Generation and electrophilic substitution reactions of 3-lithio-2-methyleneaziridines

Article abstract of DOI:10.1016/j.tet.2006.06.083

2-Methyleneaziridinyl anions can be produced by selective deprotonation of the parent aziridine at C-3 using sec-BuLi/TMEDA. Subsequent reaction with a wide variety of electrophiles including MeI, ICH₂CH₂CH₂CH₂C

Full text of DOI:10.1016/j.tet.2006.06.083

Tetrahedron 62 (2006) 8447–8457
Generation and electrophilic substitution reactions
of 3-lithio-2-methyleneaziridines
a
Cyril Montagne, Natacha Prevost, Jason J. Shiers, Gildas Prie, Sabitur Rahman,
b
a
b
ꢀ
ꢀ a
Jerome F. Hayesc and Michael Shipmana,
*
aDepartment of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK
bSchool of Chemistry, University of Exeter, Stocker Road, Exeter, Devon EX4 4QD, UK
cGlaxoSmithKline, Old Powder Mills, Tonbridge, Kent TN11 9AN, UK
Received 7 April 2006; revised 8 June 2006; accepted 22 June 2006
Available online 17 July 2006
Abstract—2-Methyleneaziridinyl anions can be produced by selective deprotonation of the parent aziridine at C-3 using sec-BuLi/TMEDA.
Subsequent reaction with a wide variety of electrophiles including MeI, ICH2CH2CH2CH2Cl, PhCH2Br, allyl bromide, Me3SiCl, Bu3SnCl,
PhCHO and Ph2CO provides the corresponding C-3 substituted derivatives in moderate to good yields (43–91%). In the case of homochiral
methyleneaziridines bearing an (S)-a-methylbenzyl group on nitrogen, high levels of diastereocontrol (up to 90%de) can be achieved in this
lithiation/alkylation sequence.
Ó 2006 Elsevier Ltd. All rights reserved.
H
1. Introduction
Me
Ph
H
N
Me
Ph
NaNH (2.5 eq),
2
NH
NH , –78°C, 1 h
2-Methyleneaziridines are emerging as powerful vehicles
for chemical synthesis. Recently, these highly strained
heterocycles have been shown to participate in a number
of useful transformations including [3+4] cycloadditions,1
multi-component reactions,2 radical cascades,3 and several
palladium-catalysed processes.4–6 Of course, for these reac-
tions to be of broad scope and utility, concise methods for the
synthesis of these N-heterocycles are required. Simple 2-
methyleneaziridines can easily be made in high yield by
reaction of the corresponding 2-bromoallylamines with so-
dium amide in liquid ammonia.7 This remarkable cyclisation
tolerates considerable structural variation with respect to the
substituents on nitrogen and the double bond, and proceeds
with net stereochemical inversion at the trigonal carbon
atom undergoing substitution.8 For example, cyclisation of
(E)-1 yields (Z)-2 in excellent yield (Scheme 1). Other routes
to the parent heterocycles are also known.9
3
93%
Br
(E)-1
(Z)-2
Scheme 1. Facile synthesis of C-3 unsubstituted methyleneaziridines by
ring closure.
manner to that illustrated in Scheme 1, an alternative ap-
proach based upon C-3 functionalisation of a preformed
2-methyleneaziridine appeared more flexible and direct
ꢀ
(Scheme 2). Early work by Quast and Weise Velez had
established the potential suitability of this approach by
showing that 1-tert-butyl-2-methyleneaziridine 3 (R¼tBu;
R1, R2¼H) can be deprotonated with sec-butyllithium at
ꢀ78 ꢁC to give organolithium 4 (R¼tBu; R1, R2¼H) and
further alkylated with a limited range of electrophiles
R
N
R
N
To assemble substrates for Lewis acid catalysed intramolec-
ular [3+4] cycloadditions,1 efficient routes to methyleneazir-
idines bearing C-3 substituents were required. The synthesis
of such derivatives has little literature precedent.10 Whilst
they might conceivably be prepared by ring closure of the
appropriately substituted vinyl bromide in an analogous
1. sec-BuLi, TMEDA
2. Electrophile (E )
+
1
1
3
R
R
E
2
2
3
5
R
R
R
N
1
R
Li
2
4
R
Keywords: Aziridines; Organolithiums; Strained compounds.
* Corresponding author. Fax: +44 24765 24429; e-mail: m.shipman@
warwick.ac.uk
Scheme 2. Strategy for the functionalisation of C-3 substituted methylene-
aziridines.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.083

8448
C. Montagne et al. / Tetrahedron 62 (2006) 8447–8457
(MeOD, MeI or Me3SiCl) to yield 5 (R¼tBu; R1, R2¼H;
E¼D, Me3Si or Me).10a In the present article, the scope
and limitations of this approach to C-3 substituted methyl-
eneaziridines are examined in detail. Using a range of differ-
ent methyleneaziridines and electrophiles, it is determined
that this method provides a highly practical approach to
many C-3 substituted methyleneaziridines.11 Moreover,
using simple chiral, non-racemic methyleneaziridines
(R¼(S)-CHMePh), useful levels of asymmetric induction
can be achieved in this process.
Br
Br
R
1
2
2
14 (R = R = Me);
1
2
15 (R , R = –(CH ) –)
2 5
1
R
PhCH NH or c-hexNH ,
2
2
2
1,2-dichlorobenzene, heat
44-84%
Br
H
1
2
2 16 (R = CH Ph; R = R = Me);
R
2
N
1
2
2
17 (R = c-hex; R = R = Me);
R
1
1
R
18 (R = CH Ph, R , R = –(CH ) –)
2
2 5
NaNH , NH
2
3
47-75%
2. Results and discussion
2.1. Precursor synthesis
6, 8 and 9
Scheme 3. Synthesis of new methyleneaziridines 6, 8 and 9.
The lithiation/alkylation reactions of wide range of methyl-
eneaziridines have been studied. Eleven different methyl-
eneaziridines 2, 6–13 were prepared for use in these
investigations (Fig. 1). In most instances, the compounds
were made according to published procedures by sodium
amide induced cyclisation of the corresponding 2-bromo-
allylamine [(Z)-7,8 (E)-7,8 10,12 11,13 12,13 (Z)-2,8 (E)-28
and 132d]. The examples incorporating the a-methylbenzyl
substituent were produced as the (S)-enantiomer.
with 1.5–2.0 equiv of sec-BuLi/tetramethylethylenediamine
(TMEDA) in diethyl ether at ꢀ78 ꢁC for 7.5 h.10a Herein, the
lithiation of 6–10 was achieved under very similar condi-
tions and was conducted in THF at ꢀ78 ꢁC using a small
excess of sec-BuLi (1.1–1.5 equiv) and TMEDA (1.1–
1.2 equiv) as cosolvent. Complete lithiation at Cꢀ3 was
achieved in ꢂ6 h under these conditions. Quenching the
lithiated methyleneaziridines with electrophiles and warm-
ing to room temperature provided the C-3 substituted
products 19–30 in good to excellent yields (Scheme 4 and
Table 1). In most cases, a small excess of the electrophile
was used (1.2–1.5 equiv). However, for the synthesis of azir-
idines 29 and 30, the electrophile was used as the limiting
reagent (0.9 equiv). This was necessary because aziridines
28–30 could not be purified by chromatography due to their
instability, and excess 1-chloro-4-iodobutane and tributyltin
chloride were difficult to remove by distillation. The range
of carbon-based electrophiles that can be used in this chem-
istry is quite broad. Successful alkylations were realised
using a variety of alkyl iodides (Table 1, entries 1, 2, 8 and
12), benzyl bromide (Table 1, entry 11), benzophenone
(Table 1, entry 4) and benzaldehyde (Table 1, entry 3). In
the case of 1-chloro-4-iodobutane, selective displacement
of the iodide was observed (Table 1, entry 12). No diastereo-
selectivity was witnessed in the reaction with benzaldehyde
and 21 was produced as ca. 1:1 mixture of diastereomers.
Heteroatom-based electrophiles can also be used (Table 1,
entries 5 and 13). This chemistry accommodates consider-
able changes in the methyleneaziridine structure. Variation
in the extent of substitution of the exocyclic double bond
is well tolerated (Table 1, entries 1, 6–8 and 11). Further-
more, changes in the nature of the N-substituent are possible
(Table 1, entry 1 and 9) although no reaction is witnessed
with N-trityl-2-methyleneaziridine (Table 1, entry 14). The
selective lithiation of N-benzyl substituted derivatives 6–9
at C-3 is especially notable, with no competitive benzylic de-
protonation being observed. Unfortunately, initial attempts
to extend this chemistry to the synthesis of 3,30-disubstituted
CH Ph
2
CH Ph
2
CH Ph
2
CH Ph
2
N
N
N
N
6
(Z)-7
(E)-7
8
H
Me
Ph
c-Hex
N
c-Hex
N
CPh
N
3
N
9
10
11
12
Ph
H
H
N
H
N
Me
Ph
Me
Ph
Me
N
(Z)-2
(E)-2
13
Figure 1. Substrates for lithiation/alkylation studies.
Three new methyleneaziridines, namely 6, 8 and 9, were
made by a simple two-step sequence. Ring opening14 of
1,1-dibromocyclopropane 1415 with benzylamine and cyclo-
hexylamine yielded vinyl bromides 16 and 17, respectively
(Scheme 3). In a similar manner, opening of 1516 with
benzylamine provided 18. For 16 and 18, the ring opening
was performed at 170 ꢁC and high yields (68–84%) were
obtained. Using cyclohexylamine (bp 134 ꢁC), the opening
was conducted at 120 ꢁC, which may account for the
reduced yield of 17 (44%). Ring closure of bromides 16–
18 with sodium amide7,8 proceeded uneventfully to provide
methyleneaziridines 6, 8 and 9 in moderate to good yields.
1. sec-BuLi, TMEDA,
R
N
R
N
–78°C, THF
2.2. Lithiation/electrophilic substitution reactions
using simple methyleneaziridines
3
2. R –X, –78°C
rt
1
1
R
R
3
R
2
2
R
6-10
19-30 R
ꢀ
In the original study by Quast and Weise Velez, it was
established that complete lithiation of 1-tert-butyl-2-methyl-
eneaziridine at C-3 could be accomplished by treatment
Scheme 4. Functionalisation of simple methyleneaziridines via deproto-
nation/alkylation.

