Enantioselective Synthesis of 2-(2-Arylcyclopropyl)glycines: Conformationally Restricted Homophenylalanine Analogs

Article abstract of DOI:10.1002/hlca.200490000

Starting from simple aromatic aldehydes and acetylfuran, (E)-1-(furan-2-yl)-3-arylprop-2-en-1-ones (2) were synthesized in high yields. Cyclopropanation of the C=C bond with trimethylsulfoxonium iodide (Me ₃SO⁺I^-) furnished (furan-2-yl)(2-arylcyclopropyl)methanones 3 in 90-97% yields. Selective conversion of cyclopropyl ketones to their (E)- and (Z)-oxime ethers 5 and oxazaborolidine-catalyzed stereoselective reduction of the C=N bond followed by separation of the formed diastereoisomers, furnished (2-arylcyclopropyl)(furan-2-yl)methanamines 6 in optically pure form and high yield. Oxidation of the furan ring of (S,S,S)-, (S,R,R)-, (R,S,S)-, and (R,R,R)-6a afforded the four stereoisomers of α-(2-phenylcyclopropyl) glycine (1a).

Full text of DOI:10.1002/hlca.200490000

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Helvetica Chimica Acta Vol. 87 (2004)
Enantioselective Synthesis of 2-(2-Arylcyclopropyl)glycines:
Conformationally Restricted Homophenylalanine Analogs
by Ayhan S. Demir* and ÷zge Sesenoglu
Department of Chemistry, Middle East Technical University, TR-06531Ankara
(e-mail: asdemir@metu.edu.tr)
and
Dincer ‹lk¸1) and Cengiz Arici1)
Department of Engineering Physics, Hacettepe University, Beytepe, TR-06532 Ankara
Dedicated to Professor Wolfgang Steglich on the occasion of his 70th birthday
Starting from simple aromatic aldehydes and acetylfuran, (E)-1-(furan-2-yl)-3-arylprop-2-en-1-ones (2)
were synthesized in high yields. Cyclopropanation of the CˆC bond with trimethylsulfoxonium iodide
‡
(Me3SO IÀ) furnished (furan-2-yl)(2-arylcyclopropyl)methanones 3 in 90 97% yields. Selective conversion of
cyclopropyl ketones to their (E)- and (Z)-oxime ethers 5 and oxazaborolidine-catalyzed stereoselective
reduction of the CˆN bond followed by separation of the formed diastereoisomers, furnished (2-
arylcyclopropyl)(furan-2-yl)methanamines 6 in optically pure form and high yield. Oxidation of the furan
ring of (S,S,S)-, (S,R,R)-, (R,S,S)-, and (R,R,R)-6a afforded the four stereoisomers of a-(2-phenylcyclopropyl)
glycine (1a).
Introduction. Conformationally restricted a-amino acids [1] are important tools
for studying the spatial requirements for receptor affinity and the biological activity of
natural amino acids and peptides [2]. Replacement of natural amino acids in bioactive
peptides by conformationally restricted amino acids has led to a better understanding
of their bioactive conformations [3][4]. Since l-Glu is a major neurotransmitter in the
mammalian central nervous system, its mimetics are of possible interest in studies on
(and eventually for the treatment of) pathological processes such as Alzheimer×s or
Huntington×s disease, as well as Parkinsonism or neuronal damage resulting from
cerebral ischemia and epilepsy [5].
The importance of l-Glu triggered the synthesis of analogs, ones that are even more
specifically agonistic than l-Glu, that activate both metabotropic and ionotropic
glutamate receptors [6]. Among these, a-carboxycyclopropylglycines (CCGs) are the
most prominent; the extended conformer of l-Glu, which is equivalent to CCG-I and
-II, activates the metabotropic Glu receptor, and the NMDA receptor is activated by a
folded conformer of l-Glu, which is equivalent to CCG-III and -IV [7].
Several methods have been described in the literature for the enantioselective
synthesis of CCG derivatives [7 10], but there are few examples of enantioselective
syntheses of (arylcyclopropyl)-substituted glycines. Actually, a-(2-phenylcyclopropyl)-
glycine (1a) seems to be the only example. Silverman and Zelechonok [11] described
1
)
Authors responsible for X-ray crystal-structure analyses.

Helvetica Chimica Acta Vol. 87 (2004)
107
the synthesis of racemic trans-1a from trans-2-phenylcyclopropane-1-carbaldehyde in
34% yield by means of the Strecker synthesis. This compound was designed to probe the
mechanism of the silver(I)-peroxydisulfate and silver(II)-picolinate oxidation of
amino acids and whether an a-amino radical is an important intermediate in either
reaction. The multistep enantioselective synthesis of this compound from (S)-serine was
described by Bernabe and co-workers [12], the key step being the dibromocyclopropa-
nation of tert-butyl 2,2-dimethyl-4-(2-phenylethenyl)-1,3-oxazolidine-3-carboxylate.
An analogous sequence was also followed, starting from (R)-serine. The absolute
configuration of the cyclopropane ring was determined by NMR techniques.
Optically active furan-2-amine derivatives have received much attention due to
their importance as building blocks for the synthesis of a considerable number of N-
containing natural products such as a-amino acids [13], b-lactams [14], indolizidines
[15], quinolizidines [16], and piperidine alkaloids [17].
The development of an enantioselective synthesis capable of producing both
enantiomers of furan-2-amines would allow access to many interesting compounds. In
connection with some other projects, we, thus, developed a new method for the
enantioselective synthesis of furan-2-amines and amino acids. Some preliminary results
in this context have already been reported [18].
In a previous paper [9a], we described the stereoselective synthesis of CCG-I and
-II starting from 1,3-di(2-furyl)prop-2-en-1-one (Scheme 1). The method covers the
selective formation of the corresponding (E)- and (Z)-oximes, enantioselective
reduction of their ethers with chiral oxazaborolidine complexes, and oxidation of the
furan rings [18].
Scheme 1
As an extension of our studies, we report herein a new representative method for
the stereoselective synthesis of all stereoisomers of trans-a-(2-phenylcyclopropyl)gly-
cine (1a) and precursor derivatives thereof, i.e., conformationally restricted analogs of
homophenylalanine.

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Helvetica Chimica Acta Vol. 87 (2004)
Results and Discussion. As shown in Scheme 2, the 1-(furan-2-yl)-3-arylprop-2-
en-1-ones 2a e were chosen as starting materials for the synthesis of the target
molecules, where the CˆC bond serves as a cyclopropane-ring precursor and the furyl
ring as a masked carboxylate. Compounds 2a e were readily synthesized from 2-
acetylfuran and different aryl aldehydes in basic medium in 70 95% yield. SimmonsÀ-
Smith cyclopropanation in the next step gave the products in very low yields [19], since
a,b-unsaturated carbonyl and carboxyl compounds are generally unreactive under
these conditions. Fortunately, trimethylsulfoxonium iodide turned out to be the choice
Scheme 2
‡
i) Me3SO IÀ, DMSO, NaH. ii) For (E)-oxime ethers: NH2OH ¥ HCl, NaOH, EtOH, H2O; for (Z)-oxime ethers:
NH2OH ¥ HCl, NaOAc, EtOH. iii) BnBr, NaH, DMF. iv) Chiral amino alcohol, such as (À)-9 (see Table 2),
BH3 ¥ SMe2, THF. v) O3, CH2Cl2, À 788; or RuO2, NaIO4, r.t

