Intramolecular Kulinkovich-de Meijere reactions of various disubstituted alkenes bearing amide groups

Article abstract of DOI:10.1016/j.tet.2008.06.067

A range of amides fitted with (E) or (Z) disubstituted alkene groups were prepared and evaluated in intramolecular Kulinkovich-de Meijere reactions. The corresponding aminocyclopropanes were obtained with high diastereoselectivity. Good yields could be achieved with substrates bearing suitable substitutions at the olefin moieties.

Full text of DOI:10.1016/j.tet.2008.06.067

Tetrahedron 64 (2008) 8878–8898
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Intramolecular Kulinkovich–de Meijere reactions of various
disubstituted alkenes bearing amide groups
a
a
a
b
`
Claire Madelaine , Nouara Ouhamou , Angele Chiaroni , Emeline Vedrenne ,
Laurence Grimaud b, Yvan Six a
,
*
a Institut de Chimie des Substances Naturelles, UPR 2301 du C.N.R.S., Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France
b
´
Ecole Nationale Supe´rieure des Techniques Avance´es, Laboratoire Chimie et Proce´de´s, 32 Bd Victor, 75739 Paris Cedex 15, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 April 2008
Received in revised form 10 June 2008
Accepted 17 June 2008
Available online 21 June 2008
A range of amides fitted with (E) or (Z) disubstituted alkene groups were prepared and evaluated in
intramolecular Kulinkovich–de Meijere reactions. The corresponding aminocyclopropanes were obtained
with high diastereoselectivity. Good yields could be achieved with substrates bearing suitable
substitutions at the olefin moieties.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Kulinkovich–de Meijere reaction
Ligand exchange
Metathesis
Titanium
Titanacyclopropanes
R2
R1
1. Introduction
R2
R1
R1
OiPr
OiPr
OiPr
Ti
OiPr
2
MgX
+ XTi(OiPr)3
Ti
The reaction of tertiary carboxylic amides with titanium alkox-
ides of the form XTi(OiPr)3 (X¼Me, Cl, OiPr) and excess amounts of
Grignard reagents (normally more than 2 equiv when XsMe) is
a powerful method for the preparation of aminocyclopropanes
(Kulinkovich–de Meijere reaction).1–4 In the presence of alkenes,
the putative intermediate titanacyclopropane species A initially
formed can undergo ligand exchange to give complex B, which
leads to cyclopropane products resulting from alkene–amide
coupling (Scheme 1).5,6 This process is essentially limited to mon-
osubstituted alkenes, even using cyclic Grignard reagents such as
cyclo-pentylmagnesium chloride or cyclo-hexylmagnesium chlo-
ride, which have been shown to generally drive the equilibrium
towards the formation of complex B.7 Good yields have nonetheless
been obtained from disubstituted alkenes in the special cases
where they were part of conjugated polyene systems or geo-
metrically constrained rings.8–10
B
A
O
O
R4
R4
R3
R3
R3
R3
N
N
R5
R5
R2
R1
R4
R4
N
N
R5
R5
Scheme 1. Kulinkovich–de Meijere reactions, without or with alkene ligand exchange.
poorly efficient because of competitive intermolecular reactions,
they were found to be totally diastereoselective. A mechanistic
hypothesis was formulated to account for the stereochemistry of
the desired products, supported by a study published afterwards by
Casey et al.12
In order to improve these intramolecular reactions, we decided
to investigate the effect of an additional functional group on the
substrate. Indeed, a suitable group might coordinate to the titanium
intermediate complex C and direct the ligand exchange elementary
step (Scheme 2). Our strategy for a rapid access to various sub-
strates was to prepare them by cross-metathesis from the parent
compound N-but-3-enyl-N-phenylacetamide 1a.
A few years ago, we reported a study dealing with intra-
molecular Kulinkovich–de Meijere reactions starting from a few (Z)
and (E) N-hex-3-enyl acetamides.11 Although these reactions were
* Corresponding author. Tel.: þ33 (0)1 6982 3086; fax: þ33 (0)1 6907 7247.
E-mail address: yvan.six@icsn.cnrs-gif.fr (Y. Six).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.06.067

C. Madelaine et al. / Tetrahedron 64 (2008) 8878–8898
8879
results in the preparation of 1b as well as the cross-metathesis of 1a
with excess amounts of allyl alcohol, 3-buten-1-ol or 4-penten-1-
ol, readily granting access to compounds 1c–h (Table 1, entries 1–
7).14 We recently reported that a catalytic amount of a boron-based
Lewis acid such as chlorocatecholborane could enhance the effi-
ciency of cross-metathesis reactions involving nitrogen-containing
alkenes.15 Compounds 1i–l were prepared in moderate to excellent
yields using this method, with high diastereoselectivity in favour of
the E isomers (Table 1, entries 8–11).
For comparison purposes, n-butyl derivatives (E)-1m and (Z)-
1m were prepared in pure diastereoisomeric form following in-
dependent routes (Scheme 3). A range of pure (Z) alkenyl amides
were also synthesised from alcohol (Z)-1c, obtained by standard
cleavage of the para-methoxybenzyl (PMB) protected compound
(Z)-1n.16 This (Z) homoallylether, as well as the analogous benzyl
derivative (Z)-1e, was prepared as a single diastereoisomer using
the chemistry of Sato, namely via the intermediary of titanacyclo-
propene complexes generated from the corresponding alkynes
(Scheme 4).17,18
OiPr
B
iPrO
Ti(OiPr)4
Ti
O
O
cC5H9MgCl
B
N
N
N
Ph
Ph
Ph
OiPr
Ti
cross-
Intramolecular
Kulinkovich-de Meijere
reaction
OiPr
C
metathesis
O
B
Ph
N
1a
Scheme 2. Intramolecular Kulinkovich–de Meijere reaction with substrate-directed
ligand exchange.
2. Results and discussion
Using Grubbs second generation catalyst, the cross-coupling
metathesis of 1a with various alkenes turned out to be of poor ef-
ficiency and feeble reproducibility due to double-bond migration
and/or competition with homo-coupling processes. The use of
a catalytic amount of 2,6-dichloro-1,4-benzoquinone (DQ), which
inhibits double-bond migration,13 gave satisfactory and reliable
With alkenyl amides 1b–q in hand, they were submitted to the
intramolecular Kulinkovich–de Meijere reaction conditions.
The results are presented in Table 2, as well as that obtained from
the reference compound 1a (entry 1).5,19 In agreement with our
Table 1
Preparation of alkenyl amides 1b–l by cross-metathesis using Grubbs second generation catalyst
Entry
Starting alkene(s)
Methoda
Product
Yield % (E/Z ratio)
O
N
Ph
1
1a
A
1b
1c
60 (85:15)
Ph
N
O
O
2
1a (1.0 equiv) and 3-buten-1-ol (4.0 equiv)
A
71 (75:25)b
N
Ph
OH
O
3
1a (1.0 equiv) and 3-buten-1-ol (4.0 equiv)
1a (1.0 equiv) and 3-buten-1-ol (4.0 equiv)
1a (1.0 equiv) and 3-buten-1-ol (4.0 equiv)
1a (1.0 equiv) and allyl alcohol (4.0 equiv)
1a (1.0 equiv) and 4-penten-1-ol (4.0 equiv)
1a (1.0 equiv) and methyl acrylate (1.0 equiv)
1a (1.0 equiv) and tert-butyl acrylate (1.0 equiv)
1a (1.0 equiv) and phenylvinylsulfone (1.0 equiv)
A
A
A
A
A
B
B
B
1d
1e
1f
66 (85:15)c
59 (85:15)c
60 (85:15)c
33 (89:11)c
45 (80:20)c
91 (>98:2)
72 (>98:2)
44 (>98:2)
N
Ph
OTBS
OBn
O
4
N
Ph
O
5
N
OMe
OBn
Ph
O
6
1g
1h
1i
N
Ph
O
7
N
OBn
Ph
O
O
O
8
N
N
N
CO2Me
Ph
Ph
Ph
9
1j
CO2tBu
10
1k
SO2Ph
O
11
1a (1.0 equiv) and styrene (1.0 equiv)
B
1l
44 (>98:2)
N
Ph
Ph
a
Method A: the cross-metathesis reaction was performed in the presence of a catalytic amount of DQ. Method B: reaction was performed in the presence of a catalytic
amount of chlorocatecholborane (see Section 4 for details).
b
Combined yield for the cross-metathesis reaction, protection of the alcohol function as a tert-butyldimethylsilyl ether 1d, purification and deprotection under acidic
conditions (see Ref. 14).
c
Combined yield for the cross-metathesis reaction and protection of the alcohol function either as a tert-butyldimethylsilyl, a benzyl or a methyl ether (see Ref. 14).

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C. Madelaine et al. / Tetrahedron 64 (2008) 8878–8898
1. MsCl, Et3N, CH2Cl2, 0 °C
O
O
LAH
2. PhNH2, MeCN, Δ
HO
Diglyme / THF, Δ
3. Ac2O, pyridine, 0 °C to 20 °C
N
N
HO
nBu
nBu
nBu
nBu
Ph
Ph
ref. 38
67% (3 steps)
(E) only
(E)-1m
nBu
TsCl, pyridine
CHCl3, 20 °C
PhNHAc, nBu4NHSO4 (5% eq.)
nBu
(Z) only,
KOH, toluene, 80 °C
HO
TsO
78%
63%
(Z)-1m
commercially available
Scheme 3. Synthesis of alkenes (E)-1m and (Z)-1m.
1. n-BuLi
THF, -78 °C
1. PhNH2, AcONa
MeCN, Δ
2. AcCl, NaOH
DCM, 20 °C
O O
S
O
TsCl, pyridine
CHCl3, 20 °C
TsO
2.
, -55 °C
HO
O
O
N
Ph
OR
70% (R = Bn)
75% (R = PMB)
66% (R = Bn)
73% (R = PMB)
86% (R = Bn)
OR
OR
OR
92% (R = PMB)
DHP, pTsOH, 20 °C
(Z)-1o (R = THP)
(Z)-1p (R = Ac)
Ti(OiPr)4
86%
OR
OR
cC5H9MgCl
Et2O
DDQ
O
O
DCM/H2O
H2O
-70 °C to -30 °C
20 °C
Ac2O, pyridine, 20 °C
72%
(Z)-1c
(R = H)
N
N
Ph
Ph
OiPr
74%
(R = PMB)
Ti
iPrO
76% (R = Bn)
74% (R = PMB)
(Z)-1e (R = Bn)
(Z)-1n (R = PMB)
tBuCOCl, pyridine, DCM, 20 °C
(Z)-1q
(R = tBu)
84%
Scheme 4. Synthesis of (Z) alkenes 1c, 1e and 1n–1q.
previous report,11 all the diastereoisomerically pure compounds 1
used were converted into the corresponding aminocyclopropanes
2 with complete diastereoselectivity (entries 2, 4, 6, 8, 9, 17–21
and 24). Yet, when the starting materials were diastereoisomeric
mixtures, the cis/trans ratios of the products 2 were usually found
to be significantly lower than the original (E)/(Z) ratios of the alkene
substrates (entries 3, 5, 7, 12, 23). However, this can be simply
explained by a faster reaction of the (Z) diastereoisomers relative to
the (E) diastereoisomers: the conversions were not complete and
proportions of (E) diastereoisomers were higher in the recovered
starting materials than at the beginning of the reactions.
The relative configurations of the asymmetric carbon atoms in
the products 2 were established on the basis of the 3J coupling
constants between the vicinal protons born by the cyclopropane
ring, whenever these could be measured accurately (3Jcisz8.5 Hz;
3Jtransz5.0 Hz).20 When signal overlap prevented the de-
termination of these coupling constants, the signals of the endo-
cyclic methylene protons geminal to the nitrogen atom were
examined. The following reliable empirical rule was used: for the
cis diastereoisomers, two triplets of doublets (3Jz10.0 and 4.5 Hz in
the 3.00–3.15 ppm region and 3Jz10.0 and 6.5 Hz in the 3.95–
4.05 ppm region); for the trans diastereoisomers, a doublet of
triplets (3Jz10.0 and 8.5 Hz in the 2.85–2.90 ppm region) and
a triplet of doublets (3Jz10.0 and 3.5 Hz in the 3.90–3.95 ppm re-
gion). In the case of the isolated single diastereoisomer of com-
pound 2b prepared from (E)-1b, this empirical rule and the
cyclopropane proton vicinal coupling constants were in agreement
with the X-ray crystallographic structure obtained from single
crystals. A cis relationship between the nitrogen-containing fused
ring and the N,N-acetylphenylaminoethyl substituent was evi-
denced (Fig. 1). This, as well as all the other results, unequivocally
supports our earlier proposal stating that the reaction gives cis
products from (E) alkenes and trans products from (Z) alkenes in
a diastereospecific fashion (Scheme 5).11
According to our initial hypothesis, compounds 1b, 1d, 1e, 1f, 1h,
1n and 1o bearing functional groups susceptible to coordinate to
the titanium atom and favour ligand exchange, all gave better
results than the reference compounds (E)- and (Z)-1m (entries 2,
5–10, 12, 19 and 20 vs entries 17 and 18). The reaction of the free
alcohol 1c was also attempted, with an unsurprisingly poor result
(entries 3 and 4). Quite remarkably, the aminocyclopropane prod-
uct 2b was obtained in 24% yield from 1b, which is rather sub-
stantial given the opportunities for unwanted intermolecular
side-reactions offered by both molecules under the reaction con-
ditions. The silyl ether 1d was converted into aminocyclopropane
2d in 38% yield, which suggests that the tert-butyldimethylsilyloxy
group could coordinate to the metal centre quite efficiently. This is
surprising but after all not unconceivable given the small size of the
titanium atom. Importantly, the reaction of amides 1e and 1f fitted
with more suitable coordinating benzyloxy or methoxy groups
furnished the corresponding products 2e and 2f in best yields
(entries 7–10). The better coordinating ability of the less bulky
methoxyethyl compound 1f was evidenced, and the very satisfac-
tory 78% yield observed for the formation of aminocyclopropane 2f
is comparatively close to the 90% yield achieved from the mono-
substituted alkene 1a (entry 1).
In contrast, the lithium or magnesium salts of alcohol 1c, which
could have been foreseen as excellent ligand exchange directing
functions in the light of literature precedence,21–25 led to the
cyclopropylamine products only in poor yield and low conversion
(entries 23 and 24). These results can be paralleled with a report
published by Sato et al. 10 years ago, where alkoxides appeared
to behave as more sterically demanding groups than the tert-
butyldimethylsilyloxy group in the Ti(OiPr)4/iPrMgCl-mediated
cyclisation of enynes and allenynes.26 Indeed, the same kind
of effect seems to operate here (compare the results obtained
with the alkoxides 1r and 1s with those obtained with the TBS
compound 1d).

C. Madelaine et al. / Tetrahedron 64 (2008) 8878–8898
8881
Table 2
Intramolecular Kulinkovich–de Meijere reactions performed on alkenyl amides 1a–sa
Entry
Alkenyl amide 1 (E/Z ratio)
Aminocyclopropane productb
Yield % (cis/trans ratio)b
905,19
Unreacted 1 % (E/Z ratio)
O
N
1
1a
2a
0
Ph
N
Ph
O
O
N
N
1b (>98:2)c
2b
24 (>98:2)
8 (>98:2)
Ph
N
2
Ph
Ph
Ph
N
N
N
N
O
O
OH
3
4
1c (75:25)
1c (0:100)
2c
2c
9 (64:36)
89 (79:21)
N
Ph
OH
Ph
O
OH
OTBS
OBn
OH
10 (<2:98)
62 (<2:98)
N
O
Ph
Ph
5
6
1d (85:15)
1d (98:2)d
2d
2d
38 (68:32)
24 (98:2)
17 (98:2)
N
Ph
Ph
OTBS
34 (>98:2)
O
7
1e (85:15)
2e
53 (79:21)
16 (87:13)
N
Ph
OBn
OBn
Ph
N
8
1e (0:100)
1e (0:100)
1f (90:10)
2e
2e
2f
44 (<2:98)
50 (<2:98)e
78 (92:8)
14 (<2:98)
O
OBn
N
Ph
Ph
Ph
N
N
N
9
24 (<2:98)
O
OMe
OBn
10
18 (Not determined)
N
Ph
OMe
OBn
O
11
1g (89:11)
2g
Traces
4 (Not determined)
N
Ph
Ph
OBn
O
12
13
14
1h (80:20)
1i (>98:2)
1j (>98:2)
2h
2i
24 (68:32)
0, See text
0, See text
25 (95:5)
23 (>98:2)
0
N
OBn
Ph
N
Ph
CO2Me
O
N
CO2Me
Ph
Ph
Ph
N
N
CO2tBu
O
O
2j
N
N
CO2tBu
SO2Ph
Ph
Ph
Ph
15
16
1k (>98:2)
1l (>98:2)
2a
2l
11
62 (>98:2)
23 (>98:2)
Ph
N
Ph
O
0, See text
N
O
Ph
Ph
N
17
18
1m (100:0)
1m (0:100)
2m
2m
18 (>98:2)
12 (<2:98)
41 (>98:2)
52 (<2:98)
N
N
Ph
Ph
N
N
O
N
Ph
Ph
OPMB
O
OPMB
19
1n (0:100)
2n
33 (<2:98)e
49 (<2:98)
Ph
N
Ph
(continued on next page)

8882
C. Madelaine et al. / Tetrahedron 64 (2008) 8878–8898
Table 2 (continued )
Entry
Alkenyl amide 1 (E/Z ratio)
Aminocyclopropane productb
Yield % (cis/trans ratio)b
Unreacted 1 % (E/Z ratio)
26 (<2:98)
O
OTHP
OTHP
20
1o (0:100)
2o
2c
2q
2c
23 (<2:98)e
N
Ph
Ph
N
OH
OPiv
OH
O
OAc
21
22
23
1p (0:100)
1q (0:100)
1r (75:25)f
8 (<2:98)e
4 (<2:98)
27 (<2:98)
73 (80:20)
N
N
Ph
N
Ph
O
OPiv
0e
Ph
Ph
N
O
17 (66:34)
N
Ph
OLi
Ph
N
O
OH
OMgCl
24
1s (0:100)g
2c
21 (<2:98)e
49 (<2:98)
N
Ph
Ph
N
a
b
c
The Kulinkovich–de Meijere reactions were performed using 1.5 equiv of Ti(OiPr)4 and 4.0 equiv of c-C5H9MgCl, in diethyl ether unless otherwise stated.
The major diastereoisomer of the product 2 is represented; cis and trans refer to the relative configurations of the nitrogen atom and the side chain on the cyclopropane ring.
The pure (E) diastereoisomer of compound 1b, obtained by chromatography and crystallisation, was used. The reaction was performed in THF because of the poor solubility
of this compound in diethyl ether.
d
A 98:2 mixture of (E) and (Z) diastereoisomers of alkenyl amide 1d was obtained by purifying unreacted starting material from the crude product of the previous
experiment run on a 85:15 mixture of (E) and (Z) diastereoisomers.
e
The reaction was performed in toluene.
f
Compound 1c was treated with n-BuLi (1.0 equiv) prior to the addition of Ti(OiPr)4 (1.5 equiv) and cyclo-pentylmagnesium chloride (4.0 equiv).
g
Compound (Z)-1c was treated with cyclo-pentylmagnesium chloride (1.0 equiv) prior to the addition of Ti(OiPr)4 (1.5 equiv) and cyclo-pentylmagnesium chloride
(4.0 equiv).
benzyl alcohol were detected in the crude reaction product. Both
diastereoisomers of 1e were converted into the corresponding di-
astereoisomeric aminocyclopropanes 2e with essentially the same
efficiency (entries 7 and 8). The reaction of (Z)-1e was found to be
slightly better in toluene than in diethyl ether (entries 8 and 9),
while the corresponding para-methoxybenzyl ether (Z)-1n and the
THP acetal (Z)-1o proved to be less effective substrates (entries 19
and 20 vs entry 9).
The case of esters (Z)-1p and (Z)-1q was especially interesting: it
was hoped that in the event of a poorly efficient intramolecular
Kulinkovich–de Meijere reaction, the roles of the amide and the
ester functions could be reversed, i.e., the amide group could act as
a ligand exchange directing group to favour an intramolecular
Kulinkovich reaction at the ester function, delivering a cyclo-
propanol. This is normally a poorly efficient process when di-
substituted alkenes are involved (Scheme 6, top).28 When the
reaction was attempted from the acetate ester (Z)-1p, the fastest
process appeared to be an intermolecular Kulinkovich reaction, and
therefore the main reaction product was de-acylated compound
(Z)-1c. Aminocyclopropane trans-2c was also isolated in 8% yield,
presumably resulting from a tandem intermolecular Kulinkovich
reaction/intramolecular Kulinkovich–de Meijere reaction (Table 2,
Figure 1. Ortep view of compound 2b. Displacement ellipsoids are drawn at the 30%
entry 21 and Scheme 6, middle). This is supported by the fact that
the magnesium alkoxide (Z)-1s generated from (Z)-1c could give
the same product (entry 24), although a tandem intramolecular
Kulinkovich–de Meijere reaction/intermolecular Kulinkovich re-
action could also be considered. Switching the acetyl group to
a bulkier, less reactive pivaloyl derivative (Z)-1q did not improve
the reaction (entry 22). As a control experiment, the Kulinkovich
reaction of alkenyl ester 3, bearing a 2-benzyloxyethyl group, was
attempted and an exclusive intermolecular mechanistic pathway
was observed, delivering alcohol 4 and cyclopropanol 5 (Scheme 6,
bottom).
probability level.
In the case of the benzyloxy group, the influence of its distance
to the olefin function was evaluated. The results established that
the optimal spacer consisted of two methylene groups as in com-
pound 1e: the higher homologue 1h was converted in significantly
lower yield (24%, entry 12), while the reaction of allyl benzyl ether
1g only afforded traces of the expected aminocyclopropane (entry
11). The intermediate titanium complex most probably underwent
b
-elimination of the benzyloxy group,27 as extensive amounts of

