1H, d, J¼15.5 Hz), 3.41
(1H, d, J¼15.5 Hz), 3.00–2.96 (1H, m), 2.67–2.63 (1H, m),
1.97–1.85 (1H, m), 1.84–1.55 (5H, m), 1.55–1.45 (1H, m),
1.40–1.28 (2H, m); 13C NMR (100 MHz, CDCl3) d 174.8
(s), 133.9 (s), 116.9 (t), 55.0 (t), 53.5 (d), 51.3 (q), 45.9 (d),
28.7 (t), 24.8 (t), 23.8 (t), 21.6 (t); MS (FAB) m/z 278 (MHþ:
81Br), 276 (MHþ: 79Br), 196; HRMS (ESþ): calcd for
C11H19BrNO2 276.0599; found 276.0599.
3.4.1. 3-[N-(2-Bromo-2-propenyl)amino]-propan-1-ol
(7). Compound 6 (4.0 g, 53.3 mmol) was treated with
K2CO3 (7.36 g, 53.3 mmol) and 2,3-dibromopropene
(4.82 g, 24.1 mmol) in THF (50 mL) for 2 days according
to General method C. Work-up and chromatography (30%

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N. Prevost, M. Shipman / Tetrahedron 58 (2002) 7165–7175
7171
3.4.5. 3-[N-(2-Bromo-3-methyl-2-butenyl)amino]-3-phe-
nylpropan-1-ol (15). To 1,1-dibromo-2,2-dimethylcyclo-
propane 1419 (1.37 g, 6.01 mmol) in 1,2-dichlorobenzene
(10 mL) was added 1018 (2.00 g, 13.2 mmol) dropwise then
potassium carbonate (0.83 g, 6.01 mmol). The mixture was
heated for 72 h at 1608C then allowed to cool to room
temperature. Aqueous 2 M NaOH solution (10 mL) was
added followed by diethyl ether (15 mL). The organic layer
was separated, washed with brine (2£10 mL) then dried
(MgSO4). After removal of the diethyl ether on a rotary
evaporator, the 1,2-dichlorobenzene was removed by
distillation (608C/15 mm Hg). Purification by column
chromatography (30% EtOAc in petroleum ether using
silica pretreated with Et3N) gave 15 (906 mg, 51%) as a
colourless oil. IR (film) 3344, 2914, 1736, 1449,
m/z 310 (MHþ: 81Br), 308 (MHþ: 79Br), 271, 269; HRMS
(ESþ): calcd for C12H23BrNO3 308.0861; found 308.0859.
3.5. General method D: synthesis of phenylselenides (8,
12, 24, 40, 41a, 41b)
To a stirred solution of the corresponding alcohol
(1 M equiv.) in THF at 08C were added freshly prepared
N-phenylselenophthalimide (N-PSP) (1.7–2.0 M equiv.)
and tri-n-butylphosphine (1.7–2.0 M equiv.). After 4 h,
the solvent was removed under reduced pressure and the
residue purified by column chromatography.
3.5.1. (2-Bromo-2-propenyl)-(3-phenylseleno-propyl)-
amine (8). Compound 7 (0.50 g, 2.57 mmol) was reacted
with N-PSP (1.55 g, 5.16 mmol) and PBu3 (1.04 g,
5.14 mmol) in THF (15 mL) according to General method
D. Column chromatography (10% EtOAc in petroleum
ether) gave 8 (0.60 g, 70%) as a colourless oil. IR (film)
3324, 3062, 2929, 2822, 1629, 1572, 1470 cm21; 1H NMR
(400 MHz, CDCl3) d 7.56–7.48 (2H, m), 7.32–7.20 (3H,
m), 5.76 (1H, s), 5.55 (1H, s), 3.42 (2H, s), 2.99 (2H, t,
J¼7.3 Hz), 2.67 (2H, t, J¼6.8 Hz), 1.90 (2H, m), 1.53 (1H,
bs); 13C NMR (100 MHz, CDCl3) d 133.5 (s), 132.6 (d),
130.3 (s), 129.0 (d), 126.8 (d), 117.6 (t), 57.3 (t), 47.3 (t),
30.3 (t), 25.5 (t); MS (CI) m/z 336 (MHþ: 80Se, 81Br), 334
(MHþ: 80Se, 79Br), 332 (MHþ: 78Se, 79Br); HRMS (ESþ):
calcd for C12H17BrNSe 333.9709; found 333.9706.
1050 cm21 1H NMR (400 MHz, CDCl3) d 7.35–7.20
;
(5H, m), 3.82 (1H, dd, J¼8.0, 4.8 Hz), 3.78–3.71 (2H, m),
3.44 (1H, d, J¼13.9 Hz), 3.40–2.80 (2H, bs), 3.34 (1H, d,
J¼13.9 Hz), 1.93–1.81 (2H, m), 1.84 (3H, s), 1.54 (3H, s);
13C NMR (100 MHz, CDCl3) d 142.8 (s), 134.0 (s), 128.6
(d), 127.3 (d), 126.8 (d), 120.3 (s), 61.7 (t), 61.3 (d), 51.1 (t),
39.5 (t), 25.4 (q), 20.4 (q); MS (EI) m/z 299 (Mþ: 81Br), 297
(Mþ: 79Br), 254, 252; HRMS (EI): calcd for C14H20NOBr
297.0728; found 297.0723. Anal. calcd for C14H20BrNO: C,
56.38; H, 6.76; N, 4.69%. Found C, 56.94; H, 6.84; N,
4.50%.
3.4.6. (1R p,2S p)-N-(2-Bromo-2-propenyl)-2-hydroxy-
methyl-cyclohexylamine (23). To a slurry of lithium
aluminium hydride (0.27 g, 7.11 mmol) in THF (9 mL) at
08C was added 38 (0.70 g, 2.53 mmol) in THF (2 mL)
dropwise. The solution was refluxed for 1 h, recooled to 08C
then water (1 mL) added dropwise (CAUTION). The
precipitated salts were filtered off and washed with THF.