Helvetica Chimica Acta Vol. 87 (2004)
109
Table 1. Absolute Configurations and Reaction Yields (in %) of Compounds 2
6
Substituent
2
3
4
5
6a)
a: Arˆ C6H5
90
95
84 (E)
77 (Z)
92 (E)
96 (Z)
45 (S,S,S)
41 S,R,R)
46 (R,S,S)
43 (R,R,R)
40 (S,S,S)
43 (S,R,R)
39 (R,S,S)
44 (R,R,R)
44 (S,S,S)
(
b: Arˆ 2-ClC6H4
95
89
75
70
97
96
95
90
83 (E)
78 (Z)
95 (E)
95 (Z)
c: Arˆ 3-MeC6H4
d: Arˆ 4-(MeO)C6H4
e: Arˆ 2-Naphthyl
86 (E)
77 (Z)
89 (E)
90 (Z)
44 (S,S,S)
41( R,S,S)
43 (R,R,R)
46 (S,S,S)
74 (E)
82 (Z)
87 (E)
96 (Z)
41 S,S,S)b)
44 (R,S,S)b)
45 (R,R,R)
42 (S,S,S)
(
78 (E)
80 (Z)
76 (E)
83 (Z)
39 (S,R,R)b)
40 (R,S,S)b)
44 (R,R,R)
a) For the formation of chiral oxazaborolidines, (À)-(1R,2S)-norephedrine (9) was used. b) Stereoisomers
could not be separated.
for the cyclopropanation of the enone CˆC bond, giving rise to 3a 3e in 90 97%
yield after only 20 min reaction time in DMSO.
In the next step, ketones 3a e were selectively converted to the oximes (E)- and
(Z)-4a e in good yields. Reaction of 3a e with H2NOH ¥ HCl/NaOH gave the (E)-
oximes (74 86%), whereas reaction with H2NOH ¥ HCl/AcONa in EtOH led to (Z)-
oximes (77 82%), with only small amounts of the corresponding opposite isomers
being formed. Assignment of the (E)/(Z)-configuration, which is crucial for the
1
stereocontrol of the final products [18], was made by H-NMR analyses and was
supported by X-ray crystal-structure analyses of (E)-4a, (E)-4c, and (Z)-4c (see Figs. 1,
2, and 3, resp.).
The crystal structure of compound (E)-4a is shown in Fig. 1. Intramolecular bond distances and angles,
calculated from the final coordinates, are close to the average of values found in organic molecules. The shortest
intermolecular distances between non-H-atoms are 2.745(6) [O(2),N(1'); (1 À x, À y,1 À z)] and 2.929 ä
[N(1),N(1'); (1 À x, À y,1 À z)]. The ring moieties are practically planar, with maximum deviations of 0.0158(1)
and 0.0210(1) ä for C(1) and C(13), respectively. The dihedral angle between the least-squares planes of the two
rings is 63.758.
In compound (E)-4c (Fig. 2), there are H-bonds between the N- and O-atoms of neighboring molecules,
which results in dimeric structures. The distance O(2)ÀH ¥¥¥ N(1') (À x, À y, À z) is 2.763 ä, with an angle of
139.588. The H-bridged centrosymmetric dimers are oriented along the c-axis of the orthorombic unit cell. The
shortest interdimeric contact distances, which are less than the sum of the Van der Waals radii, are 2.44
[H(1),H(7''A); (1 À x, À y, À z)]; 2.63 [O(2),H(10); (À1 ‡ x,y,z)], and 2.75 ä [H(2), O(1); (À x, À y, À z)]. The
furyl ring is planar, with double-bond lengths of 1.331(3) (C(1)ˆC(2)) and 1.345(2) ä (C(3)ˆC(4)). The
phenyl ring is also planar with CÀC distances between 1.379(3) and 1.394(2) ä. The dihedral angle between the
least-squares planes of the furyl and phenyl rings is 40.518.

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Helvetica Chimica Acta Vol. 87 (2004)
Fig. 1. X-Ray crystal structure of (E)-4a
Fig. 2. X-Ray crystal structure of (E)-4c
Crystals of (Z)-4c consist of H-bridged centrosymmetric dimers lined up along the b-axis of the monoclinic
unit-cell in a zig-zag mode (Fig. 3). The intermolecular H-bond (O(2)ÀH(2') ¥¥¥ N(1) within the dimer is 2.81 ä
long, with an angle of 1468 (symmetry code: 1 À x,1 À y, À z). In addition to the intermolecular H-bonds, several
interdimeric contacts shorter than the sum of the Van der Waals radii are observed. The shortest of these contact
distances have the following values: 2.23 [H(7A),H(2'); (1 À x,1 À y, À z)]; 2.75 [H(7B),O(2); (1 ‡ x,y,z)], and
2.81ä [H(8),C(2); ( x,1/2 À y, À 1/2 ‡ z)]. The network of H-bonds and other intermolecular interactions hold
the structure together. The furyl and the phenyl rings are planar, with a maximum deviation of 0.016(3) and
0.033(5) ä for C(2) and C(13), respectively. A least-squares-plane calculation shows that the dihedral angle
between these two moieties is 88.61(11)8.
The configuration of the oximes 4 could also be determined by analysis of the 1H-NMR resonances of the
furyl rings: HÀC(3) of (E)-4a appeared as a d at 6.81ppm, whereas the same H-atom in ( Z)-4a showed a
downfield shift, appearing at 7.52 ppm.
The purity of (E)- and (Z)-4a 4e was demonstrated by GLC (gas/liquid
chromatography) analysis of the corresponding O-benzyl oximes 5a 5e obtained in
high yields with BnBr and NaH in DMF. No isomerization was observed during this
conversion. All these oxime ethers were viscous oils and were purified by flash

Helvetica Chimica Acta Vol. 87 (2004)
111
Fig. 3. X-Ray crystal structure of (Z)-4c
chromatography (FC). We also synthesized these O-benzyl oximes directly from the
enones in the presence of O-benzylhydroxylamine hydrochloride. However, this
procedure gave a mixture of isomers, which was separated by FC to afford the (E)- and
(Z)-oxime ethers in only 28 and 36% yield, respectively.
Oxime ethers are compounds often used for the conversion of CˆO to NH2 groups
[20]. Even more so, acetophenone oxime ethers can be stereoselectively converted to
amines with BH3/oxazaborolidine complexes in high enantiomeric excess [21].
For the oxazaborolidine-catalyzed enantioselective reduction of the O-benzylox-
imes 5a 5e with BH3 ¥ SMe2 to 6a 6e, 5a was used as the reference starting material,
and different reaction conditions were applied (Table 2). The highest selectivity was
obtained when the borane/amino alcohol/oxime ether ratio was ca. 2.5 :1.25 :1.0. The
amino alcohols 7 9 were used to form the oxazaborolidine complexes [22]. As shown
in Table 2, they gave comparable results in terms of both selectivity and yield. For
commercial reasons, compound 9 was used in most cases. After usual work-up, the
diastereoisomeric mixtures of amines were separated by FC to give (S,S,S)- and
(S,R,R)-6a. Under the same conditions, the reduction of (Z)-5a gave (R,R,R)- and
Table 2. Oxazaborolidine-Catalyzed Reduction of (E)- and (Z)-4a to Different Stereoisomers of 6 with BH3 ¥
SMe2 in the Presence of Chiral Aminoalcohols (7 9). The absolute configurations of the products were assigned
by comparing their optical rotations with literature data.
Product
(S,S,S)-6a [%]
(R,R,R)-6a [%]
(S,R,R)-6a [%]
(R,S,S)-6a [%]
43
4139
44
45
45
46
43
4141
45
46

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Helvetica Chimica Acta Vol. 87 (2004)
(R,S,S)-6a. Similar results were obtained with 5b 5e, as substrates affording 6b e in
pure form and good yields (Table 1). The absolute configurations of the products were
determined by comparison of their specific rotations with published values. The results
of the above enantioselective reduction, i.e., formation of (S)-amine from (E)-oxime
ether, and vice versa, were in accordance with our preliminary results (synthesis of
CCG enantiomers) [9a]. The purity of the products was determined by NMR
spectroscopy. Both the yields and purities of the isolated amines 6a showed that the
reductions occurred with high selectivity. The high diastereo- and enantioselectivities of
the process and the finding that the diastereoisomers can be purified by FC make our
method valuable.
The effect of the O-protecting group on the reduction of oxime ethers was also
investigated. When the reduction was carried out with a (Z)-O-methyl oxime of type 5a
in the presence of oxazaborolidine complexes with 9, very low selectivities were
observed. As suggested previously [18], the benzyl group is superior to aliphatic groups,
probably for steric and electronic reasons.
The oxidation of the furan ring of 6a was first attempted by ozonolysis at low
temperature, followed by the formation of the HCl salt. However, this method gave low
yields of 1a and many side products. Fortunately, RuO2/NaIO4 oxidation [23], followed
by HCl-salt formation, afforded the product in high yield.
As proposed for related catalytic systems [18a], the formation of low-energy cis-
pentalane is favored because the b-binding of BH3 ¥ THF to oxazaborolidine forms very
strained trans-pentalane, which is disfavored. As apparent from Table 1, the config-
uration of the oxime ether is the dominant factor with respect to the stereoselective
formation of the amines 6. It appears that the oxime N-atom rather than the C-atom is
responsible for the high selectivity.
Conclusions. We have described a very efficient route for the stereoselective
synthesis of a-(2-arylcyclopropyl)glycines from readily accessible 3-aryl-1-(2-furyl)-
‡
prop-2-en-1-ones 2. Cyclopropanation with trimethylsulfoxonium iodide (Me3SO IÀ),
selective formation of (E)- and (Z)-oxime ethers 5, oxazaborolidine-catalyzed
reduction to 6, and separation of the formed diastereoisomers furnished (2-arylcyclo-
propyl)-2-furylmethanamines, a-(2-arylcyclopropyl)glycine precursors, in optically
pure form and high yields. As a representative example, the oxidation of the furan
rings of (S,S,S)-, (S,R,R)-, (R,S,S)-, and (R,R,R)-6a furnished the corresponding
isomers of a-(2-phenylcyclopropyl)glycine (1a). Our approach benefits from the fact
that all compounds required can be readily prepared, that diastereoisomer formation
proceeds in high yields, and that the absolute configurations of the final products (1)
can be controlled by choosing the appropriate stereoisomerically pure O-benzyloxime.
Experimental Part
General. Flash chromatography (FC): silica gel 60 (40 63 mm). Optical rotations: Autopol IV automatic
polarimeter. 1H- and 13C-NMR Spectra: Bruker DPX-400 (400 and 100 MHz, resp.); chemical shifts d in ppm
rel. to SiMe4, coupling constants J in Hz.
General Procedure for the Synthesis of Enones 2a 2e. To a stirred soln. of the arene-aldehyde (1equiv.) in
H2O (ca. 2 ml per mmol) at r.t. was added a 0.1% aq. KOH soln. (100 mg in 10 ml of H2O). After stirring the
mixture for 15 min at r.t., acetylfuran (1.33 equiv.) was added at once, and the mixture was stirred for 12 h