C. Madelaine et al. / Tetrahedron 64 (2008) 8878–8898
8883
R
R
iPrO
iPrO OiPr
O
OiPr
O
R
R
Ti
C
Ti
OiPr
OiPr
O
O
R
SE2 (back)
SE2 (back)
Ti
R
N
N
Ph
N
R
Ph
Ph
ligand
exchange
OiPr
N
Ph
N
N
N
N
Ph
Ph
Ph
(cis)-2
(E)-1
iPrO
iPrO OiPr
Ti
O
OiPr
O
O
Ti
R
C
O
Ti
R
Ph
N
ligand
exchange
OiPr
Ph
N
Ph
R
(trans)-2
(Z)-1
Scheme 5. The diastereospecific transformation of alkenyl amides 1 into bicyclic aminocyclopropanes 2.
Ti(OiPr)4, iPrMgBr
O
O
O
Et2O, -45 °C to 0 °C
OR
C
HO
HO
+
N
N
O
Ph
Ph
Ph
93%
CO2R
(addition)
OH
OH
O
Ti
iPrO
(58 : 42)
1i
1j
R = Me
R = tBu
OiPr
O
O
Ti(OiPr)4, iPrMgBr
Et2O, -45 °C to 0 °C
Ac
N
C
(ligand exchange)
O
O
HO
< 5%
OR
OiPr
OH
O
O
H
Ti
O
OiPr
N
OH
Ti
Ph
2i
2j
Ti(OiPr)4
OiPr
HO
cC5H9MgCl
E
Ac
N
CO2R
Toluene, 20 °C
+
N
N
N
Ph
Ac
Ph
Ph
Ac
(Z)-1c (44%)
Ph
Ti OR
OiPr
O
D
OiPr
iPrO
(Z)-1p
trans-2c (8%)
Ti
H3O+
O
O
O
MeTi(OiPr)3, cC5H9MgCl
Ac
N
Ph
Ph
OBn
OBn
Et2O, 20 °C
N
N
RO
O
HO
Ph
91%
OH
3
4
F
O
6
OiPr
OH
iPrO
RO
N
iPrO
Ti
O
O
;
5
O
OH
Ti
OH
Ti
OBn
O
OiPr
iPrO
OiPr
OiPr
0%
observed by NMR
in the crude product
HO
OiPr
RO
N
Ph
Ph
Scheme 6. Intramolecular Kulinkovich reactions starting from a monosubstituted and
a disubstituted alkenyl ester (top).28 Reaction of substrate (Z)-1p (middle) and alkenyl
ester 3 (bottom).
H
H3O+
G
(iPrO)2Ti=O
CO2R
CO2iPr
[Ti], iPrO
a,b-Unsaturated esters 1i and 1j led to complex mixtures of
N
N
Ph
Ph
7
products. This is perhaps not surprising, since the expected donor–
acceptor-substituted cyclopropane products 2i and 2j might be
unstable.29,30 However, ketone 6 and vinylogous carbamate 7 were
isolated in low yield in both cases. The mechanism leading to these
products is unclear: 2i and 2j are not likely intermediates, and the
following tentative explanation may be proposed (Scheme 7). The
initially generated bicyclic titanacyclopropane C might react in part
with 1i or 1j according to an addition at the ester carbonyl group.
After departure of the alkoxy leaving group, one could tentatively
invoke a hydride transfer from an iso-propyloxy ligand of the tita-
nium atom, which would result in the release of acetone and the
formation of a stabilised titanium enolate D that would be hydro-
lysed to the ketone 6. Alternatively, ligand exchange with 1i or 1j
from complex C would deliver E. In contrast with the five-mem-
bered ring closure normally observed, formation of a six-mem-
bered ring F might then occur at least as a side-process. After
carbon–oxygen bond cleavage giving the metallated iminium G,
proton loss could be faster than aminocyclopropane ring formation,
O
Ph
N
Ph
Ph
C
N
1l
8
Ph
Scheme 7. Proposed mechanism for the formation of unexpected compounds 6 and 7.
Formation of compound 8.
corresponding iso-propyl ester, which is documented under these
conditions,31,32 would yield compound 7 after hydrolysis.
No expected aminocyclopropane could be isolated from the
styrene-derivated alkenyl amide 1l either, but careful analysis of
the crude product revealed the presence of a major compound in
about 30% yield. Its NMR data was consistent with cyclic enamine
structure 8, the latter could be formed according to a similar
pathway as 7 (Scheme 7). Unsurprisingly, this molecule could not
be isolated by flash column chromatography on silica gel. In-
terestingly, when the Kulinkovich–de Meijere reaction was
for which the required overlap of the
system and the small lobe of the C–Ti orbital would be geo-
metrically difficult to achieve. Finally, transesterification to the
p
*
orbital of the iminium
attempted from the a,b-unsaturated sulfone 1k, the only products
isolated, apart from starting material (62%), were the amino-
cyclopropane 2a (11%) and alkenyl amide 1a (8%), both having lost
s

8884
C. Madelaine et al. / Tetrahedron 64 (2008) 8878–8898
the sulfone moiety. A parallel can be made between this observa-
tion and recent results reported by the group of Ollivier involving
oxygen-substituted alkenes,32 and a similar mechanism could
operate here.
An attempt to apply our method to the reaction of indole
derivative (Z)-9 bearing a suitable benzyloxyethyl group met little
success with a 14% yield, showing that the observed improvement
may be valid only for N-aryl substrates (Scheme 8). In spite of this
disappointing result, we were able to successfully perform the
thermal cyclisation of aminocyclopropane (trans)-10 according to
our previously described method,33 for which no substrate with
this degree of substitution had been tested so far.
a PureSolv solvent purification system (Innovative Technology Inc.).
Chloroform was passed through a column containing a 10 cm high
amount of silica gel of the type specified above. cyclo-Pentylmag-
nesium chloride 2 M solution in diethyl ether was purchased from
Sigma–Aldrich or Fluka and titrated once a month according to
a previously reported method.18 The preparation of N-but-3-enyl-
N-phenylacetamide 1a has already been described elsewhere.5,19
4.2. Cross-metathesis of 1a with alkenes, method A
Typically,
0.30 mmol, 53 mg) and Grubbs second generation catalyst (2.0%
equiv, 60 mol, 40 mg) were added to a solution of alkenyl amide
2,6-dichloro-1,4-benzoquinone
(10%
equiv,
m
1a (1.0 equiv, 3.0 mmol, 0.57 g) and requisite alkene (4.0 equiv,
12 mmol) in freshly distilled CH2Cl2 (15 mL). The mixture was
heated at reflux for 7 days. After cooling, the reaction medium was
concentrated under reduced pressure to afford the crude product.
N
Ti(OiPr)4
OBn
(trans)-10
N
N
H
O
cC5H9MgCl
THF, 20 °C
N
H
OBn
14%
(Z)-9
4.2.1. N,N0-(Hex-3-ene-1,6-diyl)bis(N-phenylethanamide) (1b)
The general procedure for the cross-metathesis of 1a (method
A) was adapted to the synthesis of the homo-coupling product 1b
using 1a (2.0 equiv, 0.81 mmol, 0.15 g), CH2Cl2 (4.0 mL), 2,6-
pTSA (0.1 eq.)
PhCl, Δ
N
N
H
80%
dichloro-1,4-benzoquinone (10% equiv, 40
m
mol, 7.2 mg) and
mol, 6.9 mg).
11 (cis / trans- 40 : 60)
Grubbs second generation catalyst (2.0% equiv, 8.1
m
BnO
The crude product was obtained as a green solid (0.17 g). The E/Z
diastereoisomeric ratio of the expected alkenyl diamide 1b was
85:15 as estimated by 13C NMR spectroscopy. Purification by flash
column chromatography (EtOAc/heptane, gradient from 30% to
100%, then MeOH/EtOAc 5%) yielded starting compound 1a (56 mg,
0.30 mmol, 36%) and diamide 1b (85 mg, 0.24 mmol, 60%). The (E)
isomer of 1b could be obtained in pure form by performing
a crystallisation from EtOAc.
Note: in the absence of 2,6-dichloro-1,4-benzoquinone (DQ), the
efficiency and rate of the preparation of the homo-coupling product
1b proved to be strongly dependent on the batch of catalyst used,
with isolated yields ranging from 0% to 85%.
Scheme 8. Cyclopropanation of (Z)-9 followed by cyclisation to 11.
3. Conclusion
In summary, alkenyl amides bearing a 2-alkyloxyethyl sub-
stitution at the carbon–carbon double bond are the best substrates
among the range of (Z) and (E) disubstituted alkenes investigated
for intramolecular Kulinkovich–de Meijere reactions. The corre-
sponding aminocyclopropanes could indeed be obtained in satis-
factory yields (up to 78%), which is a marked improvement over
Kulinkovich–de Meijere reactions performed with ordinary di-
substituted alkene substrates. Various transformations have been
developed starting from this kind of bicyclic cyclopropylamines,
which make them attractive intermediates for the construction of
polycyclic nitrogen-containing molecules.19,33,34 As an example of
application, aminocylopropane trans-2d was recently oxidised
electrochemically to afford a stable endoperoxide compound in one
step, that displayed moderate but interesting activity against the
chloroquine-resistant FcB1 strain of Plasmodium falciparum.34
Finally, the present method appears to be essentially restricted to
N-aryl alkenyl amide substrates and could not be extended to N-
alkyl amides or alkenyl esters. We will devote further work to try
and overcome this limitation.
4.2.1.1. (E)-N,N0-(Hex-3-ene-1,6-diyl)bis(N-phenylethanamide) ((E)-
1b). Colourless crystals. Mp 171.3–172.4 ꢀC. IR (neat): 2916, 1647,
1590, 1490, 1444, 1402, 1295, 1177 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d
1.81 (s, 6H), 2.19 (dddd, J¼8.0, 7.0, 3.5, 1.5 Hz, 4H), 3.71 (dd, J¼8.0,
7.0 Hz, 4H), 5.39 (tt, J¼3.5, 1.5 Hz, 2H), 7.15 (br d, J¼7.5 Hz, 4H),
7.30–7.47 (m, 6H). 13C NMR (75.5 MHz, CDCl3):
d 22.7, 30.9, 48.3,
127.7, 128.1, 128.9, 129.5, 142.9, 170.1. MS (ESþ) m/z 373 (MNaþ).
HRMS (ESþ) m/z calcd for C22H26N2NaO2 (MNaþ) 373.1892, found
373.1884.
4.2.1.2. (Z)-N,N0-(Hex-3-ene-1,6-diyl)bis(N-phenylethanamide) ((Z)-
1b). 13C NMR (75.5 MHz, CDCl3), characteristic signal:
d 25.9 (allylic
CH2).
4. Experimental
4.1. General
4.2.2. N-(6-Hydroxyhex-3-enyl)-N-phenylethanamide (1c)
A mixture of AcOH and H2O (3:1, 5.3 mL) was added to a solution
of 1d (E/Zz75:25, 1.0 equiv, 0.79 mmol, 0.27 g, see Section 4.2.3 for
preparation) in THF (1.3 mL). After 16 h of stirring at 20 ꢀC, the
solvents were removed under reduced pressure (heptane was
added to carry AcOH away) to yield a yellow oil (0.20 g). Purification
by flash column chromatography (EtOAc/heptane, gradient from
30% to 100%) yielded pure alcohol 1c (0.18 g, 0.77 mmol, 97%) in an
E/Z ratio of 75:25 as evaluated by 1H and 13C NMR spectroscopies.
NMR spectra were recorded with AM 300, AVANCE 300 (1H at
300 MHz, 13C at 75.5 MHz) and AVANCE 500 (1H at 500 MHz, 13C at
125.8 MHz) Bruker spectrometers. Chemical shifts are given in
parts per million, referenced to the peak of tetramethylsilane, de-
fined at
d
d
¼0.00 (1H NMR), or the solvent peak of CDCl3, defined at
¼77.0 (13C NMR). Flash column chromatography was performed
on SDS Chromagel silica gel 60 (35–70 mm) or Merck neutral alu-
mina gel 90 (activity I, II or II-III). In some cases, a few drops of
triethylamine were added to the solvent/alumina gel mixture
during the preparation of the column. All reactions were carried out
under argon. The temperatures mentioned are the temperatures of
the cold baths used. THF and diethyl ether were purified using
4.2.2.1. N-(6-Hydroxyhex-3-enyl)-N-phenylethanamide (1c) (E/Zz
75:25). Colourless oil. IR (neat): 3391, 1646, 1636, 1594, 1495, 1398,
1298, 1051, 702 cmꢁ1. MS (ESþ) m/z 234 (MHþ), 253, 256 (MNaþ),
257. HRMS (ESþ) m/z calcd for C14H19NNaO2 (MNaþ) 256.1313,
found 256.1304.

C. Madelaine et al. / Tetrahedron 64 (2008) 8878–8898
8885
4.2.2.2. (E)-N-(6-Hydroxyhex-3-enyl)-N-phenylethanamide ((E)-1c).
1H NMR (300 MHz, CDCl3):
1.82 (s, 3H), 2.16–2.36 (m, 4H), 3.03 (br s,
(EtOAc/heptane, gradient from 10% to 50%, then MeOH/EtOAc,
gradient from 0% to 5%) yielded a 35:65 mixture of the expected
cross-product 1c and hex-3-ene-1,6-diol (1.7 g).
d
1H), 3.61 (t, J¼6.5 Hz, 2H), 3.76 (t, J¼7.5 Hz, 2H), 5.46–5.52 (m, 2H),
7.14–7.21 (m, 2H), 7.30–7.48 (m, 3H). 13C NMR (75.5 MHz, CDCl3):
Sodium hydride (60% in oil, 4.6 equiv, 19 mmol, 0.75 g) was
added portionwise at 0 ꢀC to a solution of the preceding mixture in
THF (26 mL), followed by tetra-n-butylammonium iodide (6.6%
equiv, 0.27 mmol, 98 mg) and benzyl bromide (6.5 equiv, 26 mmol,
3.1 mL). After 18 h of stirring at 20 ꢀC, Et2O (35 mL) and 1 N HCl aq
solution (30 mL) were added. The organic layer was separated, and
the aqueous phase was extracted with Et2O (30 mL). The combined
organic layers were dried over Na2SO4, filtered and concentrated to
afford a brown oil (4.1 g). Benzylation proved to be incomplete,
probably because of aging of the NaH used, and purification by flash
column chromatography (EtOAc/heptane, gradient from 10% to
60%, then MeOH/EtOAc, gradient from 0% to 5%) yielded a 80:20
mixture of the expected benzylated cross-product 1e and alcohol 4
(0.96 g, see Section 4.8.1 for analytical data), as well as alkenyl al-
cohol 1c (83 mg, 0.36 mmol, 9%).
In order to obtain pure 1e, the preceding mixture of 1e and 6-
(benzyloxy)hex-3-en-1-ol was dissolved in CH2Cl2 (0.50 mL) and
added dropwise to a solution of tert-butyldimethylsilyl chloride
(0.50 mmol, 76 mg) and imidazole (0.50 mmol, 34 mg) in CH2Cl2
(2.0 mL). After 2 h 30 min of stirring at 20 ꢀC, Et2O (10 mL) and H2O
(10 mL) were added. The organic layer was separated, washed with
H2O (2ꢂ5.0 mL), then dried over Na2SO4, filtered and concentrated
to afford a yellow oil (0.92 g). Purification by flash column chroma-
tography (EtOAc/heptane, gradient from 10% to 100%) yielded pure
d
22.5, 30.8, 35.7, 48.5, 61.6, 127.7, 127.9, 128.6, 129.3, 129.4, 142.7,
170.4. See Section 4.6.1 for the analytical data of (Z)-1c.
4.2.3. N-(6-(tert-Butyldimethylsilyloxy)hex-3-enyl)-N-
phenylethanamide (1d)
The general procedure for the cross-metathesis of 1a (method
A) was applied to 3-buten-1-ol starting from 3.0 mmol of 1a.
Purification of the crude product (1.3 g) by flash column chroma-
tography (EtOAc/heptane, gradient from 10% to 50%, then MeOH/
EtOAc, gradient from 0% to 5%) yielded starting alkenyl amide 1a
(0.14 g, 0.72 mmol, 24%) and a mixture of the expected cross-
product 1c, hex-3-ene-1,6-diol35,36 and diamide 1b (0.68 g).
This mixture was dissolved in CH2Cl2 (5.0 mL) and added
dropwise to a solution of tert-butyldimethylsilyl chloride (1.7 equiv,
5.0 mmol, 0.75 g) and imidazole (1.7 equiv, 5.0 mmol, 0.34 g) in
CH2Cl2 (20 mL). After 18 h of stirring at 20 ꢀC, Et2O (15 mL) and H2O
(10 mL) were added. The organic layer was separated, washed with
H2O (10 mL) and brine (10 mL), then dried over Na2SO4, filtered and
concentrated to afford a black oil (1.2 g). Purification by flash col-
umn chromatography (EtOAc/heptane, gradient from 10% to 50%,
then MeOH/EtOAc 5%) yielded 1,6-di(tert-butyldimethylsilylox-
y)hex-3-ene (E/Zz56:44, 20 mg, 59 mmol), pure alkenyl amide 1d
(0.70 g, 2.0 mmol, 66%) in an E/Z ratio of 85:15 as evaluated by GC/
MS and diamide 1b (55 mg, 0.16 mmol, 10%).
(6-(benzyloxy)hex-3-enyloxy)(tert-butyl)dimethylsilane
(0.16 g,
0.49 mmol) and alkenyl amide 1e (0.77 g, 2.4 mmol, 59%) both in an
4.2.3.1. 1,6-Di(tert-butyldimethylsilyloxy)hex-3-ene (E/Zz79:21). Pale
E/Z ratio of z85:15 as estimated by 13C NMR spectroscopy.
yellow oil. IR (neat): 2952, 2927, 2894,1252,1094, 831, 810, 772 cmꢁ1
.
MS (ESþ) m/z 367 (MNaþ), 368. HRMS (ESþ) m/z calcd for
18H40NaO2Si2 (MNaþ) 367.2465, found 367.2464.
4.2.4.1. (6-(Benzyloxy)hex-3-enyloxy)(tert-butyl)dimethylsilane (E/Zz
85:15). Colourless oil. IR (neat): 2952, 2925, 2854, 1253, 1096, 968,
833, 811, 773, 732, 695 cmꢁ1. MS (ESþ) m/z 343 (MNaþ), 344,
382. Anal. Calcd for C19H32O2Si: C 71.19, H 10.06. Found: C 71.05, H
10.19.
C
4.2.3.2. (E)-1,6-Di(tert-butyldimethylsilyloxy)hex-3-ene. 1H
NMR
(300 MHz, CDCl3):
d
0.04 (s, 12H), 0.89 (s, 18H), 2.21 (tdd, J¼7.0, 4.0,
1.5 Hz, 4H), 3.61 (t, J¼7.0 Hz, 4H), 5.46 (tt, J¼4.0, 1.5 Hz, 2H). 13C
NMR (75.5 MHz, CDCl3):
d
ꢁ5.3, 18.4, 26.0, 36.4, 63.2, 128.6.
4.2.4.2. (E)-(6-(Benzyloxy)hex-3-enyloxy)(tert-butyl)dimethylsilane.
1H NMR (300 MHz, CDCl3):
d 0.04 (s, 6H), 0.89 (s, 9H), 2.22 (tdd,
4.2.3.3. (Z)-1,6-Di(tert-butyldimethylsilyloxy)hex-3-ene. 1H
NMR
J¼7.0, 3.5, 1.5 Hz, 2H), 2.32 (tdd, J¼7.0, 3.5, 1.5 Hz, 2H), 3.48 (t,
(300 MHz, CDCl3), characteristic signals:
(75.5 MHz, CDCl3), characteristic signals:
d
2.28 (m, 4H). 13C NMR
31.2, 62.9, 127.6.
J¼7.0 Hz, 2H), 3.61 (t, J¼7.0 Hz, 2H), 4.50 (s, 2H), 5.50 (tt, J¼3.5,
d
1.5 Hz, 2H), 7.22–7.37 (m, 5H). 13C NMR (75.5 MHz, CDCl3):
d
ꢁ5.3,
18.3, 25.9, 33.2, 36.4, 63.2, 70.1, 72.9, 127.5, 127.6, 128.3, 128.5, 128.7,
138.5.
4.2.3.4. N-(6-(tert-Butyldimethylsilyloxy)hex-3-enyl)-N-phenylethan-
amide (1d) (E/Zz85:15). Yellow oil. IR (neat): 2953, 2927, 2855,
1661, 1596, 1495, 1390, 1360, 1093, 969, 833, 811, 773, 699 cmꢁ1. MS
(ESþ) m/z 348 (MHþ), 370 (MNaþ), 371. Anal. Calcd for C20H33NO2Si:
C 69.11, H 9.57. Found: C 69.08, H 9.39.
4.2.4.3. (Z)-(6-(Benzyloxy)hex-3-enyloxy)(tert-butyl)dimethylsilane.
1H NMR (300 MHz, CDCl3), characteristic signals: 2.39 (m, 2H). 13
d C
NMR (75.5 MHz, CDCl3), characteristic signals:
d 62.8, 69.9.
4.2.3.5. (E)-N-(6-(tert-Butyldimethylsilyloxy)hex-3-enyl)-N-phenyl-
4.2.4.4. N-(6-(Benzyloxy)hex-3-enyl)-N-phenylethanamide (1e) (E/
Zz85:15). IR (neat): 2928, 2853, 1656, 1651, 1639, 1634, 1594, 1494,
1393, 1362, 1097, 1074, 735, 697 cmꢁ1. MS (ESþ) m/z 346 (MNaþ).
HRMS (ESþ) m/z calcd for C21H25NNaO2 (MNaþ) 346.1783, found
346.1779.
ethanamide ((E)-1d). 1H NMR (300 MHz, CDCl3):
d 0.02 (s, 6H), 0.87
(s, 9H), 1.80 (s, 3H), 2.12–2.31 (m, 4H), 3.57 (t, J¼7.0 Hz, 2H), 3.72 (t,
J¼7.5 Hz, 2H), 5.32–5.52 (m, 2H), 7.15 (dd, J¼7.0, 1.5 Hz, 2H), 7.35 (tt,
J¼7.0, 1.5 Hz, 1H), 7.40 (t, J¼7.0 Hz, 2H). 13C NMR (75.5 MHz, CDCl3):
d
ꢁ5.3,18.3, 22.8, 25.9, 31.1, 36.2, 48.7, 63.1,127.8,128.2,128.6,129.0,
129.6, 143.1, 170.1.
4.2.4.5. (E)-N-(6-(Benzyloxy)hex-3-enyl)-N-phenylethanamide ((E)-
1e). 1H NMR (300 MHz, CDCl3):
d
1.80 (s, 3H), 2.23 (dt, J¼8.0, 7.0 Hz,
4.2.3.6. (Z)-N-(6-(tert-Butyldimethylsilyloxy)hex-3-enyl)-N-phenyl-
2H), 2.29 (td, J¼7.0, 6.0 Hz, 2H), 3.46 (t, J¼7.0 Hz, 2H), 3.73 (t,
ethanamide ((Z)-1d). 1H NMR (300 MHz, CDCl3), characteristic
J¼7.0 Hz, 2H), 4.49 (s, 2H), 5.36–5.58 (m, 2H), 7.11–7.43 (m,10H). 13
C
signals:
d
0.86 (s, 9H), 1.81 (s, 3H), 3.56 (t, J¼7.0 Hz, 2H). 13C NMR
NMR (75.5 MHz, CDCl3): d 22.7, 31.0, 33.0, 48.6, 70.0, 72.8, 127.4,
(75.5 MHz, CDCl3), characteristic signals:
d
48.5, 62.7.
127.6, 127.8, 128.2, 128.3, 128.6, 128.8, 129.6, 138.4, 143.0, 170.2. See
Section 4.5.1 for the analytical data of (Z)-1e.
4.2.4. N-(6-(Benzyloxy)hex-3-enyl)-N-phenylethanamide (1e)
The general procedure for the cross-metathesis of 1a (method
A) was applied to 3-buten-1-ol starting from 4.0 mmol of 1a.
Purification of the crude product by flash column chromatography
4.2.5. N-(6-Methoxyhex-3-enyl)-N-phenylethanamide (1f)
The general procedure for the cross-metathesis of 1a (method
A) was applied to 3-buten-1-ol starting from 3.9 mmol of 1a.

