Observations on the direct amidocyclopropanation of alkenes using organozinc carbenoids

Article abstract of DOI:10.1016/j.tet.2007.03.027

A series of amidocyclopropanes were prepared by direct amidocyclopropanation of alkenes, using organozinc carbenoids generated from readily available diethoxymethylamides. The amidocyclopropanation of monosubstituted alkenes led to selective formation of the trans-amidocyclopropane in most cases, but with more substituted alkenes, the stereochemical outcome of the cyclopropanation reactions was unpredictable. The amidocyclopropane products can be readily elaborated to structurally interesting cyclopropane containing amino acids or amino alcohols.

Full text of DOI:10.1016/j.tet.2007.03.027

Tetrahedron 63 (2007) 6462–6476
Observations on the direct amidocyclopropanation of alkenes
using organozinc carbenoids
a
b
a
William B. Motherwell,a, Guillaume Begis, David E. Cladingboel, Laure Jerome
*
ꢀ
and Tom D. Shepparda
aDepartment of Chemistry, Christopher Ingold Laboratories, University College London, 20 Gordon Street, London WC1H 0AJ, UK
bAstraZeneca R&D Charnwood, Bakewell Road, Loughborough LE11 5RH, UK
Received 22 January 2007; revised 28 February 2007; accepted 2 March 2007
Available online 12 March 2007
Abstract—A series of amidocyclopropanes were prepared by direct amidocyclopropanation of alkenes, using organozinc carbenoids gener-
ated from readily available diethoxymethylamides. The amidocyclopropanation of monosubstituted alkenes led to selective formation of the
trans-amidocyclopropane in most cases, but with more substituted alkenes, the stereochemical outcome of the cyclopropanation reactions was
unpredictable. The amidocyclopropane products can be readily elaborated to structurally interesting cyclopropane containing amino acids or
amino alcohols.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
diethoxymethylamide carbenoid precursors for the construc-
tion of densely functionalised amidocyclopropanes.
The aminocyclopropyl unit is present in a wide range of
biologically active natural products and pharmaceuticals.1
Traditional approaches to the synthesis of aminocyclopro-
panes include the Curtius rearrangement of cyclopropylcar-
boxylic acids,2 the reduction of nitrocyclopropanes,3 the
reductive amination of cyclopropanone acetals4 and the cy-
clopropanation of enamines.5 More recently, de Meijere has
demonstrated a new titanium mediated cyclopropanation of
amides or nitriles using 1,2-dimetallic derivatives of mono-
substituted alkenes.6 By way of contrast however, the search
for simple and experimentally convenient methods for the
direct addition of heteroatom substituted carbenoids to un-
activated alkenes has proven to be more elusive, with direct
alkoxycyclopropanation and aminocyclopropanation requir-
ing the use of such reagents as stoichiometric Fischer car-
bene complexes.7 As an extension of our earlier studies on
the cyclopropanation of alkenes using organozinc carb-
enoids prepared from simple carbonyl compounds8 or their
derived acetals,9 we have previously demonstrated that
orthoformates are useful precursors for direct alkoxycyclo-
propanation.10 More recently, we have also shown that
diethoxymethylpyrrolidinone can be used for generation of
an amidosubstituted organozinc carbenoid,11 and that selec-
tion of a chiral oxazolidinone congener leads to an asymmet-
ric version of this amidocyclopropanation reaction.12 In the
present paper, we wish to report, in full, our detailed obser-
vations on the scope and limitations of simple achiral
2. Results and discussion
From a mechanistic standpoint, we envisaged that the evolu-
tion of a suitably functionalised amidoorganozinc carbenoid
from a diethoxymethylamide 1 could proceed as shown in
Scheme 1. Thus, coordination of a Lewis acid (either
ZnCl2 or Me3SiCl) to one of the ethoxy groups of the amide
1 leads to the formation of cation 2, which can be reduced by
two electron delivery from metallic zinc to give the organo-
zinc derivative 3. Lewis acid mediated SN1 displacement of
the remaining ethoxy group by chloride then formally leads
to the organozinc carbenoid, which could exist as either the
tetrahedral form 4 or the planar iminium form 5.
The diethoxymethylamide carbenoid precursors 12–17 were
initially prepared by heating the corresponding amides 6–11
in a large excess of triethyl orthoformate in the presence of
a catalytic amount of aluminium chloride according to
a literature procedure (Scheme 2 and Table 1).13 However,
this method is inconvenient, particularly on larger scales,
due to the difficulty in removing the large excess of orthofor-
mate, and hence alternative methods were investigated. We
found that the diethoxymethyl derivative of pyrrolidinone
6 (entry 1) could be conveniently prepared on a 10 g scale
using only 2.6 equiv of triethyl orthoformate in the presence
of chlorotrimethylsilane and a catalytic amount of triphenyl-
phosphine at room temperature. After purification by distil-
lation, the dialkoxymethyllactam 12 was obtained in 61%
yield. In a similar fashion, diethoxymethyloxazolidinone
13 (entry 2) was obtained in 60% yield (10 g scale) using
* Corresponding author. Tel.: +44 (0)2076797533; fax: +44
(0)2076797524; e-mail: w.b.motherwell@ucl.ac.uk
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.027

W. B. Motherwell et al. / Tetrahedron 63 (2007) 6462–6476
6463
O
O
O
O
R2
R2
R2
R2
R1
EtO
N
R1
EtO
N
R1
N
R1
N
N
-Me3SiOEt
Zn
OEt
OEt
SiMe3
EtO
EtO
ZnCl
Cl
Cl
ClSiMe3
1
2
3
-Me3SiOEt
O
O
R2
R2
R1
Cl
N
R1
ZnCl
Cl
4
ZnCl
5
Scheme 1.
2.6 equiv of orthoester and a catalytic quantity of acetyl
chloride. This latter procedure is the most convenient but
was not generally applicable to the preparation of the other
diethoxymethyl derivatives. It is notable that in this case
the starting oxazolidinone is insoluble in the reaction mix-
ture and gradually dissolves as the reaction progresses, and
this gradual dissolution may well be important for the suc-
cess of the reaction. The yields are essentially comparable
to the AlCl3 catalysed reactions, and these methods avoid
the requirement for a large excess of triethyl orthoformate
and the associated purification problems which then arise.
With the required diethoxymethylamides in hand, the amido-
cyclopropanation of a wide range of alkenes was investi-
gated using zinc, chlorotrimethylsilane and zinc chloride
(Scheme 3 and Table 2). In the initial reactions, zinc amal-
gam was employed as the metal source. Although easily
handled, the amalgam is undesirable due to the toxicity
and environmental issues associated with the use of mercury
and its salts. Moreover, we have also observed that the zinc
amalgam has a tendency to form hard spheres during the
course of the cyclopropanation reactions, which can lead
to variable yields, presumably due to the large decrease in
the available surface area of the metal. To this end, we
were keen to investigate alternative metal sources, and the
use of zinc dust, together with a catalytic quantity of cop-
per(I) chloride, was found to be a perfectly acceptable
substitute, giving the amidocyclopropanes in comparable
yields (entry 1). The formation of hard metal spheres during
the course of the reactions is also no longer observed.
O
R3
O
a, b or c
R2
EtO
N
R3
R2
N
H
OEt
Scheme 2. Reagents and conditions: (a) (EtO)3CH, AlCl3, 155 ꢀC (Method
A); (b) (EtO)3CH, cat. Me3SiCl, cat. PPh3, CH2Cl2, rt (Method B); (c)
(EtO)3CH, cat. AcCl, rt (Method C).
Table 1
Entry
Amide
O
Product
Yield
O
EtO
1
70,a 61b
N
HN
EtO
R2
6
12
O
R3
Zn (Hg) or
Zn, CuCl
ZnCl2
Me3SiCl
Et2O
O
R3
O
O
EtO
N
R2
EtO
N
R1
H
67,a 60c
+
2
3
4
N
O
HN
O
EtO
H
OEt
R1
7
13
O
O
Scheme 3.
OEt
OEt
N
63a
NH
The cyclopropane products 39–65 were obtained in moder-
ate to good yields with a wide variety of alkenes. All of
the carbenoid precursors could be employed in the amido-
cyclopropanation reaction with the exception of diethoxy-
methylphthalimide 14. Since the phthalimide functional
group is known to be reduced under dissolving metal condi-
tions,14 this observation is perhaps unsurprising. As antici-
pated, the amidocyclopropanation of electron-rich alkenes
(entries 8 and 10) proceeded in higher yield than the amido-
cyclopropanation of electron-deficient alkenes (entry 9) and
in the cyclopropanation of diene 38 (entry 23), chemoselec-
tive cyclopropanation of the more electron-rich alkene was
observed. In terms of the steric environment, mono (entries
1–3, 8, 10–13, 16, 18, 19 and 24–26), di (entries 4–6, 9, 14,
15, 20, 21 and 27), tri (entries 7, 22 and 23) and tetrasubsti-
tuted (entry 17) alkenes were all readily cyclopropanated un-
der the reaction conditions and a variety of functional groups
including esters, ethers, halides and silyl groups were toler-
ated. In the case of highly volatile alkenes (entry 17), it was
more effective to carry out the cyclopropanation reaction
O
14
O
O
8
O
OEt
OEt
93a
N
NH
9
15
EtO
H
N
OEt
N
71a
O
5
O
O
O
16
10
O
O
N
Ph
OEt
17
6
18a
N
H
Ph
EtO
11
a
Method A.
Method B.
Method C.
b
c

6464
W. B. Motherwell et al. / Tetrahedron 63 (2007) 6462–6476
Table 2
Table 2. (continued)
Entry
Alkene
Product (major)
trans:cis Yield
or exo:endo
Entry
Alkene
Product (major)
trans:cis Yield
or exo:endo
O
O
O
N
O
N
88,a
Ph
H
H
Ph
1
2
11.5:1
83b
10
2:1
56a
H
H
O
18
Ph
Ph
39
O
27
48
O
N
Ph
H
1.1:1
70a,c
O
N
H
Me3Si
H
11
12
>95:5
>95:5
58a
19
Ph
H
40
Me3Si
28
49
t
O
N
Bu
H
3
4
>95:5
61a
O
N
H
H
PhH2CMe2Si
t
39a
Bu
20
H
41
PhH2CMe2Si
50
29
n
O
N
Bu
n
Bu
H
n
Bu
—
83a
O
H
O
N
n
H
Bu
H
42
21
Ph
O
H
13
7:1
66b
O
n
O
30
Bu
O
N
Ph
51
n
Bu
H
H
5
1:1
52a
H
n
Bu
n
Bu
22
43
N
H
14
15
(>5:95)e
66b
O
H
H
H
H
H
H
31
52
N
6
7
10:1
66a
H
H
O
23
44
1:1
28b
O
N
Me
H
32
N
1.3:1
63a
53
H
O
O
24
45
O
O
N
O
O
O
16
1:2
19b
O
H
O
N
EtO
H
H
Et
54
33
O
H
57a
n
8
2:1
Bu
O
O
O
Et
N
n
22,b
Bu
25
Me
Me
Me
H
17
18
—
36b,d
46
Me
55
34
O
N
O
O
O
Me
O
H
O
Ph
9
1:1
9a
N
H
15:1
57b
n
Et
Bu
O
H
n
Bu
18
Ph
Et
47
26
56
(continued)
(continued)

W. B. Motherwell et al. / Tetrahedron 63 (2007) 6462–6476
6465
Table 2. (continued)
Table 2. (continued)
Entry
Alkene
Product (major)
trans:cis Yield
or exo:endo
Entry
Alkene
Product (major)
trans:cis Yield
or exo:endo
O
t
Bu
O
N
O
N
46a
27
(>5:95)e
22b
H
19
>95:5
O
H
H
H
t
31
20
H
Bu
57
65
a
Zn(Hg) method.
Zn/CuCl method.
The carbenoid precursor was added by syringe pump over 2 h.
Reaction carried out at room temperature.
Selectivities in parentheses refer to purified material.
b
c
d
e
H
OEt
O
OEt
O
H
20
2.6:1
34b
H
H
N
O
O
58a
35
at room temperature. The stereochemistry of the major
products was assigned on the basis of H NMR coupling
1
constants and simple proton decoupling experiments where
required. In most cases, a preference for the formation of
the less-hindered trans-amidocyclopropane was observed.
However, the overall trends in selectivity from substrate to
substrate are difficult to rationalise. In general, monosubsti-
tuted alkenes tend to favour the formation of the trans isomer
with varying degrees of selectivity with larger substituents
leading to a higher preference for trans-cyclopropanation.
Interestingly, the presence of an allylic ether group reversed
this selectivity (entry 16), but an allylic or vinylic ester did
not (entries 8, 10 and 13). This may indicate that coordina-
tion of the ether oxygen to the zinc carbenoid during, cyclo-
propanation can influence the stereochemical outcome and
we might expect this to be more favourable for an ether
than an ester. The trends for more substituted alkenes are
much more difficult to rationalise. Cyclohexene 23 showed
a strong preference for the formation of the exo-cyclopro-
pane (entry 6), whereas for indene 31 the reverse was true
(entries 14 and 27). Apparently similar systems such as
methylcyclohexene 24 and carene 37 showed contrasting
selectivities in the cyclopropanation reaction (entries 7
and 22). A speculative explanation using a quadrant model
(Fig. 1) in which one quadrant (A) is largely unhindered,
but the adjacent quadrant (B) is sterically congested might
help to explain these results. Thus a monosubstituted alkene
(R2¼H) fits into the ‘pocket’ with the R1 substituent occupy-
ing the unhindered quadrant A in transition state (i). When
a second substituent is present on the alkene (R2sH), the
larger steric hindrance in quadrant B can lead to the cis tran-
sition state (ii) becoming the favoured pathway, in which the
two alkyl groups occupy quadrants C and D where there is
only moderate steric hindrance.
O
O
O
N
Cl
MeO
H
21
(1:16)e
11b
Cl
MeO
36
O
59
Me
H
H
H
H
22
—
58b
O
N
37
O
60
O
O
O
N
EtO
Me
Me
23
1:11
38b
H
CO2Et
H
38
61
Ph
O
O
56a
N
24
6:1
H
H
18
Ph
62
Ph
Ph
Ph
N
H
25
13.5:1
14a
H
H
A possible transition state in line with such a model is shown
in Figure 2, in which the zinc atom is located in quadrant D,
and the orientation of the pyrrolidine ring is controlled by
coordination of the lactam oxygen to the metal centre. This
places the lactam carbonyl in quadrant C and the methylene
adjacent to the nitrogen in quadrant B, leaving quadrant A
largely empty. Thus, a monosubstituted alkene (R2¼H) can
approach the carbenoid relatively easily with the R1 group
located in quadrant A, leading to a preference for trans-
cyclopropane formation (i). With more substituted alkenes
(R2sH), the unfavourable interaction between the lactam
hydrogen atoms and R2 in the exo transition state (i) leads to
18
Ph
Ph
63
O
O
N
34b
H
26
—
18
64
(continued)