C. Montagne et al. / Tetrahedron 62 (2006) 8447–8457
Table 1. Alkylation of simple methyleneaziridines
8449
Entry
Aziridine
R
R1
R2
Electrophile
Product
R3
%Yielda
1
2
3
4
5
6
7
8
6
6
6
6
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
CPh3
Me
Me
Me
Me
Me
Me
H
Me
Me
Me
Me
Me
H
MeI
19
20
21
22
Me
79
73
74b
73
63
62
73
61
64
64
86
70c
91c
0
(E)-PhCH]CHCH2CH2CH2I
PhCHO
Ph2CO
Me3SiCl
Ph2CO
Ph2CO
(2-furanyl)CH2CH2CH2I
MeI
Me3SiCl
CH2CH2CH2CH]CHPh
CH(OH)Ph
C(OH)Ph2
SiMe3
C(OH)Ph2
C(OH)Ph2
CH2CH2CH2(2-furanyl)
Me
SiMe3
CH2Ph
CH2CH2CH2CH2Cl
SnBu3
n/a
6
23
(Z)-7
(E)-7
8
9
9
10
10
10
11
(Z)-24
(E)-24
25
26
27
28
29
30
n/a
Me
–(CH2)5–
9
Me
Me
H
H
H
Me
Me
H
H
H
10
11
12
13
14
PhCH2Br
ClCH2CH2CH2CH2I
Bu3SnCl
PhCH2Br
H
H
a
Isolated yield after purification by silica gel chromatography or distillation.
Produced as a separable mixture of two diastereomers (21a: 35%; 21b: 39%).
Yield based upon electrophile which was used as limiting reagent (0.9 equiv).
b
c
methyleneaziridines by repeating the lithiation/alkylation
sequence on the alkylated products have not been fruitful.
the exocyclic double bond leads to a significant improvement
in the level of diastereoselectivity observed (Table 2, entries
1, 3, 5 and 9), with substitution cis to the aziridine nitrogen
giving the greatest improvement. Thus, high levels of dia-
stereocontrol (80–90% de) were achieved using 2-isopropyl-
idineaziridine (S)-13 with a range of electrophiles, producing
35–40 in moderate to good yields (Table 2, entries 7–12).
With the exception of 36, the alkylated products were readily
isolated as single diastereomers after silica gel chromato-
graphy. For (Z)-2, high selectivities (up to 86%) were ob-
tained in some instances (Table 2, entry 6). The relative
stereochemistry within (Z)-34 and 39 have been unambigu-
ously established by X-ray crystallography (Fig. 2).19 All
the other alkylated aziridines 31–40 are tentatively assigned
as having the same configuration at C-3 in the major
diastereomer.
2.3. Diastereocontrolled lithiation/alkylation reactions
Since a new asymmetric centre is produced at C-3 during the
lithiation/alkylation sequence (Scheme 2), it was of interest
to establish if any stereochemical control could be achieved
ꢀ
in this transformation. Indeed, Quast and Weise Velez had
attempted this in the lithiation/alkylation reactions of
1-methyl-2-methyleneaziridine by using an external chiral
ligand [(S,S)-(+)-1,4-bis(dimethylamino)-2,3-dimethoxy-
butane] as cosolvent. Unfortunately, the levels of enantio-
selectivity achieved were very modest (12.4% ee).10b,17
We reasoned that much better levels of asymmetric induc-
tion might be achieved by incorporating a chiral, non-
racemic element within the nitrogen substituent of the
aziridine such that it might exert influence and control on
the lithiation/alkylation process. For this study, the a-methyl-
benzyl group was chosen as the chiral control element
because of its simplicity, low cost and widespread use in
asymmetric synthesis.18
The origin of the large differences in the levels of diastereo-
selectivity observed in the lithiation/alkylation of aziridines
(E)-2 and (Z)-2, 12 and 13 remains unclear. As aziridinyl
anions are normally configurationally stable, we suggest
that the selectivity in these reactions most likely arises
from diastereocontrol in the initial lithiation of the aziridine
ring. At first glance, the methyl groups on the alkene termi-
nus appear too remote to exert any increased bias in the
stereoselectivity of this process. However, the stereochem-
ical analysis is complicated by the fact that these enantio-
merically pure methyleneaziridines exist as mixtures of
diastereomers as a result of N-inversion. In an attempt to
ascertain if the dynamics of nitrogen inversion play a role
in the selectivity of the lithiation process, we have quantified
the effect of alkene substitution on the rate of inversion. To
simplify the analysis, N-benzyl substituted derivatives 6,
(Z)-7, (E)-7 and N-benzylmethyleneaziridine (41)12 were
used as the populations of the N-invertomers were equal.
The diastereocontrolled alkylation reactions of four chiral
methyleneaziridines, namely (E)-2, (Z)-2, 12 and 13 were
studied (Scheme 5 and Table 2). Treatment of homochiral
(S)-12withsec-BuLi andTMEDA inTHFfor7 h, thenbenzyl
bromide, provided 31 in good yield but as an inseparable
53:47 mixture of diastereomers (14% de before purification)
(Table 2, entry 1). Using benzophenone as electrophile, an in-
crease in diastereoselectivity was witnessed (Table 2, entry 2
cf. entry 1). Interestingly, a similar trend was seen for (E)-2
(Table 2, entry 4 cf. entry 3) and (Z)-2 (Table 2, entry 6 cf.
entry 5). Moreover, the introduction of methyl groups on
H
N
H
N
1
1. sec-BuLi, TMEDA,
The H NMR spectra of the methyleneaziridines were re-
Me
Ph
Me
3
Ph
–78°C, THF
corded over a range of temperatures at 500 MHz and rate
constants obtained for the exchanging signals ascertained
by line shape matching with simulated spectra produced
using WINDNMR.20 From the rate constants, the Gibbs
free energy of activation (DGz) for the inversion process
was determined for each aziridine by use of Eyring plots.
3
2. R –X, –78°C
rt
1
1
R
R
R
2
2
R
R
2, 12 or 13
31-40
Scheme 5. Diastereocontrolled deprotonation/alkylation of homochiral
methyleneaziridines.
The following data were obtained: 41, DGz¼43.5 kJ molꢀ1
;

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C. Montagne et al. / Tetrahedron 62 (2006) 8447–8457
Table 2. Diastereoselective alkylations with homochiral methyleneaziridines
Entry
Aziridine
R1
R2
Electrophile
Product
R3
%Yielda
Crude %deb
1
2
3
4
5
6
7
8
12
12
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
H
H
Me
Me
H
PhCH2Br
Ph2CO
PhCH2Br
Ph2CO
PhCH2Br
Ph2CO
MeI
31
32
CH2Ph
C(OH)Ph2
CH2Ph
C(OH)Ph2
CH2Ph
C(OH)Ph2
Me
Bu
70c
70d,e
51f
68d
59f
83d
47
14
56
26
56
48
86
80
n.d.
88
84
88
90
(E)-2
(E)-2
(Z)-2
(Z)-2
13
13
13
13
13
(E)-33
(E)-34
(Z)-33
(Z)-34
35
36
37
38
39
H
Me
Me
Me
Me
Me
Me
BuI
53g
68
9
PhCH2Br
CH2]CHCH2Br
Ph2CO
CH2Ph
10
11
12
CH2CH]CH2
C(OH)Ph2
SiMe3
63
43d
80
13
Me3SiCl
40
a
Isolated yield of major diastereomer after purification by silica gel chromatography unless otherwise stated.
Ratio determined by 1H NMR analysis prior to purification.
Isolated as a 53:47 mixture of diastereomers.
To remove excess Ph2CO, treated with NaBH4 in EtOH prior to purification.
Isolated as a 80:20 mixture of diastereomers.
Combined yield of separated diastereomers.
b
c
d
e
f
g
Isolated as a 93:7 mixture of diastereomers.
H
N
H
N
All other solvents and reagents were used as received or
purified by standard protocols. All experiments were per-
formed under an inert atmosphere in oven-dried glassware.
Column chromatography was carried out using Matrex silica
60. Optical rotations were determined using an Optical
Activity Ltd AA1000 Polarimeter. Melting points were
measured using Gallenkamp MPD350 apparatus and are
reported uncorrected. Infrared spectra were recorded on a
Nicolet MAGNA 550 or Perkin–Elmer ‘Spectrum One’
Me
H
Ph
Me
H
Ph
HO
Ph
HO
Ph
Ph
(Z)-34
Ph
39
Figure 2. Determination of relative stereochemistry in (Z)-34 and 39 by
X-ray crystallography.
1
FT-IR spectrometer with internal calibration. H and 13C
(Z)-7, DGz¼52.0 kJ molꢀ1; (E)-7, DGz¼54.2 kJ molꢀ1 and
6, DGz¼57.2 kJ molꢀ1 (at 298 K). From these measurements,
it is apparent that the N-inversion barrier is raised by alkene
substitution. However, it remains to be established if this is an
important factor in the observed changes in diastereoselectiv-
ity witnessed in the lithiation/alkylation reactions of (E)- and
(Z)-2, 12 and 13 and work focused on uncovering the origin of
the selectivity in these reactions is ongoing.
NMR spectra were recorded at 300 and 75 MHz, respec-
tively, on a Bruker ACF-300 or AM-300; or at 400 and
100 MHz, respectively, on a Bruker DRX-400, DPX-400
or AV-400 spectrometer. Low-resolution mass spectra were
recorded on a Kratos Profile HV3 or Micromass Quattro II
mass spectrometer fitted with an electron ionisation source,
or an Esquire 2000 platform with electrospray ionisation.
High-resolution mass spectra were obtained using a Finnigan
MAT 95XP, Finnigan MAT 900XLT, Micromass 70-VSEQ
or VG-7070E instrument. Elemental analyses were carried
out on a Perkin–Elmer 2400 CHN or Carlo Erba 1160
elemental analyser.
3. Conclusions
It has been established that lithiation/alkylation of methyl-
eneaziridines provides a convenient method for the synthesis
of a wide range of C-3 substituted derivatives. Good yields
are obtained in many cases and the reaction tolerates consid-
erable variation in the structure of both the methylene-
aziridine and the electrophile. Highly diastereoselective
alkylations can be achieved with a-methylbenzyl substituted
methyleneaziridines (up to 90% de). The best levels of selec-
tivity arise when the alkene substituent cis to the aziridine
nitrogen is larger than a hydrogen. This chemistry provides
a general approach to C-3 substituted methyleneaziridines
and as such will assist in the development of new applica-
tions of these N-heterocycles in synthesis.