8886
C. Madelaine et al. / Tetrahedron 64 (2008) 8878–8898
Purification of the crude product (1.8 g) by flash column chroma-
tography (EtOAc/heptane, gradient from 10% to 50%, then MeOH/
EtOAc, gradient from 0% to 5%) yielded a 28:72 mixture of the
expected cross-product 1c and hex-3-ene-1,6-diol (1.4 g).
48.2, 70.4, 71.7, 127.4, 127.5, 127.7, 128.0, 128.2, 128.4, 129.5, 130.6,
138.2, 142.8, 170.1.
4.2.6.3. (Z)-N-(5-(Benzyloxy)pent-3-enyl)-N-phenylethanamide ((Z)-
Sodium hydride (60% in oil, 4.7 equiv, 12 mmol, 0.47 g) was
added portionwise to a solution of the preceding mixture (0.92 g) in
THF (10 mL) at 0 ꢀC, followed by methyl iodide (4.7 equiv, 12 mmol,
0.73 mL). After 16 h 30 min of stirring at 20 ꢀC, Et2O (30 mL) and
0.3 N HCl aq solution (30 mL) were added. The organic layer was
separated, and the aqueous phase was extracted with Et2O
(2ꢂ30 mL). The combined organic layers were dried over Na2SO4,
filtered and concentrated to afford a brown oil (0.93 g). Purification
by flash column chromatography (EtOAc/heptane, gradient from
10% to 50%) yielded pure alkenyl amide 1f (0.38 g, 1.5 mmol, 60%) in
an E/Z ratio of 85:15 as evaluated by GC/MS.
1g). 13C NMR (75.5 MHz, CDCl3), characteristic signals:
d 26.1, 65.6,
72.0.
4.2.7. N-(7-(Benzyloxy)hept-3-enyl)-N-phenylethanamide (1h)
The general procedure for the cross-metathesis of 1a (method
A) was applied to 4-penten-1-ol starting from 1.2 mmol of 1a.
Purification of the crude product by flash column chromatography
(EtOAc/heptane, gradient from 10% to 50%, then MeOH/EtOAc,
gradient from 0% to 5%) yielded starting alkenyl amide 1a (0.11 g,
0.59 mmol, 50%) and a 28:72 mixture of the expected N-(7-
hydroxyhept-5-enyl)-N-phenylethanamide and oct-4-ene-1,8-diol
(0.41 g).
4.2.5.1. N-(6-Methoxyhex-3-enyl)-N-phenylethanamide (1f) (E/Zz
85:15). Yellow oil. IR (neat): 2926, 2866, 1657, 1651, 1595, 1495,
1393, 1296, 1113, 967, 700 cmꢁ1. MS (ESþ) m/z 270 (MNaþ), 271.
HRMS (ESþ) m/z calcd for C15H21NNaO2 (MNaþ) 270.1410, found
270.1465.
Sodium hydride (60% in oil, 4.0 equiv, 4.8 mmol, 0.19 g) was
added portionwise to a solution of the preceding mixture in THF
(4.4 mL) at 0 ꢀC, followed by tetra-n-butylammonium iodide (3.7%
equiv, 44 mmol, 16 mg) and benzyl bromide (4.0 equiv, 4.8 mmol,
0.58 mL). After 5 h of stirring at 20 ꢀC, Et2O (10 mL) and 0.3 N HCl aq
solution (10 mL) were added. The organic layer was separated, and
the aqueous phase was extracted with Et2O (10 mL). The combined
organic layers were dried over Na2SO4, filtered and concentrated to
afford a green oil (1.1 g). Purification by flash column chromatog-
raphy (EtOAc/heptane 20%) yielded pure alkenyl amide 1h (0.18 g,
0.54 mmol, 45%) with an E/Z ratio of 80:20 as estimated by GC/MS.
4.2.5.2. (E)-N-(6-Methoxyhex-3-enyl)-N-phenylethanamide ((E)-
1f). 1H NMR (300 MHz, CDCl3):
d 1.81 (s, 3H), 2.17–2.34 (m, 4H),
3.32 (s, 3H), 3.37 (t, J¼6.5 Hz, 2H), 3.74 (t, J¼7.5 Hz, 2H), 5.41–5.48
(m, 2H), 7.13–7.20 (m, 2H), 7.30–7.47 (m, 3H). 13C NMR (75.5 MHz,
CDCl3):
d 22.7, 31.0, 32.8, 48.5, 58.4, 72.3, 127.7, 128.1, 128.6, 128.7,
129.5, 143.0, 170.1.
4.2.7.1. N-(7-(Benzyloxy)hept-3-enyl)-N-phenylethanamide (1h) (E/
Zz80:20). Yellow oil. IR (neat): 2931, 2853, 1656, 1595, 1494, 1392,
1296, 1099, 1074, 968, 735, 697 cmꢁ1. MS (ESþ) m/z 346, 360
(MNaþ). HRMS (ESþ) m/z calcd for C22H27NNaO2 (MNaþ) 360.1939,
found 360.1955.
4.2.5.3. (Z)-N-(6-Methoxyhex-3-enyl)-N-phenylethanamide ((Z)-
1f). 1H NMR (300 MHz, CDCl3), characteristic signals:
d 1.83 (s, 3H),
3.30 (s, 3H), 3.35 (t, J¼6.5 Hz, 2H). 13C NMR (75.5 MHz, CDCl3),
characteristic signals:
d 25.9, 27.8, 72.1.
4.2.6. N-(5-(Benzyloxy)pent-3-enyl)-N-phenylethanamide (1g)
The general procedure for the cross-metathesis of 1a (method
A) was applied to allyl alcohol starting from 0.95 mmol of 1a.
Purification of the crude product by flash column chromatography
(EtOAc/heptane, gradient from 10% to 50%, then MeOH/EtOAc,
gradient from 0% to 5%) yielded starting alkenyl amide 1a (0.10 g,
0.53 mmol, 56%) and a mixture of the expected N-(5-hydroxypent-
3-enyl)-N-phenylethanamide and but-2-ene-1,4-diol (0.18 g).
Sodium hydride (60% in oil, 3.0 equiv, 2.8 mmol, 0.11 g) was
added portionwise to a solution of the preceding mixture in THF
(2.5 mL) at 0 ꢀC, followed by tetra-n-butylammonium iodide (2.7%
4.2.7.2. (E)-N-(7-(Benzyloxy)hept-3-enyl)-N-phenylethanamide ((E)-
1h). 1H NMR (300 MHz, CDCl3):
d
1.65 (tt, J¼7.5, 6.5 Hz, 2H), 1.81 (s,
3H), 2.06 (br td, J¼7.5, 6.5 Hz, 2H), 2.20 (tdd, J¼7.5, 6.5, 1.5 Hz, 2H),
3.45 (t, J¼6.5 Hz, 2H), 3.71 (t, J¼7.5 Hz, 2H), 4.48 (s, 2H), 5.39 (AB
part of an ABX2Y2 system, dA¼5.34 ppm, dB¼5.44 ppm, JAB¼15.5 Hz,
JAX¼6.5 Hz, JAY¼1.5 Hz, JBX¼1.0 Hz, JBY¼6.5 Hz, 2H), 7.11–7.21 (m,
2H), 7.22–7.48 (m, 8H). 13C NMR (75.5 MHz, CDCl3):
d 22.7, 29.0,
29.3, 30.9, 48.6, 69.6, 72.7, 126.9, 127.4, 127.5, 127.7, 128.1, 128.2,
129.5, 131.9, 138.5, 143.0, 170.0.
4.2.7.3. (Z)-N-(7-(Benzyloxy)hept-3-enyl)-N-phenylethanamide ((Z)-
equiv, 26
mmol, 9.6 mg) and benzyl bromide (3.0 equiv, 2.8 mmol,
1h). 1H NMR (300 MHz, CDCl3), characteristic signals:
d 3.39 (t,
0.33 mL). After 2 h of stirring at 20 ꢀC, Et2O (10 mL) and 0.3 N HCl aq
solution (10 mL) were added. The organic layer was separated, and
the aqueous phase was extracted with Et2O (10 mL). The combined
organic layers were dried over Na2SO4, filtered and concentrated to
afford a yellow oil (0.56 g). Purification by flash column chroma-
tography (EtOAc/heptane, gradient from 10% to 40%) yielded pure
1,4-di(benzyloxy)but-2,3-ene (E/Zz97:3, 0.21 g, 0.80 mmol)37 and
pure alkenyl amide 1g (97 mg, 0.31 mmol, 33%) with an E/Z ratio of
89:11 as estimated by 13C NMR spectroscopy.
J¼6.5 Hz, 2H), 3.78 (t, J¼7.5 Hz, 2H). 13C NMR (75.5 MHz, CDCl3),
characteristic signals:
d 48.4, 69.8.
4.3. Cross-metathesis of 1a with alkenes, method B
Typically, the reaction was performed in a 25 mL Schlenk flask
equipped with a condenser. A solution of alkenyl amide 1a
(1.0 equiv, 1.0 mmol, 0.19 g), requisite alkene (1.0 equiv, 1.0 mmol)
and B-chlorocatecholborane (10% equiv, 0.10 mmol, 15 mg) in tol-
uene (5.0 mL) was degassed once. Grubbs second generation cat-
4.2.6.1. N-(5-(Benzyloxy)pent-3-enyl)-N-phenylethanamide (1g) (E/
Zz89:11). Yellow oil. IR (neat): 2928, 2852, 1652, 1594, 1494, 1392,
1295, 1093, 1070, 1026, 970, 736, 697 cmꢁ1. MS (ESþ) m/z 202, 310
(MHþ), 332 (MNaþ), 333, 460. HRMS (ESþ) m/z calcd for
alyst (5.0% equiv, 50 mmol, 42 mg) was added and the reaction
mixture was then heated at 80 ꢀC for 12 h. After cooling, methanol
was added and after 30 min, the solvents were removed in vacuo.
C
20H23NNaO2 (MNaþ) 332.1626, found 332.1609.
4.3.1. (E)-Methyl 5-(N-phenylethanamido)pent-2-enoate ((E)-1i)
The general procedure for the cross-metathesis of 1a (method B)
4.2.6.2. (E)-N-(5-(Benzyloxy)pent-3-enyl)-N-phenylethanamide ((E)-
1g). 1H NMR (300 MHz, CDCl3):
1.81 (s, 3H), 2.29 (m, 2H), 3.78 (t,
J¼7.5 Hz, 2H), 3.95 (dd, J¼4.5, 1.0 Hz, 2H), 4.47 (s, 2H), 5.56–5.74 (m,
2H), 7.07–7.62 (m, 10H). 13C NMR (75.5 MHz, CDCl3):
22.6, 30.6,
was applied to methyl acrylate (1.0 equiv, 1.0 mmol, 90 mL). Puri-
d
fication of the crude product by flash column chromatography
(Et2O/petroleum ether, 80%) yielded pure (E)-1i (0.22 g, 0.91 mmol,
91%) as a pale green oil. IR (neat): 2948, 1723, 1658, 1593, 1495,
d

C. Madelaine et al. / Tetrahedron 64 (2008) 8878–8898
8887
1439, 1397, 1278, 1208, 1169, 1034 cmꢁ1. 1H NMR (300 MHz, CDCl3):
729 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d
0.89 (t, J¼7.0 Hz, 3H), 1.27–
d
1.83 (s, 3H), 2.46 (tdd, J¼7.5, 7.0, 1.5 Hz, 2H), 3.71 (s, 3H), 3.86 (t,
1.38 (m, 4H), 2.01 (qd, J¼6.5, 1.0 Hz, 2H), 2.44 (qd, J¼6.5, 1.0 Hz, 2H),
3.00 (s, 3H), 4.21 (t, J¼6.5 Hz, 2H), 5.47 (AB part of an ABX2Y2 sys-
tem, dA¼5.36 ppm, dB¼5.58 ppm, JAB¼15.5 Hz, JAX¼6.5 Hz,
JAY¼1.0 Hz, JBX¼1.0 Hz, JBY¼6.5 Hz, 2H). 13C NMR (75.5 MHz, CDCl3):
J¼7.5 Hz, 2H), 5.86 (dt, J¼15.5, 1.5 Hz, 1H), 6.89 (dt, J¼15.5, 7.0 Hz,
1H), 7.18 (d, J¼7.0 Hz, 2H), 7.33–7.49 (m, 3H). 13C NMR (75.5 MHz,
CDCl3): d 22.4, 30.3, 47.1, 51.1, 122.4, 127.8, 127.8, 129.6, 142.4, 145.3,
166.3, 170.0. MS (ESþ) m/z 270 (MNaþ).
d
13.8, 22.1, 31.3, 32.2, 32.4, 37.4, 69.6,123.3,134.9. MS (ESþ) m/z 229
(MNaþ). HRMS (ESþ) m/z calcd for C9H18NaO3S (MNaþ) 229.0874,
found 229.0893.
4.3.2. (E)-tert-Butyl 5-(N-phenylethanamido)pent-2-enoate
((E)-1j)
(E)-Oct-3-enyl methanesulfonate (1.0 equiv, 3.1 mmol, 0.64 g)
was added to a solution of aniline (3.0 equiv, 9.4 mmol, 0.85 mL) in
acetonitrile (3.0 mL). After 38 h of stirring at reflux, the mixture
was cooled and concentrated under reduced pressure. Et2O (50 mL)
and 1 N NaOH aq solution (20 mL) were added. The organic layer
was separated, and the aqueous phase extracted with Et2O (25 mL).
The combined organic layers were dried over sodium sulfate, fil-
tered and concentrated under reduced pressure to afford an orange
oil (1.2 g). This oil was dissolved in pyridine (7.5 mL), and acetic
anhydride (4.0 equiv, 12 mmol, 1.2 mL) was added dropwise at 0 ꢀC.
After 3 h of stirring at 20 ꢀC, the mixture was diluted with CH2Cl2
(50 mL) and then washed successively with organic layer was
separated, washed with 1 N NaOH aq solution (50 mL), H2O
(50 mL), 1 N HCl aq solution (2ꢂ50 mL) and H2O (50 mL). The or-
ganic layer was dried over sodium sulfate, filtered and concentrated
under reduced pressure to afford a red oil (1.6 g). Purification by
flash column chromatography (EtOAc/heptane, gradient from 10%
to 20%) yielded pure (E)-1m (0.56 g, 2.3 mmol, 74%) as a yellow oil.
IR (neat): 2955, 2924, 2854,1859,1595,1494,1450,1436,1392,1361,
The general procedure for the cross-metathesis of 1a (method B)
was applied to tert-butyl acrylate (1.0 equiv, 3.0 mmol, 0.44 mL).
Purification of the crude product by flash column chromatography
(Et2O/petroleum ether, 80%) yielded pure (E)-1j (0.62 g, 2.1 mmol,
72%) as a viscous colourless oil. IR (neat): 2976, 2932, 1709, 1652,
.
1595, 1494, 1392, 1366, 1290, 1150, 976 cmꢁ1 1H NMR (300 MHz,
CDCl3):
d
1.46 (s, 9H), 1.83 (s, 3H), 2.44 (tdd, J¼7.5, 7.0, 1.5 Hz, 2H),
3.83 (t, J¼7.5 Hz, 2H), 5.76 (dt, J¼15.5, 1.5 Hz, 1H), 6.75 (dt, J¼15.5,
7.0 Hz, 1H), 7.16 (br d, J¼7.0 Hz, 2H), 7.31–7.47 (m, 3H). 13C NMR
(75.5 MHz, CDCl3):
d 22.6,28.0, 30.3, 47.6, 80.0, 124.7, 127.9, 128.0,
129.7, 142.7, 143.7, 165.4, 170.1. MS (ESþ) m/z 174, 256, 312 (MNaþ),
313. HRMS (ESþ) m/z calcd for C17H23NNaO3 (MNaþ) 312.1576,
found 312.1552.
4.3.3. (E)-N-Phenyl-N-(4-(phenylsulfonyl)but-3-enyl)ethanamide
((E)-1k)
The general procedure for the cross-metathesis of 1a (method B)
was applied to phenyl vinyl sulfone (1.0 equiv, 1.0 mmol, 0.17 g).
Purification of the crude product by flash column chromatography
(Et2O/petroleum ether, 80%) yielded pure (E)-1k (0.14 g, 0.44 mmol,
44%). Colourless oil. IR (neat): 3056, 2935, 1654, 1592, 1494, 1444,
1295, 968, 771, 699 cmꢁ1 1H NMR (300 MHz, CDCl3):
. d 0.87 (t,
J¼7.0 Hz, 3H), 1.21–1.37 (m, 4H), 1.82 (s, 3H), 1.96 (qd, J¼6.5, 1.5 Hz,
2H), 2.21 (tdd, J¼7.5, 6.5, 1.0 Hz, 2H), 3.74 (t, J¼7.5 Hz, 2H), 5.39 (AB
part of an ABX2Y2 system, dA¼5.34 ppm, dB¼5.44 ppm, JAB¼15.5 Hz,
JAX¼6.5 Hz, JAY¼1.0 Hz, JBX¼1.5 Hz, JBY¼6.5 Hz, 2H), 7.17 (m, 2H),
1397, 1311, 1146, 1085, 824 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 1.78
(s, 3H), 2.49 (qd, J¼7.0, 1.5 Hz, 2H), 3.85 (t, J¼7.0 Hz, 2H), 6.38 (dt,
J¼15.0, 1.5 Hz, 1H), 6.90 (dt, J¼15.0, 7.0 Hz, 1H), 7.08 (br d, J¼7.5 Hz,
2H), 7.31–7.46 (m, 3H), 7.50–7.66 (m, 3H), 7.87 (br d, J¼7.0 Hz, 2H).
7.30–7.48 (m, 3H). 13C NMR (75.5 MHz, CDCl3):
d 13.6, 21.8, 22.5,
30.8, 31.2, 31.9, 48.5, 126.1, 127.5, 127.9, 129.3, 132.5, 142.8, 169.7. MS
(ESþ) m/z 246 (MHþ), 268 (MNaþ), 269, 513 (2MNaþ), 514. HRMS
(ESþ) m/z calcd for C16H23NNaO (MNaþ) 246.1858, found 246.1861.
13C NMR (75.5 MHz, CDCl3):
d 22.5, 29.7, 46.6, 127.5, 127.7, 128.0,
129.1, 129.7, 131.9, 133.2,140.2, 142.2, 143.1, 170.2. MS (ESþ) m/z 349,
352 (MNaþ), 353, 365.
4.4.2. (Z)-N-(Oct-3-enyl)-N-phenylethanamide ((Z)-1m)
4.3.4. (E)-N-Phenyl-N-(4-phenylbut-3-enyl)ethanamide ((E)-1l)
The general procedure for the cross-metathesis of 1a (method B)
was applied to styrene (1.0 equiv, 4.0 mmol, 0.46 mL). Purification
of the crude product by flash column chromatography (Et2O/pe-
troleum ether, 60%) yielded pure (E)-1l (0.47 g, 1.8 mmol, 44%). Pale
yellow oil. IR (neat): 2930, 1651, 1594, 1493, 1392, 1297, 964, 741,
para-Toluenesulfonyl chloride (1.3 equiv, 65 mmol, 12 g por-
tionwise) was added portionwise to a solution of (Z)-oct-3-en-1-ol
(1.0 equiv, 50 mmol, 7.7 mL) and pyridine (1.5 equiv, 75 mmol,
6.1 mL) in CHCl3 (25 mL) at 0 ꢀC. After 18 h of stirring at 20 ꢀC, the
reaction mixture was diluted with Et2O (0.10 L) and then washed
successively with 1 N HCl aq solution (0.10 L), saturated NaHCO3 aq
solution (0.10 L) and H2O (50 mL). The organic layer was dried over
magnesium sulfate, filtered and concentrated under reduced
pressure to afford a colourless oil (11 g). Purification by flash col-
umn chromatography (EtOAc/heptane, gradient from 0% to 5%)
yielded pure (Z)-oct-3-enyl 4-methylbenzenesulfonate (8.9 g,
32 mmol, 63%) as a colourless oil. IR (neat): 2957, 2927, 2865, 1360,
693 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d
1.82 (s, 3H), 2.45 (tdd, J¼7.5,
7.0, 1.5 Hz, 2H), 3.85 (t, J¼7.5 Hz, 2H), 6.12 (dt, J¼16.0, 7.0 Hz, 1H),
6.40 (dt, J¼16.0, 1.5 Hz, 1H), 7.13–7.45 (m, 10H). 13C NMR (75.5 MHz,
CDCl3): d 22.7, 31.4, 48.4, 125.9, 127.0, 127.7, 127.7, 128.1, 128.3, 129.5,
131.7, 137.3, 142.9, 170.1. MS (ESþ) m/z 266 (MHþ), 288 (MNaþ), 289.
HRMS (ESþ) m/z calcd for C18H19NNaO (MNaþ) 288.1364, found
288.1362.
1180, 961, 910, 815, 661 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 0.87 (t,
J¼6.5 Hz, 3H), 1.22–1.34 (m, 4H), 1.96 (q, J¼6.5 Hz, 2H), 2.39 (q,
J¼7.0 Hz, 2H), 2.44 (s, 3H), 4.00 (t, J¼7.0 Hz, 2H), 5.22 (m, 1H), 5.47
(m, 1H), 7.34 (d, J¼8.5 Hz, 2H), 7.78 (d, J¼8.5 Hz, 2H). 13C NMR
4.4. Synthesis of amides (E)-1m and (Z)-1m
4.4.1. (E)-N-(Oct-3-enyl)-N-phenylethanamide ((E)-1m)
(75.5 MHz, CDCl3): d 13.8, 21.5, 22.1, 26.8, 26.9, 31.4, 69.7, 122.5,
Methanesulfonyl chloride (1.1 equiv, 3.8 mmol, 0.29 mL) was
added dropwise to a solution of (E)-3-octen-1-ol38 (1.0 equiv,
3.4 mmol, 0.44 g) and triethylamine (1.1 equiv, 3.8 mmol, 0.53 mL)
in CH2Cl2 (14 mL) at 0 ꢀC. After 45 min of stirring at 20 ꢀC, the re-
action mixture was diluted with CH2Cl2 (20 mL), and then washed
with saturated NaHCO3 aq solution (2ꢂ10 mL) and H2O (10 mL).
The organic layer was dried over magnesium sulfate, filtered and
concentrated under reduced pressure to afford fairly pure (E)-oct-
3-enyl methanesulfonate (0.64 g, 3.1 mmol, 90%) as a yellow oil that
was used in the next step without further purification. IR (neat):
2957, 2926, 2857, 1466, 1350, 1170, 1091, 1055, 952, 913, 838, 795,
127.7, 129.7, 133.0, 133.7, 144.6. MS (ESþ) m/z 195, 227, 305 (MNaþ).
Anal. Calcd for C15H22O3S: C 63.80, H 7.85. Found: C 63.67, H 7.98.
Potassium hydroxide (powdered, 2.0 equiv, 30 mmol, 2.0 g) and
tetra-n-butylammonium hydrogen sulfate (5% equiv, 0.75 mmol,
0.25 g) were added successively to a suspension of N-phenyl-
acetamide (1.1 equiv, 17 mmol, 2.2 g) in toluene (45 mL). The
mixture was stirred at 20 ꢀC for 3 h, then heated to 80 ꢀC. (Z)-Oct-3-
enyl 4-methylbenzenesulfonate (1.0 equiv, 15 mmol, 4.2 g) was
added and the reaction medium was stirred for 6 h at 80 ꢀC. After
cooling, the mixture was diluted with Et2O (50 mL) and 1 N HCl aq
solution (50 mL). The organic layer was separated, and the aqueous