6466
W. B. Motherwell et al. / Tetrahedron 63 (2007) 6462–6476
A
R2
H
R1
H
R2
H
R1
A
B
B
R2
H
R1
H
H
H
R2
H
R1
C
D
C
D
N
N
O
O
N
N
O
O
trans or exo
cis or endo
(i)
(ii)
Figure 1.
B
A
B
A
The cyclopropanes formed in these reactions are suitable for
further elaboration into derivatives of potential utility for in-
corporation as rigid conformational locks in a wide variety
of systems, such as chiral ligands or drug molecules
(Scheme 5). The oxazolidinone ring in cyclopropane 57
was opened under basic conditions to yield the aminoalcohol
71, which was BOC protected and oxidised to the corre-
sponding N-cyclopropylglycine derivative 73. Similarly,
the benzoxazolidine ring in 65 can be opened using Super
Hydride16 to give the indenocyclopropylcatecholamine 74
in moderate yield. The cyclopropylsilane 50 was oxidised
under Tamao–Fleming conditions to give the corresponding
amidocyclopropanol 75 in 35% yield. These examples pro-
vide a brief illustration of the interesting cyclopropylamino
acid and aminoalcohol units that can readily be prepared
using amidoorganozinc carbenoids. Densely functionalised
cyclopropylamino acid 73 was obtained in only four steps
from the cheap commercially available alkene 20.
2
R1
H
H
H
H
H
H
R
H
R1
H
H
N
H
R2
N
C
D
C
D
Zn
Zn
Cl
Cl
O
O
(i)
(ii)
Figure 2.
apreferencefortheendo transitionstate (ii) inwhichR1 isclose
to the zinc atom and R2 close to the lactam carbonyl group.
The use of a large excess of chlorotrimethylsilane in the
reaction precluded direct amidocyclopropanation of allylic
alcohols, but a preliminary experiment (Scheme 4) with allyl
benzene 18 demonstrated that the cyclopropane 39 could be
produced in the absence of the silicon electrophile by
employing a larger excess of zinc chloride (30% conversion).
When these alternative conditions were applied to the cyclo-
propanation of allyl alcohol, amidocyclopropyl alcohol 67
was obtained in low yield (8%, diastereomeric ratio trans:cis
2:1). However, when 2-cyclohexen-1-ol 68 was cyclopropa-
nated under the same conditions, the only isolated product
was the ethyl ether 69, again in 8% yield. Cyclopropane
ether 69 is probably formed by initial displacement of the
hydroxy group with ethanol under the Lewis acidic condi-
tions and then subsequent cyclopropanation of the allylic
ether 70. Alkene 70 was synthesised by alkylation of the al-
cohol 68, and cyclopropanated under the same conditions to
give the same cyclopropane 69 in 20% yield (diastereomeric
ratio >8:1). Interestingly, the ethyl ether appears to direct
the approach of the organozinc carbenoid to the same face
of the ring.15 The exo-cyclopropane is also formed selec-
tively in a similar fashion to the cyclopropanation of cyclo-
hexene above (Table 2, entry 6).
O
O
OH
NR
OH
O
c
a
N
NBOC
H
H
H
H
H
H
t
t
t
Bu
Bu
Bu
73
57
71 R = H
72 R = BOC
b
OH
d
e
O
NH
O
N
O
H
H
H
H
H
65
H
74
O
N
N
H
H
O
N
H
H
a
H
HO
PhH2CMe2Si
Ph
50
75
H
Ph
Scheme 5. Reagents and conditions: (a) LiOH, EtOH, H2O, 49%; (b)
BOC2O, Et3N, CH2Cl2, 72%; (c) KMnO4, NaOH, BuOH, H2O, 84%; (d)
t
18
39
LiEt3BH, THF, 34%; (e) TBAF, THF, rt then 30% H2O2, KHCO3, MeOH,
35%.
O
N
a
a
H
HO
Finally, from a practical viewpoint, it would be much more
convenient to avoid the need for preparation of the orthoester
derived carbenoid precursors. As both the introduction of the
diethoxymethyl group itself and the cyclopropanation reac-
tion are carried out in the presence of Lewis acids, we
decided to investigate whether the two processes could be
combined into a one-pot reaction (Scheme 6). Thus, triethyl
orthoformate was added dropwise to a mixture of alkene 18,
oxazolidinone 7, zinc, copper chloride, chlorotrimethyl-
silane and zinc chloride and to our delight, the amidocyclo-
propane was obtained directly in 33% yield, comparable to
the 38% overall yield obtained in the separate steps described
H
HO
66
67
OR
H
H
H
N
EtO
H
69
O
68 R = H
70 R = Et
b
Scheme 4. Reagents and conditions: (a) 12, ZnCl2, Zn, CuCl, Et2O, 8% (67),
8% (69 from 68), 20% (69 from 70); (b) NaH, DMF, EtI, 33% based on
recovered 68.

W. B. Motherwell et al. / Tetrahedron 63 (2007) 6462–6476
6467
O
s), DMSO (d¼2.56 ppm, qn) or D2O (4.79, s) as the internal
standard. Chemical shifts are quoted in ppm using the
following abbreviations: s, singlet; d, doublet; t, triplet; q,
quartet; qn, quintet; m, multiplet; br, broad or a combination
of these. The coupling constants (J) are measured in Hertz.
13C NMR spectra were recorded at 75 MHz on a Bruker
AMX300 spectrometer, at 100 MHz on a Bruker AMX400
spectrometer or at 125 MHz on a Bruker Avance 500 spec-
trometer in the stated solvent using the central reference of
CHCl3 (d¼77.0 ppm, t), DMSO (d¼39.52 ppm, septet) as
the internal standard. Chemical shifts are reported to the
nearest 0.1 ppm. Mass spectra and elemental analysis were
performed at the Department of Chemistry, University
College London.
O
N
a
H
Ph
H
Ph
18
56
Scheme 6. Reagents and conditions: (a) 7, (EtO)3CH, Me3SiCl, ZnCl2, Zn,
CuCl, Et2O, 33%.
above. Although, the alkoxycyclopropanation of alkenes
with orthoformates proceeds under similar conditions,10 no
alkoxycyclopropane was observed, implying that the reac-
tion between the amide and orthoester is overwhelmingly
favoured. We are currently optimising this new approach
and investigating its scope for the direct preparation of
amidocyclopropanes from a wide range of amide precursors.
4.1.1. 2,3-Dihydro-1-isoindolinone 9.14 Tin powder
(41.7 g, 0.35 mol, 2.6 equiv) was added to a vigorously
stirred suspension of phthalimide (20 g, 0.14 mol, 1 equiv)
in a mixture of glacial acetic acid (100 mL) and concentrated
hydrochloric acid (50 mL). The reaction mixture was heated
at reflux for 2 h and then filtered hot. The filtrate was concen-
trated and the residue partitioned between dichloromethane
(300 mL) and water (150 mL). The organic layer was sepa-
rated and the aqueous layer extracted with dichloromethane
(2ꢂ50 mL). The combined organic extracts were dried
(MgSO4), filtered and concentrated. The crude product was
purified twice by flash column chromatography (EtOAc)
and then triturated in toluene to give the lactam 9 (4.2 g,
31.5 mmol, 23%) as a white solid; mp 149–150 ꢀC (lit.14
150–151 ꢀC); IR (CH2Cl2): nmax 3214 (br s), 1658
3. Conclusion
In summary, the amidocyclopropanation of alkenes using di-
alkoxymethylamides as zinc carbenoid precursors consti-
tutes an effective method for functionalised cyclopropane
preparation, and enables a range of highly functionalised
aminocyclopropane derivatives to be accessed, which cannot
readily be obtained using existing methods. These amido-
cyclopropane units can be readily elaborated into cyclopropyl
containing aminoalcohol or amino acid motifs.
4. Experimental
4.1. General
(s) cmꢁ1 1H NMR (400 MHz, CDCl3): d 4.48 (s, 2H,
;
CH2), 7.18 (br s, 1H, NH), 7.47–7.60 (m, 4H, Ar-H); 13C
NMR (100 MHz, CDCl3): d 45.8, 123.2, 123.6, 128.0,
131.7, 132.6, 143.7, 172.6.
All reactions were carried out in oven-dried glassware under
a nitrogen atmosphere unless otherwise indicated. Diethyl
ether, tetrahydrofuran, toluene and dichloromethane were
used following purification from an anhydrous engineering
zeolite drying apparatus. Methanol and ethanol were dis-
tilled from magnesium turnings and iodine. Anhydrous di-
methylformamide was obtained from the Aldrich chemical
company. Triethylamine was distilled from potassium
hydroxide before use. Chlorotrimethylsilane was distilled
from calcium hydride immediately prior to use. Styrene,
cyclohexene, indene, 1,2-dihydronaphthalene and 3-carene
were distilled before use. All other chemicals were used as
supplied unless otherwise indicated. Column chromato-
graphy was carried out using BDH (40–60 mm) silica gel
and analytical thin layer chromatography was carried out us-
ing Merck Kieselgel aluminium-backed plates coated with
silica gel. Components were visualised using combinations
of ultra-violet lights, iodine, ceric ammonium molybdate,
phosphomolybdic acid and potassium permanganate. Melt-
ing points were determined using a Reichert hot-stage appa-
ratus and are uncorrected. Optical rotations were measured
using a Perkin–Elmer 241 (sodium D-line, 529 nm) polari-
meter and [a]D values are given in 10ꢁ1 deg cm2 gꢁ1, concen-
tration (c) in g/100 mL. Infrared (IR) spectra were recorded
on a Perkin–Elmer 1605 Fourier transform spectrometer and
4.1.2. General procedure for synthesis of diethoxymethyl-
amides 12–17. A mixture of amide (6.7 mmol), aluminium
chloride (1.0 mmol, 0.15 equiv) and triethyl orthoformate
(22 mL, 0.13 mol, 20 equiv) was heated at 155 ꢀC for 24–
72 h. The reaction mixture was allowed to cool to room tem-
perature and then quenched with saturated aqueous sodium
bicarbonate (25 mL). The aqueous phase was extracted
with diethyl ether (50 mL then 2ꢂ25 mL) and the combined
organic extracts were washed with brine (25 mL), dried
(Na2SO4), filtered and concentrated. The crude product
was purified by flash column chromatography.
4.1.2.1. N-Diethoxymethylpyrrolidin-2-one 12 (alter-
native procedure). Chlorotrimethylsilane (1.5 mL,
11.7 mmol) was added dropwise to a stirred solution of
pyrrolidinone (10 g, 117.6 mmol), triethyl orthoformate
(50 mL, 300.6 mmol) and triphenylphosphine (50 mg,
0.2 mmol) in dichloromethane (200 mL) under nitrogen.
The resulting solution was stirred overnight at room temper-
ature then poured into water (70 mL) and saturated sodium
bicarbonate (50 mL). The layers were separated and the
organic layer washed with brine (50 mL), dried (Na2SO4)
and concentrated. The residue was distilled under reduced
pressure to give 12 as a colourless liquid (bp 101–103 ꢀC
at 3 mbar [lit.17 84–86 ꢀC at 1 mmHg], 13.42 g, 61%).
1
were recorded as thin films (NaCl plate). H NMR spectra
were recorded at 300 MHz on a Bruker AMX300 spectro-
meter, at 400 MHz on a Bruker AMX400 spectrometer or at
500 MHz on a Bruker Avance 500 spectrometer in the stated
solvent using residual protic solvent CHCl3 (d¼7.26 ppm,
4.1.2.2. N-Diethoxymethyl-2-oxazolidinone 13 (alter-
native procedure). Acetyl chloride (1 mL, 14 mmol)