The filtrate was dried (MgSO4) and the solvent removed
under reduced pressure. Column chromatography (90%
EtOAc in petroleum ether) gave 23 (0.42 g, 67%) as a pale
yellow oil. IR (film) 3329, 2919, 2847, 1629, 1449, 1091,
881 cm21; 1H NMR (400 MHz, CDCl3) d 5.78 (1H, s), 5.55
(1H, s), 3.93 (1H, dd, J¼11.1, 8.0 Hz), 3.63 (1H, dd,
J¼11.1, 3.5 Hz), 3.54 (1H, d, J¼14.8 Hz), 3.44 (1H, d,
J¼14.8 Hz), 3.05 (1H, bs), 2.92–2.87 (1H, m), 1.95–1.85
(1H, m), 1.83–1.72 (1H, m), 1.65–1.53 (2H, m), 1.52–1.30
(6H, m); 13C NMR (100 MHz, CDCl3) d 132.8 (s), 118.2 (t),
65.6 (t), 57.0 (d), 55.1 (t), 38.9 (d), 28.0 (t), 26.1 (t), 23.1 (t),
22.9 (t); MS (FAB) m/z 250 (MHþ: 81Br), 248 (MHþ: 79Br);
HRMS (ESþ): calcd for C10H19BrNO 248.0650; found
248.0650.
3.5.2. (2-Bromo-2-propenyl)-(1-phenyl-3-phenylseleno-
propyl)-amine (12). Compound 11 (1.11 g, 4.11 mmol)
was reacted with N-PSP (2.11 g, 6.98 mmol) and PBu3
(1.72 mL, 6.90 mmol) in THF (40 mL) according to General
method D. Column chromatography (0!5% EtOAc in
petroleum ether) gave 12 (1.26 g, 75%) as a colourless oil.
1
IR (film) 3335, 3060, 2927, 1622, 1468 cm21; H NMR
(400 MHz, CDCl3) d 7.46–7.40 (2H, m), 7.35–7.30 (2H,
m), 7.30–7.20 (6H, m), 5.64 (1H, s), 5.54 (1H, d,
J¼1.6 Hz), 3.76 (1H, t, J¼6.9 Hz), 3.32 (1H, d,
J¼15.2 Hz), 3.19 (1H, d, J¼15.2 Hz), 2.87–2.75 (2H, m),
2.12–1.97 (2H, m), 1.72 (1H, bs); 13C NMR (100 MHz,
CDCl3) d 142.4 (s), 133.6 (s), 132.5 (d), 130.1 (s), 129.0 (d),
128.5 (d), 127.5 (d), 127.4 (d), 126.8 (d), 117.9 (t), 60.5 (d),
54.9 (t), 38.2 (t), 24.1 (t); MS (CI) m/z 412 (MHþ: 80Se,
81Br), 410 (MHþ: 80Se, 79Br), 408 (MHþ: 78Se, 79Br);
HRMS (CI): calcd for C18H21BrNSe 410.0022; found
410.0016. Anal. calcd for C18H20BrNSe: C, 52.83; H,
4.93; N, 3.42%. Found C, 53.07; H, 5.02; N, 3.37%.
3.4.7. (2-Bromo-2-propenyl)-(4-hydroxybutyl)-carbamic
acid tert-butyl ester (39). To a stirred solution of 27
(0.50 g, 2.40 mmol) in dichloromethane was added triethyl-
amine (335 mL, 2.40 mmol), di-tert-butyl dicarbonate
(524 mg, 2.40 mmol) and a catalytic amount of DMAP.
After stirring overnight, the solvent was removed in vacuo.
Purification by column chromatography (80% EtOAc in
petroleum ether) gave 39 (678 mg, 92%) as a colourless oil.
3.5.3. (1R p,2S p)-N-(2-Bromo-2-propenyl)-2-phenyl-
selenomethyl-cyclohexylamine (24). Compound 23
(0.42 g, 1.69 mmol) was reacted with N-PSP (1.03 g,
3.41 mmol) and PBu3 (0.84 mL, 3.37 mmol) in THF
(20 mL) according to General method D. Column chroma-
tography (0!10% EtOAc in petroleum ether) gave 24
(0.55 g, 84%) as a colourless oil. IR (film) 3344, 3052, 2919,
1
2847, 1629, 1470 cm21; H NMR (400 MHz, CDCl3) d
IR (film) 3436, 2970, 2929, 2858, 1680, 1403, 1152 cm21
;
7.53–7.50 (2H, m), 7.26–7.19 (3H, m), 5.75 (1H, s), 5.51
(1H, s), 3.39 (1H, d, J¼15.1 Hz), 3.32 (1H, d, J¼15.1 Hz),
3.20 (1H, dd, J¼12.0, 5.9 Hz), 2.85 (1H, dd, J¼12.0,
8.5 Hz), 2.84–2.80 (1H, m), 1.90–1.80 (1H, m), 1.68–1.45
(5H, m), 1.45–1.25 (4H, m); 13C NMR (100 MHz, CDCl3)
d 134.2 (s), 132.5 (d), 131.1 (s), 129.0 (d), 126.6 (d), 117.2
1H NMR (400 MHz, CDCl3) d 5.67 (1H, s), 5.53 (1H, s),
4.01 (2H, bs), 3.64 (2H, t, J¼6.2 Hz), 3.24 (2H, bs), 2.20–
1.75 (1H, bm), 1.63–1.50 (4H, m), 1.44 (9H, s); 13C NMR
(100 MHz, CDCl3) d 155.3 (s), 129.8 (s), 116.5 (t), 80.2 (s),
62.3 (t), 54.7 (t), 46.5 (t), 29.6 (t), 28.3 (q), 24.5 (t); MS (CI)

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N. Prevost, M. Shipman / Tetrahedron 58 (2002) 7165–7175
7172
(t), 55.24 (t), 55.21 (d), 40.1 (d), 29.4 (t), 28.8 (t), 27.8 (t),
23.3 (t), 22.2 (t); MS (CI) m/z 390 (MHþ: 80Se, 81Br), 388
(MHþ: 80Se, 79Br), 386 (MHþ: 78Se, 79Br), 232, 230; HRMS
(ESþ): calcd for C16H23BrSeN 388.0179; found 388.0179.