4.2. General method A: synthesis of amines 16–18
To a stirred solution of dibromocyclopropane 14 or 15
(1.0 M equiv) in 1,2-dichlorobenzene was added the
amine (2.2–3.0 M equiv) and potassium carbonate (1.00–
1.05 M equiv). The mixture was then heated at 120 or
170 ꢁC for 65–72 h. On cooling to room temperature, sodium
hydroxide (2 M aqueous solution) was added. The mixture
was extracted with diethyl ether, the combined organic ex-
tracts washed with brine then dried over MgSO4. Diethyl
ether was removed under reduced pressure and 1,2-dichloro-
benzene by distillation (60 ꢁC/15 mmHg). Further purifica-
tion by column chromatography gave the title amines.
4. Experimental
4.1. General
4.2.1. N-(2-Bromo-3-methyl-2-butenyl)-1-benzylamine
(16). Compound 14 (5.00 g, 21.9 mmol), benzylamine
(5.17 g, 48.2 mmol) and potassium carbonate (3.18 g,
23.0 mmol) in 1,2-dichlorobenzene (40 mL) were reacted
according to general method A for 72 h at 170 ꢁC. After
Anhydrous solvents were purchased in Sure/SealÔ bottles
from Sigma–Aldrich Co., or dried prior to use by distillation.

C. Montagne et al. / Tetrahedron 62 (2006) 8447–8457
8451
work-up, column chromatography (10% EtOAc in petro-
leum ether) gave 16 (4.68 g, 84%) as a pale yellow oil. IR
crude product, which was purified by bulb-to-bulb distilla-
tion to afford 6 (1.31 g, 73%) as a pale yellow oil. IR
(film) 3448, 2978, 2932, 1735, 1644 cmꢀ1
;
1H NMR
(film) 1799, 1496, 1452 cmꢀ1 1H NMR (400 MHz,
;
(300 MHz, CDCl3) 7.40–7.26 (m, 5H), 3.74 (s, 2H), 3.59
(s, 2H), 1.96 (s, 3H), 1.78 (s, 3H); 13C NMR (75 MHz,
CDCl3) 140.4, 134.1, 128.8, 128.7, 127.4, 121.9, 53.0,
51.9, 25.9, 21.0; MS (CI) m/z 254 (MH+: 81Br), 252 (MH+:
79Br); HRMS (CI) calcd for C12H17BrN 254.0544, found
254.0537.
DMSO-d6 at 90 ꢁC) 7.36–7.25 (m, 5H), 3.62 (s, 2H), 2.06
(s, 2H), 1.72 (s, 3H), 1.66 (s, 3H); 13C NMR (75 MHz,
CDCl3) 138.9, 128.4, 128.2, 127.1, 124.2, 104.1, 62.4,
31.7, 20.4, 19.1; MS (CI) m/z 173 (M+); HRMS (CI) calcd
for C12H16N (MH+) 174.1282, found 174.1276; Anal. Calcd
for C12H16N: C, 83.40; H, 8.80; N, 8.15%. Found: C, 83.20;
H, 8.75; N, 8.10%.
4.2.2. N-(2-Bromo-3-methyl-2-butenyl)-1-cyclohexyl-
amine (17). Compound 14 (10.0 g, 43.9 mmol), cyclohexyl-
amine (9.58 g, 96.6 mmol) and potassium carbonate (6.08 g,
44.0 mmol) in 1,2-dichlorobenzene (40 mL) were reacted
according to general method A for 72 h at 120 ꢁC. After
work-up, column chromatography pretreated with triethyl-
amine (10% EtOAc and 0.5% Et3N in petroleum ether)
gave 17 (4.76 g, 44%) as a pale orange oil. IR (film) 3329,
4.2.5. N-Benzyl-2-cyclohexylideneaziridine (8). A three-
necked flask was fitted with a cold-finger condenser and
a
gas inlet. Iron(III) nitrate nonahydrate (3.4 mg,
8.42 mmol) was added and the system was flushed with
CaCl2 dried ammonia. A dry ice/acetone mixture was added
to the condenser and ammonia (40 mL) was condensed into
the flask. Sodium (0.195 g, 8.48 mmol) was added in small
portions, each time waiting for the disappearance of the
blue colouration prior to the next addition. A solution of
18 (1.00 g, 3.40 mmol) in Et2O (2 mL) was added slowly
to the grey suspension, which was subsequently stirred for
1.5 h. The mixture was diluted with diethyl ether (20 mL)
and quenched by the dropwise addition of water (10 mL)
(Caution). After the ammonia had evaporated, diethyl ether
(20 mL) was added and the mixture was stirred for 2 min.
The organic phase was separated and washed successively
with 0.1 M acetic acid (20 mL), 10% NaOH (20 mL) and
brine (20 mL), dried over MgSO4 and filtered. Removal of
the solvent under reduced pressure followed by column
chromatography (5–10% EtOAc in petroleum ether) gave
8 (0.340 g, 47%) as a pale yellow oil. IR (film) 3063,
3028, 2921, 2850, 1792, 1599, 1446, 1276 cmꢀ1; 1H NMR
(300 MHz, CDCl3) 7.42–7.30 (m, 5H), 3.89 (br s, 1H),
3.51 (br s, 1H), 2.74–1.85 (m, 6H), 1.63–1.54 (m, 6H); 13C
NMR (100 MHz, CDCl3) 138.9, 128.4, 128.3, 127.2,
121.4, 112.1, 62.8, 31.3, 30.2, 28.0, 27.8, 26.6; MS (EI)
m/z 213 (M+); HRMS (EI) calcd for C15H19N 213.1518,
found 213.1519.
1
2929, 2852, 1444, 1111, 1009 cmꢀ1; H NMR (400 MHz,
CDCl3) 3.54 (s, 2H), 2.36 (m, 1H), 1.88 (s, 3H), 1.81 (s,
3H), 1.81–1.79 (m, 2H), 1.77–1.68 (m, 2H), 1.65–1.50 (m,
2H), 1.25–1.08 (m, 5H); 13C NMR (100 MHz, CDCl3)
132.8, 122.1, 54.5, 50.5, 33.5, 26.1, 25.5, 24.9, 20.5; MS
(EI) m/z 247 (M+: 81Br), 245 (M+: 79Br); HRMS (EI) calcd
for C11H20NBr 245.0779, found 245.0770; Anal. Calcd for
C11H20NBr: C, 53.67; H, 8.19; N, 5.69%. Found: C, 53.41;
H, 8.46; N, 5.61%.
4.2.3. N-(2-Bromo-2-cyclohexylideneethyl)-1-benzyl-
amine (18). Compound 15 (5.00 g, 18.7 mmol), benzyl-
amine (5.99 g, 55.9 mmol) and potassium carbonate
(2.70 g, 19.5 mmol) in 1,2-dichlorobenzene (40 mL) were
reacted according to general method A for 65 h at 170 ꢁC.
After work-up, column chromatography pretreated with tri-
ethylamine (5–10% EtOAc in petroleum ether) gave 18
(3.73 g, 68%) as a pale yellow oil. IR (film) 3336, 3062,
1
3026, 2923, 2851, 1640, 1604, 1447, 696 cmꢀ1; H NMR
(400 MHz, CDCl3) 7.22–7.36 (m, 5H), 3.70 (s, 2H), 3.60
(s, 2H), 2.45 (br t, J¼5.8 Hz, 2H), 2.22 (br t, J¼5.9 Hz,
2H), 1.92 (s, 1H), 1.54–1.62 (m, 4H), 1.49–1.54 (m, 2H);
13C NMR (100 MHz, CDCl3) 141.2, 140.1, 128.4, 128.2,
127.0, 119.1, 52.1, 51.4, 35.8, 31.4, 28.0, 27.3, 26.4; MS
(EI) m/z 293 (M+: 81Br), 291 (M+: 79Br); HRMS (EI) calcd
for C15H20BrN 293.0779, found 293.0779.
4.2.6. 2-Isopropylidene-1-(cyclohexyl)aziridine (9). To
a three-necked flask fitted with a cold-finger condenser
and a gas inlet was added sodium amide (9.93 g,
255 mmol). The system was flushed with CaCl2 dried
ammonia then a dry ice/acetone mixture was added to the
condenser and ammonia (90 mL) was condensed into the
flask. Compound 17 (2.10 g, 8.53 mmol) was added, then
the mixture stirred for 3 h. Diethyl ether was added followed
by the dropwise addition of water (Caution). After the
ammonia had evaporated, water and diethyl ether were
added and the mixture stirred for 2 min. The organic phase
was separated and the aqueous phase extracted with diethyl
ether (2ꢃ). The combined organic extracts were washed suc-
cessively with 10% NaOH and brine, dried over MgSO4 and
filtered. The solvent was removed under reduced pressure to
give the crude product, which was purified by bulb-to-bulb
distillation (90 ꢁC/1 mmHg) to afford 9 (1.05 g, 75%) as a
colourless oil. IR (film) 3027, 2929, 2852, 1792, 1444,
4.2.4. 1-Benzyl-2-(1-methylethylidene)aziridine (6). A
three-necked flask was fitted with a cold-finger condenser
and a gas inlet. Iron(III) nitrate nonahydrate (12.0 mg,
0.03 mmol) was added and the system was flushed with
CaCl2 dried ammonia. A dry ice/acetone mixture was added
to the condenser and ammonia (50 mL) was condensed into
the flask. Sodium (0.600 g, 26.1 mmol) was added in small
portions, each time waiting for the disappearance of the
blue colouration prior to the next addition. After cooling to
ꢀ78 ꢁC, a solution of 16 (2.65 g, 10.4 mmol) in a small vol-
ume of diethyl ether was added slowly to the grey suspen-
sion. After 1 h, the mixture was diluted with diethyl ether
and quenched by the dropwise addition of water (Caution).
After the ammonia had evaporated, diethyl ether was added
and the mixture was stirred for 2 min. The organic phase was
separated and washed successively with 0.1 M acetic acid,
10% NaOH and brine, dried over MgSO4 and filtered. The
solvent was removed under reduced pressure to give the
1367, 1229, 1127, 1019 cmꢀ1
;
1H NMR (400 MHz,
CDCl3) 2.05–1.84 (m, 3H), 1.79 (s, 3H), 1.78–1.71 (m,
3H), 1.72 (s, 3H), 1.70–1.61 (m, 1H), 1.60–1.49 (m, 1H),
1.46–1.28 (m, 2H), 1.25–1.07 (m, 3H); 13C NMR
(100 MHz, CDCl3) 124.0, 103.0, 66.8, 32.9, 29.1, 25.8,

8452
C. Montagne et al. / Tetrahedron 62 (2006) 8447–8457
24.8, 20.9, 19.9; MS (EI) m/z 165 (M+); HRMS (EI) calcd for
C11H19N 165.1517, found 165.1522.