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W. B. Motherwell et al. / Tetrahedron 63 (2007) 6462–6476
was added to a stirred suspension of oxazolidin-2-one
(10 g, 113.8 mmol) in triethyl orthoformate (50 mL,
300.6 mmol). The suspension was stirred overnight at
room temperature and then the reaction mixture was distilled
under reduced pressure to give diethoxymethyloxazolidi-
none as a colourless liquid (120–122 ꢀC at 0.9 mmHg,
12.9 g, 60%).
4.1.2.8. N-Benzyl-N-diethoxymethylacetamide 17.
Yellow oil; IR (film): nmax 2978 (m), 2933 (w), 1670 (s),
1497 (w) cmꢁ1 1H NMR (400 MHz, 353 K, DMSO):
;
d 1.10 (t, J¼7.1, 6H, 2ꢂMe), 2.05 (s, 2.1H, COCH3), 2.98
(s, 0.9H, COCH3), 3.37–3.63 (m, 4H, 2ꢂCH2CH3), 4.41
(s, 0.6H, PhCH2N), 4.50 (s, 1.4H, PhCH2N), 5.58 (br s,
0.3H, CH), 6.00 (br s, 0.7H, CH), 7.16–7.35 (m, 5H, Ar-
H); 13C NMR (major rotamer, 100 MHz, 353 K, DMSO):
d 14.0, 21.4, 43.7, 61.2, 102.2, 125.8, 126.7, 127.3, 138.9,
169.0; MS (CI+) m/z (%): 252 (M+H, 3), 206 (62), 150
(100), 103 (61), 91 (68); HRMS: M+H, found 252.16019.
C14H22NO3 requires 252.15997.
4.1.2.3. N-Diethoxymethylpyrrolidin-2-one 12. Pale
yellow oil; IR (film): nmax 2977 (s), 2897 (m), 1693
1
(s) cmꢁ1; H NMR (300 MHz, CDCl3): d 1.20 (t, J¼7.0,
6H, 2ꢂMe), 1.96–2.03 (m, 2H, CH2CH2N), 2.41 (t, J¼8.2,
2H, CH2CON), 3.42 (t, J¼7.3, CH2N), 3.48 (dq, J¼9.4,
7.0, 2H, 2ꢂCHHMe), 3.62 (dq, J¼9.4, 7.0, 2H, 2ꢂ
CHHMe), 5.87 (s, 1H, CH); 13C NMR (75 MHz, CDCl3):
d 14.5, 17.8, 31.4, 40.5, 61.9, 98.8, 175.2; MS (FAB) m/z
(%): 210 (M+Na, 100), 142 (25); HRMS: M+Na, found
210.11009. C9H17NO3Na requires 210.11061.
4.1.3. Benzyldimethyl(vinyl)silane 29. A solution of benzyl
chloride (1.15 mL, 10 mmol) in dry diethyl ether (10 mL)
was added dropwise to a mixture of magnesium turnings
(0.24 g, 10 mmol) and iodine (two crystals) in dry diethyl
ether (10 mL) under nitrogen. The reaction mixture was
stirred for 1 h and dimethylvinylchlorosilane (1.64 mL,
12 mmol) was added dropwise. The reaction mixture was
heated at reflux for 16 h and then quenched carefully with sat-
urated aqueous ammonium chloride (20 mL). The organic
layer was separated and the aqueous layer was extracted
with diethyl ether (2ꢂ20 mL). The combined organic
extracts were dried (MgSO4), filtered and concentrated in
vacuo. The crude product was purified by flash column
chromatography (petrol) to give 29 as a colourless oil
(1.09 g, 62%); IR (CDCl3): nmax 3024, 2957, 2893 (w),
1601, 1493 (s), 1452 (w), 1404 cmꢁ1; 1H NMR (500 MHz,
CDCl3): d 0.57 (s, 6H, 2ꢂMe), 2.15 (s, 2H, CH2), 5.67 (dd,
J¼20.3, 3.8, 1H, CH]CHH), 5.97 (dd, J¼14.7, 3.8, 1H,
CH]CHH), 6.13 (dd, J¼20.3, 14.7, 1H, CH]CH2), 6.99–
7.02 (m, 2H, Ar-H), 7.05–7.09 (m, 1H, Ar-H), 7.18–7.23
(m, 2H, Ar-H); 13C NMR (125 MHz, CDCl3): d ꢁ3.7, 25.8,
124.0, 128.1, 128.2, 132.2, 138.2, 139.9; MS (EI) m/z (%):
176 (M+, 13), 91 (17), 85 (100); HRMS: M+, found
176.10155. C11H16Si requires 176.10158.
4.1.2.4. N-Diethoxymethyl-2-oxazolidinone 13. Pale
yellow oil; IR (film): nmax 2979 (w), 2904 (w), 1747
1
(s) cmꢁ1; H NMR (400 MHz, CDCl3): d 1.25 (t, J¼7.1,
6H, Me), 3.53–3.73 (m, 6H, CH2N and 2ꢂCH2Me), 4.39
(t, J¼8.2, 2H, CH2CH2N), 5.74 (s, 1H, CH); 13C NMR
(100 MHz, CDCl3): d 14.8, 38.6, 62.6, 62.8, 101.3, 157.4;
MS (CI+) m/z (%): 190 (M+H, 2), 144, 100, 116 (12), 103
(100), 75 (14), 44 (16); HRMS: M+H, found 190.10785.
C8H16NO4 requires 190.10793.
4.1.2.5. N-Diethoxymethylphthalimide 14. White solid;
mp 73–74 ꢀC (lit.18 73 ꢀC); IR (film): nmax 2977 (w), 1774
(m), 1720 (s), 1694 (w), 1469 (w) cmꢁ1
;
1H NMR
(300 MHz, CDCl3): d 1.25 (t, J¼7.1, 6H, 2ꢂCH3), 3.62
(dq, J¼9.4, 7.1, 2H, 2ꢂCHHMe), 3.77 (dq, J¼9.4, 7.1,
2H, 2ꢂCHHMe), 6.09 (s, 1H, CH), 7.68–7.77 (m, 2H,
Ar-H), 7.82–7.90 (m, 2H, Ar-H); 13C NMR (75 MHz,
CDCl3): d 14.8, 63.4, 99.8, 123.6, 131.7, 134.3, 166.6; MS
(CI+) m/z (%): 249 (M+, 100), 175 (56), 147 (78); HRMS:
M+, found 249.09952. C13H15NO4 requires 249.1001.
4.1.4. Ethyl 2-allyloxyacetate 33.19 Sodium hydride (60%
dispersion in mineral oil, 1.76 g, 44 mmol) was added por-
tionwise to a solution of ethyl glycolate (4.16 g, 40 mmol)
in anhydrous DMF (20 mL) under nitrogen at 0 ꢀC. After
stirring for 30 min, allyl bromide (3.8 mL, 44 mmol) was
added dropwise and the reaction mixture was allowed to
warm to room temperature. After stirring for 90 min at
room temperature, water (20 mL) was added and the reac-
tion mixture extracted with ether (3ꢂ30 mL). The combined
organic layers were washed with brine, dried (MgSO4) and
concentrated and the residue was distilled to afford two frac-
tions: Fraction 1 (bp 52–54 ꢀC, 14 mbar) contained a mixture
of the alkene 33 and DMF (2:1 ratio), Fraction 2 (bp 64–
65 ꢀC, 10 mbar, lit.19 70–74 ꢀC at 20 mmHg) contained the
alkene 33. The two fractions were combined and dissolved
in ether (30 mL) and washed with saturated lithium chloride
(2ꢂ20 mL), dried (MgSO4) and concentrated to give the
alkene as a colourless liquid (1.37 g, 9.5 mmol, 24%); IR
4.1.2.6. 2-Diethoxymethyl-2,3-dihydro-1-isoindoli-
none 15. Brown oil; IR (film): nmax 2977 (m), 2932 (w),
1
1694 (s), 1620 (w), 1470 (m), 1452 (w) cmꢁ1; H NMR
(400 MHz, CDCl3): d 1.25 (t, J¼7.0, 6H, 2ꢂMe), 3.57
(dq, J¼9.5, 7.0, 2H, 2ꢂCHHCH3), 3.74 (dq, J¼9.5, 7.0,
2H, 2ꢂCHHCH3), 4.49 (s, 2H, CH2N), 6.23 (s, 1H, CH),
7.45–7.51 (m, 2H, Ar-H), 7.58 (t, J¼7.5, 1H, Ar-H), 7.87
(d, J¼7.5, 1H, Ar-H); 13C NMR (100 MHz, CDCl3):
d 14.8, 44.2, 62.5, 99.2, 123.2, 124.1, 128.0, 132.0, 132.1,
142.0, 168.9; MS (CI+) m/z (%): 236 (M+H, 6), 190 (44),
134 (59), 103 (46); HRMS: M+H, found 236.12847.
C13H18NO3 requires 236.12866.
4.1.2.7. 3-(Diethoxymethyl)benzoxazolin-2-one 16.
Red oil; IR (film): nmax 2980, 1786 (s), 1625 (w); 1H NMR
(400 MHz, DMSO): d 1.16 (t, J¼7.1, 6H, 2ꢂMe), 3.60
(dq, J¼9.6, 7.1, 2H, 2ꢂCHHMe), 3.73 (dq, J¼9.6, 7.1,
2H, 2ꢂCHHMe), 6.11 (s, 1H, CH), 7.16–7.24 (m, 2H, Ar),
7.34–7.39 (m, 2H, Ar); 13C NMR (100 MHz, DMSO):
d 14.6, 62.4, 101.4, 110.0, 111.9, 122.9, 124.2, 127.7,
141.9, 152.4; MS (CI+) m/z (%): 237 (M+, 70), 205 (75),
193 (100), 104 (70); HRMS: M+H, found 238.10832.
C12H16NO4 requires 238.10793.
1
(film): nmax 2984, 2941, 2909, 2876, 1755 (s) cmꢁ1; H
NMR (500 MHz, CDCl3): d 1.29 (t, J¼7.2, 3H, Me), 4.07
(s, 2H, CH2O), 4.10 (dt, J¼5.8, 1.5, 2H, CH2CH), 4.22 (q,
J¼7.2, CH2Me), 5.26 (dq, J¼10.3, 1.5, 1H, CHH]CH),
5.33 (dd, J¼17.1, 1.5, CHH]CH), 5.93 (ddt, J¼17.1,
10.3, 5.8, CH]CHH); 13C NMR (100 MHz, CDCl3):
d 14.1, 60.8, 67.1, 72.3, 118.2, 133.6, 170.3.