Helvetica Chimica Acta Vol. 87 (2004)
113
(monitored by TLC). Then, the mixture was acidified with H2SO4, extracted with Et2O (3 Â 30 ml), dried
(MgSO4), and concentrated under reduced pressure. The products were purified by FC (Hex/AcOEt 6 :1 !
3 :1 ).
(E)-1-(Furan-2-yl)-3-phenylprop-2-en-1-one (2a). Yield: 90%. Colorless solid. M.p. 81 83 8 (hexane/
Et2O). 1H-NMR (400 MHz, CDCl3): 6.61( dd, J ˆ 1.7, 3.6, 1 H); 7.34 (dd, J ˆ 0.5, 3.6, 1H); 7.41 7.53 ( m, 3 H);
7.54 (d, JAB ˆ 15.8, 1 H); 7.63 7.72 (m, 3 H); 7.91( d, JAB ˆ 15.8, 1 H). 13C-NMR (100 MHz, CDCl3): 112.9; 117.
9; 121.6; 129.1; 129.5; 130.7; 134.8; 144.3; 146.9; 154.1; 178.4.
(E)-3-(2-Chlorophenyl)-1-(furan-2-yl)prop-2-en-1-one (2b). Yield: 95%. Viscous oil. 1H-NMR (400 MHz,
CDCl3): 6.60 (dd, J ˆ 1.6, 3.5, 1 H); 7.35 7.55 (m, 5 H); 7.44 (d, JAB ˆ 15.8, 1 H); 7.60 (d, J ˆ 0.5, 1H); 8.21
(d, JAB ˆ 15.8, 1 H). 13C-NMR (100 MHz, CDCl3): 112.5; 117.5; 124.2; 127.0; 127.9; 130.3; 131.1; 133.3; 135.6;
139.7; 139.7; 146.5; 153.7; 177.7.
(E)-1-(Furan-2-yl)-3-(3-methylphenyl)prop-2-en-1-one (2c). Yield: 89%. Viscous oil. 1H-NMR (400 MHz,
CDCl3): 2.21( s, 3 H); 6.41( dd, J ˆ 1.4, 3.4, 1 H); 7.01 7.12 (m, 2 H); 7.1 7 (d, J ˆ 3.5, 1H); 7.25 7.27 ( m, 2 H);
7.31( d, JAB ˆ 15.8, 1 H); 7.47 (br. s, 1H); 7.65 ( d, JAB ˆ 15.8, 1 H). 13C-NMR (100 MHz, CDCl3): 21.6; 112.8;
117.5; 121.3; 126.1; 129.1; 129.5; 131.7; 135.0; 138.7; 144.3; 146.5; 154.2; 177.9.
(E)-1-(Furan-2-yl)-3-(4-methoxyphenyl)prop-2-en-1-one (2d). Yield: 75%. Viscous oil. 1H-NMR
(400 MHz, CDCl3): 3.71( s, 3 H); 6.54 (dd, J ˆ 1.6, 3.5, 1 H); 6.81 (d, JAB ˆ 8.7, 2 H); 7.15 (d, J ˆ 3.6, 1H); 7.27
(d, JAB ˆ 15.8, 1 H); 7.57 (d, JAB ˆ 8.7, 2 H); 7.59 (d, J ˆ 0.6, 1H); 7.71( d, JAB ˆ 15.9, 1 H). 13C-NMR (100 MHz,
CDCl3): 55.6; 112.8; 114.7; 117.0; 119.2; 127.9; 130.6; 144.1; 146.1; 154.4; 162.1; 178.1.
(E)-1-(Furan-2-yl)-3-(2-naphthyl)prop-2-en-1-one (2e). Yield: 70%. Viscous oil. 1H-NMR (400 MHz,
CDCl3): 6.51( dd, J ˆ 1.6, 3.4, 1 H); 7.27 (d, J ˆ 3.5, 1H); 7.39 7.75 ( m, 1 0 H).13C-NMR (100 MHz, CDCl3):
112.6; 117.7; 121.7; 127.1; 127.7; 128.2; 129.1; 131.2; 132.6; 133.8; 134.8; 144.4; 146.6; 146.7; 153.4; 154.3; 178.3.
General Procedure for the Cyclopropanation of Compounds of Type 2. To a stirred soln. of NaH (1equiv.)
‡
in DMSO (ca. 2 ml per mmol) under Ar gas at r.t. was added Me3SO IÀ (1.3 equiv.). After stirring for 15 min,
the enone (2a e; 1equiv.), in DMSO ( ca. 1ml per mmol) was added at once with a syringe. The resulting dark
mixture was stirred for 20 min at r.t., and poured onto ice-water, which was extracted with Et2O (3 Â 75 ml). The
combined org. layers were dried (MgSO4) and concentrated under reduced pressure. The crude products were
purified by FC (hexane/AcOEt 6 :1 ! 3 :1 ).
(Furan-2-yl)(2-phenylcyclopropyl)methanone (3a). Yield: 95%. Colorless solid. M.p. 91 93 8 (hexane/
Et2O). 1H-NMR (400 MHz, CDCl3): 1.52 (ddd, J ˆ 4.0, 6.8, 8.1, 1 H); 1.91 (ddd, J ˆ 4.1, 5.1, 9.1, 1 H); 2.74
(ddd, J ˆ 4.0, 6.5, 9.0, 1H); 2.83 ( ddd, J ˆ 4.1, 5.2, 8.1, 1 H); 6.62 (dd, J ˆ 1.7, 3.5, 1 H); 7.11 7.31 (m, 6 H); 7.67
(d, J ˆ 1.5, 1 H). 13C-NMR (100 MHz, CDCl3): 18.9; 28.9; 29.4; 112.3; 116.7; 126.2; 126.5; 127.6; 140.3; 146.4;
153.2; 187.2. Anal. calc. for C14H12O2 (212.24): C 79.22, H 5.70; found: C 79.38, H 5.62.
[2-(2-Chlorophenyl)cyclopropyl](furan-2-yl)methanone (3b). Yield: 97%. Viscous oil. 1H-NMR
(400 MHz, CDCl3): 1.57 (ddd, J ˆ 4.2, 6.9, 8.1, 1 H); 1.84 (ddd, J ˆ 4.3, 6.7, 8.3, 1H); 2.71 ( ddd, J ˆ 5.1, 6.8,
8.0, 1H); 2.85 ( ddd, J ˆ 4.3, 7.1, 8.1, 1 H); 6.54 (dd, J ˆ 1.6, 3.4, 1 H); 7.13 7.32 (m, 5 H); 7.62 (d, J ˆ 1.0, 1 H).
13C-NMR (100 MHz, CDCl3): 17.1; 26.9; 27.1; 112.1; 116.7; 126.5; 127.1; 127.7; 129.1; 135.4; 137.4; 146.3; 152.8;
186.7. Anal. calc. for C14H11ClO2 (264.69): C 68.16, H 4.49; found: C 68.36, H 4.61.
(Furan-2-yl)[2-(3-methylphenyl)cyclopropyl]methanone (3c). Yield: 96%. Viscous oil. 1H-NMR
(400 MHz, CDCl3): 1.27 1.31 (m, 1H); 1.72 1.76 ( m, 1H); 2.23 ( s, 3 H); 2.50 2.53 (m, 1H); 2.69 2.73
(m, 1H); 6.31( dd, J ˆ 1.3, 3.5, 1 H); 6.31 7.18 (m, 5 H); 7.49 (s, 1 H). 13C-NMR (100 MHz, CDCl3): 19.2; 21.3;
29.3; 29.7; 112.7; 116.8; 123.6; 127.4; 127.7; 128.8; 138.3; 140.6; 146.4; 153.7; 187.3. Anal. calc. for C15H14O2
(226.27): C 79.62, H 6.24; found: C 79.48, H 6.33.
(Furan-2-yl)[2-(4-methoxyphenyl)cyclopropyl]methanone (3d). Yield: 95%. Viscous oil. 1H-NMR
(400 MHz, CDCl3): 1.34 (ddd, J ˆ 4.1, 6.7, 8.1, 1 H); 1.75 (ddd, J ˆ 4.2, 5.1, 9.1, 1 H); 2.63 (ddd, J ˆ 4.1, 6.7, 9.2,
1H); 2.78 ( ddd, J ˆ 4.1, 5.2, 8.3, 1 H); 3.84 (s, 3 H); 6.51( dd, J ˆ 1.7, 3.5, 1 H); 6.74 (d, JAB ˆ 8.6, 2 H); 7.01
(d, JAB ˆ 8.6, 2 H); 7.10 (d, J ˆ 3.4, 1H); 7.50 ( s, 1 H). 13C-NMR (100 MHz, CDCl3): 19.1; 29.2; 29.4; 55.5; 112.6;
114.3; 116.5; 127.8; 132.7; 146.3; 153.8; 158.8; 187.4. Anal. calc. for C15H14O3 (242.27): C 74.36, H 5.82; found: C
74.58, H 5.61.
(Furan-2-yl)[2-(2-naphthyl)cyclopropyl]methanone (3e). Yield: 90%. Viscous oil. 1H-NMR (400 MHz,
CDCl3): 1.55 1.61 (m, 1H); 1.86 1.90 ( m, 1H); 2.77 2.87 ( m, 2 H); 6.47 (dd, J ˆ 1.6, 3.5, 1 H); 7.15 7.73
(m, 9 H). 13C-NMR (100 MHz, CDCl3): 19.3; 29.5; 30.1; 112.7; 117.0; 124.9; 125.2; 125.9; 126.7; 127.8; 128.1;
128.6; 132.8; 133.8; 138.2; 146.7; 153.7; 187.4. Anal. calc. for C18H14O2 (262.30): C 82.42, H 5.38; found: C 82.57, H
5.21.
General Procedure for the Synthesis of Oximes of Type 4. Method A ((E)-oximes): The ketone (3a e;
5 mmol), NH2OH ¥ HCl (6 mmol), and NaOH (6 mmol) were mixed in anh. EtOH (15 ml) and stirred under