8888
C. Madelaine et al. / Tetrahedron 64 (2008) 8878–8898
phase extracted with Et2O (2ꢂ50 mL). The combined organic layers
were dried over sodium sulfate, filtered and concentrated under
reduced pressure to afford a yellow oil (3.8 g). Purification by flash
column chromatography (EtOAc/heptane, gradient from 0% to 30%)
yielded pure (Z)-1m (2.9 g, 12 mmol, 78%) as a yellow oil. IR (neat):
organic layer). The organic phase was then washed with 1 N NaOH
aq solution (30 mL), dried over sodium sulfate, filtered and con-
centrated under reduced pressure to afford a viscous dark brown oil
(1.0 g). This oil was dissolved in CH2Cl2 (20 mL). Acetyl chloride
(1.5 equiv, 5.4 mmol, 0.37 mL) was added at 0 ꢀC, followed by 1 N
NaOH aq solution (20 mL). After 20 min of vigorous stirring, the
organic layer was separated, washed with 1 N HCl aq solution
(20 mL) and H2O (20 mL), then dried over sodium sulfate, filtered
and concentrated under reduced pressure to afford a viscous dark
brown oil (1.1 g). Purification by flash column chromatography
(EtOAc/heptane, gradient from 10% to 30%) yielded pure N-(6-
(benzyloxy)hex-3-ynyl)-N-phenylethanamide (0.82 g, 2.5 mmol,
70%) as a colourless oil. IR (neat): 2912, 2860,1657, 1595, 1494, 1391,
2956, 2928, 2858, 1662, 1595, 1495, 1394, 1298 cmꢁ1
.
1H NMR
(300 MHz, CDCl3):
d
0.86 (t, J¼6.5 Hz, 3H), 1.22–1.35 (m, 4H), 1.83 (s,
3H), 1.97 (q, J¼7.0 Hz, 2H), 2.28 (q, J¼7.5 Hz, 2H), 3.72 (t, J¼7.5 Hz,
2H), 5.23–5.52 (m, 2H), 7.18 (br d, J¼7.5 Hz, 2H), 7.31–7.47 (m, 3H).
13C NMR (75.5 MHz, CDCl3):
d 13.8, 22.1, 22.7, 25.7, 26.9, 31.6, 48.6,
125.5, 127.7, 128.1, 129.5, 132.2, 143.0, 170.1. MS (ESþ) m/z 268
(MNaþ).
4.5. Synthesis of amides (Z)-1e and (Z)-1n
1362, 1299, 1097, 737, 697 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 1.82
(s, 3H), 2.36–2.46 (m, 4H), 3.51 (t, J¼7.0 Hz, 2H), 3.82 (t, J¼7.0 Hz,
4.5.1. (Z)-N-(6-(Benzyloxy)hex-3-enyl)-N-phenylethanamide
((Z)-1e)
2H), 4.52 (s, 2H), 7.16–7.23 (m, 2H), 7.23–7.43 (m, 8H). 13C NMR
(75.5 MHz, CDCl3): d 17.7, 19.7, 22.3, 47.8, 68.3, 72.4, 77.9, 78.1, 127.2,
n-Butyllithium (1.2 M in hexanes, 1.0 equiv, 9.0 mmol, 7.4 mL)
was added dropwise to a solution of 4-benzyloxybut-1-yne39
(1.0 equiv, 9.0 mmol 1.4 g) in THF (30 mL) at ꢁ78 ꢀC. The purple
solution was allowed to warm to ꢁ50 ꢀC in 35 min and 1,3,2-
dioxathiolane-2,2-dioxide40,41 (1.0 equiv, 9.0 mmol, 1.1 g) was
added. The mixture, which turned yellow, was stirred for 2 h at that
temperature and the cold bath was then removed. Saturated NH4Cl
aq solution (40 mL) and Et2O (20 mL) were added. The organic layer
was separated and the aqueous phase was extracted with Et2O
(2ꢂ40 mL). The combined organic layers were dried over MgSO4,
filtered and concentrated under reduced pressure to afford a yellow
oil (1.8 g). Purification by flash column chromatography (EtOAc/
heptane, gradient from 10% to 20%) yielded pure 6-(benzyloxy)hex-
3-yn-1-ol (1.2 g, 6.0 mmol, 66%) as a colourless oil. IR (neat): 3392,
127.2, 127.5, 127.7, 127.9, 129.2, 137.8, 142.6, 169.7. MS (ESþ) m/z 344
(MNaþ), 345. HRMS (ESþ) m/z calcd for C21H23NNaO2 (MNaþ)
344.1626, found 344.1592.
Titanium(IV) iso-propoxide (2.0 equiv, 2.0 mmol, 0.59 mL) was
added at ꢁ70 ꢀC to a suspension of N-(6-(benzyloxy)hex-3-ynyl)-
N-phenylethanamide (1.0 equiv, 1.0 mmol, 0.32 g) in Et2O (20 mL),
followed by cyclo-pentylmagnesium chloride (1.8 M in Et2O,
4.0 equiv, 4.0 mmol, 2.2 mL) dropwise. The resulting yellow mix-
ture was allowed to warm to ꢁ30 ꢀC in 5 min and maintained at
that temperature for 15 min, by which time it had become orange.
The reaction medium was then hydrolysed at ꢁ30 ꢀC with 0.3 N HCl
aq solution (40 mL) and allowed to warm to 20 ꢀC. The mixture was
diluted with Et2O (30 mL). The organic layer was separated and the
aqueous phase was extracted with Et2O (2ꢂ30 mL). The combined
organic layers were dried over sodium sulfate, filtered and con-
centrated under reduced pressure to afford an orange oil (0.37 g).
Purification of the crude product by two successive flash column
chromatographies (silica gel, EtOAc/heptane, gradient from 10% to
20%, then neutral alumina gel, same solvent system) yielded
starting alkyne (36 mg, 0.11 mmol, 11%) and pure (Z)-1e (0.25 g,
0.76 mmol, 76%) as a colourless oil. IR (neat): 2856,1651,1595,1494,
2865, 1454, 1362, 1095, 1043, 735, 696 cmꢁ1
CDCl3):
2.39 (tt, J¼6.5, 2.5 Hz, 2H), 2.47 (tt, J¼7.0, 2.5 Hz, 2H), 2.54
(br s, 1H, OH), 3.55 (t, J¼7.0 Hz, 2H), 3.63 (t, J¼6.5 Hz, 2H), 4.53 (s,
.
1H NMR (300 MHz,
d
2H); 7.23–7.38 (m, 5H). 13C NMR (75.5 MHz, CDCl3):
d 20.0, 23.0,
61.0, 68.5, 72.8, 77.8, 78.8, 127.6, 127.6, 128.3, 137.8. MS (ESþ) m/z
209, 227 (MNaþ), 228. HRMS (ESþ) m/z calcd for C13H16NaO2
(MNaþ) 227.1048, found 227.1078. Anal. Calcd for C13H16O2: C 76.44,
H 7.90. Found: C 76.13, H 7.97.
1392, 1360, 1296, 1093, 1026, 735, 697 cmꢁ1
CDCl3):
1.82 (s, 3H), 2.24–2.36 (m, 4H), 3.44 (t, J¼7.0 Hz, 2H), 3.73
(t, J¼7.5 Hz, 2H), 4.48 (s, 2H), 5.36–5.55 (m, 2H), 7.15 (br d, J¼7.5 Hz,
2H), 7.23–7.44 (m, 8H). 13C NMR (75.5 MHz, CDCl3):
22.7, 25.9,
.
1H NMR (300 MHz,
para-Toluenesulfonyl chloride (1.2 equiv, 7.2 mmol, 1.4 g) was
added portionwise at 0 ꢀC to a solution of 6-(benzyloxy)hex-3-yn-
1-ol (1.0 equiv, 6.0 mmol, 1.2 g) and pyridine (1.5 equiv, 9.0 mmol,
0.73 mL) in CHCl3 (6 mL). After 24 h of stirring at 20 ꢀC, the reaction
mixture was diluted with Et2O (30 mL), and then washed succes-
sively with 0.3 N HCl aq solution (30 mL), saturated NaHCO3 aq
solution (30 mL) and H2O (30 mL). The organic layer was dried over
magnesium sulfate, filtered and concentrated under reduced
pressure to afford a yellowish oil (2.2 g). Purification by flash col-
umn chromatography (EtOAc/heptane, gradient from 5% to 20%)
yielded pure 6-(benzyloxy)hex-3-ynyl 4-methylbenzenesulfonate
(1.8 g, 5.1 mmol, 86%) as a colourless oil. IR (neat): 2359, 1359, 1188,
1174, 1096, 970, 899, 814, 738, 698, 661 cmꢁ1. 1H NMR (300 MHz,
d
d
27.9, 48.5, 69.7, 72.7, 127.4, 127.5, 127.7, 127.7, 128.0, 128.0, 128.2,
129.5, 138.4, 143.0, 170.1. MS (ESþ) m/z 309, 346 (MNaþ), 347. HRMS
(ESþ) m/z calcd for C21H25NNaO2 (MNaþ) 346.1783, found 346.1797.
4.5.2. (Z)-N-(6-(4-Methoxybenzyloxy)hex-3-enyl)-N-
phenylethanamide ((Z)-1n)
n-Butyllithium (1.2 M in hexanes, 1.0 equiv, 25 mmol, 21 mL)
was added dropwise over 30 min to a solution of 1-((but-3-ynyl-
oxy)methyl)-4-methoxybenzene42 (1.0 equiv, 25 mmol, 4.8 g) in
THF (50 mL) at ꢁ70 ꢀC. The solution was stirred for 30 min at
ꢁ70 ꢀC (black colour), and 1,3,2-dioxathiolane-2,2-dioxide40,41
(1.0 equiv, 25 mmol, 3.2 g) was added. The mixture was stirred for
30 min at ꢁ70 ꢀC, and then allowed to warm to ꢁ50 ꢀC over 2 h. The
cold bath was removed, and a mixture of H2O (0.50 mL) and con-
centrated H2SO4 (0.40 mL) was added. The reaction medium was
stirred for 1 h (hydrolysis was monitored by TLC analysis). NaOH aq
solution (1 N, 50 mL) was then added. The organic layer was sep-
arated and the aqueous phase was extracted with Et2O (2ꢂ0.20 L).
The combined organic layers were dried over MgSO4, filtered and
concentrated under reduced pressure to afford a brown oil (5.4 g).
Purification by flash column chromatography (EtOAc/heptane,
gradient from 10% to 30%) yielded pure 6-(4-methoxybenzyloxy)-
hex-3-yn-1-ol (4.3 g, 18 mmol, 73%) as a viscous colourless oil. IR
(neat): 3401, 2864, 1612, 1512, 1244, 1173, 1089, 1032, 820 cmꢁ1. 1H
CDCl3):
d
2.40 (tt, J¼7.0, 2.5 Hz, 2H), 2.43 (s, 3H), 2.51 (tt, J¼7.0,
2.5 Hz, 2H), 3.50 (t, J¼7.0 Hz, 2H), 4.05 (t, J¼7.0 Hz, 2H), 4.52 (s, 2H),
7.23–7.38 (m, 7H), 7.79 (d, J¼8.5 Hz, 2H). 13C NMR (75.5 MHz,
CDCl3):
d 19.6, 19.9, 21.5, 68.0, 68.3, 72.8, 75.1, 79.4, 127.5, 127.5,
127.8, 128.3, 129.7, 132.8, 138.0, 144.7. MS (ESþ) m/z 381 (MNaþ),
382. Anal. Calcd for C20H22O4S: C 67.01, H 6.19. Found: C 66.91, H
6.36.
6-(Benzyloxy)hex-3-ynyl 4-methylbenzenesulfonate (1.0 equiv,
3.6 mmol, 1.3 g) was added to a mixture of aniline (3.0 equiv,
11 mmol, 1.0 mL) and sodium acetate (1.0 equiv, 3.6 mmol, 0.50 g)
in acetonitrile (5.0 mL) at reflux. After 46 h of stirring at reflux, the
reaction medium was cooled and diluted with CH2Cl2 (30 mL), then
washed with 1 N HCl aq solution (2ꢂ30 mL) to remove the excess
amount of aniline (the protonated alkylated aniline remained in the

C. Madelaine et al. / Tetrahedron 64 (2008) 8878–8898
8889
NMR (300 MHz, CDCl3):
d
2.38 (tt, J¼6.5, 2.5 Hz, 2H), 2.45 (tt, J¼7.0,
had become brown. The reaction medium was then hydrolysed at
ꢁ30 ꢀC with 0.3 N HCl aq solution (0.10 L), and allowed to warm to
20 ꢀC. The organic layer was separated and the aqueous phase was
extracted with Et2O (2ꢂ0.10 L). The combined organic layers were
dried over sodium sulfate, filtered and concentrated under reduced
pressure to afford a viscous yellow oil (1.5 g). Purification of the
crude product by two successive flash column chromatographies
(neutral alumina gel, EtOAc/heptane, gradient from 10% to 30%)
yielded starting alkyne (0.19 g, 0.55 mmol, 14%) and (Z)-1n (1.0 g,
3.0 mmol, 74%, contaminated with traces of starting alkyne) as
a viscous colourless oil. IR (neat): 2933, 2855,1651,1512,1495,1392,
2.5 Hz, 2H), 2.73 (br s, 1H, OH), 3.52 (t, J¼7.0 Hz, 2H), 3.63 (t,
J¼6.5 Hz, 2H), 3.78 (s, 3H), 4.46 (s, 2H), 7.06 (AA0BB0 system,43
dA¼6.87 ppm, dB¼7.25 ppm, K¼5.0 Hz, L¼8.0 Hz, N¼8.5 Hz (M
could not be measured accurately), 4H). 13C NMR (75.5 MHz,
CDCl3):
d 19.9, 22.9, 55.0, 60.9, 68.1, 72.3, 77.8, 78.7, 113.6, 129.2,
129.9, 159.1. MS (ESþ) m/z 257 (MNaþ). HRMS (ESþ) m/z calcd for
C
14H18NaO3 (MNaþ) 257.1154, found 257.1142.
para-Toluenesulfonyl chloride (1.05 equiv, 18 mmol, 3.4 g) was
added portionwise at 0 ꢀC to a solution of 6-(4-methoxybenzylox-
y)hex-3-yn-1-ol (1.0 equiv, 17 mmol, 4.0 g) in pyridine (4.0 equiv,
68 mmol, 5.5 mL). After 1.5 h of stirring at 20 ꢀC and 15 h of
standing at 0 ꢀC (fridge), the reaction mixture was diluted with Et2O
(70 mL), and then washed successively with 1 N HCl aq solution
(70 mL), saturated NaHCO3 aq solution (70 mL) and H2O (70 mL).
The organic layer was dried over magnesium sulfate, filtered and
concentrated under reduced pressure to afford 6-(4-methox-
ybenzyloxy)hex-3-ynyl 4-methylbenzenesulfonate (6.1 g, 16 mmol,
92%) as a colourless oil that was used in the next step without
further purification. IR (neat): 2861, 1511, 1358, 1245, 1188, 1173,
1300, 1245, 1089, 1032, 700 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 1.81
(s, 3H), 2.23–2.35 (m, 4H), 3.42 (t, J¼7.0 Hz, 2H), 3.73 (t, J¼7.5 Hz,
2H), 3.79 (s, 3H), 4.41 (s, 2H), 5.34–5.55 (m, 2H), 7.05 (AA0BB0 sys-
tem,43 dA¼6.86 ppm, dB¼7.23 ppm, K¼5.0 Hz, L¼8.0 Hz, N¼8.5 Hz
(M could not be measured accurately), 4H), 7.15 (br d, J¼7.5 Hz, 2H),
7.28–7.44 (m, 3H). 13C NMR (75.5 MHz, CDCl3):
d 22.7, 25.9, 27.9,
48.4, 55.1, 69.3, 72.4, 113.6,127.7, 127.7, 128.0,128.0,129.1 and 129.5,
130.5, 143.0, 159.0, 170.1. MS (ESþ) m/z 376 (MNaþ), 377. Anal. Calcd
for C22H27NO3: C 74.76, H 7.70. Found: C 74.74, H 7.84.
1094, 969, 898, 813, 757 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 2.38 (tt,
J¼7.0, 2.5 Hz, 2H), 2.42 (s, 3H), 2.50 (tt, J¼7.0, 2.5 Hz, 2H), 3.47 (t,
J¼7.0 Hz, 2H), 3.78 (s, 3H), 4.05 (t, J¼7.0 Hz, 2H), 4.44 (s, 2H), 7.05
(AA0BB0 system,43 dA¼6.87 ppm, dB¼7.24 ppm, K¼5.0 Hz, L¼8.0 Hz,
N¼8.5 Hz (M could not be measured accurately), 4H), 7.55 (AA0BB0
system,43 dA¼7.32 ppm, dB¼7.78 ppm, K¼3.5 Hz, L¼7.5 Hz,
N¼8.5 Hz (M could not be measured accurately), 4H). 13C NMR
4.6. Synthesis of amides (Z)-1c, (Z)-1o, (Z)-1p and (Z)-1q
4.6.1. (Z)-N-(6-Hydroxyhex-3-enyl)-N-phenylethanamide ((Z)-1c)
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (1.0 equiv,
3.0 mmol, 0.69 g) was added to a solution of PMB ether (Z)-1n
(contaminated with about 4% of N-(6-(4-methoxybenzyloxy)hex-
3-ynyl)-N-phenylethanamide) (1.0 equiv, 3.0 mmol, 1.1 g) in a mix-
ture of CH2Cl2 (30 mL) and H2O (2.0 mL). After 2.5 h of stirring at
20 ꢀC, a precipitate had formed and the red mixture was filtered.
The solution was diluted with Et2O (70 mL), washed with saturated
NaHCO3 aq solution (100 mL), dried over sodium sulfate, filtered
and concentrated under reduced pressure to afford a viscous yel-
low-orange oil (1.0 g). Purification by flash column chromatography
(EtOAc/heptane, gradient from 20% to 100%) yielded pure alcohol
(Z)-1c (0.52 g, 2.2 mmol, 74%) as a colourless oil. IR (neat): 3394,
(75.5 MHz, CDCl3): d 19.6, 19.9, 21.5, 55.1, 68.0, 68.0, 72.4, 75.0, 79.4,
113.7, 127.8, 129.2, 129.7, 130.0, 132.8, 144.7, 159.1. MS (ESþ) m/z 411
(MNaþ), 412. HRMS (ESþ) m/z calcd for C21H24NaO5S (MNaþ)
411.1242, found 411.1222.
6-(4-Methoxybenzyloxy)hex-3-ynyl 4-methylbenzenesulfonate
(1.0 equiv, 14 mmol, 5.5 g) was added to a mixture of aniline
(3.0 equiv, 43 mmol, 4.0 mL) and sodium acetate (1.0 equiv,
14 mmol, 2.0 g) in acetonitrile (20 mL). After 20 h of stirring at
reflux, the mixture was cooled, diluted with CH2Cl2 (50 mL) and
washed successively with 1 N HCl aq solution (60 mL), 1 N NaOH aq
solution (60 mL) and H2O (60 mL). It was then dried over sodium
sulfate, filtered and concentrated under reduced pressure to afford
a viscous brown oil (4.4 g). This oil was dissolved in CH2Cl2 (50 mL).
Acetyl chloride (1.5 equiv, 21 mmol, 1.5 mL) was added at 0 ꢀC,
followed by 1 N NaOH aq solution (45 mL). After 5 min of vigorous
shaking, the organic layer was separated, washed with 1 N HCl aq
solution (50 mL) and H2O (50 mL), then dried over sodium sulfate,
filtered and concentrated under reduced pressure to afford a
viscous yellow oil (4.6 g). Purification by flash column chromatog-
raphy (EtOAc/heptane, gradient from 10% to 30%) yielded pure N-
(6-(4-methoxybenzyloxy)hex-3-ynyl)-N-phenylethanamide (3.7 g,
11 mmol, 75%) as a viscous colourless oil. IR (neat): 2910, 2859,
2928, 2873, 1633, 1594, 1495, 1396, 1296, 1047, 1024, 729, 699 cmꢁ1
1H NMR (300 MHz, CDCl3):
1.83 (s, 3H), 2.20 (br s, 1H, OH), 2.26–
.
d
2.38 (m, 4H), 3.64 (t, J¼6.5 Hz, 2H), 3.73 (t, J¼7.5 Hz, 2H), 5.43–5.57
(m, 2H), 7.18 (br d, J¼7.5 Hz, 2H), 7.32–7.48 (m, 3H). 13C NMR
(75.5 MHz, CDCl3):
d 22.7, 25.8, 30.9, 49.0, 61.9, 127.9, 128.0, 128.2,
128.6, 129.7, 143.0, 170.5. MS (ESþ) m/z 253, 254, 256 (MNaþ), 257.
Anal. Calcd for C14H19NO2: C 72.07, H 8.21. Found: C 72.01, H 8.43.
4.6.2. (Z)-N-Phenyl-N-(6-(tetrahydro-2H-pyran-2-yloxy)hex-3-
enyl)ethanamide ((Z)-1o)
para-Toluenesulfonic acid (1.0% equiv, 8.0
added to a mixture of alcohol (Z)-1d (1.0 equiv, 0.80 mmol, 0.19 g)
and dihydropyrane (1.1 equiv, .88 mmol, 83 L). After 4 h of stirring
mmol, 1.4 mg) was
m
1656, 1651, 1495, 1392, 1300, 1244, 1091, 1031 cmꢁ1
.
1H NMR
at 20 ꢀC, the mixture was diluted with diethyl ether (20 mL) and
washed with saturated Na2CO3 aq solution (20 mL). The aqueous
layer was extracted with diethyl ether (2ꢂ20 mL). The combined
organic layers were dried over sodium sulfate, filtered and con-
centrated under reduced pressure to afford a colourless oil (0.26 g).
Purification by flash column chromatography (EtOAc/heptane,
gradient from 10% to 50%) yielded pure homoallylic ether (Z)-1o
(0.22 g, 0.69 mmol, 86%) as a colourless oil. IR (neat): 2939, 2868,
(300 MHz, CDCl3): 1.82 (s, 3H), 2.35–2.45 (m, 4H), 3.48 (t,
d
J¼7.0 Hz, 2H), 3.79 (s, 3H), 3.82 (t, J¼7.0 Hz, 2H), 4.45 (s, 2H), 7.06
(AA0BB0 system,43 dA¼6.87 ppm, dB¼7.25 ppm, K¼5.0 Hz, L¼8.0 Hz,
N¼8.5 Hz (M could not be measured accurately), 4H), 7.19 (br d,
J¼7.5 Hz, 2H), 7.29–7.43 (m, 3H). 13C NMR (125.8 MHz, CDCl3):
d
17.8, 19.8, 22.4, 47.9, 54.9, 68.1, 72.2, 78.0, 78.2, 113.5, 127.7, 127.9,
129.0, 129.4, 130.0, 142.6, 158.9, 169.9. MS (ESþ) m/z 374 (MNaþ),
375. HRMS (ESþ) m/z calcd for C22H25NNaO3 (MNaþ) 374.1732,
found 374.1717.
1657, 1595, 1495, 1391, 1120, 1073, 1028, 982, 700 cmꢁ1
.
1H NMR
(300 MHz, CDCl3): 1.43–1.90 (m, 6H), 1.83 (s, 3H), 2.24–2.35 (m,
d
Titanium(IV) iso-propoxide (2.0 equiv, 8.0 mmol, 2.4 mL) was
added at ꢁ70 ꢀC to a solution of N-(6-(4-methoxybenzyloxy)hex-3-
ynyl)-N-phenylethanamide (1.0 equiv, 4.0 mmol, 1.4 g) in Et2O
(80 mL), followed by cyclo-pentylmagnesium chloride (2.0 M in
Et2O, 4.0 equiv, 16 mmol, 7.8 mL) dropwise over 20 min. The
resulting yellow mixture was allowed to warm to ꢁ30 ꢀC in 5 min
and maintained at that temperature for 45 min, by which time it
4H), 3.37 (dt, J¼9.5, 7.0 Hz, 1H), 3.48 (m, 1H), 3.71 (dt, J¼9.5, 7.0 Hz,
1H), 3.74 (t, J¼7.5 Hz, 2H), 3.84 (ddd, J¼11.0, 7.5, 3.5 Hz, 1H), 4.56
(dd, J¼4.0, 3.0 Hz, 1H), 5.36–5.55 (m, 2H), 7.17 (br d, J¼7.5 Hz, 2H),
7.31–7.47 (m, 3H). 13C NMR (75.5 MHz, CDCl3):
d 19.4, 22.7, 25.3,
25.9, 27.9, 30.5, 48.4, 62.1, 66.7, 98.6, 127.6, 127.7, 128.1, 128.1, 129.5,
142.9, 170.1. MS (ESþ) m/z 340 (MNaþ), 341. HRMS (ESþ) m/z calcd
for C19H27NNaO3 (MNaþ) 340.1889, found 340.1899.