W. B. Motherwell et al. / Tetrahedron 63 (2007) 6462–6476
6469
4.1.5. Ethyl 2-(cyclopent-2-enyl)acetate 35.20 Acetyl chlo-
ride (3 mL, 42.4 mmol) was added dropwise to a solution of
ethanol (30 mL) at 0 ꢀC. 2-(Cyclopent-2-enyl)acetic acid
(2 g, 15.9 mmol) was added dropwise to the solution at
0 ꢀC. The resulting mixture was allowed to warm to room
temperature and was then heated at reflux for 4 h. After con-
centration under reduced pressure the residue was dissolved
in chloroform and concentrated under reduced pressure again
to give a biphasic mixture. The mixture was extracted with
dichloromethane (10 mL) and the combined organic layers
were dried over MgSO4 and concentrated under reduced
pressure. The crude product was purified by flash chromato-
graphy (4:1 petrol–ether) to give the ester as a pale yellow oil
(1.6 g, 65%); IR (film): nmax 2907 (s), 1732 (s), 1614 (w),
(3ꢂ20 mL), ethanol (3ꢂ20 mL) and ether (3ꢂ20 mL) and
then dried under vacuum.
4.1.8. Zinc dust for cyclopropanation reactions. A suspen-
sion of commercially available zinc dust (5 g, 76.5 mmol) in
2% hydrochloric acid (15 mL) was stirred for 10 min and
then filtered and the collected zinc dust washed with water
(3ꢂ20 mL), acetone (3ꢂ20 mL), ethanol (3ꢂ20 mL) and
ether (3ꢂ20 mL) and then dried under vacuum.
4.1.9. General procedure for the cyclopropanation of al-
kenes using zinc amalgam. A solution of diethoxymethyl-
amide (2.11 mmol) in dry diethyl ether (3 mL) was added via
a motorised syringe pump over 4–6 h to a vigorously stirred
mixture of zinc amalgam (1.38 g, 21.1 mmol), zinc chloride
(1.0 M solution in diethyl ether, 2.11 mL, 2.11 mmol),
chlorotrimethylsilane (1.34 mL, 10.56 mmol) and alkene
(1.06 mmol) in dry diethyl ether (5.5 mL) under nitrogen
at reflux. The mixture was stirred at reflux overnight and
then allowed to cool to room temperature. The reaction
was quenched with saturated aqueous sodium bicarbonate
solution (20 mL) and after stirring for 20 min, the mixture
was filtered through Celite and the separated zinc washed
with diethyl ether (20 mL) and dichloromethane (20 mL).
The organic solvents were removed in vacuo and the aque-
ous layer was extracted with diethyl ether (3ꢂ20 mL). The
combined organic extracts were washed with brine
(20 mL), dried (MgSO4), filtered and concentrated in vacuo.
The crude product was then purified by flash column chro-
matography to give the amidocyclopropane(s).
1
1259 (s), 1148 (s), 1032 (s) cmꢁ1; H NMR (500 MHz,
CDCl3): d 1.26 (t, J¼7.2, 3H, CH3), 1.42–1.50 (m, 1H,
CHHCHCH2), 2.07–2.16 (m, 1H, CHHCHCH2), 2.25–2.33
(m, 2H, CH2C]O), 2.33–2.42 (m, 2H, CH2CH]CH),
3.04–3.12 (m, 1H, CHCH]CH), 4.14 (q, J¼7.2, 2H,
CH2CH3), 5.65–5.68 (m, 1H, CH]CH), 5.74–5.78 (m, 1H,
CH]CH); 13C NMR (125 MHz, CDCl3): d 14.3, 29.6,
31.8, 40.5, 41.8, 60.2, 131.4, 133.7, 173.0; MS (EI) m/z
(%): 153 (MꢁH, 33), 79 (75), 57 (100); HRMS: MꢁH, found
153.09115. C9H13O2 requires 153.09101.
4.1.6. (E)-Ethyl 3,7-dimethylocta-2,6-dienoate 38.21 So-
dium hydride (60% mineral oil dispersion, 0.312 g,
7.80 mmol) was washed three times with hexane under nitro-
gen. The resulting solid was suspended in dry THF (10 mL)
and cooled to 0 ꢀC. A solution of triethyl phosphonoacetate
(1.75 g, 7.8 mmol) in tetrahydrofuran (6 mL) was added
with stirring at 0 ꢀC, and the mixture was stirred at this tem-
perature for further 30 min. A solution of 6-methyl-5-hepten-
2-one (0.74 g, 5.9 mmol) in tetrahydrofuran (5 mL) was
added and the resulting mixture was stirred at 0 ꢀC for 1 h
and then allowed to warm to room temperature and stirred
for 16 h. The residue was then poured into a mixture of ether
(50 mL) and a saturated aqueous ammonium chloride
(20 mL). The ether layer was separated and the aqueous layer
extracted with ether (2ꢂ20 mL). The combined organic
layers were dried over MgSO4 and concentrated under re-
duced pressure. The crude product (approximately 75:25
E:Z) was purified by column chromatography (3% tBuOMe
in hexane) to give 1.03 g of a mixture of (E) and (Z) isomers
as a colourless oil and 187 mg of the pure E isomer as a col-
ourless oil(89% overall yield). The pure E isomer was used in
the cyclopropanation reaction; IR (film): nmax 1643 (s), 1385
4.1.10. General procedure for cyclopropanation of al-
kenes using Zn/CuCl. A solution of diethoxymethylamide
(2.12 mmol) in diethyl ether (3 mL) was added dropwise
via syringe pump (0.6 mL hꢁ1) to a vigorously stirred reflux-
ing mixture of zinc dust (1.4 g, 21.5 mmol), copper(I) chlo-
ride (140 mg, 1.4 mmol), zinc chloride (1.0 M solution in
Et2O, 1 mL, 1 mmol), alkene (1.06 mmol) and chlorotri-
methylsilane (1.4 mL, 11 mmol) in diethyl ether (5 mL). The
reaction mixture was refluxed overnight, then quenched by
addition of saturated sodium bicarbonate solution (4 mL),
filtered and washed the resulting solids with ether
(10 mL). The biphasic mixture was extracted with ether
(3ꢂ20 mL) and the combined organic layers washed with
brine (30 mL), dried (MgSO4) and concentrated. The residue
was purified by column chromatography to give the amido-
cyclopropane.
1
(w), 1223 (w), 1142 cmꢁ1; H NMR (400 MHz, CDCl3):
d 1.28 (t, J¼7.1, 3H, CH3CH2), 1.60 (s, 3H, CH3CCH3),
1.68 (s, 3H, CH3CCH3), 2.15 (s, 3H, CH3C]CH), 2.16 (m,
4H, 2ꢂCH2), 4.15 (q, J¼7.1, 2H, CH2CH3), 5.03–5.1 (m,
1H, CHCOO), 5.66 (br s, 1H, Me2C]CH); 13C NMR
(125 MHz, CDCl3): d 14.3, 17.7, 18.8, 25.7, 26.0, 40.9,
59.5, 115.6, 123.0, 132.5, 159.8, 166.9; MS (EI) m/z (%):
196 (M+,10), 151 (33), 123 (60), 97 (52), 83 (100); HRMS:
M+, found 196.14572. C12H20O2 requires 196.14632.
4.1.11. General procedure for cyclopropanation of al-
kenes without TMSCl. A solution of diethoxymethylamide
(2.12 mmol) in diethyl ether (2 mL) was added dropwise via
syringe pump (0.6 mL hꢁ1) to a vigorously stirred refluxing
mixture of zinc dust (1.4 g, 21.5 mmol), copper(I) chloride
(140 mg, 1.4 mmol), zinc chloride (1.0 M solution in Et2O,
5.4 mL, 5.4 mmol), alkene (1.06 mmol) in diethyl ether
(1 mL). The reaction mixture was refluxed overnight, then
quenched by addition of saturated sodium bicarbonate solu-
tion (4 mL), filtered and washed the resulting solids with
ether (10 mL). The biphasic mixture was extracted with
ether (3ꢂ20 mL) and the combined organic layers washed
with brine (30 mL), dried (MgSO4) and concentrated. The
residue was purified by column chromatography to give
the amidocyclopropane.
4.1.7. Preparation of zinc amalgam. Zinc dust (10.0 g,
153 mmol) was added portionwise to a vigorously stirred
solution of mercury(II) chloride (2.0 g, 7.20 mmol) in con-
centrated hydrochloric acid (2 mL) and water (30 mL).
The suspension was stirred for 10 min and then filtered and
the zinc amalgam washed with water (3ꢂ20 mL), acetone

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W. B. Motherwell et al. / Tetrahedron 63 (2007) 6462–6476
4.1.12. Procedure for cyclopropanation of allyl benzene
using oxazolidinone 7 and triethyl orthoformate. Zinc
chloride (1.0 M solution in Et2O, 2.7 mL, 2.70 mmol) and
chlorotrimethylsilane (2.45 mL, 18.9 mmol) were added to
a suspension of oxazolidinone (238 mg, 2.70 mmol) in ether
(5 mL) and the solution heated at reflux for 10 min. Zinc dust
(1.32 g, 20.3 mmol) and copper(I) chloride (132 mg,
1.32 mmol) were added followed by a solution of allyl
benzene (165 mg, 1.39 mmol) in ether (2 mL). The reaction
mixture was then heated at reflux and triethyl orthoformate
(2.3 mL, 13.5 mmol) was added dropwise via syringe
pump (0.25 mL hꢁ1). After heating under reflux overnight,
saturated sodium bicarbonate solution (4 mL) was added
and the resulting suspension was filtered and washed the
solids with ether (10 mL). The biphasic mixture was ex-
tracted with ether (3ꢂ20 mL) and the combined organic
layers washed with brine (30 mL), dried (MgSO4) and con-
centrated. The residue was purified by column chromato-
graphy to give the amidocyclopropane 56 as a colourless
oil (100 mg, 0.46 mmol, 33%).
31.5, 32.4, 48.0, 126.1, 127.8, 127.9, 136.8, 176.7; MS
(EI) m/z (%): 201 (M+, 7), 172 (21), 144 (24), 130 (69),
115 (100), 103 (72), 91 (52), 77 (74); HRMS: M+, found
201.11549. C13H15NO requires 201.11482.
4.1.15. trans-1-(2-tert-Butylcyclopropyl)-2-pyrrolidinone
41. Colourless oil; IR (film): nmax 2955 (s), 2868, 1694 (s),
1
1462, 1421 (s) cmꢁ1; H NMR (trans, 500 MHz, CDCl3):
d 0.67–0.74 (m, 2H, CH2CHN), 0.81 (s, 9H, C(CH3)3),
0.86 (ddd, J¼9.9, 6.8, 4.1, 1H, CHCHN), 1.84–1.94 (m,
2H, CH2CH2N), 2.29 (t, J¼8.2, 2H, CH2CO), 2.47 (dt,
J¼7.5, 4.1, 1H, CHN), 3.26 (t, J¼7.1, 2H, CH2N); 13C
NMR (trans, 125 MHz, CDCl3): d 8.7, 17.9, 28.1, 28.1,
29.0, 29.5, 31.8, 47.5, 175.8; MS (EI) m/z (%): 181 (M+,
20), 166 (10), 124 (100), 96 (29), 81 (23), 69 (14), 57
(12); HRMS: M+, found 181.146380. C11H19NO requires
181.146655.
4.1.16. ( )-1-((2S,3S)-2,3-Dibutylcyclopropyl)pyrrolidin-
2-one 42. Colourless oil; IR (film): nmax 2954 (s), 2924 (s),
1
2856, 1694 (s), 1416 cmꢁ1; H NMR (500 MHz, CDCl3):
4.1.13. 1-(2-Benzylcyclopropyl)-2-pyrrolidinone (trans
and cis) 39. Colourless oil; IR (mixture of trans and cis,
film): nmax 2992, 2958, 1688 (s), 1495, 1454, 1421
d 0.68–0.79 (m, 3H), 0.82 (t, J¼7.0, 3H, Me), 0.83 (t,
J¼7.0, 3H, CH3), 1.14–1.36 (m, 10H), 1.45–1.53 (m, 1H),
1.87–1.96 (m, 2H, CH2CH2N), 2.25 (dd, J¼6.4, 4.2, 1H,
CHN), 2.32 (t, J¼8.0, 2H, CH2CO), 3.20–3.31 (m, 2H,
CH2N); 13C NMR (125 MHz, CDCl3): d 13.9, 14.0, 18.8,
22.4, 22.5, 24.1, 25.5, 27.5, 31.0, 31.6, 31.6, 32.5, 36.6,
49.0, 176.6; MS (EI) m/z (%): 237 (M+, 43), 194 (21), 180
(100), 138 (15), 124 (35), 98 (53), 86 (35), 67 (13), 55
(15); HRMS: M+, found 237.2084. C15H27NO requires
237.20925.
1
(s) cmꢁ1; H NMR (trans, 500 MHz, CDCl3): d 0.75 (ddd,
J¼7.5, 6.1, 5.8, 1H, CHHCHN), 0.95 (ddd, J¼9.4, 5.8,
4.1, 1H, CHHCHN), 1.28 (dtdd, J¼9.4, 6.8, 6.1, 3.5, 1H,
CHCHN), 1.86–1.93 (m, 2H, CH2CH2N), 2.32 (t, J¼8.0,
2H, CH2CO), 2.50–2.55 (m, 2H, CHN and CHHAr), 2.70
(dd, J¼14.7, 6.8, 1H, CHHAr), 3.16 (t, J¼7.0, 2H, CH2N),
7.18–7.30 (m, 5H, Ar-H); 13C NMR (trans, 125 MHz,
CDCl3): d 12.1, 17.8, 19.0, 31.6, 31.6, 38.0, 47.2, 125.9,
128.2, 140.5, 175.8. 1H NMR (cis, 500 MHz, CDCl3):
d 0.71 (ddd, J¼6.4, 6.0, 4.6, 1H, CHHCHN), 1.00 (ddd,
J¼8.9, 8.0, 6.0, 1H, CHHCHN), 1.34 (tddd, J¼8.9, 7.1,
6.4, 4.9, 1H, CHCHN), 1.94–2.01 (m, 2H, CH2CH2N),
2.19 (dd, J¼14.4, 8.9, 1H, CHHAr), 2.38–2.42 (m, 2H,
CH2CO), 2.66 (ddd, J¼8.0, 7.1, 4.6, 1H, CHN), 3.02 (dd,
J¼14.4, 4.9, 1H, CHHAr), 3.29–3.39 (m, 2H, CH2N),
7.18–7.30 (m, 5H, Ar-H); 13C NMR (cis, 125 MHz,
CDCl3): d 10.3, 18.2, 18.5, 30.4, 31.6, 33.8, 49.1, 125.8,
128.2, 141.1, 176.9; MS (FAB) m/z (%): 216 (M+H, 100),
124 (63), 91 (29); HRMS: M+, found 215.13149.
C14H17NO requires 215.1310.
4.1.17. ( )-1-((1R,2R,3S)-2,3-Dibutylcyclopropyl)pyrro-
lidin-2-one and ( )-1-((1S,2R,3S)-2,3-dibutylcyclopro-
pyl)pyrrolidin-2-one 43. Colourless oil; IR (mixture of
trans and cis, film): nmax 2956 (s), 2929 (s), 2857, 1699
1
(s), 1464, 1417 cmꢁ1; H NMR (trans, 400 MHz, CDCl3):
d 0.88 (t, J¼7.1, 6H, 2ꢂMe), 0.98–1.02 (m, 2H, 2ꢂCHBu),
1.22–1.50 (m, 12H, 6ꢂCH2), 1.98 (tt, J¼8.1, 7.0, 2H,
CH2CH2N), 2.01 (t, J¼3.8, 1H, CHN), 2.32 (t, J¼8.1, 2H,
CH2CO), 3.25 (t, J¼7.0, 2H, CH2N); 13C NMR (trans,
100 MHz, CDCl3): d 14.1, 18.0, 22.6, 23.5, 23.5, 26.8,
1
31.8, 37.8, 47.4, 175.6; H NMR (cis, 400 MHz, CDCl3):
d 0.88 (t, J¼7.2, 6H, 2ꢂMe), 0.91–0.98 (m, 2H, 2ꢂCHBu),
1.16–1.51 (m, 12H, 6ꢂCH2), 1.98 (tt, J¼8.2, 7.7, 2H,
CH2CH2N), 2.31 (t, J¼8.2, 2H, CH2CO), 2.38 (t, J¼7.7,
1H, CHN), 3.25 (t, J¼7.0, 2H, CH2N); 13C NMR (cis,
100 MHz, CDCl3): d 14.1, 18.9, 19.8, 22.9, 23.4, 31.0,
32.4, 33.4, 48.8, 178.5; MS (EI) m/z (%): 238 (M+H, 100),
194 (25), 180 (95), 138 (13), 124 (43), 98 (73), 86 (43), 67
(10), 55 (13), 41 (34); HRMS: M+, found 237.20916.
C15H27NO requires 237.20925.
4.1.14. 1-(2-Phenylcyclopropyl)-2-pyrrolidinone (trans
and cis) 40. Colourless oil; IR (mixture of trans and cis,
film): nmax 2980 (s), 2886 (s), 1680 (s), 1499, 1459 cmꢁ1
;
1H NMR (trans, 500 MHz, CDCl3): d 1.28 (dt, J¼7.7, 6.3,
1H, CHHCHN), 1.39 (ddd, J¼9.8, 6.3, 4.6, 1H, CHHCHN),
1.96–2.03 (m, 2H, CH2CH2N), 2.17 (ddd, J¼9.9, 6.3, 3.6,
1H, CHCHN), 2.39 (t, J¼8.1, 2H, CH2CO), 2.78 (ddd,
J¼7.7, 4.6, 3.6, 1H, CHN), 3.35–3.40 (m, 2H, CH2N),
7.10–7.19 (m, 3H, Ar-H), 7.22–7.28 (m, 2H, Ar-H); 13C
NMR (trans, 125 MHz, CDCl3): d 14.7, 18.1, 22.7, 31.8,
34.9, 47.5, 126.1, 126.4, 128.4, 140.4, 175.9. 1H NMR
(cis, 500 MHz, CDCl3): d 1.37 (ddd, J¼9.1, 7.8, 6.8, 1H,
CHHCHN), 1.45–1.53 (m, 1H, CHHCH2N), 1.56–1.65 (m,
2H, CHHCHN and CHHCH2N), 2.10–2.22 (m, 3H, CHCHN
and CH2CO), 2.64 (ddd, J¼9.5, 8.5, 4.8, 1H, CHHN), 2.79
(td, J¼7.8, 4.9, 1H, CHN), 2.85 (ddd, J¼9.5, 8.0, 6.8, 1H,
CHHN), 7.07–7.14 (m, 3H, Ar-H), 7.17–7.21 (m, 2H,
Ar-H); 13C NMR (cis, 125 MHz, CDCl3): d 10.7, 18.0, 21.7,
4.1.18. 1-Bicyclo[4.1.0]hept-7-yl-2-pyrrolidinone (exo
and endo) 44. Colourless oil; IR (mixture of exo and
endo, film): nmax 2927 (s), 2853 (s), 1682 (s), 1418
(s) cmꢁ1 1H NMR (exo, 500 MHz, C6D6): d 0.93–1.00
;
(m, 2H), 1.03–1.11 (m, 4H), 1.21 (tt, J¼8.0, 7.0, 2H,
CH2CH2N), 1.65–1.79 (m, 4H), 1.97 (t, J¼8.0, 2H,
CH2CO), 2.22 (t, J¼3.7, 1H, CHN), 2.57 (t, J¼7.0, 2H,
CH2N); 13C NMR (exo, 125 MHz, C6D6): d 17.2, 18.1,
21.6, 22.7, 31.6, 36.9, 46.4, 174.4. 1H NMR (endo,
500 MHz, C6D6): d 0.87–0.92 (m, 2H, 2ꢂCHCHN),