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Helvetica Chimica Acta Vol. 87 (2004)
reflux for 12 h. The reaction was monitored by TLC. The hot soln. was filtered and evaporated. The remaining
solid was dissolved in H2O and extracted with Et2O. The org. layer was washed with H2O and brine, and dried
(MgSO4). Evaporation of the solvent afforded the crude (E)-oxime, which was purified either by FC (hexane/
AcOEt 5 :1 ! 3 :1) or recrystallization (hexane/Et2O).
Method B ((Z)-oximes): The ketone (3a e; 5 mmol), NH2OH ¥ HCl (6 mmol), and NaOAc (6 mmol)
were mixed in anh. EtOH (15 ml) and stirred under reflux for 12 h. The reaction was monitored by TLC. The hot
soln. was filtered and evaporated. The remaining solid was dissolved in H2O and extracted with Et2O. The org.
layer was washed with H2O and brine, and dried (MgSO4). Evaporation of the solvent afforded the crude (Z)-
oxime, which was purified either by FC (hexane/AcOEt 5 :1 ! 3 :1) or recrystallization (hexane/Et2O).
(E)-(Furan-2-yl)(2-phenylcyclopropyl)methanone Oxime ((E)-4a). Yield: 84%. Colorless solid. 1H-NMR
(400 MHz, CDCl3): 1.55 (ddd, J ˆ 5.5, 5.9, 9.2, 1H); 1.82 ( ddd, J ˆ 5.1, 6.1, 8.8, 1 H); 2.41 (ddd, J ˆ 5.6, 6.1, 9.1,
1H); 2.67 ( ddd, J ˆ 5.5, 5.8, 8.8, 1H); 6.42 ( dd, J ˆ 1.8, 3.4, 1 H); 6.81 (d, J ˆ 3.6, 1H); 7.21 7.45 ( m, 5 H); 7.42
(d, J ˆ 1.8, 1 H); 9.87 (br. s, 1 H). 13C-NMR (100 MHz, CDCl3): 17.5; 21.8; 28.7; 112.8; 113.1; 128.2; 130.5; 143.5;
145.4; 151.2; 152.0. Anal. calc. for C14H13NO2 (227.26): C 73.99, H 5.77, N 6.16; found: C 73.71, H 5.63, N 5.92.
(Z)-(Furan-2-yl)(2-phenylcyclopropyl)methanone Oxime ((Z)-4a). Yield: 77%. Viscous oil. 1H-NMR
(400 MHz, CDCl3): 1.34 (ddd, J ˆ 5.6, 6.9, 8.1, 1 H); 1.62 (ddd, J ˆ 5.1, 7.3, 8.0, 1 H); 2.31 (ddd, J ˆ 5.3, 7.0, 8.3,
1H); 2.45 ( ddd, J ˆ 5.3, 6.8, 7.9, 1H); 6.51( dd, J ˆ 1.6, 3.2, 1 H); 7.11 7.24 (m, 5 H); 7.40 (d, J ˆ 1.0, 1 H); 7.52
(d, J ˆ 3.3, 1 H); 10.12 (br. s, 1 H). 13C-NMR (100 MHz, CDCl3): 14.9; 22.6; 25.1; 111.1; 117.9; 125.9; 126.2;
128.3; 141.7; 143.4; 145.8; 146.9.
(E)-[2-(2-Chlorophenyl)cyclopropyl](furan-2-yl)methanone Oxime ((E)-4b). Yield: 83%. Viscous oil.
1H-NMR (400 MHz, CDCl3): 1.21 (ddd, J ˆ 5.6, 6.7, 8.9, 1H); 1.72 ( ddd, J ˆ 5.5, 6.5, 9.1, 1 H); 2.34 (ddd, J ˆ 6.0,
6.9, 9.2, 1H); 2.84 ( ddd, J ˆ 6.1, 7.1, 8.9, 1 H); 6.31 (dd, J ˆ 1.9, 3.4, 1 H); 6.52 (dd, J ˆ 0.4, 3.6, 1H); 7.01 7.27
(m, 4 H); 7.32 (dd, J ˆ 0.4, 1.7, 1 H); 9.91 (br.s, 1 H). 13C-NMR (100 MHz, CDCl3): 15.5; 18.9; 21.9; 111.0; 111.5;
127.2; 127.3; 127.8; 129.7; 135.7; 139.2; 143.8; 149.4; 150.5. Anal. calc. for C14H12ClNO2 (261.70): C 64.25, H 4.62,
N 5.35; found: C 64.52, H 4.73, N 5.52.
(Z)-[2-(2-Chlorophenyl)cyclopropyl](furan-2-yl)methanone Oxime ((Z)-4b). Yield: 78%. Viscous oil.
1H-NMR (400 MHz, CDCl3): 1.24 (ddd, J ˆ 5.1, 6.3, 9.1, 1 H); 1.52 (ddd, J ˆ 6.1, 6.4, 8.9, 1 H); 2.31 (ddd, J ˆ 5.5,
6.1, 8.7, 1 H); 2.55 (ddd, J ˆ 5.7, 6.1, 9.0, 1 H); 6.42 (dd, J ˆ 1.6, 3.5, 1 H); 7.01 7.24 (m, 4 H); 7.30 (d, J ˆ 1.1,
1H); 7.42 ( d, J ˆ 3.4, 1H); 9.81(br. s, 1 H). 13C-NMR (100 MHz, CDCl3): 15.9; 22.8; 23.9; 113.4; 119.4; 127.9;
128.1; 128.5; 130.6; 136.9; 140.4; 143.8; 147.2; 147.7.
(E)-(Furan-2-yl)[2-(3-methylphenyl)cyclopropyl]methanone Oxime ((E)-4c). Yield: 86%. Colorless solid.
1H-NMR (400 MHz, CDCl3): 1.31 1.36 (m, 1H); 1.63 1.67 ( m, 1H); 2.23 2.25 ( m, 1H); 2.25 ( s, 3 H); 2.45
2.50 (m, 1H); 6.32 ( t, J ˆ 1.5, 1 H); 6.57 (d, J ˆ 3.2, 1H); 6.78 7.15 ( m, 4 H); 7.36 (s, 1H); 8.51(br. s, 1 H).
13C-NMR (100 MHz, CDCl3): 16.0; 20.2; 21.8; 24.1; 111.2; 111.5; 123.6; 127.3; 127.4; 128.8; 138.4; 141.7; 143.7;
149.6; 150.3. Anal. calc. for C15H15NO2 (241.29): C 74.67, H 6.27, N 5.81; found: C 74.83, H 6.43, N 5.62.
(Z)-(Furan-2-yl)[2-(3-methylphenyl)cyclopropyl]methanone Oxime ((Z)-4c). Yield: 77%. Colorless solid.
1H-NMR (400 MHz, CDCl3): 1.19 1.24 (m, 1 H); 1.49 1.54 (m, 1H); 2.22 2.27 ( m, 2 H); 2.27 (s, 3 H); 6.46
(dd, J ˆ 1.7, 3.3, 1 H); 6.86 7.15 (m, 4 H); 7.38 (br. s, 2 H); 8.74 (br. s, 1 H). 13C-NMR (100 MHz, CDCl3): 15.5;
21.8; 23.0; 25.6; 112.7; 118.4; 123.7; 127.4; 128.7; 138.3; 140.6; 142.1; 143.2; 146.7; 147.5.
(E)-(Furan-2-yl)[2-(4-methoxyphenyl)cyclopropyl]methanone Oxime ((E)-4d). Yield: 74%. Viscous oil.
1H-NMR (400 MHz, CDCl3): 1.25 1.28 (m, 1H); 1.53 1.57 ( m, 1H); 2.18 2.21( m, 1H); 2.47 2.51( m, 1 H);
3.65 (s, 3 H); 6.41( dd, J ˆ 1.7, 2.8, 1 H); 6.56 (d, J ˆ 2.7, 1H); 6.75 ( d, JAB ˆ 8.5, 2 H); 7.12 (d, JAB ˆ 8.6, 2 H); 7.49
(s, 1H); 8.71(br. s, 1 H). 13C-NMR (100 MHz, CDCl3): 15.6; 19.8; 22.6; 55.6; 111.1; 111.5; 112.4; 114.2; 114.3;
127.9; 133.7; 143.7; 149.6; 150.2; 158.3. Anal. calc. for C15H15NO3 (257.28): C 70.02, H 5.88, N 5.05; found: C
68.74, H 5.66, N 4.91.
(Z)-(Furan-2-yl)[2-(4-methoxyphenyl)cyclopropyl]methanone Oxime ((Z)-4d). Yield: 82%. Viscous oil.
1H-NMR (400 MHz, CDCl3): 1.18 1.21 (m, 1 H); 1.48 1.51 (m, 1H); 2.17 2.27 ( m, 2 H); 3.61( s, 3 H); 6.47
(dd, J ˆ 1.6, 3.4, 1 H); 6.47 (d, JAB ˆ 8.5, 2 H); 7.01( d, JAB ˆ 8.4, 2 H); 7.35 (br. s, 2 H); 9.02 (br. s, 1 H).
13C-NMR (100 MHz, CDCl3): 15.0; 22.7; 25.1; 55.6; 112.5; 114.3; 118.4; 127.8; 134.2; 143.1; 146.4; 146.6; 147.5;
158.5.
(E)-(Furan-2-yl)[2-(2-naphthyl)cyclopropyl]methanone Oxime ((E)-4e). Yield: 78%. Viscous oil.
1H-NMR (400 MHz, CDCl3): 1.43 1.48 (m, 1 H); 1.73 1.78 (m, 1H); 2.32 2.37 ( m, 1H); 2.64 2.69
(m, 1H); 6.30 ( d, J ˆ 1.6, 1 H); 6.58 (d, J ˆ 3.3, 1H); 7.14 7.69 ( m, 8 H); 8.83 (br. s, 1 H). 13C-NMR
(100 MHz, CDCl3): 16.0; 20.4; 24.5; 111.2; 111.6; 125.0; 125.2; 125.6; 126.5; 126.8; 127.8; 128.6; 132.7; 133.9;
139.3; 143.7; 149.8; 150.1. Anal. calc. for C18H15NO2 (277.32): C 77.96, H 5.45, N 5.05; found: C 77.79, H 5.52, N
4.91.