(0.127 g, 1.2 mmol) was added. After work-up, purification
by column chromatography (5% EtOAc and 0.5% Et3N in
petroleum ether) gave 21a (after washing with n-pentane)
(0.098 g, 35%) and 21b (0.109 g, 39%) as white solids.
Compound 21a: mp 101–102 ꢁC; IR (film) 3157, 2858,
4.3. General method B: lithiation/electrophile trapping
of methyleneaziridines (2, 6–10, 12 and 13)
1
1800, 1490, 1452, 1054, 698 cmꢀ1; H NMR (400 MHz,
To a stirred solution of the aziridine (1.0 M equiv) in THF at
ꢀ78 ꢁC, was added TMEDA (1.1–1.2 M equiv) and sec-
BuLi (1.1–1.5 M equiv) dropwise. The reaction was stirred
at ꢀ78 ꢁC for 3.5–7 h, then quenched with the electrophile
(0.9–1.5 equiv) and allowed to warm to room temperature
overnight. Water was added, the layers separated, and the
aqueous phase extracted with diethyl ether (2ꢃ). The com-
bined organic extracts were dried over MgSO4, filtered and
the solvent removed under reduced pressure. Purification
by column chromatography or bulb-to-bulb distillation pro-
vided the title compounds (19–40). For some reactions using
benzophenone, an additional reductive step was included in
the work-up to facilitate removal of excess electrophile
(vide infra).
CDCl3) 7.33–7.23 (m, 10H), 4.42 (dd, J¼6.0, 4.5 Hz, 1H)
4.13 (d, J¼12.9 Hz, 1H), 3.27 (d, J¼12.9 Hz, 1H), 2.41–
2.38 (m, 1H), 2.36 (d, J¼6.0 Hz, 1H), 1.74 (s, 3H), 1.59
(s, 3H); 13C NMR (100 MHz, CDCl3) 141.7, 138.5, 128.7,
128.6, 128.3, 127.59, 127.57, 126.03, 125.98, 106.0, 74.4,
61.6, 50.2, 20.5, 19.2; MS (ES) m/z 280 (MH+); HRMS
(ES) calcd for C19H22NO 280.1696, found 280.1695. Com-
pound 21b: mp 102–103 ꢁC; IR (film) 3131, 2851, 1494,
1
1447, 1252, 1036, 1024, 701 cmꢀ1; H NMR (400 MHz,
CDCl3) 7.34–7.24 (m, 10H), 4.81 (dd, J¼3.3, 1.5 Hz, 1H),
4.21 (d, J¼13.5 Hz, 1H), 3.37 (d, J¼13.5 Hz, 1H), 3.06 (d,
J¼1.5 Hz, 1H), 2.43 (d, J¼3.3 Hz, 1H), 1.73 (s, 3H), 1.50
(s, 3H); 13C NMR (100 MHz, CDCl3) 141.7, 138.3, 128.5,
128.2, 128.1, 127.6, 127.3, 126.0, 124.4, 106.5, 70.5, 60.7,
48.7, 20.7, 19.2; MS (ES) m/z 280 (MH+); HRMS (ES) calcd
for C19H22NO 280.1696, found 280.1695.
4.3.1. 1-Benzyl-2-isopropylidene-3-methylaziridine (19).
Compound 6 (0.173 g, 1 mmol) was reacted with sec-BuLi
(1.3 M in hexanes, 1.15 mL, 1.5 mmol) and TMEDA
(0.140 g, 1.2 mmol) in THF (10 mL) for 6 h in accordance
with general method B, then iodomethane (0.170 g,
1.2 mmol) was added. After work-up, purification by col-
umn chromatography (5% EtOAc and 0.5% Et3N in petro-
leum ether) gave 19 (0.148 g, 79%) as a colourless oil. IR
(film) 2965, 2923, 1806, 1495, 1452, 1147, 1021, 730,
4.3.4. (1-Benzyl-2-isopropylideneaziridin-3-yl)diphenyl-
methanol (22). Compound 6 (0.173 g, 1 mmol) was reacted
with sec-BuLi (1.3 M in hexanes, 1.15 mL, 1.5 mmol) and
TMEDA (0.140 g, 1.2 mmol) in THF (10 mL) for 6 h in
accordance with general method B, then benzophenone
(0.219 g, 1.2 mmol) in THF (1 mL) was added. After
work-up, purification by recrystallisation (EtOAc/n-pen-
tane) gave 22 (0.258 g, 73%) as a white crystalline solid.
Mp 128–129 ꢁC; IR (film) 3373, 3017, 2891, 1793, 1491,
696 cmꢀ1 1H NMR (400 MHz, CDCl3) 7.37–7.30 (m,
;
4H), 7.28–7.22 (m, 1H), 4.11 (d, J¼13.9 Hz, 1H), 3.28 (d,
J¼13.9 Hz, 1H), 2.04 (br s, 1H), 1.75 (s, 3H), 1.71 (s, 3H),
1.29 (d, J¼5.5 Hz, 3H); 13C NMR (100 MHz, CDCl3)
139.2, 130.4, 128.2, 127.9, 126.8, 103.8, 61.5, 39.4, 20.4,
18.9, 17.4; MS (ES) m/z 188 (MH+); HRMS (ES) calcd for
C13H18N 188.1434, found 188.1432.
1
1444, 1319, 1123, 1017, 742 cmꢀ1; H NMR (400 MHz,
CDCl3) 7.41 (d, J¼7.0 Hz, 2H), 7.31–7.13 (m, 13H), 4.04
(d, J¼13.0 Hz, 1H), 3.79 (s, 1H), 3.65 (d, J¼13.0 Hz, 1H),
3.08 (s, 1H), 1.64 (s, 3H), 1.30 (s, 3H); 13C NMR
(100 MHz, CDCl3) 146.6, 145.2, 137.6, 128.8, 128.3,
127.93, 127.86, 127.4, 126.9, 126.8, 126.5, 126.2, 123.9,
106.7, 74.5, 60.7, 51.0, 20.1, 19.5; MS (ES) m/z 356
(MH+); HRMS (ES) calcd for C25H26NO 356.2009, found
356.2010.
4.3.2. (E)-1-Benzyl-2-isopropylidene-3-(5-phenylpent-4-
enyl)aziridine (20). Compound 6 (0.519 g, 3 mmol) was re-
acted with sec-BuLi (1.2 M in hexanes, 3.75 mL, 4.5 mmol)
and TMEDA (0.420 g, 3.6 mmol) in THF (20 mL) for 6 h in
accordance with general method B, then [(E)-5-iodo-pent-
1-enyl]benzene (0.979 g, 3.6 mmol) in THF (7 mL) was
added. After work-up, purification by column chromato-
graphy (5% EtOAc and 0.5% Et3N in petroleum ether)
gave 20 (0.697 g, 73%) as a slightly yellow oil. IR (film)
4.3.5. 1-Benzyl-2-isopropylidene-3-trimethylsilylazir-
idine (23). Compound 6 (0.173 g, 1 mmol) was reacted
with sec-BuLi (1.3 M in hexanes, 1.15 mL, 1.5 mmol) and
TMEDA (0.140 g, 1.2 mmol) in THF (10 mL) for 6 h in ac-
cordance with general method B, then chlorotrimethylsilane
(0.130 g, 1.2 mmol) was added. After work-up, purification
by column chromatography (5% EtOAc and 0.5% Et3N in
petroleum ether) gave 23 (0.155 g, 63%) as a colourless
oil. IR (film) 2962, 2914, 1789, 1453, 1247, 836,
3027, 2947, 1792, 1486, 1449, 702 cmꢀ1
;
1H NMR
(400 MHz, CDCl3) 7.32–7.28 (m, 9H), 7.24–7.20 (m, 1H),
6.31 (d, J¼15.8 Hz, 1H), 6.14 (dt, J¼15.8, 6.8 Hz, 1H),
4.20 (d, J¼13.3 Hz, 1H), 3.28 (d, J¼13.3 Hz, 1H), 2.14 (q,
J¼6.8 Hz, 2H), 2.05 (t, J¼5.7 Hz, 1H), 1.79 (s, 3H), 1.76
(s, 3H), 1.66–1.55 (m, 2H), 1.49–1.39 (m, 2H); 13C NMR
(100 MHz, CDCl3) 139.1, 137.8, 130.6, 130.2, 129.9,
128.5, 128.4, 128.3, 127.1, 126.8, 125.9, 104.0, 62.0, 44.0,
32.6, 31.8, 27.1, 20.6, 19.0; MS (ES) m/z 318 (MH+);
HRMS (EI+) calcd for C23H27N 317.2138, found 317.2142.
697 cmꢀ1 1H NMR (400 MHz, CDCl3) 7.35–7.28 (m,
;
4H), 7.27–7.22 (m, 1H), 4.39 (d, J¼13.1 Hz, 1H), 2.90 (d,
J¼13.1 Hz, 1H), 1.78 (s, 3H), 1.73 (s, 3H), 1.24 (s, 1H),
ꢀ0.10 (s, 9H); 13C NMR (100 MHz, CDCl3) 139.3, 129.4,
128.4, 128.1, 127.0, 101.2, 64.2, 35.7, 20.3, 18.9, ꢀ2.8;
MS (ES) m/z 246 (MH+); HRMS (ES) calcd for
C15H24NSi 246.1673, found 246.1674.
4.3.3. (1-Benzyl-2-isopropylideneaziridin-3-yl)phenyl-
methanol (21). Compound 6 (0.173 g, 1 mmol) was reacted
with sec-BuLi (1.3 M in hexanes, 1.15 mL, 1.5 mmol) and
TMEDA (0.140 g, 1.2 mmol) in THF (10 mL) for 6 h in
accordance with general method B, then benzaldehyde
4.3.6. (Z)-(1-Benzyl-2-ethylideneaziridin-3-yl)diphenyl-
methanol (24). Compound (Z)-7 (0.200 g, 1.26 mmol) was
reacted with sec-BuLi (1.3 M in hexanes, 1.25 mL,
1.63 mmol) and TMEDA (0.174 g, 1.50 mmol) for 5 h in

C. Montagne et al. / Tetrahedron 62 (2006) 8447–8457
8453
THF (10 mL) according to general method B, then benzo-
phenone (0.297 g, 1.63 mmol) in THF (1 mL) was added.