W. B. Motherwell et al. / Tetrahedron 63 (2007) 6462–6476
6471
0.93–1.13 (m, 4H), 1.29 (tt, J¼7.9, 6.9, 2H, CH2CH2N),
1.65–1.79 (m, 4H), 1.93 (t, J¼7.9, 2H, CH2CO), 2.04 (t,
J¼7.7, 1H, CHN), 2.79 (t, J¼6.9, 2H, CH2N); 13C NMR
(endo, 125 MHz, C6D6): d 13.0, 18.9, 20.2, 22.5, 30.9,
34.0, 48.0, 176.7; MS (EI) m/z (%): 179 (M+, 100), 150
(32), 136 (15), 124 (20), 108 (10), 98 (32), 94 (30), 79
(19), 72 (30), 59 (57), 55 (48); HRMS: M+, found
179.13102. C11H17NO requires 179.1310.
4H, 4ꢂOCH2CH), 1.63 (dd, J¼8.7, 5.8, 2H), 1.67–1.71
(m, 2H), 1.89–2.03 (m, 8H, 4ꢂCH2CH2N), 2.25–2.31 (m,
4H, 2ꢂCH2), 2.37 (t, J¼8.4, 4H, 2ꢂCH2), 2.69 (t, J¼6.8,
2H, 2ꢂCHN), 2.99 (dd, J¼8.5, 5.7, 2H, 2ꢂCHN), 3.20–
3.36 (m, 6H), 3.49 (dt, J¼8.9, 7.5, 2H), 3.85–3.98 (m, 8H,
4ꢂOCH2CH); 13C NMR (diastereomeric mixture of trans
and cis, 125 MHz, CDCl3): d 10.9, 11.0, 13.3, 18.3, 18.4,
19.2, 20.5, 20.8, 22.9, 23.7, 23.8, 24.3, 26.2, 29.3, 30.3,
30.4, 38.6, 38.7, 40.4, 48.0, 48.9, 67.1, 67.2, 67.3, 172.2,
174.0, 176.4, 176.5; MS (EI) m/z (%): 296 (M+H, 100),
183 (60), 165 (65), 138 (85), 98 (64), 71 (14), 57 (27), 41
(49); HRMS: M+H, found 296.22254. C17H30NO3 requires
296.22234.
4.1.19. 1-(1-Methylbicyclo[4.1.0]hept-7-yl)-2-pyrrolidi-
none (exo and endo) 45. Colourless oil; IR (mixture of
exo and endo, film): nmax 2929 (s), 2861, 1693 (s), 1492
(w), 1412 cmꢁ1 1H NMR (mixture of exo and endo,
;
500 MHz, C6D6): d 0.73 (td, J¼7.9, 2.6, 1H, CHCHN),
0.90 (ddd, J¼7.5, 4.1, 1.7, 1H, CHCHN), 0.96–1.22 (m,
14H), 1.27–1.35 (m, 4H, CH2CH2N), 1.47–1.66 (m, 4H),
1.75–1.90 (m, 5H), 1.91–1.96 (m, 2H), 1.98–2.03 (m, 2H),
2.09 (d, J¼4.2, 1H, CHN), 2.66 (dt, J¼9.3, 7.0, 1H), 2.68
(dt, J¼9.3, 7.0, 1H), 2.78 (dt, J¼9.3, 7.0, 1H), 2.80 (dt,
J¼9.3, 6.3, 1H); 13C NMR (mixture of exo and endo,
125 MHz, C6D6): d 18.2, 18.6, 19.0, 20.4, 21.6, 21.7, 21.7,
21.9, 22.1, 22.3, 22.4, 23.2, 23.5, 27.8, 28.0, 30.5, 31.0,
31.4, 41.2, 41.4, 47.9, 48.1, 175.2, 176.6; MS (EI) m/z
(%): 193 (M+, 67), 178 (45), 164 (20), 150 (15), 124 (10),
108 (83), 98 (53), 93 (55), 86 (100), 79 (18), 55 (14).
HRMS: M+, found 193.14610. C12H19NO requires
193.14655.
4.1.22. [2-(2-Oxopyrrolidin-1-yl)-cyclopropyl]benzoate
(trans and cis) 48. Colourless oil; IR (mixture of trans and
cis, film): nmax 2961, 1726 (s), 1689 (s), 1615 (w), 1452,
1420 (s) cmꢁ1
;
1H NMR (trans, 500 MHz, CDCl3):
d 1.40–1.43 (m, 2H), 1.89–1.98 (m, 2H, CH2CH2N), 2.36
(t, J¼8.4, 2H, CH2CO), 2.80 (ddd, J¼7.8, 7.0, 5.4, 1H,
CHN), 3.33–3.43 (m, 2H, CH2N), 4.44 (q, J¼5.4, 1H,
CHOCO), 7.38–7.42 (m, 2H, Ar-H), 7.51–7.56 (m, 1H,
Ar-H), 7.90–7.94 (m, 2H, Ar-H); 13C NMR (trans,
125 MHz, CDCl3): d 11.2, 18.5, 29.0, 31.5, 48.2, 50.6,
1
128.4, 129.3, 129.3, 133.2, 166.8, 176.7. H NMR (cis,
500 MHz, CDCl3): d 1.44–1.48 (m, 2H, CH2CHN), 1.95–
2.07 (m, 2H, CH2CH2N), 2.37 (t, J¼8.4, 2H, CH2CO),
2.85 (ddd, J¼9.0, 6.6, 1.8, 1H, CHN), 3.45–3.53 (m, 2H,
CH2N), 4.33 (ddd, J¼6.6, 5.4, 1.8, 1H, CHO), 7.38–7.42
(m, 2H, Ar-H), 7.51–7.56 (m, 1H, Ar-H), 7.90–7.94 (m,
2H, Ar-H); 13C NMR (cis, 125 MHz, CDCl3): d 14.0, 18.5,
31.4, 31.6, 47.4, 52.6, 128.4, 129.3, 129.6, 133.3, 167.1,
176.2; MS (EI) m/z (%): 245 (M+, 74), 216 (24), 162 (61),
154 (22), 141 (86), 124 (100), 114 (100), 106 (89), 94
(87), 84 (90), 77 (86); HRMS: M+, found 245.10578.
C14H15NO3 requires 245.10519.
4.1.20. 2-Ethylhexyl-[2-(2-oxopyrrolidin-1-yl)-cyclopro-
pyl]carboxylate (trans and cis) 46. Colourless oil; IR (dia-
stereomeric mixture of trans and cis, film): nmax 2961 (s),
2934 (s), 2875, 2862, 1741 (s), 1698 (s), 1460 (s), 1420
(s) cmꢁ1; 1H NMR (diastereomeric mixture of trans-cyclo-
propanes, 500 MHz, CDCl3): d 0.74 (t, J¼7.2, 12H,
4ꢂCH3), 1.05–1.21 (m, 10H), 1.22 (td, J¼7.6, 5.5, 2H),
1.26–1.51 (m, 8H), 1.80–1.93 (m, 4H, 2ꢂCH2CH2N), 2.10
(tt, J¼8.8, 5.5, 2H, 2ꢂOCOCH), 2.22 (t, J¼8.3, 4H,
2ꢂCH2CO), 2.57 (ddd, J¼7.4, 5.3, 1.8, 2H, 2ꢂCHN),
3.26–3.38 (m, 4H, 2ꢂCH2N), 3.97 (ddd, J¼7.4, 4.4, 1.8,
2H, 2ꢂCHOCO); 13C NMR (diastereomeric mixture of
trans-cyclopropanes, 125 MHz, CDCl3): d 11.5, 13.6, 17.8,
22.3, 25.0, 29.2, 31.1, 31.3, 46.6, 47.0, 51.7, 175.8, 176.2,
4.1.23. 1-(2-Trimethylsilanylcyclopropyl)-2-pyrrolidi-
none 49. Colourless oil; IR (film): nmax 2954 (s), 2894,
1694 (s), 1419 (s) cmꢁ1 1H NMR (trans, 500 MHz,
;
CDCl3): d ꢁ0.12 (ddd, J¼11.3, 8.2, 5.3, 1H, CHSi), ꢁ0.06
(s, 9H, Si(CH3)3), 0.63 (ddd, J¼8.2, 6.5, 4.8, 1H,
CHHCHN), 0.89 (ddd, J¼11.3, 4.8, 3.6, 1H, CHHCHN),
1.84–1.94 (m, 2H, CH2CH2N), 2.31 (t, J¼8.0, 2H,
CH2CO), 2.50 (ddd, J¼6.5, 5.3, 3.6, 1H, CHN), 3.18–3.22
(m, 2H, CH2N); 13C NMR (trans, 125 MHz, CDCl3):
d ꢁ2.6, 4.2, 8.6, 18.0, 29.1, 31.2, 47.2, 175.8; MS (EI) m/z
(%): 197 (M+, 40), 182 (66), 168 (36), 154 (27), 142 (66),
124 (11), 73 (100), 59 (22); HRMS: M+, found 197.12332.
C10H19NOSi requires 197.12355.
1
176.7. H NMR (diastereomeric mixture of cis cyclopro-
panes, 300 MHz, CDCl3): d 0.83 (t, J¼7.3, 12H, 4ꢂCH3),
1.13–1.57 (m, 20H), 1.89–2.01 (m, 4H, 2ꢂCH2CH2N),
2.19 (tt, J¼8.2, 5.6, 2H, 2ꢂOCOCH), 2.34 (t, J¼8.1, 4H,
2ꢂCH2CO), 2.65–2.70 (m, 2H, 2ꢂCHN), 3.26–3.43 (m,
4H, 2ꢂCH2N), 4.14 (td, J¼7.1, 4.1, 1H, 2ꢂCHOCO), 4.15
(td, J¼7.1, 4.1, 1H, 2ꢂCHOCO); 13C NMR (diastereomeric
mixture of cis cyclopropanes, 125 MHz, CDCl3): d 11.2,
11.6, 13.8, 18.3, 22.5, 25.0, 25.3, 28.7, 29.4, 31.3, 31.5,
31.6, 47.0, 48.1, 49.7, 176.3, 176.5; MS (EI) m/z (%): 268
(M+H, 49), 140 (99), 124 (32), 112 (87), 99 (28), 84 (11),
69 (42), 57 (100), 41 (73); HRMS: M+H, found
268.19116. C15H26NO3 requires 268.19124.
4.1.24. 1-[2-(Benzyldimethylsilanyl)-cyclopropyl]-2-
pyrrolidinone 50. Colourless oil; IR (film): nmax 2953
1
(m), 2891 (w), 1689 (s), 1493 (m), 1419 (m) cmꢁ1; H
NMR (500 MHz, CDCl3): d ꢁ0.10 (s, 3H, SiMe), ꢁ0.08
(ddd, J¼11.3, 8.2, 5.3, 1H, CHSi), ꢁ0.05 (s, 3H, SiMe),
0.64 (ddd, J¼8.2, 6.7, 5.0, 1H, CHHCHN), 0.92 (ddd,
J¼11.3, 5.0, 3.7, 1H, CHHCHN), 1.87–1.95 (m, 2H,
CH2CH2N), 2.13 (s, 2H, CH2Ph), 2.34 (t, J¼8.0, 2H,
CH2CO), 2.61 (ddd, J¼6.7, 5.3, 3.7, 1H, CHN), 3.16 (t,
J¼7.0, 2H, CH2N), 6.99–7.06 (m, 3H, Ar-H), 7.15–7.20
(m, 2H, Ar-H); 13C NMR (125 MHz, CDCl3): d ꢁ4.8,
ꢁ4.6, 2.7, 8.4, 18.0, 25.2, 29.1, 31.9, 47.0, 124.0, 128.1,
4.1.21. 2-Ethylhexyl-[1-methyl-2-(2-oxopyrrolidin-1-yl)-
cyclopropyl]carboxylate (trans and cis) 47. Colourless
oil; IR (diastereomeric mixture of trans and cis, film): nmax
2975 (s), 2931 (s), 2865, 1700 (s), 1459 (w), 1419
1
(w) cmꢁ1; H NMR (diastereomeric mixture of trans and
cis, 500 MHz, CDCl3): d 0.85 (t, J¼7.0, 24H, 8ꢂCH3),
1.04 (t, J¼6.8, 2H), 1.18–1.35 (m, 46H), 1.49–1.56 (m,