chloride (527 mL, 6.81 mmol) dropwise over 20 min. The
mixture was allowed to warm to room temperature and
stirred for a further 3 h. The mixture was extracted with
ether (130 mL), washed with water (2£60 mL) then brine
(60 mL), dried (MgSO4) and the solvent removed in vacuo.
To a stirred solution of diphenyl diselenide (2.12 g,
6.79 mmol) in ethanol (40 mL) at 08C was added sodium
borohydride (517 mg, 13.7 mmol) portionwise. The
mesylate (2.56 g) in ethanol (3 mL) prepared above was
added and the solution heated to reflux for 3 h. On cooling to
room temperature, water (10 mL) was added dropwise. The
layers were separated and the aqueous layer extracted with
EtOAc (3£40 mL). The combined organic extracts were
washed with brine (40 mL), dried (MgSO4) and the solvent
removed in vacuo. Subsequent column chromatography
(5% EtOAc in petroleum ether) gave 16 (2.48 g, 83% over
two steps) as a colourless oil. IR (film) 3324, 2909, 1577,
1475, 1019 cm21; 1H NMR (400 MHz, CDCl3) d 7.45–7.40
(2H, m), 7.35–7.20 (8H, m), 3.71 (1H, t, J¼6.7 Hz), 3.40
(1H, d, J¼14.4 Hz), 3.29 (1H, d, J¼14.4 Hz), 2.84–2.73
(2H, m), 2.15–1.97 (2H, m), 1.88 (3H, s), 1.50 (3H, s); 13C
NMR (100 MHz, CDCl3) d 142.7 (s), 133.6 (s), 132.5 (d),
130.1 (s), 129.0 (d), 128.4 (d), 127.6 (d), 127.3 (d), 126.7
(d), 121.6 (s), 60.5 (d), 50.9 (t), 38.6 (t), 25.5 (q), 24.1 (t),
20.5 (q); MS (EI) m/z 437 (Mþ: 80Se, 79Br), 254; HRMS
(EI): calcd for C20H24NSeBr 437.0257; found 437.0257.
Anal. calcd for C20H24NSeBr: C, 54.93; H, 5.53; N, 3.20%.
Found C, 54.96; H, 5.71; N, 3.10%.
3.5.4. (2-Bromo-2-propenyl)-(4-phenylseleno-butyl)-car-
bamic acid tert-butyl ester (40). Compound 39 (0.20 g,
0.65 mmol) was reacted with N-PSP (0.39 g, 1.29 mmol)
and PBu3 (0.32 mL, 1.28 mmol) in THF (5 mL) according
to General method D. Column chromatography (0!5%
EtOAc in petroleum ether) gave 40 (0.219 g, 75%) as a
yellow oil. IR (film) 3062, 2970, 2924, 1690, 1403 cm21
;
1H NMR (400 MHz, CDCl3) d 7.49–7.47 (2H, m), 7.26–
7.21 (3H, m), 5.66 (1H, m), 5.53 (1H, bs), 4.04 and 3.97
(2H, 2£bs), 3.21 (2H, m), 2.91 (2H, t, J¼6.7 Hz), 1.70–1.60
(4H, m), 1.44 (9H, s); 13C NMR (100 MHz, CDCl3) d 155.4
(s), 155.1 (s), 132.6 (d), 130.2 (s), 130.1 (s), 129.9 (s), 129.7
(s), 129.1 (d), 126.8 (d), 117.0 (t), 116.4 (t), 80.1 (s), 54.7 (t),
54.2 (t), 46.3 (t), 46.1 (t), 28.3 (q), 28.1 (t), 27.5 (t), 27.4 (t);
MS (CI) m/z 450 (MHþ: 80Se, 81Br), 448 (MHþ: 80Se, 79Br),
446 (MHþ: 78Se, 79Br); HRMS (ESþ): calcd for C18H27-
BrSeNO2 448.0390; found 448.0387.
3.5.5. (2-Bromo-2-propenyl)-(3-phenylseleno-1-phenyl-
ethyl-propyl)-amine (41a). Compound 20a (0.20 g,
0.67 mmol) was reacted with N-PSP (0.405 g, 1.34 mmol)
and PBu3 (0.33 mL, 1.32 mmol) in THF (8 mL) according
to General method D. Column chromatography (2% EtOAc
in petroleum ether) gave 41a (0.23 g, 78%) as a yellow oil.