To remove unreacted benzophenone, the crude material
was dissolved in EtOH (20 mL) and cooled to 0 ꢁC. Sodium
borohydride (0.108 g, 2.85 mmol) was added and the mix-
ture allowed to warm to room temperature. After stirring
for 4 h, the reaction was quenched by the dropwise addition
of NH4Cl solution, then basified using NaHCO3 solution.
The resulting mixture was extracted with Et2O (3ꢃ25 mL)
and the combined organic phases washed with brine
(75 mL), dried (MgSO4) and evaporated. Column chromato-
graphy (2% EtOAc in petroleum ether) gave (Z)-24 (0.267 g,
62%) as a colourless oil, which crystallised on standing. Mp
87–89 ꢁC; IR (film) 3444, 3058, 3028, 1785, 1600, 1493,
1H NMR (400 MHz, CDCl3) 7.40–7.29 (m, 6H), 6.28 (dd,
J¼3.1, 1.9 Hz, 1H), 5.92 (dd, J¼3.1, 0.7 Hz, 1H), 4.16 (d,
J¼13.3 Hz, 1H), 3.22 (d, J¼13.3 Hz, 1H), 2.57 (m, 2H),
2.21 (m, 4H), 2.05 (br s, 1H), 1.66–1.54 (m, 10H); 13C
NMR (100 MHz, CDCl3) 156.1, 140.7, 139.1, 128.5,
128.3, 127.1, 127.0, 112.3, 110.0, 104.7, 62.5, 43.4, 31.8,
31.6, 30.1, 28.2, 27.9, 27.6, 26.6, 25.8; MS (EI) m/z 322
(MH+); HRMS (EI) calcd for C22H26NO 320.2014, found
320.2014.
4.3.9. 1-Cyclohexyl-2-isopropylidene-3-methylaziridine
(26). Compound 9 (0.200 g, 1.21 mmol) was reacted with
sec-BuLi (1.0 M in cyclohexane/hexane (98/2), 1.58 mL,
1.58 mmol) and TMEDA (0.169 g, 1.45 mmol) in THF
(10 mL) for 5 h in accordance with general method B, then
iodomethane (0.258 g, 1.82 mmol) was added. After work-
up, purification by column chromatography (0.5% Et3N in
petroleum ether) gave 26 (0.138 g, 64%) as a yellow oil.
1447 cmꢀ1 1H NMR (400 MHz, CDCl3) 7.36–7.08 (m,
;
15H), 5.13 (q, J¼6.8 Hz, 1H), 4.03 (d, J¼13.1 Hz, 1H),
3.66 (s, 1H), 3.63 (d, J¼13.1 Hz, 1H), 2.93 (s, 1H), 1.69
(d, J¼6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) 146.4,
144.7, 137.0, 129.8, 128.9, 128.3, 128.1, 128.0, 127.5,
127.3, 126.8, 126.3, 97.0, 74.8, 60.3, 50.2, 13.4; MS (ES)
m/z 342 (MH+); HRMS (ES) calcd for C24H24NO
342.1852, found 342.1855; Anal. Calcd for C24H23NO: C,
84.42; H, 6.79; N, 4.10%. Found: C, 84.34; H, 6.80;
N, 4.00%.
IR (film) 2924, 2852, 1798, 1444, 1173, 1147, 891 cmꢀ1
;
1H NMR (400 MHz, C6D6) 2.30–2.14 (m, 1H), 1.91 (s,
3H), 1.87 (s, 3H), 1.88–1.72 (m, 5H), 1.68–1.46 (m, 3H),
1.36 (d, J¼5.6 Hz, 3H), 1.30–1.13 (m, 3H); 13C NMR
(100 MHz, C6D6) 131.6, 100.9, 66.1, 36.3, 33.6, 32.8,
26.1, 24.7 (2C), 21.0, 19.7, 18.3; MS (CI) m/z 180 (MH+);
HRMS (CI) calcd for C12H22N 180.1752, found 180.1749.
4.3.7. (E)-(1-Benzyl-2-ethylideneaziridin-3-yl)diphenyl-
methanol (24). Compound (E)-7 (0.200 g, 1.26 mmol)
was reacted with sec-BuLi (1.3 M in hexanes, 1.25 mL,
1.63 mmol) and TMEDA (0.174 g, 1.50 mmol) in THF
(10 mL) for 5 h according to general method B, then benzo-
phenone (0.297 g, 1.63 mmol) in THF (1 mL) was added. To
remove unreacted benzophenone, the crude material was
dissolved in EtOH (20 mL) and cooled to 0 ꢁC. Sodium bo-
rohydride (0.108 g, 2.85 mmol) was added and the mixture
allowed to warm to room temperature. After stirring for
4 h, the reaction was quenched by the dropwise addition of
NH4Cl solution, then basified using NaHCO3 solution. The
resulting mixture was extracted with Et2O (3ꢃ25 mL) and
the combined organic phases washed with brine (75 mL),
dried (MgSO4) and evaporated. The product was purified
(2% EtOAc in petroleum ether) to give a colourless oil,
which crystallised on standing. Recrystallisation from ace-
tone/water gave (E)-24 (0.316 g, 73%) as clear colourless
crystals. Mp 83–86 ꢁC; IR (film) 3446 (br), 3060, 3028,
4.3.10. 1-Cyclohexyl-2-isopropylidene-3-trimethylsilyl-
aziridine (27). Compound 9 (0.200 g, 1.21 mmol) was re-
acted with sec-BuLi (1.0 M in cyclohexane/hexane (98/2),
1.58 mL, 1.58 mmol) and TMEDA (0.169 g, 1.45 mmol)
in THF (10 mL) for 5 h in accordance with general method
B, then chlorotrimethylsilane (0.199 g, 1.83 mmol) was
added. After work-up, purification by column chromato-
graphy (0.5% Et3N in petroleum ether) gave 27 (0.183 g,
64%) as a colourless oil. IR (film) 2929, 2847, 1777, 1444,
1
1239, 1106, 866, 840 cmꢀ1; H NMR (400 MHz, C6D6)
2.23–2.12 (m, 1H), 1.94 (s, 3H), 1.87 (s, 3H), 1.86–1.75
(m, 3H), 1.74–1.66 (m, 2H), 1.61–1.53 (m, 1H), 1.51–1.42
(m, 1H), 1.31–1.15 (m, 3H), 1.14–1.07 (m, 1H), 0.21 (s,
9H); 13C NMR (100 MHz, C6D6) 130.0, 99.3, 68.5, 33.9,
33.2, 32.5, 26.1, 24.82, 24.81, 21.1, 19.6, ꢀ2.7; MS (EI)
m/z 237 (M+); HRMS (EI) calcd for C14H27NSi 237.1913,
found 237.1922.
1782, 1600, 1494, 1449 cmꢀ1
;
1H NMR (300 MHz,
4.3.11. 3-Benzyl-1-cyclohexyl-2-methyleneaziridine (28).
Compound 10 (0.535 g, 3.90 mmol) was reacted with sec-
BuLi (1.4 M in hexanes, 3.06 mL, 4.28 mmol) and TMEDA
(0.498 g, 4.29 mmol) in THF (5 mL) for 3.5 h in accordance
with general method B, then benzyl bromide (0.733 g,
4.29 mmol) was added. After work-up, purification by filtra-
tion through a short plug of basic alumina (petroleum ether)
followed by bulb-to-bulb distillation of the unreacted start-
ing materials gave 28 (0.764 g, 86%) as a clear, yellow oil.
CDCl3) 7.37–7.14 (m, 15H), 5.09 (q, J¼6.8 Hz, 1H), 3.82
(d, J¼12.9 Hz, 1H), 3.68 (d, J¼12.9 Hz, 1H), 3.64 (s, 1H),
3.03 (s, 1H), 1.26, (d, J¼6.8 Hz, 3H); 13C NMR (75 MHz,
CDCl3) 146.9, 145.4, 138.1, 130.3, 129.0, 128.8, 128.5,
128.4, 127.9, 127.5, 127.1, 126.7, 97.7, 75.0, 62.0, 50.9,
14.4; MS (CI) m/z 342 (MH+); HRMS (CI) calcd for
C24H24NO 342.1852, found 342.1861.
4.3.8. 1-Benzyl-2-cyclohexylidene-3-[3-(furan-2-yl)pro-
pyl]aziridine (25). Compound 8 (0.460 g, 2.16 mmol)
was reacted with sec-BuLi (1.3 M in hexanes, 2.5 mL,
3.24 mmol) and TMEDA (0.300 g, 2.58 mmol) in THF
(20 mL) for 5 h in accordance with general method B, then
1-iodo-3-(furan-2-yl)propane (560 mg, 2.37 mmol) was
added. After work-up, purification by column chromato-
graphy (1.5% EtOAc and 0.5% Et3N in petroleum ether)
gave 25 (0.423 g, 61%) as a pale yellow oil. IR (film)
IR (film) 3028, 2828, 1770, 1496, 1451, 1165, 698 cmꢀ1
;
1H NMR (300 MHz, CDCl3) 7.34–7.27 (m, 5H), 4.74 (s,
1H), 4.68 (s, 1H), 2.93–2.80 (m, 2H), 2.12 (t, J¼6.3 Hz,
1H), 1.98–1.88 (m, 1H), 1.85–1.62 (m, 3H), 1.60–1.38 (m,
3H), 1.32–1.07 (m, 4H); 13C NMR (75 MHz, CDCl3)
141.9, 139.3, 128.9, 128.4, 126.4, 82.7, 66.9, 42.6, 39.4,
32.9, 32.4, 25.7, 24.57, 24.51; MS (EI) m/z 227 (M+);
HRMS (ES) calcd for C16H22N (MH+) 228.1752, found
228.1756; Anal. Calcd for C16H21N: C, 84.52; H, 9.32; N,
6.16%. Found: C, 84.51; H, 9.64; N, 5.93%.