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W. B. Motherwell et al. / Tetrahedron 63 (2007) 6462–6476
128.2, 139.8, 175.9; MS (EI) m/z (%): 273 (M+, 62), 258
(24), 218 (24), 182 (92), 149 (100), 121 (86), 97 (31), 91
(23); HRMS: M+, found 273.15083. C16H23NOSi requires
273.15488.
CDCl3): 8.6, 13.9, 16.6, 18.1, 29.5, 31.4, 48.8, 60.5, 67.6,
70.2, 170.0, 176.9; MS (CI+) m/z (%): 242 (M+H,
71), 214 (39), 195 (31), 138 (100); HRMS: M+H, found
242.13896. C12H20NO4 requires 242.13923.
4.1.25. trans-2-(2-Oxopyrrolidin-1-yl)cyclopropyl-
methylbenzoate 51. Colourless oil; IR (film): nmax 2924,
4.1.29. 1-(2,2,3,3-Tetramethylcyclopropyl)pyrrolidin-2-
one 55. Colourless oil; IR (film): nmax 2924 (s), 2870 (s),
1
1786 (s), 1717 (s), 1682 (s) cmꢁ1
;
1H NMR (trans,
1682 (s) cmꢁ1; H NMR (400 MHz, CDCl3): d 0.99 (s,
300 MHz, CDCl3): d 0.94 (m, 1H, CHHCHN), 1.10 (m,
1H, CHHCHN), 1.56 (m, 1H, CHCH2O), 1.97 (m, 2H,
CH2CH2N), 2.37, (t, J¼8.0, 2H, CH2CON), 2.67 (dt,
J¼7.6, 3.7, 1H, CHN), 3.31 (t, J¼7.0, 2H, CH2N), 4.17
(dd, J¼11.6, 7.6, 1H, CHHO2Ph), 4.32 (dd, J¼11.6, 6.6,
1H, CHHO2CPh), 7.44 (dd, J¼7.5, 7.9, 2H, meta-Ar), 7.56
(t, J¼7.5, 1H, para-Ar), 8.06 (d, J¼7.9, 2H, ortho-Ar);
13C NMR (trans, 75 MHz, CDCl3): 10.6, 17.3, 18.0,
30.6, 31.7, 47.5, 66.6, 128.4, 129.6, 130.2, 133.0, 166.6,
176.0; MS (CI+) m/z (%): 260 (M+H, 70), 138 (100);
HRMS: M+H, found 260.12885. C15H18NO3 requires
260.12866.
6H, 2ꢂMe), 1.08 (s, 6H, 2ꢂMe), 1.72 (s, 1H, CHN), 1.94
(m, 2H, CH2), 2.28 (t, J¼8.0, 2H, CH2CO), 3.29 (t, J 6.9,
2H, CH2N); 13C NMR (100 MHz, CDCl3): 17.6, 18.8,
22.0, 23.2, 31.0, 46.1, 48.6, 177.9; MS (EI) m/z (%): 182
(M+H, 100), 166 (15), 154 (15); HRMS: M+H, found
182.15411. C11H21NO requires 182.15448.
4.1.30. 3-(2-Benzylcyclopropyl)-2-oxazolidinone 56. Col-
ourless oil; IR (mixture of trans and cis, film): nmax 3003
(w), 2915 (w), 1742 (s), 1604 (w), 1482 (w), 1419 (w) cmꢁ1
;
1H NMR (trans, 500 MHz, CDCl3): d 0.82 (dt, J¼7.1, 6.1,
1H, CHHCHN), 1.03 (ddd, J¼9.5, 6.1, 3.5, 1H, CHHCHN),
1.36 (dtdd, J¼9.5, 6.9, 6.1, 3.5, 1H, CHCHN), 2.40
(dt, J¼7.1, 3.5, 1H, CHN), 2.59 (dd, J¼14.5, 6.9, 1H,
CHHPh), 2.72 (dd, J¼14.5, 6.9, 1H, CHHPh), 3.38–3.42
(m, 2H, CH2N), 4.19–4.25 (m, 2H, CH2O), 7.20–7.32 (m,
5H, Ar-H); 13C NMR (trans, 125 MHz, CDCl3): d 13.0,
20.3, 32.1, 37.8, 45.7, 61.8, 126.2, 128.2, 128.3, 140.5,
4.1.26. endo-1-(1,1a,6,6a-Tetrahydro-cyclopropainden-
1-yl)-pyrrolidin-2-one 52. White needles; mp 53–54 ꢀC
(CH2Cl2–petrol); IR (film): nmax 3036 (s), 2965 (s), 2912
(s), 2872 (s), 1693 (s) cmꢁ1 1H NMR (exo, 300 MHz,
;
CDCl3): d 1.12–1.26 (m, 1H, CHHCH2N), 1.62 (ddddd,
J¼11.6, 8.8, 7.9, 4.7, 3.5, 1H, CHHCH2N), 2.05–2.15 (m,
2H, CH2CO), 2.25–2.33 (m, 1H, CH2CH), 2.45 (ddd,
J¼9.4, 8.6, 3.5, 1H, CHHN), 2.68 (dd, J 7.1, 6.5, 1H,
ArCH), 2.77 (br t, J¼7.1, 1H, CHN), 2.99 (dt, J¼9.4, 7.9,
1H, CHHN), 3.05–3.12 (m, 2H, ArCH2), 7.03–7.10 (m,
3H, Ar-H), 7.29–7.34 (m, 1H, Ar-H); 13C NMR (endo,
125 MHz, CDCl3): 18.8, 23.2, 28.6, 31.1, 32.2, 34.8, 47.4,
123.7, 124.9, 125.7, 126.2, 139.7, 144.1, 177.5. MS (CI+)
m/z (%): 214 (M+H, 100), 129 (60), 98 (42), 86 (40);
HRMS: M+H, found 214.12298. C14H16NO requires
214.12318.
1
158.4. H NMR (cis, 500 MHz, CDCl3): d 0.78 (td, J¼6.3,
4.2, 1H, CHHCHN), 1.05–1.15 (m, 2H, CHHCHN and
CHCHN), 2.44 (dd, J¼15.4, 9.2, 1H, CHHPh), 2.65 (ddd,
J¼7.7, 6.9, 4.2, 1H, CHN), 3.11 (dd, J¼15.4, 5.1, 1H,
CHHPh), 3.51–3.57 (m, 2H, CH2N), 4.28–4.33 (m, 2H,
CH2O), 7.20–7.32 (m, 5H, Ar-H); 13C NMR (cis,
100 MHz, CDCl3): d 11.1, 18.7, 31.0, 33.7, 46.9, 62.0,
126.0, 128.2, 141.0, 159.7; MS (CI+) m/z (%): 218 (M+H,
17), 126 (100), 115 (11), 104 (15), 91 (22), 82 (12), 77 (7),
65 (8), 54 (9); HRMS: M+H, found 218.11777.
C13H16NO2 requires 218.11809.
4.1.27. 1-(1a,2,3,7b-Tetrahydro-1H-cyclopropa[a]naph-
thalen-1-yl)-pyrrolidin-2-one 53 (endo and exo). Colour-
4.1.31. 3-(2-tert-Butylcyclopropyl)-2-oxazolidinone 57.
Pale yellow oil; IR (film): nmax 2958, 2869 (s), 1755 (s),
1
less oil; IR (film): nmax 2926, 2856, 1693 (s) cmꢁ1
;
1H
1482 (w), 1423 cmꢁ1; H NMR (trans, 500 MHz, CDCl3):
NMR (trans, 500 MHz, CDCl3): (mixture of isomers)
d 1.40–3.05 (m, 12H, CH2 and CH), 3.25–3.42 (m, 1H),
6.90–7.15 (m, 3H, Ar-H), 7.20–7.35 (m, 1H, Ar-H); 13C
NMR (mixture of isomers, 125 MHz, CDCl3): 17.9, 18.0,
18.1, 18.6, 18.9, 19.5, 21.1, 22.3, 26.0, 27.4, 31.0, 31.7,
34.0, 37.3, 47.3, 47.7, 125.5, 125.8, 125.9, 126.1, 128.5,
128.6, 128.7, 130.3, 133.2, 133.9, 135.4, 135.5, 175.7,
177.7; MS (EI) m/z (%): 227 (M+, 10), 142 (100), 128
(25), 115 (20), 99 (62), 86 (45); HRMS: M+, found
227.13122. C15H17NO requires 227.13101.
d 0.75 (td, J¼7.3, 5.9, 1H, CHHCHN), 0.80 (ddd, J¼9.8,
5.9, 3.7, 1H, CHHCHN), 0.85 (s, 9H, 3ꢂMe), 0.95 (ddd,
J¼9.8, 7.3, 3.7, 1H, CHCHN), 2.35 (dt, J¼7.3, 3.7, 1H,
CHN), 3.45–3.50 (m, 2H, CH2N), 4.22 (m, 2H, CH2O);
13C NMR (125 MHz, CDCl3): d 9.4, 28.2, 28.7, 29.0, 30.6,
45.8, 61.6, 158.4; MS (EI) m/z (%): 183 (M+, 7), 168 (6),
127 (100), 114 (31), 82 (18), 70 (31), 55 (43), 49 (12), 42
(60); HRMS: M+H, found 184.13305. C10H18NO2 requires
184.13321.
4.1.32. ( )-Ethyl 2-((1R,2S,5S,6R)-6-(2-oxooxazolidin-3-
yl)bicyclo[3.1.0]hexan-2-yl)acetate 58a and ( )-ethyl 2-
((1R,2R,5S,6R)-6-(2-oxooxazolidin-3-yl)bicyclo[3.1.0]-
hexan-2-yl)acetate 58b. Pale yellow oil; IR (mixture of 58a
and 58b, film): nmax 2954, 1732 (s), 1417 (s) cmꢁ1; 1H NMR
(major isomer 58a, 500 MHz, CDCl3): d 1.20 (t, J¼7.2, 3H,
CH3), 1.28–1.33 (m, 1H, CHHCHCH2), 1.35–1.45 (m, 1H,
CHHCHCH2), 1.45–1.49 (m, 1H, CHCHN), 1.69–1.72 (m,
1H, CHCHN), 1.78–1.84 (m, 1H, CHHCHCHN), 1.84–
1.91 (m, 1H, CHHCHCHN), 2.20 (dd, J¼15.1, 8.2, 1H,
CHHCOO), 2.28 (t, J¼1.9, 1H, CHN), 2.32 (dd, J¼15.1,
7.1, 1H, CHHCOO), 2.62 (br q, J¼7.5, 1H, CHCH2CO),
4.1.28. Ethyl 2-cis-((2-(2-oxopyrrolidin-1-yl)cyclopro-
pyl)methoxy)acetate 54. Colourless oil; IR (film): nmax
1
2980, 1751 (s), 1690 (s) cmꢁ1; H NMR (cis, 300 MHz,
CDCl3): d 0.92 (td, J¼6.3, 4.7, 1H, CHHCHN), 1.08 (ddd,
J¼9.0, 7.7, 6.3, 1H, CHHCHN), 1.27 (t, J¼7.1, 3H, Me),
1.35–1.47 (m, 1H, CHCHN), 1.91–2.03 (m, 2H, CH2CH2N),
2.33–2.41 (m, 2H, CH2CO), 2.54–2.62 (ddd, J¼7.7, 6.8, 4.7,
1H, CHN), 3.31 (dt, J¼14.7, 7.0, 1H, CHHN), 3.37 (dd,
J¼10.0, 6.8, 1H, CHHOR), 3.44–3.57 (m, 1H, CHHN),
3.62 (dd, J¼10.0, 7.5, 1H, CHHOR), 4.05–4.25 (m, 4H,
CH2Me and CH2CO2Et); 13C NMR (cis, 125 MHz,