IR (film) 3339, 3047, 2924, 2842, 1634, 1470, 1065 cm21
;
3.5.8. (2-Bromo-2-propenyl)-(3-phenylseleno-butyl)-
amine (28). To a stirred solution of 40 (735 mg,
1.65 mmol) in dichloromethane (20 mL) was added tri-
fluoroacetic acid (1.27 mL, 16.5 mmol). After stirring
overnight, the solvent and excess trifluoroacetic acid were
removed in vacuo. The residue was dissolved in brine
(20 mL), the pH adjusted to pH 10 with 1 M aqueous K2CO3
solution, then the mixture extracted with dichloromethane
(3£30 mL). The combined organic extracts were dried
(MgSO4) and the solvent removed in vacuo. Purification by
column chromatography (30% EtOAc in petroleum ether)
gave 28 (529 mg, 92%) as a yellow oil. IR (film) 3324,
3057, 2924, 1623, 1470 cm21; 1H NMR (400 MHz, CDCl3)
d 7.50–7.47 (2H, m), 7.27–7.23 (3H, m), 5.75 (1H, s), 5.54
(1H, s), 3.42 (2H, s), 2.92 (2H, t, J¼7.3 Hz), 2.54 (2H, t,
J¼7.1 Hz), 1.76 (2H, pentet, J¼7.4 Hz), 1.60 (2H, pentet,
J¼7.3 Hz), 1.51 (1H, bs, NH); 13C NMR (100 MHz, CDCl3)
d 133.6 (s), 132.5 (d), 130.4 (s), 129.0 (d), 126.7 (d), 117.6
(t), 57.4 (t), 47.1 (t), 30.0 (t), 27.8 (t), 27.7 (t); MS (CI) m/z
350 (MHþ: 80Se, 81Br), 348 (MHþ: 80Se, 79Br), 270; HRMS
(ESþ): calcd for C13H19BrSeN 347.9866; found 347.9856.
1H NMR (400 MHz, CDCl3) d 7.52–7.50 (2H, m), 7.29–
7.26 (5H, m), 7.21–7.16 (3H, m), 5.71 (1H, s), 5.51 (1H, s),
3.40 (2H, s), 3.05–2.93 (2H, m), 2.71 (1H, m), 2.63 (2H, m),
1.93–1.80 (2H, m), 1.79–1.68 (2H, m), 1.50 (1H, bs); 13C
NMR (100 MHz, CDCl3) d 142.1 (s), 133.6 (s), 132.6 (d),
130.3 (s), 129.1 (d), 128.4 (d), 128.3 (d), 126.8 (d), 125.8
(d), 117.6 (t), 55.1 (d), 54.7 (t), 35.6 (t), 34.3 (t), 32.0 (t),
23.9 (t); MS (CI) m/z 440 (MHþ: 80Se, 81Br), 438 (MHþ:
80Se, 79Br), 436 (MHþ: 78Se, 79Br); HRMS (ESþ): calcd for
C20H25BrSeN 438.0335; found 438.0337.
3.5.6. (2-Bromo-2-propenyl)-[1-(2-phenylseleno-ethyl)-
pent-4-enyl]-amine (41b). Compound 20b (0.222 g,
0.89 mmol) was reacted with N-PSP (0.54 g, 1.79 mmol)
and PBu3 (0.44 mL, 1.77 mmol) in THF (10 mL) according
to General method D. Column chromatography (0!10%
EtOAc in petroleum ether) gave 41b (0.278 g, 81%) as a
yellow oil. IR (film) 3334, 3067, 2924, 1634, 1429 cm21
;
1H NMR (400 MHz, CDCl3) d 7.51–7.42 (2H, m), 7.27–
7.21 (3H, m), 5.84–5.75 (1H, m), 5.75 (1H, s), 5.52 (1H, s),
5.04–4.94 (2H, m), 3.39 (2H, s), 3.02–2.90 (2H, m), 2.67
(1H, pentet, J¼5.9 Hz), 2.08–2.03 (2H, m), 1.85–1.72 (2H,
m), 1.55–1.45 (2H, m), 1.40 (1H, bs); 13C NMR (100 MHz,
CDCl3) d 138.4 (d), 133.8 (s), 132.5 (d), 130.3 (s), 129.1 (d),
126.8 (d), 117.6 (t), 114.8 (t), 54.9 (d), 54.7 (t), 34.1 (t), 32.9
(t), 29.9 (t), 23.8 (t); MS (CI) m/z 390 (MHþ: 80Se, 81Br),
388 (MHþ: 80Se, 79Br), 386 (MHþ: 78Se, 79Br); HRMS
(ESþ): calcd for C16H23BrSeN 388.0179; found 388.0178.
3.6. General method E: preparation of 2-alkylidene-
aziridines (9, 13, 17, 21a, 21b, 25, 29)
To a three necked flask fitted with a dry ice condenser,
calcium chloride drying flask and gas inlet was added
sodium amide (15–30 M equiv.). The system was flushed
with ammonia then a dry/acetone mixture was added to the
condenser and ammonia condensed into the flask. The
appropriate vinyl bromide was added and the reaction
mixture stirred for 10–90 min. Diethyl ether (2–10 mL)
was added followed by the dropwise addition of water
(CAUTION) and the ammonia was allowed to evaporate.
3.5.7. (2-Bromo-3-methyl-2-butenyl)-(1-phenyl-3-
phenylseleno-propyl)-amine (16). To a stirred solution of
15 (2.03 g, 6.81 mmol) in toluene (60 mL) at 08C was added
triethylamine (0.94 mL, 6.74 mmol) then methanesulphonyl

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N. Prevost, M. Shipman / Tetrahedron 58 (2002) 7165–7175
7173
Water (2–8 mL) was added followed by diethyl ether
(2–10 mL) and the mixture stirred for 2 min. The organic
phase was separated and the aqueous phase extracted with
diethyl ether (2£10 mL). The combined organic extracts
were washed with 10% sodium hydroxide (2£5 mL), then
water (2£5 mL), dried (MgSO4) and the solvent removed
under reduced pressure to give the 2-alkylideneaziridine.
purification. IR (film) 3062, 3021, 2934, 1767,
1480 cm21 1H NMR (400 MHz, CDCl3) d 7.54–7.52
;
(2H, m), 7.29–7.26 (5H, m), 7.18–7.16 (3H, m), 4.66 (2H,
s), 3.12–2.94 (2H, m), 2.75–2.59 (2H, m), 2.06 (1H, s),
2.04 (1H, s), 2.10–1.98 (3H, m), 1.95–1.88 (2H, m); 13C
NMR (100 MHz, CDCl3) d 141.9 (s), 135.8 (s), 132.8 (d),
130.0 (s), 129.0 (d), 128.4 (d), 128.3 (d), 126.9 (d), 125.8
(d), 83.0 (t), 66.8 (d), 34.9 (t), 34.1 (t), 31.7 (t), 29.8 (t), 23.4
(t); MS (FAB) m/z 358 (MHþ: 80Se), 200, 172, 145; HRMS
(ESþ): calcd for C20H24SeN 358.1074; found 358.1072.