3086, 3062, 3028, 2923, 2850, 1794, 1592, 1446 cmꢀ1
;

8454
C. Montagne et al. / Tetrahedron 62 (2006) 8447–8457
4.3.12. 3-(4-Chlorobutyl)-1-cyclohexyl-2-methyleneazir-
idine (29). Compound 10 (0.190 g, 1.39 mmol) was reacted
with sec-BuLi (1.3 M in hexanes, 1.16 mL, 1.51 mmol) and
TMEDA (0.175 g, 1.51 mmol) in THF (5 mL) for 3.5 h in
accordance with general method B, then 1-chloro-4-iodo-
butane (0.275 g, 1.26 mmol) was added. After work-up, pu-
rification by filtration through a short plug of basic alumina
(petroleum ether) followed by bulb-to-bulb distillation of
the unreacted starting materials gave 29 (0.200 g, 70% based
on electrophile) as a clear, light yellow oil. IR (film) 2931,
(1.4 M in cyclohexane, 1.08 mL, 1.51 mmol) and TMEDA
(0.174 g, 1.50 mmol) in THF (10 mL) for 5 h in accordance
with general method B, then benzophenone (0.297 g,
1.63 mmol) in THF (1 mL) was added. After work-up, the
residue was redissolved in ethanol (20 mL) and cooled to
0 ꢁC. Sodium borohydride (0.108 g, 2.85 mmol) was added
and the solution allowed to warm to room temperature and
stirred for 4 h. The reaction was quenched with saturated
NH4Cl solution, then basified using saturated NaHCO3 solu-
tion. The resulting mixture was extracted with diethyl ether
(3ꢃ25 mL) and the combined organic extracts dried
(MgSO4), filtered and the solvent removed in vacuo. Impu-
rities were removed by distillation (140 ꢁC/0.2 mmHg) to
give 32 (0.301 g, 70%) as a pale yellow oil. IR (film)
3451, 3087, 3060, 3028, 1771, 1658, 1599, 1493,
2855, 1771, 1449, 1265, 1173, 739 cmꢀ1
;
1H NMR
(300 MHz, CDCl3) 4.67 (s, 1H), (s, 1H), 3.55 (t,
J¼6.6 Hz, 2H), 1.87–1.17 (m, 18H); 13C NMR (75 MHz,
CDCl3) 142.1, 82.3, 66.8, 44.9, 41.2, 32.9, 32.5, 32.3,
31.6, 25.7, 24.8, 24.59, 24.57; MS (CI) m/z 230 (MH+:
37Cl), 228 (MH+: 35Cl); HRMS (ES) calcd for C13H23NCl
228.1519, found 228.1518.
1448 cmꢀ1
;
1H NMR (400 MHz, CDCl3) 7.80 (d, J¼
8.3 Hz, 0.4H), 7.62–6.86 (m, 14.6H), 4.93 (s, 0.2H), 4.73
(s, 0.2H), 4.67 (s, 0.8H), 4.41 (d, J¼1.4 Hz, 0.8H), 3.74 (d,
J¼1.4 Hz, 0.8H), 3.49 (d, J¼1.4 Hz, 0.2H), 3.31 (q,
J¼6.6 Hz, 0.2H), 3.22 (q, J¼6.6 Hz, 0.8H), 2.94 (s, 0.8H),
2.90 (s, 0.2H), 1.48 (d, J¼6.6 Hz, 0.6H), 0.94 (d,
J¼6.6 Hz, 2.4H); 13C NMR (100 MHz, CDCl3) 146.4,
145.6, 144.7, 144.4, 143.0, 142.3, 137.3, 136.5, 132.5,
130.1, 128.38, 128.36, 128.2, 128.1, 128.0, 127.7, 127.57,
127.54, 127.48, 127.24, 127.17, 127.1, 127.04, 126.99,
126.7, 126.6, 126.4, 126.2, 84.8, 74.9, 50.4, 49.1, 23.1,
22.7; MS (ES) m/z 342 (MH+); HRMS (ES) calcd for
C24H24NO 342.1852, found 342.1849.
4.3.13. 1-Cyclohexyl-2-methylene-3-(tri-n-butylstannyl)-
aziridine (30). Compound 10 (0.311 g, 2.27 mmol) was
reacted with sec-BuLi (1.3 M in hexanes, 1.92 mL,
2.50 mmol) and TMEDA (0.290 g, 2.49 mmol) in THF
(5 mL) for 3.5 h in accordance with general method B,
then tri-n-butyltin chloride (0.701 g, 2.16 mmol) was added.
After work-up, purification by bulb-to-bulb distillation of
the unreacted starting materials followed by filtration
through a short plug of basic alumina (petroleum ether)
gave 30 (0.833 g, 91% based on electrophile) as a clear light
yellow oil. IR (film) 2928, 2854, 1761, 1456, 1362, 1210,
1128, 806 cmꢀ1
;
1H NMR (300 MHz, CDCl3) 4.66 (s,
4.3.16. (10S,3R)- and (10S,3S)-(E)-3-Benzyl-2-ethylidene-
1-(1-phenylethyl)aziridine (33). Compound (E)-2 (0.218 g,
1.26 mmol) was reacted with sec-BuLi (1.3 M in hexanes,
1.25 mL, 1.63 mmol) and TMEDA (0.174 g, 1.50 mmol) in
THF (10 mL) for 5 h in accordance with general method B,
then benzyl bromide (0.279 g, 1.63 mmol) was added. After
work-up, purification by column chromatography (10%
Et2O in petroleum ether) gave successively (E)-33a (0.059 g,
18%) and (E)-33b (0.108 g, 33%) as colourless oils. Com-
pound (E)-33a: IR (film) 3062, 3028, 2954, 2921, 2858,
1780, 1686, 1493, 1453 cmꢀ1; 1H NMR (300 MHz, CDCl3)
7.40–7.20 (m, 10H), 4.71 (q, J¼6.6 Hz, 1H), 2.93–2.85 (m,
3H), 2.20 (t, J¼6.3 Hz, 1H), 1.57 (d, J¼6.6 Hz, 3H), 1.47
(d, J¼6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) 144.7,
140.0, 135.1, 129.5, 128.8, 128.6, 127.8, 127.4, 126.8, 95.1,
68.4, 44.4, 39.9, 23.6, 14.9; MS (ES) 264 (MH+); HRMS
(EI) calcd for C19H20N 262.1596, found 262.1583. Com-
pound (E)-33b: IR (film) 3060, 3027, 2968, 2923, 2854,
1776, 1602, 1493 cmꢀ1; 1H NMR (300 MHz, CDCl3) 7.40–
7.01 (m, 10H), 5.33 (q, J¼6.6 Hz, 1H), 2.93 (q, J¼6.8 Hz,
1H), 2.93 (dd, J¼14.0, 5.9 Hz, 1H), 2.69 (dd, J¼14.0,
6.7 Hz, 1H), 2.16 (dd, J¼6.7, 5.9 Hz, 1H), 1.65 (d, J¼
6.7 Hz, 3H), 1.47 (d, J¼6.8 Hz, 3H); 13C NMR (75 MHz,
CDCl3) 144.7, 139.4, 135.8, 129.5, 128.7, 128.6, 127.4,
127.1, 126.5, 95.5, 68.9, 43.7, 39.6, 24.4, 15.1; MS (EI) m/z
263 (M+); HRMS (EI) calcd for C19H21N 262.1596, found
262.1612.
1H), 4.41 (s, 1H), 1.89–1.19 (m, 24H), 0.95–0.86 (m,
15H); 13C NMR (75 MHz, CDCl3) 143.5, 80.1, 69.8, 33.3,
32.7, 31.7, 29.1, 29.0, 27.3, 25.8, 24.66, 24.62, 13.7, 9.5;
MS (CI) m/z 428 (MH+); HRMS (ES) calcd for
C21H42NSn 428.2339, found 428.2342.
4.3.14. (10S,3R)- and (10S,3S)-3-Benzyl-2-methylene-1-
(1-phenylethyl)aziridine (31). Compound (S)-12 (0.200 g,
1.26 mmol) was reacted with sec-BuLi (1.0 M in cyclo-
hexane/hexane (98/2), 1.51 mL, 1.51 mmol) and TMEDA
(0.175 g, 1.51 mmol) in THF (10 mL) for 7 h in accordance
with general method B, then benzyl bromide (0.320 g,
1.87 mmol) was added. After work-up, purification by distil-
lation (170 ꢁC/1 mmHg) gave 31 (0.220 g, 70%) as a 47:53
mixture of diastereomers and as a colourless oil. IR (film)
3062, 3032, 2965, 2919, 2832, 1767, 1495, 1449, 1152,
1
830, 748, 702 cmꢀ1; H NMR (400 MHz, CDCl3) 7.37–
7.20 (m, 7H), 7.19–7.11 (m, 2H), 7.06–7.01 (m, 1H), 4.87
(s, 0.47H), 4.75 (s, 0.47H), 4.56 (s, 0.53H), 4.26 (s,
0.53H), 3.03 (q, J¼6.7 Hz, 0.47H), 2.99 (q, J¼6.7 Hz,
0.53H), 2.94–2.86 (m, 1.53H), 2.71 (dd, J¼14.3, 6.4 Hz,
0.47H), 2.18 (t, J¼6.4 Hz, 0.53H), 2.12 (t, J¼6.4 Hz,
0.47H), 1.51 (d, J¼6.7 Hz, 1.41H), 1.26 (d, J¼6.7 Hz,
1.59H); 13C NMR (100 MHz, CDCl3) 143.94, 143.90,
142.3, 141.6, 139.2, 138.7, 129.0, 128.6, 128.49, 128.47,
128.4, 128.3, 127.2, 127.1, 126.8, 126.4, 126.2, 125.9,
83.5, 83.4, 68.2, 67.6, 43.3, 42.6, 39.1, 38.9, 23.9, 23.1;
MS (EI) m/z 249 (M+); HRMS (CI) calcd for C18H20N
250.1595, found 250.1593.