Helvetica Chimica Acta Vol. 87 (2004)
115
(Z)-(Furan-2-yl)[2-(2-naphthyl)cyclopropyl]methanone Oxime ((Z)-4e). Yield: 80%. Viscous oil.
1H-NMR (400 MHz, CDCl3): 1.30 1.35 (m, 1 H); 1.47 1.53 (m, 1 H); 1 .83 1 .87 m(, 1H); 2.74 2.79
(m, 1H); 6.38 ( dd, J ˆ 1.5, 3.5, 1 H); 7.10 7.66 (m, 9 H); 8.98 (br. s, 1 H). 13C-NMR (100 MHz, CDCl3): 15.5;
23.3; 29.6; 112.5; 117.0; 118.5; 124.9; 125.4; 125.9; 126.4; 126.7; 127.9; 128.1; 128.2; 128.4; 128.7; 143.1; 146.6.
General Procedure for the Synthesis of Oxime Ethers of Type 5. To a stirred soln. of NaH (1.3 equiv.) in
DMF (ca. 10 ml per mmol) under Ar gas at 08 was added the oxime (4a e; 1equiv.), in DMF ( ca. 5 ml per
mmol). The mixture was stirred for 2 h at r.t. Benzyl bromide (1.04 equiv.) was added, and stirring was
continued overnight. Careful addition of H2O (until no more gas was observed) was followed by extraction with
AcOEt (3 Â 50 ml). The combined org. layers were dried (MgSO4) and concentrated under reduced pressure to
give the crude product, which was purified by FC (Hexane/AcOEt 6 :1 ! 4 :1 ).
(E)-(Furan-2-yl)(2-phenylcyclopropyl)methanone O-Benzyloxime ((E)-5a). Yield: 92%. Viscous oil.
1H-NMR (400 MHz, CDCl3): 1.31 (ddd, J ˆ 4.1, 6.5, 9.0, 1 H); 1.61 (ddd, J ˆ 4.1, 5.0, 8.8, 1 H); 2.20 (ddd, J ˆ 5.3,
6.0, 9.1, 1 H); 2.54 (ddd, J ˆ 5.3, 6.1, 8.7, 1 H); 5.21 (s, 2 H); 6.31( dd, J ˆ 1.9, 3.4, 1 H); 6.63 (d, J ˆ 3.1, 1 H);
7.01 7.32 ( m, 1 1 H)1.3C-NMR (100 MHz, CDCl3): 15.4; 20.4; 23.7; 76.6; 110.5; 110.9; 126.1; 127.3; 127.6; 128.0;
128.1; 128.2; 137.4; 141.2; 143.0; 149.3; 149.7. Anal. calc. for C21H19NO2 (317.38): C 79.47, H 6.03, N 4.41; found: C
79.66, H 5.84, N 4.66.
(Z)-(Furan-2-yl)(2-phenylcyclopropyl)methanone O-Benzyloxime ((Z)-5a). Yield: 96%. Viscous oil.
1H-NMR (400 MHz, CDCl3): 1.11 1.21 (m, 1 H); 1.61 1.74 (m, 1H); 2.20 2.42 ( m, 2 H); 5.12 (s, 2 H); 6.21
(dd, J ˆ 1.5, 3.3, 1 H); 7.12 7.53 (m, 1 2 H).13C-NMR (100 MHz, CDCl3): 15.6; 22.5; 25.7; 76.8; 111.9; 117.5;
125.8; 126.2; 128.2; 128.3; 128.6; 128.9; 137.6; 142.0; 142.3; 145.9; 146.2.
(E)-[2-(2-Chlorophenyl)cyclopropyl](furan-2-yl)methanone O-Benzyloxime ((E)-5b). Yield: 95%. Vis-
cous oil. 1H-NMR (400 MHz, CDCl3): 1.06 1.14 (m, 1 H); 1.56 1.64 (m, 1H); 2.22 2.27 ( m, 1H); 2.66 2.71
(m, 1H); 5.07 ( s, 2 H); 6.23 (dd, J ˆ 1.7, 3.2, 1 H); 6.43 (d, J ˆ 3.4, 1H); 6.90 7.26 ( m, 1 0 H). 13C-NMR
(100 MHz, CDCl3): 15.6; 19.6; 22.2; 77.2; 110.1; 111.7; 127.1; 127.5; 127.8; 128.2; 128.3; 128.5; 128.7; 129.6; 138.0;
143.7; 147.6; 150.4; 150.7. Anal. calc. for C21H18ClNO2 (351.83): C 71.69, H 5.16, N 3.98; found: C 71.78, H 5.23, N
3.62.
(Z)-[2-(2-Chlorophenyl)cyclopropyl](furan-2-yl)methanone O-Benzyloxime ((Z)-5b). Yield: 95%. Vis-
cous oil. 1H-NMR (400 MHz, CDCl3): 1.10 (ddd, J ˆ 3.9, 6.1, 8.1, 1 H); 1.62 (ddd, J ˆ 4.2, 5.6, 8.1, 1 H); 2.45
(ddd, J ˆ 4.9, 5.6, 8.6, 1H); 2.63 ( ddd, J ˆ 4.1, 5.1, 8.9, 1 H); 5.24 (s, 2 H); 6.42 (dd, J ˆ 1.7, 3.4, 1 H); 7.11 7.34
13
(m, 1 1 H). C-NMR (100 MHz, CDCl3): 15.2; 21.7; 23.8; 77.3; 112.4; 117.9; 127.1; 127.2; 127.5; 128.1; 128.2;
128.6; 128.7; 136.8; 138.9; 139.5; 143.4; 146.9; 147.5.
(E)-(Furan-2-yl)[2-(3-methylphenyl)cyclopropyl]methanone O-Benzyloxime ((E)-5c). Yield: 89%. Vis-
cous oil. 1H-NMR (400 MHz, CDCl3): 1.17 1.21 (m, 1H); 1.44 1.48 ( m, 1H); 2.04 2.09 ( m, 1H); 2.13
(s, 3 H); 2.27 2.32 (m, 1H); 5.07 ( s, 2 H); 6.24 (dd, J ˆ 1.8, 3.3, 1 H); 6.49 (d, J ˆ 3.3, 1H); 6.74 7.21( m, 9 H);
7.27 (d, J ˆ 1.0, 1 H). 13C-NMR (100 MHz, CDCl3): 15.9; 21.8; 23.2; 24.3; 77.6; 111.4; 111.6; 123.7; 127.4; 127.6;
128.2; 128.6; 128.8; 138.0; 138.3; 141.8; 143.7; 149.8; 150.5. Anal. calc. for C22H21NO2 (331.41): C 79.73, H 6.39, N
4.23; found: C 79.61, H 8.47, N 4.42.
(Z)-(Furan-2-yl)[2-(3-methylphenyl)cyclopropyl]methanone O-Benzyloxime ((Z)-5c). Yield: 90%. Vis-
cous oil. 1H-NMR (400 MHz, CDCl3): 1.26 1.33 (m, 1H); 1.68 1.72 ( m, 1H); 2.31 2.36 ( m, 1H); 2.38
(s, 3 H); 2.44 2.48 (m, 1H); 5.26 ( s, 2 H); 6.51( dd, J ˆ 1.7, 3.4, 1 H); 7.01 7.46 (m, 1 1 H)1.3C-NMR (100 MHz,
CDCl3): 16.1; 21.9; 23.0; 26.2; 77.4; 112.5; 118.0; 123.8; 127.2; 127.5; 128.3; 128.6; 128.8; 128.9; 138.3; 142.6; 142.9;
146.7; 146.8.
(E)-(Furan-2-yl)[2-(4-methoxyphenyl)cyclopropyl]methanone O-Benzyloxime ((E)-5d). Yield: 87%.
Viscous oil. 1H-NMR (400 MHz, CDCl3): 1.16 1.21 (m, 1H); 1.47 1.52 ( m, 1H); 2.05 2.10 ( m, 1 H);
2.31 2.36 ( m, 1H); 3.64 ( s, 3 H); 5.11 (s, 2 H); 6.31(br. s, 1H); 6.53 ( d, J ˆ 3.1, 1 H); 6.64 (d, JAB ˆ 8.5, 2 H);
6.92 (d, JAB ˆ 8.5, 2 H); 7.15 7.31 (m, 6 H). 13C-NMR (100 MHz, CDCl3): 15.6; 20.5; 23.7; 55.5; 77.4; 111.1;
111.5; 114.2; 127.9; 128.2; 128.6; 128.7; 133.7; 138.0; 143.5; 149.8; 150.5; 158.5. Anal. calc. for C22H21NO3 (347.41):
C 76.06, H 6.09, N 4.03; found: C 76.22, H 5.91, N 4.82.
(Z)-(Furan-2-yl)[2-(4-methoxyphenyl)cyclopropyl]methanone O-Benzyloxime ((Z)-5d). Yield: 96%.
Viscous oil. 1H-NMR (400 MHz, CDCl3): 1.05 1.10 (m, 1H); 1.51 1.56 ( m, 1H); 2.16 2.26 ( m, 2 H); 3.65
(s, 3 H); 5.10 (s, 2 H); 6.34 (dd, J ˆ 1.7, 3.4, 1 H); 6.73 (d, JAB ˆ 8.6, 2 H); 7.14 (d, JAB ˆ 8.5, 2 H); 7.17 7.31
(m, 7 H). 13C-NMR (100 MHz, CDCl3): 15.4; 22.7; 25.6; 55.7; 77.4; 112.5; 114.3; 117.9; 127.9; 128.1; 128.2; 128.3;
128.7; 128.9; 134.6; 138.3; 143.0; 146.8; 158.5.
(E)-(Furan-2-yl)[2-(2-naphthyl)cyclopropyl]methanone O-Benzyloxime ((E)-5e). Yield: 76%. Viscous oil.
1H-NMR (400 MHz, CDCl3): 1.35 1.49 (m, 1H); 1.52 1.78 ( m, 1H); 2.21 2.35 ( m, 1H); 2.52 2.61( m, 1 H);
5.12 (s, 2 H); 6.32 (dd, J ˆ 1.6, 3.3, 1 H); 6.59 (d, J ˆ 3.2, 1H); 7.12 7.77 ( m, 1 3 H). 13C-NMR (100 MHz,