3.6.1. N-(3-Phenylseleno-propyl)-2-methyleneaziridine
(9). Treatment of 8 (0.60 g, 1.80 mmol) with sodium
amide (1.05 g, 26.9 mmol) in ammonia (20 mL) for
25 min, according to General method E followed by work-
up gave 9 (0.40 g, 88%) as a brown oil which was
characterised and used without further purification. IR
3.6.5. N-[1-(2-Phenylseleno-ethyl)-4-pentenyl]-2-methyl-
eneaziridine (21b). Treatment of 41b (0.45 g, 1.16 mmol)
with sodium amide (675 mg, 17.3 mmol) in ammonia
(10 mL) for 20 min, according to General method E
followed by work-up gave 21b (306 mg, 86%) as a dark
yellow oil which was characterised and used without further
purification. IR (film) 3068, 2922, 2845, 1763, 1433,
1
(film) 3047, 2919, 1762, 1465 cm21; H NMR (400 MHz,
CDCl3) d 7.55–7.45 (2H, m), 7.30–7.20 (3H, m), 4.70–
4.67 (2H, m), 3.04 (2H, t, J¼7.4 Hz), 2.60 (2H, t,
J¼6.8 Hz), 2.04 (2H, s), 2.03–1.96 (2H, m); 13C NMR
(100 MHz, CDCl3) d 137.2 (s), 132.6 (d), 130.1 (s), 129.0
(d), 126.8 (d), 82.9 (t), 59.0 (t), 30.8 (t), 30.3 (t), 25.2 (t); MS
(CI) m/z 254 (MHþ: 80Se), 98; HRMS (CI): calcd for
C12H16NSe 254.0448; found 254.0446.
1166 cm21 1H NMR (400 MHz, CDCl3) d 7.52–7.49
;
(2H, m), 7.27–7.25 (3H, m), 5.85–5.73 (1H, m), 5.04–4.94
(2H, m), 4.63 (2H, s), 3.12–3.03 (1H, m), 3.00–2.97 (1H,
m), 2.20–1.93 (5H, m), 2.05 (1H, s), 2.04 (1H, s), 1.71–
1.65 (2H, m); 13C NMR (100 MHz, CDCl3) d 138.2 (d),
135.8 (s), 132.7 (d), 130.0 (s), 129.1 (d), 126.9 (d), 114.9 (t),
83.1 (t), 66.7 (d), 34.0 (t), 32.3 (t), 29.9 (t), 29.6 (t), 23.3 (t);
MS (CI) m/z 308 (MHþ: 80Se); HRMS (ESþ): calcd for
C16H22SeN 308.0917; found 308.0922.
3.6.2. N-(1-Phenyl-3-phenylseleno-propyl)-2-methyl-
eneaziridine (13). Treatment of 12 (1.00 g, 2.44 mmol)
with sodium amide (1.43 g, 36.7 mmol) in ammonia
(25 mL) for 10 min, according to General method E
followed by work-up gave 13 (729 mg, 91%) as a brown
oil which was characterised and used without further
purification. IR (film) 3060, 2930, 1772, 1574,
3.6.6. (1R p,2S p)-N-(2-Phenylselenomethyl-cyclohexyl]-
2-methyleneaziridine (25). Treatment of 24 (0.55 g,
1.42 mmol) with sodium amide (0.83 g, 21.3 mmol) in
ammonia (15 mL) for 55 min, according to General method
E followed by work-up gave 25 (416 mg, 96%) as a yellow
oil which was characterised and used without further
purification. IR (film) 3057, 2929, 2852, 1757, 1429,
1473 cm21 1H NMR (400 MHz, CDCl3) d 7.45–7.20
;
(10H, m), 4.62 (1H, s), 4.47 (1H, s), 2.99 (1H, t, J¼6.5 Hz),
2.96–2.80 (1H, m), 2.77–2.68 (1H, m), 2.35–2.25 (2H, m),
2.08 (1H, s), 2.03 (1H, s); 13C NMR (100 MHz, CDCl3) d
141.1 (s), 136.6 (s), 132.6 (d), 129.9 (s), 129.1 (d), 128.6 (d),
127.7 (d), 127.5 (d), 83.4 (t), 72.6 (d), 37.6 (t), 30.0 (t), 23.3
(t); MS (CI) m/z 330 (MHþ: 80Se), 174; HRMS (CI): calcd
for C18H20NSe 330.0761; found 330.0757.
1168 cm21 1H NMR (400 MHz, CDCl3) d 7.53–7.50
;
(2H, m), 7.26–7.23 (3H, m), 4.62 (1H, s), 4.59 (1H, s), 3.35
(1H, dd, J¼12.3, 5.3 Hz), 2.97 (1H, dd, J¼12.1, 8.9 Hz),
2.08 (1H, s), 2.07–2.03 (1H, m), 1.99 (1H, s), 2.00–1.85
(2H, m), 1.85–1.70 (2H, m), 1.60–1.45 (3H, m), 1.42–1.30
(2H, m); 13C NMR (100 MHz, CDCl3) d 136.0 (s), 132.4
(d), 130.9 (s), 129.0 (d), 126.6 (d), 82.4 (t), 68.1 (d), 40.6
(d), 29.8 (t), 29.4 (t), 28.0 (t), 22.8 (t); MS (FAB) m/z 308
(MHþ: 80Se); HRMS (ESþ): calcd for C16H22SeN
308.0917; found 308.0919.