4.3.17. [(10S,3S)-(E)-2-Ethylidene-1-(1-phenylethyl)azi-
ridin-3-yl]diphenylmethanol (34). Compound (E)-2
(0.218 g, 1.26 mmol) was reacted with sec-BuLi (1.3 M in
hexanes, 1.25 mL, 1.63 mmol) and TMEDA (0.174 g,
1.50 mmol) in THF (10 mL) for 5 h in accordance with gen-
eral method B, then benzophenone (0.297 g, 1.63 mmol) in
4.3.15. [(10S,3R)- and (10S,3S)-2-Methylene-1-(1-phenyl-
ethyl)aziridin-3-yl]diphenylmethanol (32). Compound
(S)-12 (0.200 g, 1.26 mmol) was reacted with sec-BuLi

C. Montagne et al. / Tetrahedron 62 (2006) 8447–8457
8455
THF (1 mL) was added. After work-up, the residue was re-
dissolved in ethanol (20 mL) and cooled to 0 ꢁC. Sodium
borohydride (0.108 g, 2.85 mmol) was added and the solu-
tion allowed to warm to room temperature and stirred for
4 h. The reaction was quenched with saturated NH4Cl solu-
tion, then basified using saturated NaHCO3 solution. The
resulting mixture was extracted with diethyl ether (3ꢃ
25 mL) and the combined organic extracts dried (MgSO4),
filtered and the solvent removed in vacuo. Purification by
column chromatography (10% Et2O in petroleum ether)
gave (E)-34 (0.302 g, 68%) as a colourless oil. IR (film)
and the combined organic extracts dried (MgSO4), filtered
and the solvent removed in vacuo. Column chromatography
(10% Et2O in petroleum ether) gave (Z)-34 (0.371 g, 83%)
as a colourless oil, which crystallised on standing. [a]D21
ꢀ11.4 (c 2.2, CHCl3); mp 102–105 ꢁC; IR (film) 3422,
3053, 3028, 1782, 1595, 1490, 1445 cmꢀ1 1H NMR
;
(300 MHz, CDCl3) 7.55–7.20 (m, 15H), 5.09 (q, J¼
6.6 Hz, 1H), 3.88 (s, 1H), 3.16 (q, J¼6.8 Hz, 1H), 2.93 (s,
1H), 1.08 (d, J¼6.8 Hz, 3H), 0.85 (d, J¼6.6 Hz, 3H); 13C
NMR (75 MHz, CDCl3) 146.7, 144.5, 143.8, 129.4, 128.2,
128.0, 127.8 (2C), 127.23, 127.18, 127.0, 126.9, 126.7,
126.0, 97.2, 74.6, 66.3, 50.0, 22.9, 12.9; MS (EI) m/z 355
(M+); HRMS (EI) calcd for C25H25NO 355.1936, found
355.1918; Anal. Calcd for C25H25NO: C, 84.45; H, 7.09;
N, 3.94%. Found: C, 84.40; H, 7.07; N, 3.92%.
1
3441 (br), 3057, 2966, 1778, 1598, 1491, 1447 cmꢀ1; H
NMR (300 MHz, CDCl3) 7.39–6.92 (m, 15H), 4.78 (q,
J¼6.8 Hz, 1H), 3.97 (s, 1H), 3.16 (q, J¼6.6 Hz, 1H), 3.09
(s, 1H), 1.37, (d, J¼6.8 Hz, 3H), 0.98 (d, J¼6.6 Hz, 3H);
13C NMR (75 MHz, CDCl3) 147.0, 145.4, 144.0, 129.9,
128.7, 128.5, 128.4, 127.64, 127.57, 127.4, 126.9, 126.7,
97.4, 74.7, 67.1, 51.2, 23.5, 14.3; MS (EI) m/z 355
(M+); HRMS (EI) calcd for C25H25NO 355.1936, found
355.1952.
4.3.20. (10S,3R)-2-Isopropylidene-3-methyl-1-(1-phenyl-
ethyl)aziridine (35). Compound 13 (0.200 g, 1.07 mmol)
was reacted with sec-BuLi (1.0 M in cyclohexane/hexane
(98/2), 1.39 mL, 1.39 mmol) and TMEDA (0.149 g, 1.28
mmol) in THF (8 mL) for 5 h in accordance with general
method B, then iodomethane (0.227 g, 1.60 mmol) was
added. After work-up, purification by column chromato-
graphy (0.5% Et3N in petroleum ether) gave 35 as a single
diastereomer (0.100 g, 47%) and as a yellow oil. [a]D21
ꢀ235 (c 1.01, CHCl3); IR (film) 3032, 2970, 2919, 2847,
4.3.18. (10S,3R)- and (10S,3S)-(Z)-3-Benzyl-2-ethylidene-
1-(1-phenylethyl)aziridine (33). Compound (Z)-2 (0.218 g,
1.26 mmol) was reacted with sec-BuLi (1.3 M in hexanes,
1.25 mL, 1.63 mmol) and TMEDA (0.174 g, 1.50 mmol) in
THF (10 mL) for 5 h in accordance with general method B,
then benzyl bromide (0.280 g, 1.64 mmol) was added. After
work-up, purification by column chromatography (10% Et2O
in petroleum ether) gave successively (Z)-33a (0.138 g, 42%)
and (Z)-33b (0.057 g, 17%) as colourless oils. Compound
(Z)-33a: IR (film) 3060, 3027, 2968, 2920, 1779, 1601,
1
1798, 1449, 1147, 702 cmꢀ1; H NMR (400 MHz, C6D6)
7.57–7.53 (m, 2H), 7.31–7.24 (m, 2H), 7.21–7.15 (m, 1H),
2.93 (q, J¼6.5 Hz, 1H), 1.90 (q, J¼5.6 Hz, 1H), 1.77 (s,
3H), 1.46 (d, J¼6.5 Hz, 3H), 1.42 (d, J¼5.6 Hz, 3H), 1.31
(s, 3H); 13C NMR (100 MHz, C6D6) 146.0, 131.2, 128.3,
127.5, 127.1, 102.3, 68.2, 37.6, 24.0, 20.8, 19.0, 18.1; MS
(CI) m/z 202 (MH+); HRMS (CI) calcd for C14H20N
202.1595, found 202.1605.
1
1493, 1448, 1306, 1132, 1028, 745, 695 cmꢀ1; H NMR
(300 MHz, CDCl3) 7.40–7.18 (m, 10H), 5.02 (q, J¼6.8 Hz,
1H), 2.95 (q, J¼6.6 Hz, 1H), 2.86 (d, J¼6.4 Hz, 2H), 2.17
(t, J¼6.4 Hz, 1H), 1.26 (d, J¼6.6 Hz, 3H), 1.06 (d,
J¼6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) 145.1, 139.4,
135.1, 129.3, 128.78, 128.76, 127.8, 127.6, 126.7, 95.6,
68.4, 44.0, 39.9, 23.7, 13.6; MS (EI) m/z 263 (M+); HRMS
(EI) calcd for C19H20N 262.1596, found 262.1590. Com-
pound (Z)-33b: IR (film) 3063, 3028, 2973, 2928, 1779,
4.3.21. (10S,3R)- and (10S,3S)-3-Butyl-2-isopropylidene-
1-(1-phenylethyl)aziridine (36). Compound 13 (0.200 g,
1.07 mmol) was reacted with sec-BuLi (1.0 M in cyclo-
hexane/hexane (98/2), 1.39 mL, 1.39 mmol) and TMEDA
(0.149 g, 1.28 mmol) in THF (8 mL) for 5 h in accordance
with general method B, then 1-iodobutane (0.294 g,
1.60 mmol) was added. After work-up, purification by col-
umn chromatography (0.5% Et3N in petroleum ether) gave
36 as a 93:7 mixture of diastereomers (0.137 g, 53%) and
as a yellow oil. IR (film) 3027, 2965, 2929, 2852, 1792,
1604, 1494, 1453 cmꢀ1 1H NMR (300 MHz, CDCl3)
;
7.40–7.00 (m, 10H), 5.18 (q, J¼6.8 Hz, 1H), 3.18 (q,
J¼6.6 Hz, 1H), 2.84 (dd, J¼14.0, 5.3 Hz, 1H), 2.62 (dd,
J¼14.0, 7.3 Hz, 1H), 2.17 (dd, J¼7.3, 5.3 Hz, 1H), 1.90 (d,
J¼6.6 Hz, 3H), 1.57 (d, J¼6.8 Hz, 3H); 13C NMR
(75 MHz, CDCl3) 144.4, 139.5, 135.8, 129.0, 128.7, 128.6,
127.5, 127.3, 126.5, 95.6, 67.7, 42.4, 39.6, 24.4, 14.4; MS
(EI) m/z 263 (M+); HRMS (EI) calcd for C19H20N
262.1596, found 262.1603.
1
1449, 1229, 758, 691 cmꢀ1; H NMR (400 MHz, C6D6)
Major diastereomer: 7.59–7.55 (m, 2H), 7.31–7.24 (m, 2H),
7.20–7.13 (m, 1H), 2.93 (q, J¼6.6 Hz, 1H), 1.94–1.90 (m,
1H), 1.81 (s, 3H), 1.79–1.50 (m, 4H), 1.49 (d, J¼6.6 Hz,
3H), 1.45–1.36 (m, 2H), 1.32 (s, 3H), 0.99 (t, J¼7.3 Hz,
3H); 13C NMR (100 MHz, C6D6) Major diastereomer:
146.1, 130.7, 128.3, 127.1 (2C), 102.3, 68.2, 42.6, 32.6,
30.0, 24.2, 22.9, 21.1, 19.1, 14.0; MS (CI) m/z 244 (MH+);
HRMS (CI) calcd for C17H26N 244.2065, found 244.2074.
4.3.19. (10S,3S)-(Z)-2-Ethylidene-1-(1-phenylethyl)azir-
idin-3-yl)diphenylmethanol (34). Compound (Z)-2
(0.218 g, 1.26 mmol) was reacted with sec-BuLi (1.3 M in
hexanes, 1.25 mL, 1.63 mmol) and TMEDA (0.174 g,
1.50 mmol) in THF (10 mL) for 5 h in accordance with gen-
eral method B, then benzophenone (0.297 g, 1.63 mmol) in
THF (1 mL) was added. After work-up, the residue was
redissolved in ethanol (20 mL) and cooled to 0 ꢁC. Sodium
borohydride (0.108 g, 2.85 mmol) was added and the solu-
tion allowed to warm to room temperature and stirred for
4 h. The reaction was quenched with saturated NH4Cl solu-
tion, then basified using saturated NaHCO3 solution. The re-
sulting mixture was extracted with diethyl ether (3ꢃ25 mL)
4.3.22. (10S,3R)-3-Benzyl-2-isopropylidene-1-(1-phenyl-
ethyl)aziridine (37). Compound 13 (0.200 g, 1.07 mmol)
was reacted with sec-BuLi (1.0 M in cyclohexane/hexane
(98/2), 1.39 mL, 1.39 mmol) and TMEDA (0.149 g,
1.28 mmol) in THF (8 mL) for 5 h in accordance with gen-
eral method B, then benzyl bromide (0.274 g, 1.60 mmol)
was added. After work-up, purification by column chroma-
tography (0.5% Et3N in petroleum ether) gave 37 (0.201 g,

8456
C. Montagne et al. / Tetrahedron 62 (2006) 8447–8457
68%) as a single diastereomer and as a colourless oil. [a]D22
ꢀ152 (c 1.0, CHCl3); IR (film) 3062, 3027, 2960, 2919,
4.3.25. (10S,3R)-2-Isopropylidene-1-(1-phenylethyl)-
3-trimethylsilylaziridine (40). Compound 13 (0.200 g,
1.07 mmol) was reacted with sec-BuLi (1.0 M in cyclo-
hexane/hexane (98/2), 1.39 mL, 1.39 mmol) and TMEDA
(0.149 g, 1.28 mmol) in THF (8 mL) for 5 h in accordance
with general method B, then chlorotrimethylsilane
(0.175 g, 1.61 mmol) was added. After work-up, purification
by column chromatography (0.5% Et3N in petroleum ether)
gave 40 as a single diastereomer (0.222 g, 80%) and as a col-
ourless oil. [a]2D1ꢀ133 (c 1.07, CHCl3); IR (film) 3062, 3021,
2960, 2919, 2847, 1782, 1490, 1444, 1265, 1091, 1004, 866,
830, 753, 691 cmꢀ1; 1H NMR (400 MHz, C6D6) 7.55–7.52
(m, 2H), 7.30–7.23 (m, 2H), 7.21–7.18 (m, 1H), 2.82 (q,
J¼6.5 Hz, 1H), 1.77 (s, 3H), 1.43 (d, J¼6.5 Hz, 3H), 1.32
(s, 3H), 1.20 (s, 1H), 0.24 (s, 9H); 13C NMR (100 MHz,
C6D6) 146.0, 129.5, 128.3, 127.5, 127.1, 100.4, 70.3, 33.8,
24.4, 20.8, 18.9, ꢀ2.7; MS (CI) m/z 260 (MH+); HRMS
(CI) calcd for C16H26NSi 260.1835, found 260.1824.