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Helvetica Chimica Acta Vol. 87 (2004)
CDCl3): 15.8; 20.9; 24.6; 77.2; 111.5; 117.9; 125.6; 126.4; 127.8; 128.0; 128.1; 128.2; 128.4; 128.6; 128.7; 132.6;
133.9; 138.7; 139.3; 143.6; 143.6; 149.7; 150.3. Anal. calc. for C25H21NO2 (367.44): C 81.72, H 5.76, N 3.81; found:
C 81.93, H 5.57, N 3.97.
(Z)-(Furan-2-yl)[2-(2-naphthyl)cyclopropyl]methanone O-Benzyloxime ((Z)-5e). Yield: 83%. Viscous oil.
1H-NMR (400 MHz, CDCl3): 1.12 1.24 (m, 2 H); 1.61 1.70 (m, 1H); 2.31 2.42 ( m, 1H); 5.09 ( s, 2 H); 6.27
(dd, J ˆ 1.7, 3.5, 1 H); 7.12 7.59 (m, 1 4 H).13C-NMR (100 MHz, CDCl3): 16.1; 23.4; 26.6; 77.5; 112.6; 118.2;
125.0; 125.5; 125.6; 126.5; 128.0; 128.1; 128.2; 128.4; 128.5; 134.1; 138.3; 138.9; 140.2; 142.9; 142.9; 146.5; 146.9.
General Procedure for the Synthesis of Amines 6 from Oxime-Ethers 5. To a stirred mixture of one of the
chiral amino alcohols (7 9; 1.5 equiv.) in anh. THF (ca. 5 ml per mmol) under Ar gas at r.t. was added BH3 ¥
SMe2. The mixture was stirred for 8 h at r.t., then, the oxime ether (5a e; 1equiv.) in anh. THF ( ca. 3 ml per
mmol) was added dropwise. After 48 h, 1n HCl was added, until a white precipitate was formed. Finally, aq.
NaOH soln. was added, and the layers were separated. The aq. layer was extracted with Et2O (2 Â 25 ml), and
the combined org. layers were dried (MgSO4) and evaporated. The crude products were purified by FC (hexane/
AcOEt/MeOH 1:1:1).
(S)-(Furan-2-yl)[(1S,2S)-2-phenylcyclopropyl]methanamine ((S,S,S)-6a) and (R)-(Furan-2-yl)[(1R,2R)-
20
2-phenylcyclopropyl]methanamine ((R,R,R)-6a). Yields: 45 and 43%, resp. Viscous oils. ‰aŠ ˆ ‡37.5 (c ˆ 0.5,
D
20
D
1
CHCl3) for (S,S,S)-6a, and ‰aŠ ˆ À34.5 (c ˆ 0.5, CHCl3) for (R,R,R)-6a. H-NMR (400 MHz, CDCl3): 1.27
1.31 (m, 2 H); 1.64 1.67 (m, 1 H); 2.17 2.19 (m, 1H); 2.67 (br. s, 2 H); 3.74 (d, J ˆ 8.4, 1H); 6.17 ( d, J ˆ 3.4,
1H); 6.26 ( dd, J ˆ 1.6, 3.5, 1 H); 7.18 7.65 (m, 6 H). 13C-NMR (100 MHz, CDCl3): 14.4; 21.7; 28.9; 55.6; 105.3;
110.5; 126.2; 126.5; 126.8; 128.1; 128.6; 128.7; 142.4; 158.1.
(S)-(Furan-2-yl)[(1R,2R)-2-phenylcyclopropyl]methanamine ((S,R,R)-6a) and (R)-(Furan-2-yl)[(1S,2S)-
20
2-phenylcyclopropyl]methanamine ((R,S,S)-6a). Yields: 41and 46%, resp. Viscous oils. ‰aŠ ˆ À61.4 (c ˆ 0.6,
D
20
D
1
CHCl3) for (S,R,R)-6a, and ‰aŠ ˆ ‡55.7 (c ˆ 0.6, CHCl3) for (R,S,S)-6a. H-NMR (400 MHz, CDCl3): 0.91
1.12 (m, 2 H); 1.57 1.59 (m, 1H); 1.89 1.92 ( m, 1H); 2.58 (br. s, 2 H); 3.62 (d, J ˆ 8.2, 1H); 6.11( d, J ˆ 3.2,
1H); 6.24 ( dd, J ˆ 1.7, 3.4, 1 H), 6.96 7.42 (m, 6 H). 13C-NMR (100 MHz, CDCl3): 14.2; 21.8; 28.9; 54.2; 105.2;
110.5; 126.0; 126.4; 126.8; 127.8; 128.6; 128.7; 141.9; 158.2. Anal. calc. for C14H15NO (212.28): C 78.84, H 7.09;
found: C 78.93, H 7.33.
(S)-[(1S,2S)-2-(2-Chlorophenyl)cyclopropyl](furan-2-yl)methanamine ((S,S,S)-6b) and (R)-[(1R,2R)-2-
(2-Chlorophenyl)cyclopropyl](furan-2-yl)methanamine ((R,R,R)-6b). Yields: 40 and 44%, resp. Viscous oils.
20
D
20
D
‰aŠ ˆ ‡2.6 (c ˆ 0.5, CHCl3) for (S,S,S)-6b, and ‰aŠ ˆ À56.2 (c ˆ 0.5, CHCl3) for (R,R,R)-6b. 1H-NMR
(400 MHz, CDCl3): 0.95 0.98 (m, 2 H); 1.34 1.39 (m, 1 H); 2.11 2.14 (m, 1H); 2.33 (br. s, 2 H); 3.52 (d, J ˆ
8.3, 1H); 6.12 ( d, J ˆ 3.2, 1H); 6.21( dd, J ˆ 1.8, 3.4, 1 H); 6.08 7.31 (m, 5 H). 13C-NMR (100 MHz, CDCl3):
12.4; 20.2; 28.9; 54.3; 105.3; 104.7; 126.7; 127.3; 128.7; 129.5; 135.4; 139.6; 141.8; 157.6. Anal. calc. for
C14H14ClNO (247.72): C 67.88, H 5.70; found: C 67.63, H 5.66.
(S)-[(1R,2R)-2-(2-Chlorophenyl)cyclopropyl](furan-2-yl)methanamine ((S,R,R)-6b) and (R)-[(1S,2S)-2-
(2-chlorophenyl)cyclopropyl](furan-2-yl)methanamine ((R,S,S)-6b). Yields: 43 and 39%, resp. Viscous oils.
20
D
20
D
‰aŠ ˆ À74.7 (c ˆ 0.3, CHCl3) for (S,R,R)-6b, and ‰aŠ ˆ ‡77.1( c ˆ 0.3, CHCl3) for (R,S,S)-6b. 1H-NMR
(400 MHz, CDCl3): 0.71 0.95 ( m, 2 H); 1.44 1.47 (m, 1H); 1.89 (br. s, 2 H); 2.18 2.21 (m, 1H); 3.62 ( d, J ˆ
8.3); 6.14 (d, J ˆ 3.3, 1H); 6.18 ( dd, J ˆ 1.7, 3.5, 1 H); 6.84 7.28 (m, 5 H). 13C-NMR (100 MHz, CDCl3): 12.8;
19.0; 27.9; 53.1; 105.2; 110.2; 110.4; 127.2; 129.6; 135.4; 139.9; 141.8; 158.1.
(S)-(Furan-2-yl)[(1S,2S)-2-(3-methylphenyl)cyclopropyl]methanamine ((S,S,S)-6c) and (R)-(Furan-2-
yl[(1R,2R)-2-(3-methylphenyl)cyclopropyl]methanamine ((R,R,R)-6c). Yields: 44 and 43%, resp. Viscous oils.
20
D
20
D
‰aŠ ˆ ‡78.4 (c ˆ 0.5, CHCl3) for (S,S,S)-6c, and ‰aŠ ˆ À76.3 (c ˆ 0.6, CHCl3) for (R,R,R)-6c. 1H-NMR
(400 MHz, CDCl3): 0.90 0.96 (m, 1H); 1.34 1.41( m, 1 H); 1.78 1.83 (m, 1H); 2.23 ( s, 3 H); 2.38 (br. s, 2 H);
3.47 (d, J ˆ 8.2, 1H); 6.06 ( d, J ˆ 3.1, 1 H); 6.21 (dd, J ˆ 1.9, 3.0, 1 H); 6.76 7.06 (m, 4 H); 7.26 (s, 1 H).
13C-NMR (100 MHz, CDCl3): 14.2; 21.7; 21.8; 28.6; 54.1; 105.3; 110.4; 123.4; 126.8; 127.1; 128.6; 138.2; 141.9;
142.6; 158.0. Anal. calc. for C15H17NO (227.30): C 79.26, H 7.54; found: C 79.52, H 7.68.
(S)-(Furan-2-yl)[(1R,2R)-2-(3-methylphenyl)cyclopropyl]methanamine ((S,R,R)-6c) and (R)-(Furan-2-
yl)[(1S,2S)-2-(3-methylphenyl)cyclopropyl]methanamine ((R,S,S)-6c). Yields: 44 and 41%, resp. Viscous oils.
20
D
20
D
‰aŠ ˆ À15.9 (c ˆ 0.4, CHCl3) for (S,R,R)-6c, and ‰aŠ ˆ ‡18.9 (c ˆ 0.5, CHCl3) for (R,S,S)-6c. 1H-NMR
(400 MHz, CDCl3): 0.80 0.88 (m, 2 H); 1.30 1.36 (m, 1 H); 1.69 1.74 (m, 1H); 2.20 ( s, 5 H); 3.37 (d, J ˆ 8.0,
1H); 6.05 ( d, J ˆ 2.9, 1H); 6.17 ( t, J ˆ 1.9, 1 H); 6.69 7.17 (m, 4 H); 7.21( s, 1 H). 13C-NMR (100 MHz, CDCl3):
14.3; 21.8; 22.0; 29.0; 54.1; 105.2; 110.5; 123.4; 126.4; 126.8; 128.7; 138.1; 141.8; 142.7; 158.1.
(S)-(Furan-2-yl)[(1S,2S)-2-(4-methoxyphenyl)cyclopropyl]methanamine ((S,S,S)-6d) and (R)-(Furan-2-
yl)[(1R,2R)-2-(4-methoxyphenyl)cyclopropyl]methanamine ((R,R,R)-6d). Yields: 46 and 45%, resp. Viscous
20
D
20
D
oils. ‰aŠ ˆ ‡12.4 (c ˆ 1.1, CHCl3) for (S,S,S)-6d, and ‰aŠ ˆ À9.2 (c ˆ 0.9, CHCl3) for (R,R,R)-6d. 1H-NMR