8890
C. Madelaine et al. / Tetrahedron 64 (2008) 8878–8898
4.6.3. (Z)-6-(N-Phenylethanamido)hex-3-enyl ethanoate ((Z)-1p)
Acetic anhydride (2.0 equiv, 1.8 mmol, 0.17 mL) was added to
a solution of alcohol (Z)-1c (1.0 equiv, 0.90 mmol, 0.21 g) in pyri-
dine (6.0 equiv, 5.4 mmol, 0.44 mL). The mixture was stirred for
16 h at 20 ꢀC, then diluted with Et2O (20 mL) and washed with
0.3 N HCl aq solution (2ꢂ20 mL) followed by H2O (20 mL). The
organic layer was dried over sodium sulfate, filtered and concen-
trated under reduced pressure to afford a viscous brown oil (0.22 g).
Purification by flash column chromatography (EtOAc/heptane,
gradient from 10% to 40%) yielded pure acetate (Z)-1p (0.18 g,
0.65 mmol, 72%) as a colourless oil. IR (neat): 2934,1733,1651,1595,
1495, 1391, 1362, 1234, 1032, 700 cmꢁ1. 1H NMR (300 MHz, CDCl3):
between 51 ppm and 54 ppm). Purification by two successive flash
column chromatographies (neutral alumina gel, activity II-III,
EtOAc/heptane, gradient from 0% to 100%, then EtOAc/heptane,
gradient from 0% to 20%) and by several preparative TLCs yielded
N-(2-((1R
yl)ethyl)aniline (7.3 mg, 25
ethyl)(phenyl)amino)hex-3-enyl)-N-phenylethanamide (2.7 mg,
6.6 mol, 1%), (E)-N-(6-((6-methylbicyclo[3.1.0]hexan-6-yl)(pheny-
l)amino)hex-3-enyl)-N-phenylethanamide (2.9 mg, 7.2 mol, 1%),
pure (cis)-2b (60 mg, 0.18 mmol, 24%), (E)-N-phenyl-N-(6-(phenyl-
amino)hex-3-enyl)ethanamide (18 mg, 58 mol, 8%) and starting
(E)-1b (22 mg, 64 mol, 8%).
*
,5S
*
,6R
*
)-1-methyl-2-phenyl-2-azabicyclo[3.1.0]hexan-6-
mmol, 3%), (E)-N-(6-((1-cyclopentyl-
m
m
m
m
d
1.83 (s, 3H), 2.02 (s, 3H), 2.26–2.39 (m, 4H), 3.74 (t, J¼7.5 Hz, 2H),
4.04 (t, J¼7.0 Hz, 2H), 5.36–5.55 (m, 2H), 7.18 (br d, J¼7.0 Hz, 2H),
7.31–7.49 (m, 3H). 13C NMR (75.5 MHz, CDCl3):
20.7, 22.6, 25.7,
4.7.1.1. N-(2-((1S
*
,5S
*
,6R )-1-Methyl-2-phenyl-2-azabicyclo[3.1.0]-
*
d
hexan-6-yl)ethyl)-N-phenylethanamide (cis-2b). Crystals suitable
for X-ray diffraction studies (26 mg) were obtained by recrystall-
ising (cis)-2b from heptane containing a few drops of CH2Cl2.
Crystallographic data (excluding structure factors) for the struc-
tures in this paper have been deposited with the Cambridge Crys-
tallographic Data Centre as supplementary publication no. CCDC
682237. Copies of the data can be obtained, free of charge, on ap-
plication to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: þ44
(0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk). Colourless
crystals. Mp 102.1–103.2 ꢀC. IR (neat): 3401, 2930, 1656, 1597, 1497,
26.7, 48.4, 63.5, 126.7, 127.7, 127.9, 128.6, 129.5, 142.8, 170.1, 170.8.
MS (ESþ) m/z 243, 287, 296, 298 (MNaþ), 299. Anal. Calcd for
C
16H21NO3: C 69.79, H 7.69. Found: C 70.01, H 7.82.
4.6.4. (Z)-6-(N-Phenylethanamido)hex-3-enyl 2,2-
dimethylpropanoate ((Z)-1q)
Pyridine (1.2 equiv, 0.31 mmol, 25
mL) and trimethylacetyl
chloride (1.2 equiv, 0.31 mmol, 39 L) were added successively to
m
a solution of alcohol (Z)-1d (1.0 equiv, 0.26 mmol, 60 mg) in CH2Cl2
(0.20 mL) at 0 ꢀC. The mixture was allowed to warm to 20 ꢀC and
stirred at that temperature for 18 h, then diluted with CH2Cl2
(15 mL). The solution was washed with 0.3 N HCl aq solution
(2ꢂ15 mL) and H2O (15 mL). The organic layer was dried over so-
dium sulfate, filtered and concentrated under reduced pressure to
afford a viscous brown oil (87 mg). Purification by flash column
chromatography (EtOAc/heptane, gradient from 10% to 30%) yiel-
ded pure acetate (Z)-1q (69 mg, 0.22 mmol, 84%) as a colourless oil.
IR (neat): 2360, 2340, 1724, 1657, 1596, 1495, 1394, 1284, 1151,
1396, 1363, 1070, 697 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 1.07 (td,
J¼8.5, 5.5 Hz, 1H), 1.19 (dddd, J¼13.5, 9.5, 8.5, 5.5 Hz, 1H), 1.41 (ddd,
J¼8.5, 7.5, 1.5 Hz, 1H), 1.47 (s, 3H), 1.52 (ddt, J¼13.5, 10.0, 5.5 Hz, 1H),
1.77 (s, 3H), 1.82 (dddd, J¼13.0, 10.0, 6.5, 1.5 Hz, 1H), 2.24 (dddd, J¼
13.0, 10.0, 7.5, 4.5 Hz, 1H), 3.02 (td, J¼10.0, 4.5 Hz, 1H), 3.57 (ddd,
J¼13.0,10.0, 5.5 Hz,1H), 3.85 (ddd, J¼13.0,10.0, 5.5 Hz,1H), 3.97 (td,
J¼10.0, 6.5 Hz, 1H), 6.57 (br d, J¼8.5 Hz, 2H), 6.63 (tt, J¼7.5, 1.0 Hz,
1H), 7.00 (m, 2H), 7.13 (br dd, J¼8.5, 7.5 Hz, 2H), 7.26–7.36 (m, 3H).
13C NMR (75.5 MHz, CDCl3):
d 20.3, 22.2, 22.4, 22.8, 28.5, 31.1, 46.5,
700 cmꢁ1
.
1H NMR (300 MHz, CDCl3):
d
1.17 (s, 9H), 1.83 (s, 3H),
49.2, 55.9, 113.8, 115.8, 127.6, 127.8, 128.6, 129.5, 143.1, 147.9, 170.1.
2.24–2.38 (m, 4H), 3.74 (t, J¼7.5 Hz, 2H), 4.03 (t, J¼7.0 Hz, 2H), 5.37–
MS (ESþ) m/z 335 (MHþ), 357 (MNaþ).
5.52 (m, 2H), 7.17 (br d, J¼7.5 Hz, 2H), 7.30–7.48 (m, 3H). 13C NMR
(75.5 MHz, CDCl3):
d
22.7, 25.9, 26.9, 27.1, 38.6, 48.5, 63.5, 127.0,
4.7.1.2. N-(2-((1R
*
,5S
*
,6R
*
)-1-Methyl-2-phenyl-2-azabicyclo[3.1.0]-
1.14–1.34
127.8, 128.0, 128.4, 129.6, 143.0, 170.2, 178.4. MS (ESþ) m/z 243, 329,
340 (MNaþ), 341. HRMS (ESþ) m/z calcd for C19H27NNaO3 (MNaþ)
340.1889, found 340.1868.
hexan-6-yl)ethyl)aniline. 1H NMR (300 MHz, CDCl3):
d
(m, 2H), 1.48 (ddd, J¼8.5, 7.5, 1.5 Hz, 1H), 1.54 (s, 3H), 1.63 (m, 1H),
1.87 (dddd, J¼13.5,10.0, 6.0,1.5 Hz,1H), 2.33 (dddd, J¼13.5,10.0, 7.5,
4.5 Hz, 1H), 3.16 (td, J¼10.0, 4.5 Hz, 1H), 3.16 (m, 2H), 3.63, (br s,
1H, NH), 4.05 (td, J¼10.0, 6.0 Hz, 1H), 6.50 (br d, J¼8.5 Hz, 2H),
6.60–6.74 (m, 4H), 7.12 (br dd, J¼8.5, 7.5 Hz, 2H), 7.20 (br dd, J¼8.5,
7.5 Hz, 2H).
4.7. Intramolecular Kulinkovich–de Meijere reactions
Typically, titanium(IV) iso-propoxide (1.5 equiv, 1.5 mmol,
0.44 mL) was added to a solution of the substrate under study
(1.0 equiv, 1.0 mmol) in Et2O (20 mL), followed by cyclo-pentyl-
magnesium chloride (2.0 M in Et2O, 4.0 equiv, 4.0 mmol, 2.0 mL)
dropwise at 20 ꢀC. After 20 min of stirring, water (15 mL) was
added to the dark solution, which was exposed to air, and stirring
was continued until decolouration. Et2O (50 mL) and H2O (50 mL)
were then added. The organic layer was separated, and the aqueous
phase was extracted with Et2O (50 mL). The combined organic
layers were dried over sodium sulfate and concentrated under
reduced pressure. The crude product was analysed by NMR spec-
troscopy, and then purified by flash column chromatography
(neutral alumina gel, activity II).
4.7.1.3. (E)-N-(6-((1-Cyclopentylethyl)(phenyl)amino)hex-3-enyl)-N-
phenylethanamide. Colourless oil. IR (neat): 3407, 2929, 1661, 1596,
1498, 1394, 1296, 1159, 1032 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d 1.12
(d, J¼6.5 Hz, 3H), 1.10–1.35 (m, 3H), 1.43–1.83, (m, 5H), 1.83 (s, 3H),
2.05 (dquint, J¼10.0, 8.0 Hz 1H), 2.09–2.32 (m, 4H), 3.13 (AB part of
an ABXY system, dA¼3.10 ppm, dB¼3.17 ppm, JAB¼15.0 Hz,
JAX¼10.0 Hz, JAY¼5.5 Hz, JBX¼5.5 Hz, JBY¼10.5 Hz, 2H), 3.53 (dq,
J¼10.0 and 6.5 Hz, 1H), 3.74 (t, J¼7.5 Hz, 2H), 5.44 (AB part of an
ABX2Y2 system, dA¼5.42 ppm, dB¼5.47 ppm, JAB¼15.5 Hz,
JAX¼6.0 Hz, JAY¼0.0 Hz, JBX¼0.0 Hz, JBY¼6.0 Hz, 2H), 6.64 (t,
J¼7.5 Hz, 2H), 6.72 (d, J¼8.5 Hz, 2H), 7.13–7.22 (m, 3H), 7.35 (t,
J¼7.0 Hz, 1H), 7.42 (t, J¼7.5 Hz, 2H). 13C NMR (75.5 MHz, CDCl3):
4.7.1. Reaction of alkenyl diamide (E)-1b
d 17.2, 22.8, 25.2, 25.8, 30.7, 30.9, 31.2, 31.2, 43.7, 45.1, 48.8, 59.6,
The general procedure for the intramolecular Kulinkovich–de
Meijere reactions was applied to alkenyl amide (E)-1b (1.0 equiv,
0.75 mmol, 0.26 g) in THF, under more diluted conditions (30 mL of
THF), to afford the crude product (0.42 g) as a brown oil. Analysis of
this crude product by 1H NMR spectroscopy revealed a complex
mixture of compounds. 13C NMR spectroscopy confirmed the
presence of the expected cis aminocyclopropane cis-2b, while the
corresponding trans diastereoisomer was not detected (no peak
113.5, 115.8, 127.8, 128.2, 128.3, 129.0, 129.6, 129.8, 143.2, 149.0,
170.2. MS (ESþ) m/z 309, 405 (MHþ), 427 (MNaþ). HRMS (ESþ) m/z
calcd for C27H37N2O (MHþ) 405.2906, found 405.2941; calcd for
C
27H36N2NaO (MNaþ) 427.2725, found 427.2741.
4.7.1.4. (E)-N-(6-((6-Methylbicyclo[3.1.0]hexan-6-yl)(phenyl)amino)-
hex-3-enyl)-N-phenylethanamide. Colourless oil. IR (neat): 2925,
2864, 1661, 1597, 1497, 1393, 1295, 1168, 749, 698 cmꢁ1 1H NMR
.