1
2847, 1787, 1598, 1495, 1444, 1127, 758, 697 cmꢀ1; H
NMR (400 MHz, C6D6) 7.53–7.51 (m, 2H), 7.39–7.33 (m,
2H), 7.30–7.22 (m, 4H), 7.21–7.15 (m, 2H), 2.97 (dd,
J¼13.8, 5.6 Hz, 1H), 2.92 (dd, J¼13.8, 6.9 Hz, 1H), 2.86
(q, J¼6.6 Hz, 1H), 2.15 (dd, J¼6.9, 5.6 Hz, 1H), 1.72 (s,
3H), 1.30 (s, 3H), 1.25 (d, J¼6.6 Hz, 3H); 13C NMR
(100 MHz, C6D6) 145.9, 140.0, 130.2, 129.3, 128.36,
128.32, 127.5, 127.1, 126.3, 103.0, 68.2, 44.1, 39.8, 24.1,
21.1, 19.1; MS (EI) m/z 277 (M+); HRMS (EI) calcd for
C20H23N 277.1830, found 277.1843.
4.3.23. (10S,3R)-3-Allyl-2-isopropylidene-1-(1-phenyl-
ethyl)aziridine (38). Compound 13 (0.200 g, 1.07 mmol)
was reacted with sec-BuLi (1.0 M in cyclohexane/hexane
(98/2), 1.39 mL, 1.39 mmol) and TMEDA (0.149 g,
1.28 mmol) in THF (8 mL) for 5 h in accordance with gen-
eral method B, then allyl bromide (0.189 g, 1.56 mmol)
was added. After work-up, purification by column chroma-
tography (0.5% Et3N in petroleum ether) gave 38 (0.153 g,
63%) as a single diastereomer and as a colourless oil. [a]D22
ꢀ210 (c 1.03, CHCl3); IR (film) 3073, 3027, 2970, 2919,
2852, 1798, 1644, 1490, 1454, 1372, 1219, 1137, 988,
912, 758, 702 cmꢀ1; 1H NMR (400 MHz, C6D6) 7.55–7.52
(m, 2H), 7.30–7.25 (m, 2H), 7.21–7.16 (m, 1H), 6.10–6.00
(m, 1H), 5.24–5.12 (m, 2H), 2.90 (q, J¼6.6 Hz, 1H), 2.46
(dd, J¼6.8, 5.9 Hz, 2H), 1.94 (br t, J¼5.9 Hz, 1H), 1.78 (s,
3H), 1.46 (d, J¼6.6 Hz, 3H), 1.29 (s, 3H); 13C NMR
(100 MHz, C6D6) 145.9, 136.0, 129.9, 128.3, 127.5, 127.1,
116.1, 102.9, 68.0, 42.0, 37.6, 24.2, 21.1, 19.1; MS (CI)
m/z 228 (MH+); HRMS (CI) calcd for C16H22N 228.1752,
found 228.1756.
Acknowledgements
The Engineering and Physical Sciences Research Council
(GR/R82586/02 & GR/M71923/01) and GlaxoSmithKline
are gratefully acknowledged for financial support of this
work. We are indebted to the EPSRC National Mass Spec-
trometry Service Centre for performing some of the mass
measurements.
References and notes
ꢀ
ꢀ
1. Prie, G.; Prevost, N.; Twin, H.; Fernandes, S. A.; Hayes, J. F.;
Shipman, M. Angew. Chem., Int. Ed. 2004, 43, 6517–6519.
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G. J.; Shipman, M.; Hayes, J. F. Chem. Commun. 2006,
649–651.
4.3.24. [(10S,3S)-2-Isopropylidene-1-(1-phenylethyl)azir-
idin-3-yl]diphenylmethanol (39). Compound 13 (0.200 g,
1.07 mmol) was reacted with sec-BuLi (1.0 M in cyclohex-
ane/hexane (98/2), 1.39 mL, 1.39 mmol) and TMEDA
(0.149 g, 1.28 mmol) in THF (8 mL) for 5 h in accordance
with general method B, then benzophenone (0.292 g,
1.60 mmol) in THF (1 mL) was added. After work-up, the
residue was redissolved in ethanol (15 mL) and cooled to
0 ꢁC. Sodium borohydride (0.090 g, 2.38 mmol) in ethanol
(3 mL) was added and the solution allowed to warm to
room temperature and stirred for a further 4 h. The reaction
was quenched with NH4Cl solution. The aqueous phase was
basified using NaHCO3 then extracted with diethyl ether.
The combined organic phases were dried (MgSO4), and
the solvent was removed under reduced pressure. Purifica-
tion by column chromatography (0.5% Et3N in petroleum
ether) gave 39 as a single diastereomer (0.168 g, 43%) and
as a white solid. [a]D22ꢀ111 (c 1.01, CHCl3); IR (KBr)
ꢀ
3. Prevost, N.; Shipman, M. Org. Lett. 2001, 3, 2383–2385;
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Prevost, N.; Shipman, M. Tetrahedron 2002, 58, 7165–7175.
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7. Pollard, C. B.; Parcell, R. F. J. Am. Chem. Soc. 1951, 73, 2925–
2927; For the correct structural assignments, see: Ettlinger,
M. G.; Kennedy, F. Chem. Ind. 1956, 166–167; Bottini, A. T.;
Roberts, J. D. J. Am. Chem. Soc. 1957, 79, 1462–1464.
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Chem. Soc. 2004, 126, 6868–6869 and references therein.
9. Bingham, E. M.; Gilbert, J. C. J. Org. Chem. 1975, 40, 224–
228; Wijnberg, J. B. P. A.; Wiering, P. G.; Steinberg, H.
Synthesis 1981, 901–903; De Kimpe, N.; DeSmaele, D.;
Sakonyi, Z. J. Org. Chem. 1997, 62, 2448–2452; Tehrani,
K. A.; De Kimpe, N. Tetrahedron Lett. 2000, 41, 1975–1978.
1
3293, 2975, 2916, 2853, 1444, 1135, 754, 700 cmꢀ1; H
NMR (400 MHz, CDCl3) 7.67–7.56 (m, 4H), 7.40–7.26
(m, 7H), 7.25–7.21 (m, 4H), 4.08 (s, 1H), 3.18 (t,
J¼6.6 Hz, 1H), 3.15 (s, 1H), 1.36 (s, 3H), 1.08 (s, 3H),
0.91 (d, J¼6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
147.0, 145.3, 144.5, 128.3, 128.1, 128.0, 127.3, 127.0,
126.8, 126.3, 126.1, 123.9, 107.0, 74.2, 66.6, 50.7, 23.4,
20.6, 19.5; MS (CI) m/z 370 (MH+); HRMS (CI) calcd for
C26H28NO 370.2171, found 370.2185; Anal. Calcd for
C26H27NO: C, 84.51; H, 7.37; N, 3.79%. Found: C, 84.63;
H, 7.55; N, 3.46%.

C. Montagne et al. / Tetrahedron 62 (2006) 8447–8457
8457
ꢀ
10. (a) Quast, H.; Weise Velez, C. A. Angew. Chem., Int. Ed. Engl.
1974, 13, 342–343; (b) Quast, H.; Weise Velez, C. A. Angew.
16. Borer, M.; Neuenschwander, M. Helv. Chim. Acta 1997, 80,
2486–2501.
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Chem., Int. Ed. Engl. 1978, 17, 213–214.
11. For a preliminary account of part of this work, see: Hayes, J. F.;
17. The asymmetric deprotonation of both 9 and 10 with (ꢀ)-spar-
teine/sec-BuLi (THF, ꢀ78 ꢁC) was attempted. In line with the
observations of Quast (Ref. 10b), the products formed after
alkylation with PhCH2Br were obtained in low yield and
poor enantioselectivity.
ꢀ
Prevost, N.; Prokes, I.; Shipman, M.; Slawin, A. M. Z.; Twin,
H. Chem. Commun. 2003, 1344–1345.
12. Ennis, D. S.; Ince, J.; Rahman, S.; Shipman, M. J. Chem. Soc.,
Perkin Trans. 1 2000, 2047–2053.
13. Ince, J.; Ross, T. M.; Shipman, M.; Slawin, A. M. Z.; Ennis,
D. S. Tetrahedron 1996, 52, 7037–7044.
14. Quast, H.; Risler, W. Angew. Chem., Int. Ed. Engl. 1973, 12,
414–415.
15. Skattebol, L. Acta Chem. Scand. 1963, 17, 1683–1693 and
references therein.
ꢀ
18. Juaristi, E.; Leon-Romo, J. L.; Reyes, A.; Escalante, J.
Tetrahedron: Asymmetry 1999, 10, 2441–2495.
19. These X-ray crystal structures were first reported elsewhere
[(Z)-24 (Ref. 8); 39 (Ref. 11)]. These structures are available
from the Cambridge Crystallographic Database [(Z)-24
(CCDC243138); 39 (CCDC207055)].
20. Reich, H. J. J. Chem. Educ.: Software, Series D 1996, 3D.