3.6.3. N-(3-Phenylseleno-propyl)-2-isopropylideneaziri-
dine (17). Treatment of 16 (1.0 g, 2.29 mmol) with sodium
amide (2.66 g, 68.2 mmol) in ammonia (15 mL) for 90 min,
according to General method E followed by work-up and
column chromatography (5% ethyl acetate in petroleum
ether) gave 17 (617 mg, 76%) as a yellow oil. IR (film)
1
3062, 2924, 2847, 1798, 1434 cm21; H NMR (400 MHz,
608C, CDCl3) d 7.41 (2H, m), 7.34–7.19 (8H, m), 2.96 (1H,
dd, J¼7.4, 5.9 Hz), 2.92–2.83 (1H, m), 2.72–2.63 (1H, m),
2.35–2.28 (2H, m), 2.07 (1H, bs), 1.90 (1H, s), 1.70 (3H, s),
1.30 (3H, bs); 13C NMR (100 MHz, 608C, CDCl3) d 141.9
(s), 132.6 (d), 130.2 (s), 128.9 (d), 128.3 (d), 128.0 (d),
127.4 (d), 126.7 (d), 123.8 (s), 104.1 (s), 72.6 (d), 37.6 (t),
30.3 (t), 23.7 (t), 20.7 (q), 18.9 (q); MS (CI) m/z 358 (MHþ:
80Se), 275, 200; HRMS (CI) calcd for C20H24NSe 358.1074;
found 358.1073. Anal. calcd for C20H23NSe: C, 67.41; H,
6.50; N, 3.93%. Found C, 67.79; H, 6.85; N, 3.86%.
3.6.7. N-(4-Phenylseleno-butyl)-2-methyleneaziridine
(29). Treatment of 28 (0.45 g, 1.30 mmol) with sodium
amide (0.78 g, 20.0 mmol) in ammonia (13 mL) for 45 min,
according to General method E followed by work-up gave
29 (307 mg, 89%) as a dark yellow oil which was
characterised and used without further purification. IR
(film) 3062, 2934, 2837, 1772, 1572, 1475 cm21; 1H NMR
(400 MHz, CDCl3) d 7.51–7.48 (2H, m), 7.26–7.23 (3H,
m), 4.70 (1H, s), 4.66 (1H, s), 2.95 (2H, t, J¼7.2 Hz), 2.50
(2H, t, J¼6.9 Hz), 2.01 (2H, s), 1.90–1.70 (4H, m); 13C
NMR (100 MHz, CDCl3) d 137.3 (s), 132.6 (d), 130.4 (s),
129.0 (d), 126.7 (d), 82.7 (t), 58.9 (t), 30.7 (t), 29.8 (t), 27.8
(t), 27.7 (t); MS (CI) m/z 268 (MHþ: 80Se), 114; HRMS
(ESþ): calcd for C13H18SeN 268.0604; found 268.0603.
3.6.4. N-[1-(2-Phenylseleno-ethyl)-3-phenylpropyl]-2-
methyleneaziridine (21a). Treatment of 41a (0.30 g,
0.69 mmol) with sodium amide (0.39 g, 10.0 mmol) in
ammonia (8 mL) for 20 min, according to General method E
followed by work-up gave 21a (227 mg, 93%) as a yellow
oil which was characterised and used without further
3.6.8. 3-Methylene-6-phenylpiperidine (30). To a degased
solution of 13 (100 mg, 0.305 mmol) in benzene (15 mL)

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N. Prevost, M. Shipman / Tetrahedron 58 (2002) 7165–7175
7174
under reflux was added a degased solution of AIBN (15 mg,
0.09 mmol) and tri-n-butyltin hydride (96 mL, 0.357 mmol)
in benzene (5 mL) via a syringe pump over 4.5 h. After the
addition was complete, heating was continued for a further
1.5 h. On cooling to room temperature, aqueous 2 M HCl
(3 mL) was added, the aqueous layer separated and
neutralised with 2 M NaOH solution (CAUTION). The
aqueous phase was then extracted with diethyl ether
(5£5 mL), the combined organic extracts dried (MgSO4)
and the solvent removed in vacuo. Purification by
chromatography (2% MeOH in CH2Cl2) gave 30 (36 mg,
68%) as a yellow oil. IR (film) 3288, 3057, 2924, 1644,
1439 cm21; 1H NMR (400 MHz, CDCl3) d 7.38–7.24 (5H,
m), 4.81 (1H, d, J¼1.5 Hz), 4.77 (1H, s), 3.76 (1H, dd,
J¼11.3, 2.6 Hz) 3.58 (1H, d, J¼12.6 Hz), 3.44 (1H, d,
J¼12.6 Hz), 2.54–2.47 (1H, m), 2.37–2.27 (1H, m), 2.02–
1.95 (1H, m), 1.85 (1H, bs), 1.70–1.58 (1H, m); 13C NMR
(100 MHz, CDCl3) d 145.0 (s), 144.3 (s), 128.4 (d), 127.1
(d), 126.6 (d), 108.5 (t), 61.5 (d), 53.6 (t), 36.2 (t), 33.5 (t);
MS (CI) m/z 174 (MHþ); HRMS (ESþ): calcd for 174.1282
C12H16N: found 174.1282.
(d), 125.8 (d), 108.0 (t), 55.8 (d), 52.9 (t), 38.3 (t), 34.8 (t),
32.9 (t), 32.5 (t); MS (CI) m/z 202 (MHþ), 96; HRMS
(ESþ): calcd for C14H20N 202.1595: found 202.1596.