W. B. Motherwell et al. / Tetrahedron 63 (2007) 6462–6476
6473
3.47–3.51 (m, 2H, CH2N), 4.14 (q, J¼7.2, 2H, CH2CH3),
4.22–4.27 (m, 2H, CH2OCON); 13C NMR (major isomer
58a, 125 MHz, CDCl3): d 14.2, 24.7, 24.8, 27.0, 29.7,
33.4, 36.5, 39.8, 45.7, 60.3, 61.8, 158.3, 172.5. 1H NMR (mi-
nor isomer 58b, 500 MHz, CDCl3): d 0.68–0.77 (m, 1H,
CHHCHCH2), 1.26 (t, J¼7.1, 3H, CH3), 1.60–1.65 (m,
1H, CHCHN), 1.69–1.73 (m, 1H, CHCHN), 1.73–1.79 (m,
1H, CHHCHCH2), 1.79–1.88 (m, 1H, CHHCHCHN), 1.95
(dd, J¼12.9, 8.1, 1H, CHHCHCHN), 2.28 (br t, J¼1.9,
1H, CHN), 2.40 (dd, J¼15.2, 7.1, 1H, CHHCOO), 2.46
(dd, J¼15.2, 7.6, 1H, CHHCOO), 2.56–2.65 (m, 1H,
CHCH2CO), 3.43–3.51 (m, 2H, CH2N), 4.14 (q, J¼7.1,
2H, CH2CH3), 4.19–4.28 (m, 2H, CH2OCON); 13C NMR
(minor isomer 58b, 125 MHz, CDCl3): d 14.3, 25.5, 27.0,
27.6, 28.9, 30.8, 36.6, 37.8, 45.7, 60.3, 61.8, 158.4, 173.0;
MS (CI+) m/z (%): 254 (M+H, 100), 208 (95), 166 (60),
88 (14); HRMS: M+H, found 254.13872, C13H20O4N
requires 254.13923.
2.23–2.31 (m, 1H, CHHC]CH), 3.43–3.56 (m, 2H,
CH2N), 4.12 (q, J¼7.1, 2H, CH2CH3), 4.22–4.30 (m, 2H,
CH2OC]O), 5.64 (br s, 1H, CHCOO); 13C NMR (cis,
125 MHz, CDCl3): d 14.3, 14.9, 18.9, 19.5, 22.8, 22.9,
27.0, 27.8, 40.9, 46.9, 59.5, 62.2, 115.8, 159.5, 160.4,
166.7; MS (FAB) m/z (%): 296 (M+H, 28), 250 (70), 219
(100), 163 (66), 154 (72); HRMS: M+H, found 296.18541,
C16H26O4N requires 296.18617.
4.1.36. 2-(2-Benzylcyclopropyl)-2,3-dihydro-1-isoindoli-
none 62. Pale yellow solid; mp (trans) 62–63 ꢀC (i-Pr2O);
IR (mixture of trans and cis, film): nmax 3027 (w), 2914
(w), 1685 (s), 1620 (w), 1496 (w), 1469 (m), 1453 (m),
1408 (m) cmꢁ1
;
1H NMR (trans, 500 MHz, CDCl3):
d 0.93 (td, J¼7.1, 6.0, 1H, CHHCHN), 1.15 (ddd, J¼9.6,
6.0, 4.0, CHHCHN), 1.50 (dtdd, J¼9.6, 7.1, 6.4, 3.4, 1H,
CHCHN), 2.67 (dd, J¼14.7, 7.1, 1H, CHHPh), 2.80–2.89
(m, 2H, CHN and CHHPh), 4.20 (s, 2H, CH2Ar), 7.20–
7.53 (m, 8H, Ar-H), 7.82 (td, J¼7.5, 1.0, 1H, Ar-H); 13C
NMR (trans, 125 MHz, CDCl3): d 12.8, 20.0, 31.6, 38.2,
50.1, 122.5, 123.4, 126.2, 127.9, 128.4, 128.4, 131.2,
133.2, 140.6, 140.9, 169.3. 1H NMR (cis, 500 MHz,
CDCl3): d 0.90–0.97 (m, 1H), 1.11–1.19 (m, 2H), 2.24
(dd, J¼15.0, 4.9, 1H, CHHPh), 3.03 (td, J¼7.5, 4.5, 1H,
CHN), 3.15 (dd, J¼15.0, 4.9, 1H, CHHPh), 4.30 (d,
J¼17.0, 1H, CHHAr), 4.32 (d, J¼17.0, 1H, CHHAr),
7.17–7.57 (m, 8H, Ar-H), 7.88 (td, J¼7.4, 1.0, 1H, Ar-H);
13C NMR (cis, 125 MHz, CDCl3): d 10.6, 19.2, 30.5, 34.0,
51.8, 122.6, 123.6, 125.9, 128.0, 128.3, 128.4, 131.3,
133.1, 141.1, 141.3, 170.3; MS (EI) m/z (%): 263 (M+,
13), 222 (8), 172 (100), 146 (9), 132 (7), 115 (9), 91 (29),
77 (8), 65 (8), 51 (7); HRMS: M+, found 263.13096.
C18H17NO requires 263.13101.
4.1.33. Methyl 3-(1-chloro-2-(2-oxooxazolidin-3-yl)cyclo-
propyl)-2,2-dimethylpropanoate 59.22 White solid; mp
46–49 ꢀC (petrol); IR (mixture of trans and cis, film): nmax
1634 (s), 1427 (w) cmꢁ1 1H NMR (trans, 500 MHz,
;
CDCl3): d 1.28 (s, 3H, CH3CCH3), 1.29 (s, 3H, CH3CCH3),
1.36 (dd, J¼9.0, 7.9, 1H, CHHCHN), 1.59 (ddd, J¼7.9, 5.5,
1.0, 1H, CHHCHN), 2.01 (d, J¼15.2, 1H, CHHCCHN), 2.11
(dd, J¼15.2, 1.0, 1H, CHHCCHN), 2.51 (dd, J¼9.0, 5.5, 1H,
CHN), 3.56–3.64 (m, 1H, CHHN), 3.68 (s, 3H, CH3O),
3.74–3.80 (m, 1H, CHHN), 4.25–4.37 (m, 2H, CH2OCO);
13C NMR (cis, 125 MHz, CDCl3): d 22.0, 25.8, 25.8, 36.7,
42.2, 44.5, 45.6, 48.5, 51.9, 61.9, 158.5, 177.1; MS (CI+)
m/z (%): 276 (M+H, 14), 244 (28), 216 (100), 180 (16);
HRMS: M+H, found 276.09988, C12H19O4NCl requires
276.10025.
4.1.37. N-Benzyl-N-(2-benzylcyclopropyl)acetamide 63.
Colourless oil; IR (mixture of trans and cis, film): nmax
3026 (w), 2924 (w), 1655 (s), 1603 (w), 1495 (w), 1452
4.1.34. trans-8-endo-(2-Oxooxazolidin-3-yl)-1,4,4-tri-
methyl-tricyclo[5.1.0.0]octane 60. White solid; mp 60–
64 ꢀC (petrol); [a]D20 ꢁ27.1 (c 1.0, CHCl3); IR (mixture,
(w) cmꢁ1 1H NMR (trans, 500 MHz, CDCl3): d 0.78
;
1
film): nmax 2864 (w), 1755, 1634, 1404 cmꢁ1; H NMR
(ddd, J¼7.1, 6.2, 5.5, 1H, CHHCHN), 0.95 (ddd, J¼9.5,
5.5, 4.0, 1H, CHHCHN), 1.37 (ddtd, J¼9.5, 7.5, 6.2, 3.5,
1H, CHCHN), 2.16 (s, 3H, Me), 2.33–2.44 (m, 1H, CHN),
2.42 (dd, J¼14.5, 7.5, 1H, CHCHHPh), 2.66 (dd, J¼14.5,
6.2, 1H, CHCHHPh), 4.45 (d, J¼14.8, 1H, CHHPh), 4.53
(d, J¼14.8, 1H, CHHPh), 7.08–7.12 (m, 4H, Ar-H), 7.19–
7.31 (m, 6H, Ar-H); 13C NMR (trans, 125 MHz, CDCl3):
d 15.9, 22.7, 23.3, 36.8, 37.7, 49.6, 126.3, 126.9, 128.4,
128.5, 138.1, 139.7, 173.3; MS (EI) m/z (%): 279 (M+,
65), 264 (37), 236 (100), 188 (100), 148 (74), 131 (66),
106 (52), 91 (82), 77 (24); HRMS: M+, found 279.16205.
C19H21NO requires 279.16231.
(endo, 500 MHz, CDCl3): d 0.37 (td, J¼9.4, 3.2, 1H,
CHCMe2), 0.43 (td, J¼9.4, 3.2, 1H, CHCMe2), 0.77 (s, 3H,
CH3CCHN), 0.82 (m, 1H, CHCHN), 0.98 (s, 3H, CH3CCH3),
1.02 (s, 3H, CH3CCH3), 1.30 (dd, J¼15.7, 3.2, 1H,
CHHCCH3), 1.63 (ddd, J¼15.7, 5.8, 3.2, 1H, CHHCHCHN),
2.08 (d, J¼7.7, 1H, CHN), 2.27 (dd, J¼15.7, 9.4, 1H,
CHHCCH3), 2.28 (dd, J¼15.7, 9.4, 1H, CHHCHCHN),
3.63 (t, J¼7.8, 2H, CH2N), 4.24–4.28 (m, 2H, CH2O); 13C
NMR (cis, 125 MHz, CDCl3): d 13.9, 15.1, 16.1, 16.9,
17.1, 17.7, 20.3, 21.3, 26.5, 27.8, 38.1, 46.5, 62.4, 159.8;
MS (CI+) m/z (%): 236 (M+H, 43), 149 (100), 100 (22), 88
(48); HRMS: M+H, found 236.16482, C14H22O2N requires
236.16505. Anal. Calcd for C14H21O2N: C, 71.46; H, 8.99;
N, 5.95. Found: C, 71.54; H, 9.12; N, 5.90.
4.1.38. trans-3-(2-Benzylcyclopropyl)benzoxazolin-2-one
64. Pale pink solid; mp 55–57 ꢀC (CH2Cl2–petrol); IR
(film): nmax 3063, 3026, 2924, 1771 (s), 1612 (w) cmꢁ1
;
4.1.35. (E)-Ethyl 5-(2,2-dimethyl-3-(2-oxooxazolidin-3-
yl)cyclopropyl)-3-methylpent-2-enoate 61. Pale yellow
liquid; IR (mixture of trans and cis, film): nmax 2955,
1H NMR (trans, 400 MHz, CDCl3): d 1.08–1.18 (m, 1H,
CHHCHN), 1.30–1.42 (m, 1H, CHHCHN), 1.55–1.70 (m,
1H, CHCHN), 2.73 (dt, J¼6.7, 3.4, 1H, CHN), 2.76 (dd,
J¼14.5, 7.5, 1H, CHHPh), 2.87 (dd, J¼14.5, 6.7, 1H,
CHHPh), 6.45 (d, J¼7.5, 1H, Ar-H), 6.94–7.40 (m, 8H,
Ar-H); 13C NMR (trans, 100 MHz, CDCl3): 13.3, 21.0,
28.8, 37.9, 109.0, 109.6, 122.2, 123.5, 126.5, 128.6, 128.7,
131.7, 139.7, 142.1, 154.2; MS (EI) m/z (%): 265 (M+,
65), 224 (25), 175 (55), 130 (100), 115 (50), 103 (90);
1759, 1709, 1643 (s) cmꢁ1 1H NMR (cis, 500 MHz,
;
CDCl3): d 0.74 (ddd, J¼8.9, 7.6, 5.4, 1H, CHCHN), 1.07
(s, 3H, CH3CCH3), 1.09 (s, 3H, CH3CCH3), 1.25 (br t,
J¼7.1, 3H, CH3CH2), 1.34–1.44 (m, 1H, CHHCH2), 1.76–
1.84 (m, 1H, CHHCH2), 2.10 (d, J¼7.6, 1H, CHN), 2.14
(s, 3H, CH3C]CH), 2.16–2.22 (m, 1H, CHHC]CH),