Helvetica Chimica Acta Vol. 87 (2004)
117
(400 MHz, CDCl3): 0.81 0.92 ( m, 2 H); 1.25 1.28 (m, 1H); 1.75 (br. s, 2 H); 1.26 1.29 (m, 1H); 3.40 ( d, J ˆ
8.3, 1H); 3.68 ( s, 3 H); 6.05 (d, J ˆ 3.1, 1 H); 6.19 (dd, J ˆ 1.6, 3.0, 1 H); 6.71 (dd, JAB ˆ 8.6, 2 H); 6.89 (dd, JAB
ˆ
8.6, 2 H); 7.25 (s, 1 H). 13C-NMR (100 MHz, CDCl3): 13.7; 21.0; 28.5; 54.3; 55.6; 105.1; 110.4; 114.2; 127.5; 134.6;
141.8; 158.2; 158.5. Anal. calc. for C15H17NO2 (243.30): C 74.05, H 7.04; found: C 74.33, H 7.33.
(S)-(Furan-2-yl)[(1S,2S)-2-(2-naphthyl)cyclopropyl]methanamine ((S,S,S)-6e) and (R)-2-(Furan-2-
yl)[(1R,2R)-2-(2-naphthyl)cyclopropyl]methanamine ((R,R,R)-6e). Yields: 42 and 44%, resp. Viscous oils.
20
D
20
D
‰aŠ ˆ ‡98.3 (c ˆ 0.5, CHCl3) for (S,S,S)-6e, and ‰aŠ ˆ À101.6 (c ˆ 0.6, CHCl3) for (R,R,R)-6e. 1H-NMR
(400 MHz, CDCl3): 1.01 1.14 (m, 2 H); 1.55 1.57 (m, 1H); 1.98 2.02 ( m, 1H); 2.57 (br. s, 2 H); 3.52 (d, J ˆ
8.3, 1H); 6.07 ( d, J ˆ 3.4, 1H); 6.18 (br. s, 1H); 7.12 7.74 ( m, 8 H). 13C-NMR (100 MHz, CDCl3): 14.5; 22.1;
28.6; 54.1; 105.5; 110.5; 124.4; 125.2; 125.4; 126.4; 127.7; 127.9; 128.3; 132.4; 133.4; 139.9; 142.0. Anal. calc. for
C18H17NO (263.33): C 82.10, H 6.51; found: C 82.24, H 6.68.
General Procedure for the Oxidation of the Furan Ring of Compounds of Type 6. By Ozonolysis. Through a
soln. of (S,S,S)-6a and (S,R,R)-6a (3 mmol) in MeOH (25 ml), cooled to À 788, was passed O3 for 15 min (blue
color). Then, Ar gas was bubbled at this temp. through the soln. to remove excess O3. The soln. was allowed to
warm to r.t., and HCl gas was passed through the soln. (salt formation). The crude product was purified by
recrystallization.
By Oxidation with RuO2/NaIO4. RuO2 ¥ H2O (0.066 mmol) was added to a mixture of NaIO4 (29.8 mmol) in
H2O (13 ml), MeCN (19 ml), and CCl4 (13 ml), and the mixture was stirred for 30 min. Compounds (S,S,S)- and
(S,R,R)-6a (1.8 mmol) were added, and the mixture was stirred for 2 h at r.t. The org. layer was separated, the
aq. phase was washed with CH2Cl2 (4 Â 20 ml) and brine, dried (Na2SO4), and concentrated. The residue was
Table 3. Crystallographic Dataa) of (E)-4a, (E)-4c, and (Z)-4c
(E)-4a
(E)-4c
(Z)-4c
Crystallized from
Empirical formula
Formula weight [g molÀ1
Hexane/Et2O
C14H13NO2
227.26
Hexane/Et2O
C15H15NO2
241.29
Hexane/Et2O
C15H15NO2
241.29
]
Unit-cell dimensions a [ä]
13.9937(12)
6.1683(11)
14.3233(14)
103.068(4)
1204.3(3)
monoclinic
P21/n
6.9182(11)
14.3302(12)
25.5885(14)
90
2536.8(5)
orthorombic
Pbca
7.3515(12)
14.2047(11)
12.6422(14)
91.106(2)
1319.9(3)
monoclinic
P21/c
b [ä]
c [ä]
b [8]
Cell volume [ä3]
Crystal system
Space group
Z
4
8
4
Dx [g cmÀ3
]
1.253
0.084
w/2q
1.263
0.084
w/2q
1.214
0.081
w/2q
m (MoKa) [mmÀ1
Scan type
]
qmax [8]
22.74
26.29
26.28
Absorption correction
Total reflections measured
Symmetry-independent reflections
Reflections used [I ꢀ 2s(I)]
Parameters refined
Final R
none
3406
1625
974
155
0.079
none
4282
2572
2013
163
0.046
none
4334
2071
1278
163
0.077
wR
0.245
0.295; À 0.173
0.120
0.194; À 0.325
0.240
0.346; À 0.206
Dr (max; min) [e äÀ3
]
a) Crystallographic data (excluding structure factors) for the structures reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre as deposition No. CCDC-212026 for (E)-4a,
CCDC-212027 for (E)-4c, and CCDC-212028 for (Z)-4c. Copies of the data can be obtained, free of charge, on
application to the CCDC, 12 Union Road, Cambridge CB2IEZ UK (fax: ‡ 44(1223)336033; e-mail:
deposit@ccdc.com.ac.uk).