C. Madelaine et al. / Tetrahedron 64 (2008) 8878–8898
8891
(400 MHz, CDCl3):
d
1.10 (s, 3H), 1.47 (m, 1H), 1.60 (m, 2H); 1.73 (m,
3024, 2952, 2926, 2854,1598,1501,1360,1250,1093, 832, 810 cmꢁ1
1H NMR (300 MHz, CDCl3):
.
2H),1.83 (s, 3H),1.84 (m,1H),1.99 (m, 2H), 2.19–2.33 (m, 4H), 3.25 (m,
2H), 3.75 (t, J¼7.5 Hz, 2H), 5.45 (AB part of an ABX2Y2 system,
dA¼5.44 ppm, dB¼5.47 ppm, JAB¼15.5 Hz, JAX¼5.5 Hz, JAY¼0.0 Hz,
JBX¼0.0 Hz, JBY¼5.5 Hz, 2H), 6.59–6.75 (m, 3H), 7.12–7.24 (m, 4H),
7.35 (m,1H), 7.42 (m, 2H). MS (ESþ) m/z 403 (MHþ), 425 (MNaþ), 426.
d
ꢁ0.01 (s, 6H), 0.86 (s, 9H), 1.08–1.31
(m, 2H), 1.43 (ddd, J¼8.0, 7.5, 1.0 Hz, 1H), 1.47–1.72 (m, 1H), 1.50 (s,
3H), 1.88 (dddd, J¼13.0, 10.0, 6.0, 1.0 Hz, 1H), 2.30 (dddd, J¼13.0,
10.0, 7.5, 4.5 Hz, 1H), 3.15 (td, J¼10.0, 4.5 Hz, 1H), 3.59–3.68 (m, 2H),
4.04 (td, J¼10.0, 6.0 Hz, 1H), 6.63 (d, J¼8.0 Hz, 2H), 6.64 (t, J¼8.0 Hz,
1H), 7.17 (t, J¼8.0 Hz, 2H). 13C NMR (75.5 MHz, CDCl3):
d
ꢁ5.3, 14.1,
4.7.1.5.
Yellow oil. IR (neat): 3364, 2924, 2853,1650,1599,1500,1398,1298,
970 cmꢁ1. 1H NMR (300 MHz, CDCl3):
1.82 (s, 3H), 2.16–2.37 (m,
(E)-N-Phenyl-N-(6-(phenylamino)hex-3-enyl)ethanamide
18.4, 26.0, 27.6, 28.5, 30.7, 31.9, 46.4, 55.9, 63.3, 113.9, 115.8, 128.7,
148.0. MS (ESþ) m/z 332 (MHþ), 354 (MNaþ). HRMS (ESþ) m/z calcd
for C20H34NOSi (MHþ) 332.2410, found 332.2403.
d
4H), 3.12 (t, J¼6.5 Hz, 2H), 3.55–3.85 (br s, 1H, NH), 3.76 (t, J¼7.5 Hz,
2H), 5.49 (AB part of an ABX2Y2 system, dA¼5.47 ppm, dB¼5.51 ppm,
JAB¼15.5 Hz, JAX¼5.5 Hz, JAY¼0.0 Hz, JBX¼0.0 Hz, JBY¼5.5 Hz, 2H),
6.61 (dd, J¼8.0, 1.0 Hz, 2H), 6.68 (tt, J¼7.5 and 1.0 Hz, 1H), 7.10–7.21
4.7.4.2. (1S
2-phenyl-2-azabicyclo[3.1.0]hexane (trans-2d). 1H NMR (300 MHz,
CDCl3), characteristic signals:
*
,5S
*
,6S
*
)-6-(2-(tert-Butyldimethylsilyloxy)ethyl)-1-methyl-
d
1.04 (t, J¼5.5 Hz,1H), 1.52 (s, 3H), 2.87
(m, 4H), 7.30–7.46 (m, 3H). 13C NMR (75.5 MHz, CDCl3):
d
22.8, 31.1,
(dt, J¼9.5, 8.5 Hz, 1H), 3.94 (td, J¼9.5, 3.0 Hz, 1H).
32.4, 43.1, 48.6, 112.8, 117.2, 127.9, 128.2, 129.2, 129.4, 129.5, 129.7,
143.0, 148.3, 170.3. MS (ESþ) m/z 174, 204, 216, 309 (MHþ), 310.
HRMS (ESþ) m/z calcd for C20H25N2O (MHþ) 309.1967, found
309.1975.
4.7.5. Reaction of alkenyl amide (E)-1d
The general procedure for the intramolecular Kulinkovich–de
Meijere reactions was applied to alkenyl amide 1d (recovered from
the preceding experiment, E/Z¼98:2, 1.0 equiv, 0.35 mmol, 0.12 g)
to afford the crude product (0.11 g) as a yellow oil. Analysis by 1H
NMR spectroscopy revealed the presence of the expected amino-
cyclopropane 2d in an estimated yield of about 24% (cis/
transz98:2). The crude reaction product also contained a mixture
of compounds retaining the carbon–carbon double bond (52%),
including starting material (E)-1d (34%).
4.7.2. Reaction of alkenyl amide 1c (E/Zz75:25)
The general procedure for the intramolecular Kulinkovich–de
Meijere reactions was applied to alkenyl amide 1c (E/Zz75:25,
1.0 equiv, 0.48 mmol, 0.11 g), under more diluted conditions (16 mL
of Et2O), to afford the crude product (99 mg) as a yellow oil. Anal-
ysis by 1H NMR spectroscopy revealed the presence of the expected
aminocyclopropane 2c in an estimated yield of about 9% (cis/
transz64:36, see Sections 4.7.21.1 and 4.7.22.1 for analytical data).
The crude reaction product also contained starting material 1c
(89%, E/Zz79:21 evaluated by 13C NMR by measuring the relative
heights of the peaks corresponding to the CH2 groups adjacent to
the nitrogen atom).
4.7.6. Reaction of alkenyl amide 1e (E/Zz85:15)
The general procedure for the intramolecular Kulinkovich–de
Meijere reactions was applied to alkenyl amide 1e (E/Zz85:15,
1.0 equiv, 2.3 mmol, 0.75 g), under more diluted conditions (78 mL
of Et2O), to afford the crude product (0.74 g) as a yellow oil. Analysis
by 1H NMR spectroscopy revealed the presence of the expected
aminocyclopropane 2e in an estimated yield of about 53% (cis/
transz79:21). The crude reaction product also contained a mixture
of compounds retaining the carbon–carbon double bond (31%),
including starting material 1e (16%). Purification by flash column
chromatography (neutral alumina gel, activity II, EtOAc/heptane,
gradient from 0% to 30%) yielded pure (cis)-2e (39 mg, 0.13 mmol,
5%), an unpure 80:20 mixture of (cis) and (trans)-2e (0.47 g), N-(6-
(benzyloxy)hex-3-enyl)aniline (67 mg, 0.23 mmol, 10%) and start-
ing 1e (E/Zz87:13 as measured by GC/MS, 0.12 g, 0.36 mmol, 16%).
A sample of pure (trans)-2e could be obtained by performing
a further flash column chromatography.
4.7.3. Reaction of alkenyl amide (Z)-1c
The general procedure for the intramolecular Kulinkovich–de
Meijere reactions was applied to alkenyl amide (Z)-1c (1.0 equiv,
0.26 mmol, 62 mg) with a larger amount of cyclo-pentylmagnesium
chloride (5.0 equiv) and under more diluted conditions (11 mL of
Et2O), to afford the crude product (58 mg) as a viscous brown oil.
Analysis of this crude product by 1H NMR spectroscopy revealed
the presence of the expected trans aminocyclopropane trans-2c in
an estimated yield of about 10% (see Section 4.7.22.1 for analytical
data). The cis diastereoisomer was not detected. The crude reaction
product also contained a mixture of compounds retaining the car-
bon–carbon double bond (86%), including starting material (Z)-1c
(75%). Purification by flash column chromatography (EtOAc/hep-
tane, gradient from 30% to 100%) yielded pure starting (Z)-1c
(38 mg, 0.16 mmol, 62%).
4.7.6.1. (1S
*
,5S
*
,6R )-6-(2-(Benzyloxy)ethyl)-1-methyl-2-phenyl-2-
*
azabicyclo[3.1.0]hexane (cis-2e). Colourless oil. IR (neat): 3026,
2930, 2858, 1599, 1502, 1484, 1453, 1361, 1325, 1112 cmꢁ1. 1H NMR
(300 MHz, CDCl3):
d
1.09–1.30 (m, 2H), 1.43 (ddd, J¼8.0, 7.5, 1.5 Hz,
4.7.4. Reaction of alkenyl amide 1d (E/Zz85:15)
1H),1.50 (s, 3H),1.62 (m,1H),1.85 (dddd, J¼13.0, 9.5, 6.0,1.5 Hz,1H),
2.28 (dddd, J¼13.0, 10.0, 7.5, 4.5 Hz, 1H), 3.14 (ddd, J¼10.0, 9.5,
4.5 Hz, 1H), 3.42–3.56 (m, 2H), 4.03 (td, J¼10.0, 6.0 Hz, 1H), 4.46 (s,
2H), 6.61 (d, J¼8.5 Hz, 2H), 6.63 (t, J¼7.5 Hz, 1H), 7.14 (dd, J¼8.5,
The general procedure for the intramolecular Kulinkovich–de
Meijere reactions was applied to alkenyl amide 1d (E/Zz85:15,
1.0 equiv, 2.0 mmol, 0.70 g), under more diluted conditions (68 mL
of Et2O), to afford the crude product (0.68 g) as a yellow oil. Analysis
by 1H NMR spectroscopy revealed the presence of the expected
aminocyclopropane 2d in an estimated yield of 38% (cis/
transz68:32). The crude product also contained a mixture of
compounds retaining the carbon–carbon double bond (44%), in-
cluding starting material 1d (18%). Purification by flash column
chromatography (neutral alumina gel, activity II, EtOAc/heptane,
gradient from 0% to 30%) yielded pure (cis)-2d (98 mg, 0.30 mmol,
15%) and starting 1d (E/Zz98:2 as measured by GC/MS, 0.12 g,
0.34 mmol, 17%).
7.5 Hz, 2H), 7.25–7.38 (m, 5H). 13C NMR (75.5 MHz, CDCl3):
d 20.3,
22.4, 24.6, 28.4, 30.8, 46.4, 55.8, 70.2, 72.8, 113.9, 115.8, 127.4, 127.5,
128.3, 128.6, 138.6, 147.9. MS (ESþ) m/z 308 (MHþ), 330 (MNaþ).
Anal. Calcd for C21H25NO: C 82.04, H 8.20. Found: C 81.81, H 8.26.
See Section 4.7.7 for the analytical data of (trans)-2e.
4.7.6.2. (E)-N-(6-(Benzyloxy)hex-3-enyl)aniline. Colourless oil. IR
(neat): 2925, 2854, 1603, 1506, 1319, 1101, 747, 694 cmꢁ1. 1H NMR
(300 MHz, CDCl3):
d
2.32 (q, J¼6.5 Hz, 2H), 2.36 (q, J¼6.5 Hz, 2H),
3.13 (t, J¼6.5 Hz, 2H), 3.50 (t, J¼6.5 Hz, 2H), 3.65 (br s, 1H, NH), 4.52
(s, 2H), 5.44–5.64 (m, 2H), 6.38 (br d, J¼8.5 Hz, 2H), 6.69 (br t,
* * *
4.7.4.1. (1S ,5S ,6R )-6-(2-(tert-Butyldimethylsilyloxy)ethyl)-1-methyl-
J¼7.5 Hz, 1H), 7.16 (br dd, J¼8.5, 7.5 Hz, 2H), 7.25–7.40 (m, 5H). 13
C
2-phenyl-2-azabicyclo[3.1.0]hexane (cis-2d). Yellow oil. IR (neat):
NMR (75.5 MHz, CDCl3):
d 32.5, 33.1, 43.2, 69.9, 72.9, 112.9, 117.3,

8892
C. Madelaine et al. / Tetrahedron 64 (2008) 8878–8898
127.5, 127.6, 128.4, 129.1, 129.2, 129.5, 138.4, 148.3. MS (ESþ) m/z 304
(MNaþ). HRMS (ESþ) m/z calcd for C19H23NNaO (MNaþ) 304.1677,
found 304.1648.
1H), 1.77 (m, 1H), 2.05 (dquint, J¼10.0, 8.0 Hz 1H), 2.26 (m, 1H),
2.31–2.44 (m, 3H), 3.16 (AB part of an ABXY system, dA¼3.12 ppm,
dB¼3.20 ppm, JAB¼14.5 Hz, JAX¼10.0 Hz, JAY¼6.0 Hz, JBX¼5.5 Hz,
JBY¼10.5 Hz, 2H), 3.47 (t, J¼7.0 Hz, 2H), 3.54 (dq, J¼10.0, 6.5 Hz, 1H),
4.51 (s, 2H), 5.44–5.56 (m, 2H), 6.65 (t, J¼7.5 Hz, 1H), 6.76 (br d,
4.7.7. Reaction of alkenyl amide (Z)-1e
The general procedure for the intramolecular Kulinkovich–de
Meijere reactions was applied to alkenyl amide (Z)-1e (1.0 equiv,
0.20 mmol, 65 mg), under more diluted conditions (8.0 mL of Et2O),
to afford the crude product (64 mg). Analysis of this crude product
by 1H NMR spectroscopy revealed the presence of the expected
trans aminocyclopropane trans-2e in an estimated yield of about
44%. The cis diastereoisomer was not detected. The crude reaction
product also contained a mixture of compounds retaining the car-
bon–carbon double bond (38%), including starting material (Z)-1e
(14%) and the corresponding deacetylated compound (Z)-N-(6-
(benzyloxy)hex-3-enyl)aniline (14%).
The general procedure for the intramolecular Kulinkovich–de
Meijere reactions was also applied to alkenyl amide (Z)-1e
(1.0 equiv, 0.49 mmol, 0.16 g) in toluene, under more diluted con-
ditions (20 mL of toluene), to afford the crude product (0.17 g) as
a brown oil. Analysis of this crude product by 1H NMR spectroscopy
revealed the presence of the expected trans aminocyclopropane
trans-2e in an estimated yield of about 50%. The cis diastereoisomer
was not detected. The crude reaction product also contained
a mixture of compounds retaining the carbon–carbon double bond
(38%), including starting material (Z)-1e (24%) and the corre-
sponding deacetylated compound (Z)-N-(6-(benzyloxy)hex-3-
enyl)aniline (9%). Purification of the crude product by two succes-
sive flash column chromatographies (neutral alumina gel, activity I,
EtOAc/heptane, gradient from 0% to 30%, then silica gel, EtOAc/
heptane, gradient from 0% to 5%) yielded pure starting (Z)-1e
(38 mg, 0.12 mmol, 24%) and pure (trans)-2e (68 mg, 0.22 mmol,
45%). Further purification of some collected fractions by preparative
TLC delivered pure (Z)-N-(6-(benzyloxy)hex-3-enyl)aniline (12 mg,
J¼8.5 Hz, 2H), 7.19 (br dd, J¼8.5, 7.5 Hz, 2H), 7.25–7.40 (m, 5H). 13
C
NMR (126 MHz, CDCl3): d 17.3, 25.2, 25.7, 26.3, 28.1, 30.8, 31.2, 43.4,
45.2, 59.9, 69.9, 72.9, 113.8, 116.0, 127.4, 127.5, 127.6, 128.3, 128.6,
129.0, 138.5, 149.0. MS (ESþ) m/z 282, 378 (MHþ), 400 (MNaþ).
HRMS (ESþ) m/z calcd for C26H36NO (MHþ) 378.2797, found
378.2802; calcd for C26H35NNaO (MNaþ) 400.2616, found 400.2633.
4.7.8. Reaction of alkenyl amide 1f (E/Zz90:10)
The general procedure for the intramolecular Kulinkovich–de
Meijere reactions was applied to alkenyl amide 1f (E/Zz90:10,
1.0 equiv, 0.15 mmol, 36 mg) to afford the crude product (34 mg) as
a yellow oil. Analysis by 1H NMR spectroscopy revealed the pres-
ence of the expected aminocyclopropane 2f in an estimated yield of
78% (cis/transz92:8). The crude reaction product also contained
a mixture of compounds retaining the carbon–carbon double bond
(23%), including starting material 1f (18%). Purification by flash
column chromatography (neutral alumina gel, activity II, EtOAc/
heptane, gradient from 0% to 100%) yielded pure (cis)-2f (24 mg,
0.10 mmol, 69%). Note: the starting material used was a different
batch from the one described in Section 4.2.5, hence the slightly
different E/Z ratio (90:10 vs 85:15).
4.7.8.1. (1S
*
,5S
*
,6R )-6-(2-Methoxyethyl)-1-methyl-2-phenyl-2-azabi-
*
cyclo[3.1.0]hexane (cis-2f). Colourless oil. IR (neat): 2926, 2864, 2824,
1598, 1501, 1483, 1459, 1380, 1360, 1323, 1249, 1182, 1140, 1114, 1069,
992, 745, 694 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 1.16–1.25 (m, 2H),
1.45 (td, J¼7.5, 1.0 Hz, 1H), 1.51 (s, 3H), 1.53–1.66 (m, 1H), 1.87 (dddd,
J¼13.5, 10.0, 6.5, 1.0 Hz, 1H), 2.30 (dddd, J¼13.5, 10.0, 7.5, 4.5 Hz, 1H),
3.15 (td, J¼10.0, 4.5 Hz, 1H), 3.30 (s, 3H), 3.31–3.47 (m, 2H), 4.04 (td,
J¼10.0, 6.5 Hz, 1H), 6.63 (d, J¼8.0 Hz, 2H), 6.64 (t, J¼7.5 Hz, 1H), 7.17
42
mmol, 9%) and pure (Z)-N-(6-(benzyloxy)hex-3-enyl)-N-(1-
cyclopentylethyl)aniline (3.2 mg, 8.4
mmol, 2%).
(dd, J¼8.0, 7.5 Hz, 2H). 13C NMR (75.5 MHz, CDCl3):
d 20.3, 22.5, 24.4,
28.5, 30.7, 46.5, 55.9, 58.6, 72.7,113.9, 115.9, 128.7,148.0. MS (ESþ) m/z
200, 232 (MHþ), 233, 300. HRMS (ESþ) m/z calcd for C15H22NO (MHþ)
232.1701, found 232.1706.
4.7.7.1. (1S
azabicyclo[3.1.0]hexane (trans-2e). Colourless oil. IR (neat): 2927,
2857, 1599, 1497, 1453, 1358, 1105, 748, 696 cmꢁ1 1H NMR
(300 MHz, CDCl3):
0.89 (td, J¼7.0, 5.0 Hz, 1H), 1.03 (dd, J¼6.0,
*
,5S
*
,6S
*
)-6-(2-(Benzyloxy)ethyl)-1-methyl-2-phenyl-2-
.
d
4.7.8.2. (1S
cyclo[3.1.0]hexane (trans-2f). 1H NMR (300 MHz, CDCl3), characteris-
tic signals:
2.87 (dt, J¼9.5, 8.5 Hz, 1H), 3.94 (td, J¼9.5, 3.0 Hz, 1H).
*
,5S
*
,6S
*
)-6-(2-Methoxyethyl)-1-methyl-2-phenyl-2-azabi-
5.0 Hz, 1H), 1.49 (s, 3H), 1.65 (dq, J¼14.0, 7.0 Hz, 1H), 1.80
(dq, J¼14.0, 7.0 Hz, 1H), 1.94 (ddd, J¼12.5, 8.5, 3.0 Hz, 1H), 2.29
(dddd, J¼12.5, 9.5, 8.5, 6.0 Hz, 1H), 2.86 (dt, J¼10.0, 8.5 Hz, 1H), 3.60
(t, J¼7.0 Hz, 2H), 3.93 (td, J¼10.0, 3.0 Hz, 1H), 4.54 (s, 2H), 6.74 (tt,
J¼7.5, 1.0 Hz, 1H), 6.79 (br d, J¼8.5 Hz, 2H), 7.18 (br dd, J¼8.5, 7.5 Hz,
d
4.7.9. Reaction of alkenyl amide 1g (E/Zz89:11)
The general procedure for the intramolecular Kulinkovich–de
Meijere reactions was applied to alkenyl amide 1g (E/Zz89:11,
1.0 equiv, 0.31 mmol, 96 mg) to afford the crude product (84 mg) as
a yellow oil. Analysis by 1H NMR spectroscopy revealed the
presence of the expected aminocyclopropane 2g (traces), starting
material 1g (4%) and extensive amounts of benzyl alcohol (70%).
2H), 7.23–7.38 (m, 5H). 13C NMR (75.5 MHz, CDCl3):
d 15.2, 26.5,
27.2, 30.3, 30.8, 46.5, 53.1, 70.2, 73.0, 116.4, 117.6, 127.5, 127.5, 128.3,
128.7, 138.5, 149.7. MS (ESþ) m/z 304, 308 (MHþ), 362
(MNaMeOHþ).
4.7.7.2. (Z)-N-(6-(Benzyloxy)hex-3-enyl)aniline. Colourless oil. IR
(neat): 2925, 2854, 1601, 1504, 1453, 1318, 1095, 1028, 746,
4.7.9.1. (1S
*
,5S
*
,6R
*
)-6-(Benzyloxymethyl)-1-methyl-2-phenyl-2-aza-
692 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d
2.39 (dt, J¼7.0, 6.5 Hz, 2H),
bicyclo[3.1.0]hexane (cis-2g). 1H NMR (500 MHz, CDCl3), character-
istic signals:
1H).
2.40 (q, J¼7.0 Hz, 2H), 3.16 (t, J¼7.0 Hz, 2H), 3.49 (t, J¼6.5 Hz, 2H),
4.53 (s, 2H), 5.44–5.64 (m, 2H), 6.59 (br d, J¼8.5 Hz, 2H), 6.69 (tt,
J¼7.5, 1.0 Hz, 1H), 7.16 (br dd, J¼8.5, 7.5 Hz, 2H), 7.24–7.38 (m, 5H).
d
3.15 (td, J¼10.0, 4.5 Hz, 1H), 4.05 (td, J¼10.0, 6.5 Hz,
13C NMR (126 MHz, CDCl3):
d
27.2, 28.1, 43.9, 69.7, 72.9, 113.3, 117.8,
4.7.9.2. (1S
*
,5S
*
,6S
*
)-6-(Benzyloxymethyl)-1-methyl-2-phenyl-2-aza-
127.6,127.6,128.3,128.4,128.9,129.2,138.4,147.7. MS (ESþ) m/z 243,
282 (MHþ), 283, 304 (MNaþ), 305. HRMS (ESþ) m/z calcd for
bicyclo[3.1.0]hexane (trans-2g). 1H NMR (500 MHz, CDCl3), charac-
teristic signals:
1H).
d
2.86 (dt, J¼10.0, 8.5 Hz,1H), 3.93 (td, J¼10.0, 3.5 Hz,
C
19H23NNaO (MNaþ) 304.1677, found 304.1715.
4.7.7.3. (Z)-N-(6-(Benzyloxy)hex-3-enyl)-N-(1-cyclopentylethyl)-
4.7.10. Reaction of alkenyl amide 1h (E/Zz80:20)
aniline. Colourless oil. IR (neat): 2950, 2861, 1595, 1499, 1453, 1357,
The general procedure for the intramolecular Kulinkovich–de
Meijere reactions was applied to alkenyl amide 1h (E/Zz80:20,
1.0 equiv, 0.56 mmol, 0.19 g) to afford the crude product (0.15 g) as
1097, 1028, 743, 694 cmꢁ1
.
1H NMR (500 MHz, CDCl3):
d
1.13 (d,
J¼6.5 Hz, 3H), 1.14–1.29 (m, 3H), 1.45–1.61 (m, 3H), 1.61–1.72 (m,