6474
W. B. Motherwell et al. / Tetrahedron 63 (2007) 6462–6476
HRMS: M+H, found 266.11833. C16H16NO2 requires
266.11810.
liquid (620 mg). Elution of the column with 1:1 Et2O–petrol
gave the starting alcohol (660 mg); IR (film): nmax 3028,
2922 (s), 2655 (s), 1508, 1456 (s) cmꢁ1
;
1H NMR
4.1.39. endo-3-(1,1a,6,6a-Tetrahydro-cyclopropainden-
1-yl)-3H-benzoxazolin-2-one 65. Pale pink needles; mp
185–186 ꢀC (CH2Cl2–petrol); IR (film): nmax 3042 (w),
(500 MHz, CDCl3): d 1.21 (t, J¼6.9, 3H, Me), 1.51–1.58
(m, 1H), 1.67 (dddd, 1H, J¼12.0, 9.1, 6.3, 2.5), 1.72–1.86
(m, 2H), 1.91–1.98 (m, 1H), 2.00–2.08 (m, 1H), 3.51
(dq, J¼9.1, 6.9, 1H, CHHMe), 3.57 (dq, J¼9.1, 6.9, 1H,
CHHMe), 3.81–3.86 (m, 1H, CHO), 5.75–5.79 (m, 1H,
HC]CH), 5.81–5.86 (m, 1H, HC]CH); 13C NMR
(125 MHz, CDCl3): d 15.8, 19.3, 25.2, 28.4, 63.4, 72.6,
128.0, 130.6.
3018 (w), 2926 (w), 2853 (w), 1771 (s), 1611 (w) cmꢁ1
;
1H NMR (endo, 400 MHz, CDCl3): d 2.35–2.42 (m, 1H,
CH2CH), 3.06 (t, J¼6.8, 1H, ArCH), 3.12–3.22 (m, 3H,
CH2 and CHN), 6.82–6.91 (m, 5H, Ar-H), 6.94–6.99 (m,
1H, Ar-H), 7.05 (d, J¼7.5, 1H, Ar-H), 7.34 (d, J¼6.8, 1H,
Ar-H); 13C NMR (endo, 100 MHz, CDCl3): d 21.8, 29.5,
32.0, 33.0, 109.6, 109.8, 122.2, 123.1, 123.4, 125.7, 126.1,
126.6, 131.0, 137.7, 142.3, 143.1, 154.5; MS (EI) m/z (%):
263 (M+, 65), 192 (30), 148 (40), 129 (100), 115 (50), 102
(32); HRMS: M+, found: 263.09589. C17H13NO2 requires
263.09462. Anal. Calcd for C17H13NO2: C, 77.55; H, 4.98;
N, 5.32. Found: C, 77.10; H, 4.89; N, 5.28.
4.1.43. 2-(2-tert-Butylcyclopropylamino)ethanol 71. Lith-
ium hydroxide monohydrate (1.24 g, 29.5 mmol, 30 equiv)
was added in one portion to a suspension of cyclopropane
57 (0.18 g, 0.98 mmol, 1 equiv) in a mixture of absolute eth-
anol (14 mL) and water (6 mL). The reaction mixture was
heated at reflux for 20 h and then allowed to cool to room
temperature. Most of the ethanol was removed in vacuo
and saturated aqueous ammonium chloride (5 mL) was
added to the residue. The aqueous layer was extracted with
dichloromethane (2ꢂ10 mL, then 2ꢂ5 mL) and the com-
bined organic extracts were dried (Na2SO4), filtered and
concentrated to give the aminoalcohol 71 (75 mg,
0.48 mmol, 49%) as a yellow oil; IR (film): nmax 3300 (br),
4.1.40. trans-1-(2-(Hydroxymethyl)cyclopropyl)pyrroli-
din-2-one 67. Colourless oil; IR (film): nmax 3297 (br),
1
2880, 1674 (s) cmꢁ1; H NMR (trans, 300 MHz, CDCl3):
d 0.72 (ddd, J¼7.5, 6.2, 5.9, 1H, CHHCHN), 0.90 (ddd,
J¼9.5, 5.9, 4.3, 1H, CHHCHN), 1.28–1.40 (tddd, J¼9.5,
6.2, 5.2, 3.5, 1H, CHCH2OH), 1.90–2.03 (m, 2H,
CH2CH2N), 2.32–2.41 (m, 3H, CHN and CH2CO), 3.15
(dd, J¼10.9, 9.5, 1H, CHHOH), 3.26–3.38 (m, 2H,
CH2N), 3.85 (dd, J¼10.9, 5.2, 1H, CHHOH); 13C NMR
(trans, 75 MHz, CDCl3): d 9.3, 17.8, 22.6, 30.2, 31.3,
47.3, 64.5, 177.0; MS (EI) m/z (%): 156 (M+H, 10), 138
(35), 124 (100), 96 (35), 86 (25); HRMS: M+, found:
155.09480. C8H13NO2 requires 155.09462.
1
2953 (s), 2866 (m), 1468 (m) cmꢁ1; H NMR (500 MHz,
CDCl3): d 0.34–0.41 (m, 2H, CH2CHN), 0.59 (ddd, J¼9.9,
6.2, 3.5, 1H, CHCHN), 0.77 (s, 9H, 3ꢂMe), 1.95 (dt,
J¼7.2, 3.5, 1H, CHN), 2.71–2.77 (m, 2H, CH2N), 2.90 (br
s, 2H, OH and NH), 3.57 (t, J¼5.5, 2H, CH2OH); 13C
NMR (100 MHz, CDCl3): d 9.4, 28.5, 28.9, 31.8, 33.3,
51.1, 60.5; MS (CI) m/z (%): 158 (M+H, 100), 100 (86);
HRMS: M+H, found 158.154382. C9H20NO requires
158.15448.
4.1.41. ( )-1-((1R,2R,6S,7S)-2-Ethoxybicyclo[4.1.0]hep-
tan-7-yl)pyrrolidin-2-one 69. White solid; mp 95–97 ꢀC
(CH2Cl2–petrol); IR (film): nmax 2936 (s), 2864 (s), 1682
4.1.44. tert-Butyl N-[(2-tert-butylcyclopropyl)-(2-hydroxy-
ethyl)]carbamate 72. Di-tert-butyl dicarbonate (106 mg,
0.49 mmol, 1.2 equiv) was added portionwise to a solution
of aminoalcohol 71 (64 mg, 0.407 mmol, 1 equiv) and tri-
ethylamine (0.07 mL, 0.51 mmol, 1.25 equiv) in dry di-
chloromethane (2 mL) under nitrogen. After stirring for
24 h, the reaction mixture was concentrated in vacuo. The
crude product was purified by flash column chromatography
(4:1–3:1 petrol–EtOAc) to give the title compound 72
(76 mg, 0.295 mmol, 72%) as a colourless oil; IR (film):
1
(s) cmꢁ1; H NMR (exo, 500 MHz, CDCl3): d 0.97–1.06
(m, 1H, CHHCHOEt), 1.06–1.13 (m, 1H, CHHCH2CHOEt),
1.17 (t, J¼6.9, 3H, Me), 1.30–1.36 (m, 1H, CHHCH2
CHOEt), 1.38–1.48 (m, 2H, CHCHN and CHCHOEt),
1.51–1.62 (m, 2H, CHHCHOEt and CHHCHCHN), 1.80–
1.98 (m, 3H, CH2CH2N and CHHCHCHN), 2.29 (t, J¼8.2,
2H, CH2CON), 2.51 (br t, J¼3.5, 1H, CHN), 3.26 (br
t, J¼6.8, 2H, CH2N), 3.45 (dq, J¼15.8, 6.9, 1H, CHHO),
3.73 (m, 2H, CHHO and CHO); 13C NMR (exo, 125 MHz,
CDCl3): d 15.5, 17.6, 19.9, 20.5, 21.2, 21.9, 28.0, 31.7,
35.1, 47.5, 63.0, 72.1, 175.7; MS (FAB) m/z (%): 224
(M+, 48), 178 (100); HRMS: M+, found: 224.16480.
C13H21NO2 requires 224.16505.
nmax 3450 (br), 2955 (s), 2870 (m), 1685 (s) cmꢁ1 1H
;
NMR (500 MHz, CDCl3): d 0.65 (ddd, J¼9.9, 5.8, 3.9,
1H, CHHCHN), 0.71 (ddd, J¼7.5, 6.8, 5.8, 1H, CHHCHN),
0.82 (s, 9H, 3ꢂMe), 0.85 (ddd, J¼9.9, 6.8, 3.9, 1H,
CHCHN), 1.42 (s, 9H, OC(CH3)3), 2.45 (dt, J¼7.5, 3.9,
1H, CHN), 3.29 (ddd, J¼14.6, 6.2, 4.6, 1H, CHHN), 3.41
(ddd, J¼14.6, 6.5, 4.5, 1H, CHHN), 3.57 (m, 2H,
CH2OH); 13C NMR (125 MHz, CDCl3): d 12.2, 28.4, 28.4,
29.1, 32.1, 32.2, 50.7, 62.4, 80.1, 158.2; MS (CI+) m/z
(%): 256 (MꢁH, 100), 200 (30), 182 (32), 156 (45), 147
(65), 138 (29); HRMS: MꢁH, found 256.191464.
C14H26NO4 requires 256.19126.
4.1.42. 2-Ethoxycyclohex-1-ene 70.23 Sodium hydride
(60% dispersion in mineral oil, 954 mg, 23.9 mmol) was
added portionwise to a solution of 2-cyclohexen-1-ol (2.21 g,
21.7 mmol) in anhydrous dimethylformamide (15 mL) under
nitrogen. After the addition was complete, the reaction
was cooled to 0 ꢀC and iodoethane (5.34 mL, 65.0 mmol)
was added dropwise (caution: exothermic). The reaction
mixture was then allowed to stir at room temperature for
2 h. Water (50 mL) was added and the aqueous mixture
was extracted with ether (2ꢂ80 mL). The combined organic
layers were washed with brine (50 mL), dried (MgSO4) and
concentrated. The residue was purified by column chromato-
graphy (9:1 petrol–Et2O) to give the ether as a colourless
4.1.45. [tert-Butoxycarbonyl-(2-tert-butylcyclopropyl)-
amino]acetic acid 73. An aqueous solution of sodium
hydroxide (0.5 M in water, 2.2 mL, 1.1 mmol, 4 equiv)
and potassium permanganate (0.65 M in water, 1.7 mL,
1.1 mmol, 4 equiv) were added successively to a solution

W. B. Motherwell et al. / Tetrahedron 63 (2007) 6462–6476
6475
of alcohol 72 (70 mg, 0.27 mmol, 1 equiv) in tert-butanol
(2.7 mL). The reaction mixture was stirred for 24 h and
then quenched with sodium thiosulfate (5% in water,
7.75 mL). Diethyl ether (10 mL) was added and the mix-
ture was transferred into a separating funnel. The aqueous
layer was separated and then acidified to pH 2 with an
aqueous hydrochloric acid solution (1 M) at 4 ꢀC. The mix-
ture was then extracted with EtOAc (3ꢂ10 mL) and the
combined organic extracts were dried (Na2SO4), filtered
and concentrated in vacuo to give the title compound 73
(62 mg, 0.23 mmol, 84%) as a white amorphous solid; IR
CDCl3): d 0.83 (ddd, J¼7.5, 7.1, 5.0, 1H, CHHCHN), 1.02
(ddd, J¼8.7, 7.1, 4.1, 1H, CHHCHN), 1.85–1.99 (m, 2H,
CH2CH2N), 2.33 (t, J¼8.1, 2H, CH2CO), 2.53 (ddd,
J¼8.7, 5.0, 1.6, 1H, CHN), 3.20–3.30 (m, 2H, CH2N),
3.50 (ddd, J¼7.5, 4.1, 1.6, 1H, CHOH), 4.31 (br s, 1H,
OH); 13C NMR (125 MHz, CDCl3): d 14.6, 17.9, 31.6,
32.4, 47.4, 51.1, 176.6; MS (EI) m/z (%): 141 (M+, 7), 112
(100), 98 (24), 84 (23), 69 (47); HRMS: M+, found
141.07832. C7H11NO2 requires 141.07843.
(film): nmax 3450 (br), 2954 (m), 1699 (s) cmꢁ1
;
1H
Acknowledgements
NMR (500 MHz, 328 K, CDCl3): d 0.71 (ddd, J¼9.9,
5.7, 3.9, 1H, CHHCHN), 0.75 (ddd, J¼7.4, 6.7, 5.7, 1H,
CHHCHN), 0.84 (s, 9H, 3ꢂMe), 0.87 (ddd, J¼9.9, 6.7,
3.9, 1H, CHCHN), 1.44 (s, 9H, OC(CH3)3), 2.59 (dt,
J¼7.4, 3.9, 1H, CHN), 3.83 (d, J¼17.7, 1H, CHHN),
4.04 (d, J¼17.7, 1H, CHHN), 8.73 (br s, 1H, OH); 13C
NMR (125 MHz, 328 K, CDCl3): d 12.2, 28.4, 28.4,
29.0, 32.3, 32.5, 50.0, 80.7, 156.7, 175.3; MS (CI+) m/z
(%): 272 (M+H, 33), 216 (92), 172 (52), 154 (100);
HRMS: M+H, found 272.18676. C14H26NO4 requires
272.18617.
We would like to thank AstraZeneca for providing a student-
ship (to G.B.), and the EPSRC for providing both a student-
ship (to L.J.) and a postdoctoral fellowship (to T.D.S.). We
would also like to thank Dr. Abil Aliev for providing advice
and assistance with NMR spectroscopy.
References and notes
€
€
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4.1.46. 2-(1,1a,6,6a-Tetrahydro-cyclopropa[a]inden-1-
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matography (1:9 EtOAc–petrol, then 3:7 and 1:1) to give the
catecholamine 74 as a pale pink solid (12 mg, 34%); IR
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(film): nmax 3150–3400 (br), 2924, 1659 (s), 1597 cmꢁ1
;
1H NMR (trans, 500 MHz, CDCl3): d 2.27 (br q, J¼6.7,
1H, CHCH2Ar), 2.50 (d, J¼18.0, 1H, ArCHH), 3.05 (dd,
J¼8.4, 7.0, 1H, CHAr), 3.12 (dd, J¼18.0, 7.0, 1H, ArCHH),
3.73 (t, J¼7.0, 1H, CHNH), 6.23 (br s, 1H, NH), 6.76–7.30
(m, 8H, Ar-H), 8.14 (br s, 1H, OH); 13C NMR (trans,
125 MHz, CDCl3): d 23.4, 31.3, 31.8, 39.3, 119.6, 120.5,
122.5, 124.5, 124.6, 126.5, 127.0, 127.8, 137.7, 142.7,
150.6, 165.9; MS (CI+) m/z (%): 266 (100), 238 (23,
M+H), 166 (23); HRMS: M+H, found 238.12343.
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4.1.47. 1-[2-(Hydroxycyclopropyl)]-2-pyrrolidinone 75.
Tetrabutylammonium fluoride (1 M solution in THF,
1.09 mL, 1.09 mmol) was added to a solution of cyclopro-
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hydrogencarbonate (0.11 g, 1.09 mmol) and hydrogen per-
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ꢀ
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(w), 1662 (s), 1463, 1425 cmꢁ1 1H NMR (500 MHz,
;

6476
W. B. Motherwell et al. / Tetrahedron 63 (2007) 6462–6476
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