3.6.11. 1-tert-Butoxycarbonyl-3-methylene-decahydro-
quinoline (34). To a degased solution of 25 (100 mg,
0.33 mmol) in benzene (16 mL) under reflux was added a
degased solution of AIBN (25 mg, 0.15 mmol) and tri-n-
butyltin hydride (103 mL, 0.38 mmol) in benzene (5 mL)
via a syringe pump over 5 h. After the addition was
complete, heating was continued for a further 1 h. On
cooling to room temperature, di-tert-butyl dicarbonate
(142 mg, 0.65 mmol) and triethylamine (91 mL,
0.65 mmol) were added and the mixture stirred overnight.
Removal of the solvent under reduced pressure and
subsequent column chromatography (0!1% EtOAc in
petroleum ether) gave 34 (53 mg, 65%) as a colourless oil.
1
IR (film) 3067, 2929, 2852, 1690, 1403, 1163 cm21; H
NMR (400 MHz, CDCl3) d 4.80 (1H, s), 4.73 (1H, s), 4.28
(1H, bd, J¼13.9 Hz), 4.08 (1H, bs), 3.41 (1H, d,
J¼14.3 Hz), 2.47 (1H, t, J¼13.3 Hz), 2.03–1.88 (2H, m),
1.82–1.68 (2H, m), 1.67–1.55 (2H, m), 1.55–1.25 (4H, m),
1.45 (9H, s); 13C NMR (100 MHz, CDCl3) d 154.7 (s),
143.6 (s), 109.4 (t), 79.3 (s), 52.4 (d), 45.2 (t), 35.9 (d), 32.7
(t), 30.8 (t), 28.4 (q), 25.6 (t), 23.7 (t), 19.9 (t); MS (CI) m/z
252 (MHþ), 152; HRMS (ESþ): calcd for C15H26NO2
252.1963: found 252.1965.
3.6.9. 1-tert-Butoxycarbonyl-3-methylenepiperidine (31).
To a degased solution of 9 (100 mg, 0.40 mmol) in benzene
(21 mL) under reflux was added a degased solution of AIBN
(27 mg, 0.16 mmol) and tri-n-butyltin hydride (147 mL,
0.55 mmol) in benzene (5 mL) via a syringe pump over 5 h.
After the addition was complete, heating was continued for
a further 1 h. On cooling to room temperature, di-tert-butyl
dicarbonate (173 mg, 0.79 mmol) and triethylamine
(0.11 mL, 0.79 mmol) were added and the mixture stirred
overnight. Removal of the solvent under reduced pressure
and subsequent column chromatography (5% EtOAc in
petroleum ether) gave 31 (45 mg, 58%) as a colourless oil.
3.6.12. 1-tert-Butoxycarbonyl-3-isopropylidene-6-phe-
nylpiperidine (35). To a degased solution of 17 (0.11 g,
0.31 mmol) in benzene (15 mL) under reflux was added a
degased solution of AIBN (28 mg, 0.17 mmol) and tri-n-
butyltin hydride (0.11 mL, 0.41 mmol) in benzene (5 mL)
via a syringe pump over 5 h. After the addition was
complete, heating was continued for a further 1 h. On
cooling to room temperature, di-tert-butyl dicarbonate
(134 mg, 0.61 mmol) and triethylamine (86 mL,
0.62 mmol) were added and the mixture stirred overnight.
Removal of the solvent under reduced pressure and
subsequent column chromatography (4% EtOAc in
petroleum ether) gave 35 (0.058 g, 62%) as a colourless
oil. IR (film) 2973, 2920, 1693, 1319, 1161 cm21; 1H NMR
(400 MHz, C6D6 at 778C) d 7.31–7.15 (5H, m), 5.17–5.13
(1H, m), 4.99 (1H, d, J¼15.4 Hz), 3.76 (1H, d, J¼15.4 Hz),
2.25–2.05 (2H, m), 1.98–1.88 (1H, m), 1.83–1.75 (1H, m),
1.74 (3H, s), 1.54 (3H, s), 1.43 (9H, s); 13C NMR (100 MHz,
C6D6 at 778C) d 155.1 (s), 144.3 (s), 128.2 (d), 126.6 (s),
126.3 (d), 125.8 (d), 123.4 (s), 78.7 (s), 56.4 (d), 41.9 (t),
30.0 (t), 28.1 (q), 24.6 (t), 19.30 (q), 19.28 (q); MS (EI) m/z
301 (Mþ), 244, 186; HRMS (EI): calcd for C19H27NO2
301.2042: found 301.2048. Anal. calcd for C19H27NO2: C,
75.71; H, 9.03; N, 4.65%. Found C, 75.37; H, 9.34; N,
4.44%.
IR (film) 3073, 2975, 1685, 1413 cm21
;
1H NMR
(400 MHz, CDCl3) d 4.81 (1H, s), 4.71 (1H, s), 3.86 (2H,
s), 3.43 (2H, t, J¼5.6 Hz), 2.25 (2H, t, J¼6.2 Hz), 1.64–
1.58 (2H, m), 1.45 (9H, s); 13C NMR (100 MHz, CDCl3) d
154.7 (s), 143.0 (s), 109.7 (t), 79.4 (s), 50.4 (t), 44.1 (t), 32.7
(t), 28.4 (q), 26.6 (t); MS (CI) m/z 198 (MHþ), 159, 98;
HRMS (CI): calcd for C11H20NO2 198.1494: found
198.1493.
3.6.10. 3-Methylene-6-(2-phenylethyl)-piperidine (33).