C. Madelaine et al. / Tetrahedron 64 (2008) 8878–8898
8893
a yellow oil. Analysis by 1H NMR spectroscopy revealed the pres-
ence of the expected aminocyclopropane 2h in an estimated yield
of about 24% (cis/transz68:32). The crude reaction product also
contained a mixture of compounds retaining the carbon–carbon
double bond (66%), including starting material 1h (35%). Purifica-
tion by flash column chromatography (neutral alumina gel, activity
II, EtOAc/heptane, gradient from 0% to 100%) yielded pure alkenyl
amide 1h (E/Zz95:5 as measured by GC/MS, 48 mg, 0.14 mmol,
25%). Neither (cis)-2h nor (trans)-2h was isolated in a pure form.
to afford 0.27 g of crude product. Purification by flash column
chromatography (neutral alumina gel, activity II-III, EtOAc/heptane,
gradient from 0% to 50%) yielded pure aminocyclopropane 2a5,19
(15 mg, 85 mmol, 11%), alkenyl amide 1a (11 mg, 61 mmol, 8%) and
extensively isomerised starting material 1k (0.16 g, 0.49 mmol,
62%). Indeed, this latter product consisted of 61% of (E)-1k and 39%
of a mixture of (E) and (Z)-N-phenyl-N-(4-(phenylsulfonyl)but-2-
enyl)ethanamide. In retrospect, analysis of the 1H NMR spectrum of
the crude product showed that the observed isomerisation had
occurred at the stage of the chromatographic purification.
4.7.10.1. (1R
azabicyclo[3.1.0]hexane (cis-2h). 1H NMR (300 MHz, CDCl3), char-
acteristic signals:
3.13 (tdd, J¼10.0, 4.5, 1.0 Hz, 1H), 4.01 (tdd,
J¼10.0, 6.5, 1.0 Hz, 1H).
*
,5S
*
,6R
*
)-6-(3-(Benzyloxy)propyl)-1-methyl-2-phenyl-2-
4.7.14. Reaction of alkenyl amide (E)-1l
d
The general procedure for the intramolecular Kulinkovich–de
Meijere reactions was applied to alkenyl amide (E)-1l (0.96 mmol,
0.26 g) to afford the crude product (0.25 g) as a bright yellow oil.
Analysis of this crude product by 1H and 13C NMR spectroscopy
revealed the presence of starting material in an estimated yield of
about 20%. The 1H and 13C NMR signals of the major product (about
30% yield) were found not to be consistent with the expected
aminocyclopropane structure, but rather with that of cyclic en-
amine 8. Moreover, attempted purification by flash column chro-
matography (EtOAc/heptane, gradient from 0% to 100%) yielded
starting material only (59 mg, 0.22 mmol, 23%), and the major
product could not be isolated. Nonetheless, we believe the fol-
lowing characteristic NMR data, extracted from the NMR spectra of
the crude product, can be associated with enamine structure 5. 1H
4.7.10.2. (1R ,5S ,6S )-6-(3-(Benzyloxy)propyl)-1-methyl-2-phenyl-2-
*
*
*
azabicyclo[3.1.0]hexane (trans-2h). 1H NMR (300 MHz, CDCl3),
characteristic signals:
2.85 (dtd, J¼10.0, 8.5, 2.5 Hz, 1H), 3.91 (tdd,
J¼10.0, 3.5, 1.5 Hz, 1H).
d
4.7.11. Reaction of alkenyl amide (E)-1i
The general procedure for the intramolecular Kulinkovich–de
Meijere reactions was applied to alkenyl amide (E)-1i (1.0 equiv,
0.82 mmol, 0.20 g), under more diluted conditions (33 mL of Et2O),
to afford 0.24 g of crude product. Purification by flash column
chromatography (neutral alumina gel, activity II-III, EtOAc/heptane,
gradient from 5% to 100%) yielded pure vinylogous carbamate 7
NMR (300 MHz, CDCl3):
NMR (75.5 MHz, CDCl3):
d
1.74 (s, 3H), 3.79 (t, J¼5.0 Hz, 2H). 13C
(17 mg, 66
mmol, 8%), ketone 6 (20 mg, 69
mmol, 8%) and starting
d
21.7, 22.7, 53.2, 147.8.
amide (E)-1i (46 mg, 0.19 mmol, 23%).
4.7.15. Reaction of alkenyl amide (E)-1m
4.7.11.1.
N-(5-Cyclopentyl-5-oxopentyl)-N-phenylethanamide (6)
1.46–1.85 (m, 12H), 1.82
The general procedure for the intramolecular Kulinkovich–de
Meijere reactions was applied to alkenyl amide (E)-1m (1.0 equiv,
0.20 mmol, 50 mg) to afford the crude product (44 mg) as a yellow
oil. Analysis of this crude product by 1H NMR spectroscopy revealed
the presence of the expected cis aminocyclopropane cis-2m in an
estimated yield of about 18%. The trans diastereoisomer was not
detected. The crude reaction product also contained a mixture of
compounds retaining the carbon–carbon double bond (70%), in-
cluding starting material (E)-1m (41%).
Colourless oil. 1H NMR (300 MHz, CDCl3):
d
(s, 3H), 2.46 (t, J¼7.0 Hz, 2H), 2.83 (quint, J¼8.0 Hz, 1H), 3.69 (t,
J¼7.0 Hz, 2H), 7.16 (dd, J¼8.0, 1.5 Hz, 2H), 7.30–7.47 (m, 3H). 13C
NMR (75.5 MHz, CDCl3): d 20.8, 22.8, 26.0, 27.3, 28.9, 41.1, 48.6, 51.4,
127.7, 127.9, 129.5, 142.9, 170.1, 212.8.
4.7.11.2. Isopropyl 2-methyl-1-phenyl-1,4,5,6-tetrahydropyridine-3-
carboxylate (7). Colourless oil. IR (neat): 1679, 1562, 1491, 1235,
1197, 1095, 1053 cmꢁ1 1H NMR (300 MHz, CDCl3):
. d 1.26 (d,
J¼6.0 Hz, 6H), 1.86 (tt, J¼6.5, 5.5 Hz, 2H), 2.13 (t, J¼1.0 Hz, 3H), 2.47
(t, J¼6.5 Hz, 2H), 3.49 (tq, J¼5.5, 1.0 Hz, 2H), 5.05 (sept, J¼6.0 Hz,
1H), 7.06 (dd, J¼7.5, 1.5 Hz, 2H), 7.19 (tt, J¼7.5, 1.5 Hz, 1H), 7.34 (t,
4.7.15.1. (1R
*
,5S
*
,6R
*
)-6-Ethyl-1-methyl-2-phenyl-2-azabicyclo[3.1.0]-
hexane (cis-2m). 1H NMR (500 MHz, CDCl3), characteristic signals:
d
0.82 (t, J¼7.0 Hz, 3H), 1.49 (s, 3H), 3.14 (td, J¼10.0, 4.5 Hz, 1H), 4.03
J¼7.5 Hz, 2H). 13C NMR (75.5 MHz, CDCl3):
d
20.1, 21.8, 22.3, 24.1,
(td, J¼10.0, 6.5 Hz, 1H).
52.7, 65.8, 99.3, 125.6, 127.0, 129.2, 147.0, 152.8, 168.8. MS (ESþ) m/z
218, 256, 260 (MHþ), 270, 282 (MNaþ), 314 (MNaMeOHþ).
4.7.16. Reaction of alkenyl amide (Z)-1m
The general procedure for the intramolecular Kulinkovich–de
Meijere reactions was applied to alkenyl amide (Z)-1m (1.0 equiv,
0.20 mmol, 50 mg) to afford the crude product (58 mg) as a yellow
oil. Analysis of this crude product by 1H NMR spectroscopy revealed
the presence of the expected trans aminocyclopropane trans-2m in
an estimated yield of about 12%. The cis diastereoisomer was not
detected. The crude reaction product also contained a mixture of
compounds retaining the carbon–carbon double bond (65%), in-
cluding starting material (Z)-1m (52%).
4.7.12. Reaction of alkenyl amide (E)-1j
The general procedure for the intramolecular Kulinkovich–de
Meijere reactions was applied to alkenyl amide (E)-1j (1.0 equiv,
0.80 mmol, 0.23 g), under more diluted conditions (32 mL of Et2O),
to afford the crude product (0.18 g) as a brown viscous oil. Analysis
by 1H NMR spectroscopy showed the complete consumption of the
starting material and revealed the presence of vinylogous carba-
mate 7 (about 24% yield). Analysis by 13C NMR spectroscopy
allowed to estimate the amount of ketone 6 (about 9% yield). Pu-
rification of the crude product by flash column chromatography
(neutral alumina gel, activity II-III, EtOAc/heptane, gradient from 0%
4.7.16.1. (1R
hexane (trans-2m). 1H NMR (300 MHz, CDCl3), characteristic sig-
nals:
*
,5S
*
,6S
*
)-6-Ethyl-1-methyl-2-phenyl-2-azabicyclo[3.1.0]-
to 50%) yielded pure vinylogous carbamate 7 (25 mg, 96
and impure ketone 6 (29 mg) that we were not able to isolate in
m
mol, 12%)
d
1.47 (s, 3H), 2.87 (dt, J¼10.0, 8.5 Hz, 1H), 3.93 (td, J¼10.0,
3.5 Hz, 1H).
completely pure form.
4.7.17. Reaction of alkenyl amide (Z)-1n
4.7.13. Reaction of alkenyl amide (E)-1k
The general procedure for the intramolecular Kulinkovich–de
Meijere reactions was applied to alkenyl amide (Z)-1o (1.0 equiv,
0.70 mmol, 0.25 g) in toluene, under more diluted conditions
(28 mL of toluene), to afford the crude product (0.24 g) as a viscous
The general procedure for the intramolecular Kulinkovich–de
Meijere reactions was applied to alkenyl amide (E)-1k (1.0 equiv,
0.78 mmol, 0.26 g), under more diluted conditions (35 mL of Et2O),

8894
C. Madelaine et al. / Tetrahedron 64 (2008) 8878–8898
yellow oil. Analysis by 1H NMR spectroscopy revealed the presence
of the expected trans aminocyclopropane trans-2n in an estimated
yield of about 29%. The cis diastereoisomer was not detected. The
crude reaction product also contained a mixture of compounds
retaining the carbon–carbon double bond (57%), including starting
material (Z)-1n (53%). Purification of the crude product by two
successive flash column chromatographies (neutral alumina gel,
activity II-III, EtOAc/heptane, gradient from 0% to 20%, then EtOAc/
heptane, gradient from 0% to 5%) yielded pure (trans)-2n (77 mg,
0.23 mmol, 33%), pure (Z)-N-(6-(4-methoxybenzyloxy)hex-3-eny-
(20 mL of toluene), to afford the crude product (0.16 g) as an oil.
Analysis by 1H NMR spectroscopy revealed the presence of the
expected trans aminocyclopropane trans-2o in an estimated yield
of about 34%. The cis diastereoisomer was not detected. The crude
reaction product also contained a mixture of compounds retaining
the carbon–carbon double bond (48%). Purification of the crude
product by two successive flash column chromatographies (neutral
alumina gel, activity I, EtOAc/heptane, gradient from 0% to 100%,
then silica gel, EtOAc/heptane, gradient from 0% to 10%) yielded
pure (trans)-2o (35 mg, 0.12 mmol, 23%), (Z)-N-(1-cyclo-
pentylethyl)-N-(6-(tetrahydro-2H-pyran-2-yloxy)hex-3-enyl)ani-
l)aniline (11 mg, 36 mmol, 5%) and pure starting (Z)-1n (0.12 g,
0.34 mmol, 49%). Further purification of some collected fractions by
line (7.7 mg, 21 mmol, 4%), pure (Z)-N-(6-(tetrahydro-2H-pyran-2-
preparative TLC delivered (Z)-N-(1-cyclopentylethyl)-N-(6-(4-
yloxy)hex-3-enyl)aniline (12 mg, 43 mmol, 9%) and pure starting
methoxybenzyloxy)hex-3-enyl)aniline (6.6 mg, 16
mmol, 2%).
(Z)-1o (42 mg, 0.13 mmol, 26%).
4.7.17.1. (1S ,5S ,6S )-6-(2-(4-Methoxybenzyloxy)ethyl)-1-methyl-2-
*
*
*
4.7.18.1. (1S
*
,5S
*
,6S )-1-Methyl-2-phenyl-6-(2-(tetrahydro-2H-pyran-
*
phenyl-2-azabicyclo[3.1.0]hexane (trans-2n). Colourless oil. IR
2-yloxy)ethyl)-2-azabicyclo[3.1.0]hexane (trans-2o). Colourless oil.
Mixture of two diastereoisomers (55:45). IR (neat): 2925, 2867,1600,
(neat): 2931, 2856, 1599, 1511, 1495, 1245, 1092, 1033, 818, 751, 730,
696 cmꢁ1. 1H NMR (500 MHz, CDCl3):
d
0.88 (td, J¼7.0, 4.5 Hz, 1H),
1496, 1119, 1076, 1060, 1031, 750, 695 cmꢁ1 1H NMR (300 MHz,
.
1.02 (dd, J¼6.0, 5.0 Hz, 1H), 1.48 (s, 3H), 1.71 (AB part of an ABX2Y
system, dA¼1.64 ppm, dB¼1.78 ppm, JAB¼14.0 Hz, JAX¼7.0 Hz,
JAY¼7.0 Hz, JBX¼7.0 Hz, JBY¼7.0 Hz, 2H), 1.94 (ddd, J¼12.5, 9.0,
3.0 Hz,1H), 2.29 (dddd, J¼12.5, 9.5, 8.5, 6.0 Hz,1H), 2.86 (ddd, J¼9.5,
9.0, 8.5 Hz, 1H), 3.57 (m, 2H), 3.79 (s, 3H), 3.93 (td, J¼9.5, 3.0 Hz,
1H), 4.48 (s, 2H), 6.74 (tt, J¼7.5, 1.0 Hz, 1H), 6.79 (dd, J¼8.5, 1.0 Hz,
2H), 7.06 (AA0BB0 system,43 dA¼6.87 ppm, dB¼7.26 ppm, K¼5.0 Hz,
L¼8.0 Hz, N¼8.5 Hz (M could not be measured accurately), 4H), 7.19
CDCl3):
d
0.88 (m, 1H),1.05 (dd, J¼6.0, 5.0 Hz, 1H), 1.49 and 1.50 (2ꢂs,
3H), 1.50–1.90 (m, 8H), 1.96 (ddd, J¼12.5, 8.5, 3.5 Hz, 1H), 2.31 (dddd,
J¼12.5, 9.5, 8.5, 6.0 Hz, 1H), 2.88 (dt, J¼9.5, 8.5 Hz, 1H), 3.45–3.58 (m,
2H), 3.82–3.93 (m, 2H), 3.94 (ddd, J¼10.0, 9.5, 3.5 Hz, 1H), 4.63 and
4.64 (2ꢂt, J¼4.5 Hz, 1H), 6.71–6.88 (m, 3H), 7.21 and 7.22 (2ꢂdd,
J¼8.5, 7.0 Hz, 2H). 13C NMR (126 MHz, CDCl3):
d 15.2 and 15.3, 19.6
and 19.7, 25.5, 25.5, 26.6, 30.3, 30.7, 30.8, 53.3, 62.3 and 62.4, 63.7,
67.2 and 67.3, 98.9 and 99.0, 116.5, 117.7, 128.8, 149.7. MS (ESþ) m/z
298, 302 (MHþ), 303, 324 (MNaþ). HRMS (ESþ) m/z calcd for
(dd, J¼8.5, 7.5 Hz, 2H). 13C NMR (126 MHz, CDCl3):
d 15.3, 26.6, 27.2,
30.3, 30.8, 46.6, 53.2, 55.3, 70.0, 72.7, 113.8, 116.4, 117.6, 128.7, 129.2,
130.6, 149.7, 159.1. MS (ESþ) m/z 338 (MHþ), 360 (MNaþ). Anal.
Calcd for C22H27NO2: C 78.30, H 8.06. Found: C 77.99, H 8.09.
C
19H28NO2 (MHþ) 302.2120, found 302.2094.
4.7.18.2. (Z)-N-(1-Cyclopentylethyl)-N-(6-(tetrahydro-2H-pyran-2-
yloxy)hex-3-enyl)aniline. Colourless oil. Mixture of two di-
astereoisomers. IR (neat): 2943, 2867, 1596, 1500, 1136, 1120, 1075,
4.7.17.2. (Z)-N-(6-(4-Methoxybenzyloxy)hex-3-enyl)aniline. Colour-
less oil. IR (neat): 2961, 1737, 1651, 1512, 1455, 1245, 909, 727,
1030, 985, 744, 692 cmꢁ1 1H NMR (300 MHz, CDCl3):
. d 1.15 (d,
695 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d
2.37 (q, J¼6.5 Hz, 2H), 2.39
J¼6.5 Hz, 3H), 1.42–1.90 (m, 14H), 2.07 (dquint, J¼10.0, 8.0 Hz, 1H),
2.18–2.45 (m, 4H), 3.17 (AB part of an ABXY system, dA¼3.13 ppm,
dB¼3.20 ppm, JAB¼15.0 Hz, JAX¼10.0 Hz, JAY¼6.0 Hz, JBX¼5.5 Hz,
JBY¼10.5 Hz, 2H), 3.40 (dt, J¼9.5, 7.0 Hz, 1H), 3.48 (m, 1H), 3.55 (dq,
J¼10.0, 6.5 Hz, 1H), 3.74 (dt, J¼9.5, 7.0 Hz, 1H), 3.86 (ddd, J¼11.0, 8.0,
3.5 Hz, 1H), 4.59 (dd, J¼4.0, 2.5 Hz, 1H), 5.41–5.59 (m, 2H), 6.65 (t,
(q, J¼6.5 Hz, 2H), 3.15 (t, J¼6.5 Hz, 2H), 3.46 (t, J¼6.5 Hz, 2H), 3.80
(s, 3H), 4.46 (s, 2H), 5.44–5.62 (m, 2H), 6.57 (dd, J¼8.5, 1.0 Hz, 2H),
6.68 (tt, J¼7.5, 1.0 Hz, 1H), 7.07 (AA0BB0 system,43 dA¼6.87 ppm,
dB¼7.26 ppm, K¼5.0 Hz, L¼8.0 Hz, N¼8.5 Hz (M could not be
measured accurately), 4H), 7.15 (dd, J¼8.5, 7.5 Hz, 2H). 13C NMR
(126 MHz, CDCl3):
d
27.3, 28.1, 43.4, 55.2, 69.4, 72.6, 112.8 and 113.8,
J¼7.5 Hz, 1H), 6.77 (d, J¼8.5 Hz, 2H), 7.20 (dd, J¼8.5, 7.5 Hz, 2H). 13
C
117.2, 128.4, 128.7, 129.2, 129.2, 130.5, 148.3, 159.2.
NMR (126 MHz, CDCl3): d 17.3, 19.6, 25.3, 25.5, 25.8, 26.3, 28.2, 30.7,
30.8, 31.2, 43.5, 45.2, 59.8, 62.3, 67.0, 98.8, 113.8, 116.0, 127.6, 128.5,
129.1, 149.1. MS (ESþ) m/z 372 (MHþ), 392, 394 (MNaþ), 395. HRMS
(ESþ) m/z calcd for C24H38NO2 (MHþ) 372.2903, found 372.2892.
4.7.17.3. (Z)-N-(1-Cyclopentylethyl)-N-(6-(4-methoxybenzyloxy)hex-
3-enyl)aniline. Colourless oil. IR (neat): 2933, 2854, 1601, 1510,
1245, 1090, 1033, 748, 692 cmꢁ1. 1H NMR (500 MHz, CDCl3):
d 1.13
(d, J¼6.5 Hz, 3H), 1.10–1.29 (m, 3H), 1.44–1.58 (m, 2H), 1.60–1.70 (m,
2H), 1.77 (m, 1H), 2.05 (dquint, J¼10.0, 8.0 Hz, 1H), 2.25 (m, 1H),
2.30–2.41 (m, 3H), 3.16 (AB part of an ABXY system, dA¼3.12 ppm,
dB¼3.19 ppm, JAB¼14.5 Hz, JAX¼10.0 Hz, JAY¼6.0 Hz, JBX¼5.5 Hz,
JBY¼10.5 Hz, 2H), 3.44 (t, J¼7.0 Hz, 2H), 3.54 (dq, J¼10.0, 6.5 Hz, 1H),
3.80 (s, 3H), 4.44 (s, 2H), 5.44–5.54 (m, 2H), 6.65 (t, J¼7.5 Hz, 1H),
6.76 (d, J¼8.5 Hz, 2H), 7.06 (AA0BB0 system,43 dA¼6.87 ppm,
dB¼7.25 ppm, K¼5.0 Hz, L¼8.0 Hz, N¼8.5 Hz (M could not be mea-
sured accurately), 4H), 7.19 (dd, J¼8.5, 7.5 Hz, 2H). 13C NMR
4.7.18.3. (Z)-N-(6-(Tetrahydro-2H-pyran-2-yloxy)hex-3-enyl)anili-
ne. Colourless oil. IR (neat): 2939, 2866,1601,1503,1136,1119,1074,
1028, 905, 868, 746, 731, 691 cmꢁ1 1H NMR (300 MHz, CDCl3):
.
d
1.45–1.89 (m, 6H), 2.37 (q, J¼6.5 Hz, 2H), 2.40 (q, J¼7.0 Hz, 2H),
3.16 (t, J¼6.5 Hz, 2H), 3.42 (dt, J¼9.5, 7.0 Hz, 1H), 3.50 (m, 1H), 3.76
(dt, J¼9.5, 7.0 Hz, 1H), 3.87 (ddd, J¼11.0, 8.0, 3.0 Hz, 1H), 4.59 (dd,
J¼4.0, 3.5 Hz, 1H), 5.46–5.62 (m, 2H), 6.61 (d, J¼8.5 Hz, 2H), 6.69 (t,
J¼7.5, 1H), 7.17 (dd, J¼8.5, 7.5 Hz, 2H). 13C NMR (75.5 MHz, CDCl3):
d
19.6, 25.5, 27.4, 28.1, 30.7, 43.5, 62.4, 66.9, 98.8, 112.9, 117.3, 128.3,
(126 MHz, CDCl3):
d
17.3, 25.3, 25.8, 26.3 and 28.2, 30.8, 31.2, 43.4,
128.7, 129.2, 148.3. MS (ESþ) m/z ESþ m/z 276 (MHþ), 298 (MNaþ).
HRMS (ESþ) m/z calcd for C17H26NO2 (MHþ) 276.1964, found
276.1961; calcd for C17H25NNaO2 (MNaþ) 298.1783, found 298.1793.
45.2, 55.3, 59.9, 69.6, 72.5, 113.8, 113.8, 116.0, 127.4, 128.6, 129.1,
129.2, 130.6, 149.1, 159.1. MS (ESþ) m/z 408 (MHþ), 430 (MNaþ), 431.
HRMS (ESþ) m/z calcd for C27H38NO2 (MHþ) 408.2903, found
408.2936; calcd for
430.2721.
C
27H37NNaO2 (MNaþ) 430.2722, found
4.7.19. Reaction of alkenyl amide (Z)-1p
The general procedure for the intramolecular Kulinkovich–de
Meijere reactions was applied to alkenyl amide (Z)-1p (1.0 equiv,
0.60 mmol, 0.17 g) in toluene, under more diluted conditions
(24 mL of toluene), to afford the crude product (0.18 g) as a vis-
cous brown oil. Analysis of this crude product by 1H NMR spec-
troscopy revealed the presence of the starting material and the
4.7.18. Reaction of alkenyl amide (Z)-1o
The general procedure for the intramolecular Kulinkovich–de
Meijere reactions was applied to alkenyl amide (Z)-1o (1.0 equiv,
0.50 mmol, 0.16 g) in toluene, under more diluted conditions