118
Helvetica Chimica Acta Vol. 87 (2004)
dissolved in MeOH (20 ml) and filtered through a small pad of Celite. Then, HCl gas was passed through the
soln. (salt formation), and the crude product was purified by recrystallization.
20
(S,S,S)-a-(2-Phenylcyclopropyl)glycine ((S,S,S)-1a). M.p. 2108 ‰aŠ ˆ ‡71.0 (c ˆ 0.4, H2O).
D
20
(R,R,R)-a-(2-Phenylcyclopropyl)glycine ((R,R,R)-1a). M.p. 2158. ‰aŠ ˆ À76.0 (c ˆ 0.2, H2O).
D
X-Ray Crystal-Structure Analyses. X-ray diffraction intensities were collected with a CAD-4 diffractometer.
Graphite monochromated MoKa radiation (l ˆ 0.71073 ä) was used. Data reduction involved Lorentz and
polarization corrections. The structures of (E)-4a (Fig. 1), (E)-4c (Fig. 2), and (Z)-4c (Fig. 3) were solved by
direct methods and refined by full-matrix least-squares techniques. All non-H-atoms were refined with
anisotropic displacement parameters. The H-atoms were placed geometrically by 0.84 1.00 ä from their parent
atoms, then a riding model with Uiso(H) ˆ 1.3Ueq(C,O) was applied. Scattering factors were taken from
International Tables for X-ray Crystallography. The following computer programs were used: CAD4-EXPRESS
[24] for for data collection and cell parameters, the SHELXL package [25] for structure solution and refinement,
and PLATON 2000 [26] for molecular graphics. For more details, see Table 3.
Financial support of the Scientific and Technical Research Council of Turkey(TUBITAK), the Turkish State
Planning Organization (for LC/MS), the Turkish Academy of Science (TUBA), and the Middle-East Technical
University (AFP 2002) is gratefully acknowledged.
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Received June 26, 2003