To a degased solution of 21a (108 mg, 0.30 mmol) in
benzene (15 mL) under reflux was added a degased solution
of AIBN (25 mg, 0.15 mmol) and tri-n-butyltin hydride
(96 mL, 0.36 mmol) in benzene (5 mL) via a syringe pump
over 5 h. After the addition was complete, heating was
continued for a further 1 h. On cooling to room temperature,
aqueous 2 M HCl (3 mL) was added, the aqueous layer
separated and neutralised with 2 M NaOH solution
(CAUTION). The aqueous phase was then extracted with
EtOAc (5£5 mL), the combined organic extracts dried
(MgSO4) and the solvent removed in vacuo. Purification by
chromatography (0.5% Et3N in EtOAc) gave 33 (38 mg,
67%) as a yellow oil. IR (film) 3288, 3062, 2924, 2847,
1649, 1444 cm21; 1H NMR (400 MHz, CDCl3) d 7.30–7.26
(2H, m), 7.20–7.16 (3H, m), 4.73 (1H, s), 4.69 (1H, s), 3.45
(1H, d, J¼13.1 Hz), 3.25 (1H, d, J¼13.1 Hz), 2.78–2.62
(3H, m), 2.44–2.37 (1H, m), 2.23–2.10 (2H, m), 1.93–1.88
(1H, m), 1.78–1.68 (2H, m), 1.30–1.19 (1H, m); 13C NMR
(100 MHz, CDCl3) d 146.0 (s), 142.2 (s), 128.4 (d), 128.3
3.6.13. 3-Methyl-6-methylene-octahydro-indolizine (37).
To a degased solution of 21b (145 mg, 0.47 mmol) in
benzene (23 mL) under reflux was added a degased solution
of AIBN (32 mg, 0.19 mmol) and tri-n-butyltin hydride
(149 mL, 0.55 mmol) in benzene (8 mL) via a syringe pump
over 5 h. After the addition was complete, heating was
continued for a further 1 h. On cooling to room temperature,
aqueous 2 M HCl (5 mL) was added, the aqueous layer
separated, washed with petroleum ether (6£5 mL),

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N. Prevost, M. Shipman / Tetrahedron 58 (2002) 7165–7175
7175
Tetrahedron Lett. 1982, 23, 5021–5024. (b) Werry, J.; Stamm,
H.; Lin, P.-Y.; Falkenstein, R.; Gries, S.; Irngartinger, H.
Tetrahedron 1989, 45, 5015–5028.
neutralised with 2 M NaOH solution (CAUTION), then
extracted with diethyl ether (5£5 mL). The ethereal extracts
were combined, dried (MgSO4) and the solvent carefully
removed on a rotary evaporator using a partial vacuum with
the water bath temperature maintained at ca. 58C.
Purification by chromatography on neutral alumina (2.5%
MeOH in CH2Cl2) gave 37 (28 mg, 39%) as a single
diastereomer (see Section 2) and as a yellow oil. IR (film)
9. (a) Dickinson, J. M.; Murphy, J. A. J. Chem. Soc., Chem.
Commun. 1990, 434–436. (b) Dickinson, J. M.; Murphy, J. A.
Tetrahedron 1992, 48, 1317–1326.
10. (a) DeKimpe, N.; Jolie, R.; DeSmaele, D. J. Chem. Soc.,
Chem. Commun. 1994, 1221–1222. (b) DeKimpe, N.;
DeSmaele, D.; Bogaert, P. Synlett 1994, 287–288.
(c) DeSmaele, D.; Bogaert, P.; DeKimpe, N. Tetrahedron
Lett. 1998, 39, 9797–9800.
1
3058, 2955, 2924, 1647, 1441, 1369, 890 cm21; H NMR
(400 MHz, C6D6) d 4.87 (1H, s), 4.82 (1H, s), 3.34 (2H, s),
3.25–3.15 (1H, m), 2.90–2.83 (1H, m), 2.35–2.28 (1H, m),
2.12–1.86 (3H, m), 1.54–1.25 (4H, m), 1.00 (3H, d,
J¼6.2 Hz); 13C NMR (100 MHz, C6D6) d 144.7 (s), 108.3
(t), 58.6 (d), 53.5 (d), 53.0 (t), 33.2 (t), 31.3 (t), 31.1 (t), 29.3
(t), 17.0 (q); MS (EI) m/z 151 (Mþ), 150 (M2Hþ) 136
(M2CHþ3 ); HRMS (EI): calcd for C10H17N 151.1361;
found 151.1364.
11. (a) Schwan, A. L.; Refvik, M. D. Tetrahedron Lett. 1993, 34,
4901–4904. (b) Molander, G. A.; Stengel, P. J. Tetrahedron
1997, 53, 8887–8912. (c) Marples, B. A.; Toon, R. C.
Tetrahedron Lett. 1999, 40, 4873–4876.
12. For a review on the use of aminyl radicals in synthesis, see:
Fallis, A. G.; Brinza, I. M. Tetrahedron 1997, 53,
17543–17594.
´
13. For a preliminary account of part of this work, see: Prevost, N.;
Acknowledgments
Shipman, M. Org. Lett. 2001, 3, 2383–2385.
14. For a compendum of available methods, see: Motherwell,
W. B.; Crich, D. Free Radical Chain Reactions in Organic
Synthesis; Academic: London, 1991.
This work was supported by a grant from EPSRC
(GR/M71923). We are indebted to the EPSRC National
Mass Spectrometry Service Centre for performing mass
spectral measurements and the EPSRC Chemical Database
Service at Daresbury.27
15. For alternative methods of synthesis, see: (a) Bingham, E. M.;
Gilbert, C. J. J. Org. Chem. 1975, 40, 224–228. Tehrani, K. A.;
DeKimpe, N. Tetrahedron Lett. 2000, 41, 1975–1978, and
Ref. 4d.
16. Clive, D. L. J.; Chittatu, G. J.; Farina, V.; Kiel, W. A.;
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