C. Madelaine et al. / Tetrahedron 64 (2008) 8878–8898
8895
corresponding deacetylated compound (Z)-1c in an estimated yield
of about 16% and 44%, respectively. Aminocyclopropane trans-2c
(11%) was detected as well (see Section 4.7.22.1 for analytical data),
while the cis diastereoisomer was not observed. Purification of the
crude product by flash column chromatography (EtOAc/heptane,
gradient from 20% to 100%) yielded pure (trans)-2c (10 mg,
pure (trans)-2c (25 mg, 0.12 mmol, 21%) and (Z)-1c (62 mg,
0.27 mmol, 49%).
Note: this reaction was also performed in Et2O, with a lower
yield of 12% for (trans)-2c as estimated by 1H NMR spectroscopy of
the crude product.
48
mmol, 8%), starting (Z)-1p (6.6 mg, 24
mmol, 4%) and pure (Z)-1c
4.7.22.1. 2-((1S
*
,5S
*
,6S )-1-Methyl-2-phenyl-2-azabicyclo[3.1.0]hexan-
*
(61 mg, 0.26 mmol, 44%).
6-yl)ethanol (trans-2c). Viscous colourless oil. IR (neat): 3354, 2929,
2867, 1599,1494,1355,1312,1034, 750, 695 cmꢁ1. 1H NMR (300 MHz,
4.7.20. Reaction of alkenyl amide (Z)-1q
CDCl3):
d
0.86 (td, J¼7.0, 5.0 Hz, 1H), 1.06 (dd, J¼6.0, 5.0 Hz, 1H), 1.50
The general procedure for the intramolecular Kulinkovich–de
Meijere reactions was applied to alkenyl amide (Z)-1q (1.0 equiv,
0.20 mmol, 64 mg) in toluene, under more diluted conditions
(8.0 mL of toluene), to afford the crude product (61 mg) as a viscous
brown oil. Analysis by 1H NMR spectroscopy revealed the presence
of the starting material and the corresponding alcohol (Z)-1c in
an estimated yield of about 35% and 12%, respectively. Traces of
aminocyclopropane trans-2c were detected as well (see Section
4.7.22.1 for analytical data), while the cis diastereoisomer was not
observed at all. Purification of the crude product by flash column
chromatography (neutral alumina gel, activity II, EtOAc/heptane,
gradient from 10% to 100%) yielded pure starting (Z)-1q (17 mg,
(s, 3H),1.68 (AB part of an ABX2Y system, dA¼1.60 ppm, dB¼1.76 ppm,
JAB¼14.0 Hz, JAX¼7.0 Hz, JAY¼7.0 Hz, JBX¼7.0 Hz, JBY¼7.0 Hz, 2H), 1.97
(ddd, J¼12.5, 9.0, 3.0 Hz, 1H), 2.31 (dddd, J¼12.5,10.0, 8.0, 6.0 Hz,1H),
2.87 (ddd, J¼9.5, 9.0, 8.0 Hz, 1H), 3.77 (t, J¼7.0 Hz, 2H), 3.94 (ddd,
J¼10.0, 9.5, 3.0 Hz,1H), 6.72–6.83 (m, 3H), 7.23 (dd, J¼8.5, 7.5 Hz, 2H).
13C NMR (75.5 MHz, CDCl3):
d 15.3, 26.5, 26.5, 30.9, 33.1, 46.3, 53.1,
62.7, 116.3, 117.7, 128.8, 149.7. MS (ESþ) m/z 218 (MHþ), 240 (MNaþ),
261, 272 (MNaMeOHþ), 305. HRMS (ESþ) m/z calcd for C14H20NO
(MHþ) 218.1545, found 218.1543. Anal. Calcd for C14H19NO: C 77.38, H
8.81. Found: C 77.03, H 8.91.
54
m
mol, 27%).
4.8. Synthesis and reaction of alkenyl ester 3
4.7.21. Reaction of alkenyl amide 1r (E/Zz75:25)
4.8.1. 6-(Benzyloxy)hex-3-enyl ethanoate (3)
n-Butyllithium (1.2 M in hexanes, 1.1 equiv, 0.85 mmol,
0.73 mL) was added at ꢁ78 ꢀC to a solution of alkenyl amide 1c (E/
Zz75:25, 1.0 equiv, 0.77 mmol, 0.18 g) in diethyl ether (15 mL).
The reaction mixture was allowed to warm to 20 ꢀC, and then the
general procedure for the intramolecular Kulinkovich–de Meijere
reactions was applied to afford the crude product (0.19 g) as
a yellow oil. Analysis by 1H NMR spectroscopy revealed the
presence of the expected aminocyclopropane 2c in an estimated
yield of about 17% (cis/transz66:34; see Sections 4.7.21.1 and
4.7.22.1 for analytical data). The crude reaction product also con-
tained a mixture of compounds retaining the carbon–carbon
double bond (79%), including starting material 1c (73%, E/Zz80:20
as estimated by 1H and 13C NMR spectroscopies). Purification by
flash column chromatography (neutral alumina gel, activity II,
EtOAc/heptane, gradient from 0% to 30%) yielded pure 2c (cis/
transz75:25 as estimated by 1H NMR spectroscopy, 21 mg,
A mixture of AcOH and H2O (3:1, 2.0 mL) was added to a solution
of (6-(benzyloxy)hex-3-enyloxy)(tert-butyl)dimethylsilane (E/Zz
85:15, 1.0 equiv, 0.30 mmol, 95 mg, see Section 4.2.4 for prepara-
tion) in THF (1.0 mL). After 17 h of stirring at 20 ꢀC, the solvents
were removed under reduced pressure (heptane was added to carry
AcOH away) to yield alcohol 4 (64 mg, E/Zz85:15 estimated by 13
C
NMR spectroscopy) as colourless crystals that were used in the next
step without further purification.
Acetic anhydride (1.2 equiv, 0.36 mmol, 34 mL) was added to
a solution of the preceding crystals (64.0 mg) in pyridine (1.0 mL) at
0 ꢀC. After 7 h of stirring at 20 ꢀC, most of the pyridine was removed
under reduced pressure. Purification by flash column chromatog-
raphy (EtOAc/heptane, gradient from 10% to 50%) yielded pure ester
3 (70 mg, 0.28 mmol, 94%) as an 85:15 mixture of E and Z
diastereoisomers (measured by 13C and 1H NMR spectroscopies).
96
m
mol, 12%).
4.8.1.1. 6-(Benzyloxy)hex-3-enyl ethanoate (3) (E/Zz85:15). Co-
lourless oil. IR (neat): 2923, 2854, 1736, 1453, 1362, 1233, 1099,
1028, 969, 735, 696 cmꢁ1. MS (ESþ) m/z 271 (MNaþ). HRMS (ESþ)
m/z calcd for C15H20NaO3 (MNaþ) 271.1310, found 271.1303.
4.7.21.1. 2-((1S
6-yl)ethanol (cis-2c). 1H NMR (500 MHz, CDCl3), characteristic
signals:
(dddd, J¼13.5, 10.0, 7.5, 4.5 Hz, 1H), 3.15 (td, J¼10.0, 5.0 Hz, 1H),
3.59–3.76 (m, 2H), 4.04 (td, J¼10.0, 6.5 Hz, 1H), 6.60–6.74 (m, 3H),
7.13–7.32 (m, 2H). 13C NMR (75.5 MHz, CDCl3), characteristic sig-
*
,5S
*
,6R
*
)-1-Methyl-2-phenyl-2-azabicyclo[3.1.0]hexan-
d
1.53 (s, 3H), 1.88 (dddd, J¼13.5, 10.0, 6.0, 1.0 Hz, 1H), 2.32
4.8.1.2. (E)-6-(Benzyloxy)hex-3-enyl ethanoate ((E)-3). 1H NMR
(300 MHz, CDCl3):
d
2.02 (s, 3H), 2.33 (td, J¼6.5, 6.0 Hz, 4H), 3.48 (t,
J¼6.5 Hz, 2H), 4.07 (t, J¼6.5 Hz, 2H), 4.51 (s, 2H), 5.51 (AB part of an
ABX2Y2 system, dA¼5.47 ppm, dB¼5.55 ppm, JAB¼15.5 Hz,
JAX¼6.0 Hz, JAY¼0 Hz, JBX¼0 Hz, JBY¼6.0 Hz, 2H), 7.21–7.42 (m, 5H).
nals:
d 20.4, 22.6, 27.6, 28.5, 30.4, 55.9, 63.0, 113.8, 116.0, 128.8.
4.7.22. Reaction of alkenyl amide (Z)-1s
13C NMR (75.5 MHz, CDCl3):
d 20.9, 31.9, 33.0, 63.9, 69.8, 72.8, 127.2,
The general procedure for the intramolecular Kulinkovich–de
Meijere reactions was applied to alkenyl amide (Z)-1s generated by
treating a solution of (Z)-1c (1.0 equiv, 0.54 mmol, 0.13 g) in toluene
(20 mL) with cyclo-pentylmagnesium chloride (1.0 equiv) at 0 ꢀC,
prior to the addition of titanium(IV) iso-propoxide (1.5 equiv) and
cyclo-pentylmagnesium chloride (4.0 equiv) at 20 ꢀC. The crude
product (0.12 g) was obtained as a viscous greenish oil. Analysis by
1H spectroscopy revealed the presence of the expected trans ami-
nocyclopropane trans-2c in an estimated yield of about 21%. The cis
diastereoisomer was not detected. The crude reaction product also
contained a mixture of compounds retaining the carbon–carbon
double bond (65%), including (Z)-1c (60%). Purification of the crude
product by flash column chromatography (neutral alumina gel,
activity II-III, EtOAc/heptane, gradient from 10% to 100%) yielded
127.5, 127.5, 128.3, 129.5, 138.4, 171.0.
4.8.1.3. (Z)-6-(Benzyloxy)hex-3-enyl ethanoate ((Z)-3). 1H NMR
(300 MHz, CDCl3), characteristic signals:
d 2.39 (m, 4H), 4.06 (t,
J¼6.5 Hz, 2H). 13C NMR (75.5 MHz, CDCl3), characteristic signals:
d
26.8, 28.0, 63.7, 69.6.
4.8.1.4. (E)-6-(Benzyloxy)hex-3-en-1-ol ((E)-4). 1H NMR (300 MHz,
CDCl3):
d
1.76 (br s, 1H), 2.27 (qd, J¼6.0, 1.0 Hz, 2H), 2.35 (qd, J¼6.5,
1.0 Hz, 2H), 3.49 (t, J¼6.5 Hz, 2H), 3.61 (t, J¼6.0 Hz, 2H), 4.51 (s, 2H),
5.52 (AB part of an ABX2Y2 system, dA¼5.48 ppm, dB¼5.56 ppm,
JAB¼15.5 Hz, JAX¼6.5 Hz, JAY¼1.0 Hz, JBX¼1.0 Hz, JBY¼6.0 Hz, 2H),
7.19–7.43 (m, 5H). 13C NMR (75.5 MHz, CDCl3):
69.8, 72.8, 127.5, 127.6, 128.1, 128.3, 130.0, 138.3.
d 33.0, 36.0, 61.8,

8896
C. Madelaine et al. / Tetrahedron 64 (2008) 8878–8898
4.8.1.5. (Z)-6-(Benzyloxy)hex-3-en-1-ol ((Z)-4). 13C NMR (75.5 MHz,
4.47 and 4.48 (2ꢂs, 2H), 6.88 and 6.91 (2ꢂd, J¼2.0 Hz,1H), 7.04–7.20
(m, 2H), 7.22–7.36 (m, 6H), 7.53 and 7.64 (2ꢂd, J¼7.5 Hz, 1H), 8.69
and 8.85 (2ꢂbr s,1H, NH). 13C NMR (75.5 MHz, CDCl3, 56:44 mixture
CDCl3), characteristic signals:
d 28.0, 30.7, 61.9, 69.4.
4.8.2. Reaction of 3
of two rotamers): d 17.9 and 19.0, 19.9 and 20.0, 21.1 and 21.6, 23.4
Methyltriiso-propoxytitane44,45 (1.5 equiv, 0.40 mmol, 95
m
L)
and 24.6, 45.2 and 48.0, 46.9 and 50.1, 68.3 and 68.5, 72.7 and 72.7,
77.3, 78.2, 78.7, 79.3, 111.1 and 111.4, 111.4 and 112.7, 117.9 and 118.5,
119.0 and 119.2, 121.6 and 121.8, 122.0 and 122.3, 126.9 and 127.3,
127.5 and 127.5, 127.5 and 127.5, 128.2 and 128.2, 136.2 and 136.2,
137.9 and 137.9, 170.5 and 170.7. MS (ESþ) m/z 347, 389 (MHþ), 411
(MNaþ), 412. HRMS (ESþ) m/z calcd for C25H28N2NaO2 (MNaþ)
411.2048, found 411.2056.
was added at 20 ꢀC to a solution of ester 6 (E/Zz85:15, 1.0 equiv,
0.26 mmol, 65 mg) in Et2O (5.0 mL), followed by cyclo-pentylmag-
nesium chloride (1.6 M in Et2O, 2.5 equiv, 0.66 mmol, 0.41 mL)
dropwise. After 20 min of stirring, water (15 mL) was added to the
brown solution, which was exposed to air, and stirring was con-
tinued until decolouration. Et2O (15 mL) and H2O (15 mL) were
then added. The organic layer was separated, and the aqueous
phase was extracted with Et2O (15 mL). The combined organic
layers were dried over Na2SO4 and concentrated under reduced
pressure to afford a colourless oil (61 mg). Analysis by 1H and 13C
NMR spectroscopies revealed the presence of alcohol 4 (91% yield
as estimated by integration of the corresponding signals in the 1H
NMR spectrum), as well as cyclopropanol 5.
The preparation of (Z)-9 was first attempted by forming and
hydrolysing
a
titanacyclopropene complex,17,18 however, with
incomplete conversion possibly due to solubility problems: tita-
nium(IV) iso-propoxide (2.0 equiv, 8.0 mmol, 2.4 mL) was added at
ꢁ70 ꢀC to a suspension of N-(2-(1H-indol-3-yl)ethyl)-N-(6-(ben-
zyloxy)hex-3-ynyl)ethanamide (1.0 equiv, 4.0 mmol, 1.5 g) in Et2O
(80 mL), followed by cyclo-pentylmagnesium chloride (1.9 M in
Et2O, 4.0 equiv, 16 mmol, 8.2 mL), dropwise. The resulting yellow
mixture was allowed to warm to ꢁ30 ꢀC in 5 min and maintained at
that temperature for 45 min, by which time it had become brown.
The reaction medium was then hydrolysed at ꢁ30 ꢀC with 0.3 N HCl
aq solution (0.10 L), and allowed to warm to 20 ꢀC. The organic layer
was separated and the aqueous phase was extracted with CH2Cl2
(2ꢂ0.15 L). The combined organic layers were dried over sodium
sulfate, filtered and concentrated under reduced pressure to afford
a viscous green oil (1.5 g). Analysis of the crude product using 1H
and 13C NMR spectroscopy revealed that it essentially contained
a 52:48 mixture of starting alkyne and wanted alkene (Z)-9.
The mixture thus obtained was then submitted to a catalytic
hydrogenation reaction mediated by palladium on barium sul-
fate:46 To a mixture of 5% palladium on barium sulfate (10% equiv,
4.8.2.1. (1R
(300 MHz, CDCl3):
1.97 (m, 7H). 13C NMR (75.5 MHz, CDCl3), characteristic signals:
16.1, 25.7, 26.2, 32.0.
*
,5S
*
,6R
*
)-6-Methylbicyclo[3.1.0]hexan-6-ol (5). 1H NMR
1.32 (s, 3H), 1.45 (dd, J¼4.5, 2.0 Hz, 2H), 1.56–
d
d
4.9. Preparation of tetrahydrocarboline 11
4.9.1. (Z)-N-(2-(1H-Indol-3-yl)ethyl)-N-(6-(benzyloxy)hex-3-enyl)-
ethanamide ((Z)-9)
Tryptamine (2.0 equiv, 12 mmol, 2.0 g) was added to a solution
of 6-(benzyloxy)hex-3-ynyl 4-methylbenzenesulfonate (1.0 equiv,
6.0 mmol, 2.2 g, see compound (Z)-1d for the preparation of this
tosylate) in acetonitrile (15 mL), and the mixture was heated at
reflux for 3 h. After cooling, the solvent was removed under re-
duced pressure, then CH2Cl2 (40 mL) and 1 N NaOH aq solution
(40 mL) were added. The organic layer was separated and the
aqueous phase was extracted with CH2Cl2 (2ꢂ40 mL). The com-
bined organic layers were dried over sodium sulfate, filtered and
concentrated under reduced pressure to afford a viscous brown oil
(4.0 g). Purification by flash column chromatography (EtOAc/hep-
tane, gradient from 20% to 100%) yielded pure N-(2-(1H-indol-3-
yl)ethyl)-6-(benzyloxy)hex-3-yn-1-amine (1.5 g, 4.4 mmol, 73%) as
a viscous yellow oil. IR (neat): 2912, 2847, 1454, 1358, 1338, 1095,
0.19 mmol, 0.40 g) and quinoline (10% equiv, 0.19 mmol, 22 mL) in
EtOAc (15 mL) was added a solution of 1.4 g of the preceding 52:48
mixture of N-(2-(1H-indol-3-yl)ethyl)-N-(6-(benzyloxy)hex-3-
ynyl)ethanamide (1 equiv,1.9 mmol) and alkene (Z)-9 (1.7 mmol) in
EtOAc (5.0 mL). The flask was flushed three times with argon, and
then three times with hydrogen. After 6 h of stirring at 20 ꢀC, 63 mL
(2.6 mmol) of H2 was absorbed. The black mixture was filtered, and
the solid rinsed with EtOAc several times. The solvent was removed
under reduced pressure to afford a viscous brown oil (1.4 g).
Analysis of the crude product using 1H and 13C NMR spectroscopy
revealed that it stilled contained about 18% of starting alkyne. The
1028, 1009, 736, 696 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 1.60 (br s,
1H, NH), 2.27–2.40 (m, 4H), 2.74 (t, J¼6.5 Hz, 2H), 2.95 (br s, 4H),
3.45 (t, J¼7.0 Hz, 2H), 4.48 (s, 2H), 6.91 (d, J¼2.5 Hz, 1H), 7.04–7.18
(m, 2H), 7.22–7.35 (m, 6H), 7.59 (d, J¼7.5 Hz,1H), 8.55 (br s, 1H, NH).
procedure was thus repeated on this crude product (65
mL of 5% Pd/
BaSO4, 65 L of quinoline, 22 mL of H2) to afford a viscous brown oil
m
(1.4 g). Purification by flash column chromatography (EtOAc/hep-
tane, gradient from 30% to 100%) yielded pure (Z)-9 (1.3 g,
3.3 mmol, 83% overall yield for the Ti-mediated and the Pd-cata-
lysed hydrogenation reactions) as a viscous yellow oil. IR (neat):
13C NMR (75.5 MHz, CDCl3):
d 19.7, 19.9, 25.6, 48.0, 49.2, 68.6, 72.7,
78.1, 78.9, 111.1, 113.4, 118.7, 118.9, 121.7, 122.0, 127.3, 127.6, 127.6,
128.3, 136.3, 138.0. MS (ESþ) m/z 144, 347 (MHþ), 348, 369 (MNaþ).
HRMS (ESþ) m/z calcd for C23H27N2O (MHþ) 347.2123, found
347.2100.
3265, 2927, 2854, 1615, 1454, 1421, 1096, 736, 696 cmꢁ1
.
1H NMR
(500 MHz, CDCl3, 53:47 mixture of two rotamers):
d 1.90 and 2.10
Acetyl chloride (1.5 equiv, 6.6 mmol, 0.45 mL) was added to
a solution of N-(2-(1H-indol-3-yl)ethyl)-6-(benzyloxy)hex-3-yn-1-
amine (1.0 equiv, 4.4 mmol, 1.5 g) in CH2Cl2 (15 mL) at 0 ꢀC. The
resulting solution was poured in a separating funnel, and 1 N NaOH
aq solution (15 mL) was added. The reaction mixture was vigor-
ously shaken for 5 min. The organic layer was separated, washed
with 1 N HCl aq solution (20 mL) and H2O (20 mL), then dried over
sodium sulfate, filtered and concentrated under reduced pressure
to afford N-(2-(1H-indol-3-yl)ethyl)-N-(6-(benzyloxy)hex-3-ynyl)-
ethanamide as a viscous yellow oil (1.7 g, 4.4 mmol, 99%) that was
used in the next step without further purification. IR (neat): 3264,
(2ꢂs, 3H), 2.26 and 2.31 (2ꢂq, J¼7.5 Hz, 2H), 2.35 and 2.37 (2ꢂq,
J¼6.5 Hz, 2H), 2.98 and 3.02 (2ꢂt, J¼7.5 Hz, 2H), 3.17 and 3.53
(2ꢂt, J¼7.5 Hz, 2H), 3.45 and 3.47 (2ꢂt, J¼6.5 Hz, 2H), 3.39 and 3.62
(t, J¼7.5 Hz, 2H), 4.49 and 4.50 (2ꢂs, 2H), 5.34–5.56 (m, 2H), 6.96
and 7.01 (2ꢂd, J¼2.0 Hz, 1H), 7.08–7.24 (m, 2H), 7.24–7.39 (m, 6H),
7.55 and 7.67 (2ꢂd, J¼8,0 Hz,1H), 8.06 and 8.15 (2ꢂbr s,1H, NH). 13
C
NMR (75.5 MHz, CDCl3, 53:47 mixture of two rotamers):
d 20.9
and 21.3, 23.2 and 24.3, 25.6 and 26.5, 27.6 and 27.6, 45.2 and 48.5,
46.8 and 49.3, 69.1 and 69.4, 72.4 and 72.5, 110.9 and 111.1, 111.3
and 112.2, 117.6 and 118.2, 118.6 and 118.8, 121.2 and 121.4, 121.9 and
122.3, 126.4 and 126.7, 127.1 and 127.5, 127.2 and 127.2, 127.2
and 127.2, 127.8 and 128.6, 127.9 and 127.9, 136.1 and 136.1, 137.9
and 138.0, 170.1 and 170.4. MS (ESþ) m/z 413 (MNaþ), 414. HRMS
(ESþ) m/z calcd for C25H30N2NaO2 (MNaþ) 413.2205, found
413.2191.
2916, 2861, 1621, 1454, 1419, 1360, 1097, 1009, 737, 697 cmꢁ1
.
1H
NMR (300 MHz, CDCl3, 56:44 mixture of two rotamers): 1.86 and
d
2.14 (2ꢂs, 3H), 2.28–2.50 (m, 4H), 2.95 (t, J¼7.0 Hz, 1.12H), 3.00 (t,
J¼8.0 Hz, 0.88H), 3.29 (t, J¼7.0 Hz, 0.88H), 3.42–3.67 (m, 5.12H),

C. Madelaine et al. / Tetrahedron 64 (2008) 8878–8898
8897
4.9.2. 3-(2-((1S
*
,5S
*
,6S
*
)-6-(2-(Benzyloxy)ethyl)-1-methyl-2-
d 16.0, 27.4, 27.9, 29.0, 29.0, 42.4, 46.9, 50.0, 63.2, 70.1, 73.1, 109.7,
azabicyclo[3.1.0]hexan-2-yl)ethyl)-1H-indole ((trans)-10)
110.7, 118.0, 119.1, 121.6, 126.9, 127.7, 127.8, 128.5, 135.8, 136.0,
Titanium(IV) iso-propoxide (1.5 equiv, 1.5 mmol, 0.44 mL) was
added at 20 ꢀC to a solution of alkenyl amide (Z)-9 (1.0 equiv,
1.0 mmol, 0.39 g) in THF (40 mL), followed by cyclo-pentylmag-
nesium chloride (1.9 M in Et2O, 4.0 equiv, 4.0 mmol, 2.1 mL)
dropwise. After 20 min of stirring, water (0.10 L) and Et2O (60 mL)
were added to the dark mixture. The organic layer was separated
and the aqueous phase was extracted with CH2Cl2 (3ꢂ0.10 L). The
combined organic layers were dried over sodium sulfate, filtered
and concentrated under reduced pressure to afford a viscous
brown oil (0.38 g). Purification of the crude product by two suc-
cessive flash column chromatographies (neutral alumina gel,
activity II, EtOAc/heptane, gradient from 30% to 100%, then MeOH/
EtOAc, gradient from 1% to 5%) yielded pure starting alkenyl amide
(Z)-9 (0.19 g, 0.49 mmol, 49%) and pure aminocyclopropane
(trans)-10 (52 mg, 0.14 mmol, 14%) as colourless crystals. Mp
124.5–125.0 ꢀC. IR (neat): 2920, 2864, 1450, 1231, 1084, 1071, 734,
138.4. MS (ESþ) m/z 375 (MHþ), 376. HRMS (ESþ) m/z calcd for
C
25H31N2O (MHþ) 375.2436, found 375.2441.
Acknowledgements
We are grateful to the Centre National de la Recherche Scientifique
´
´
´
(CNRS) and Ecole Nationale Superieure des Techniques Avancees
(ENSTA) for funding. We also warmly thank Dr. Pascal Retailleau for
his valuable help.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.06.067.
References and notes
699 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d
0.89 (t, J¼4.0 Hz, 1H), 1.02
(td, J¼7.0, 4.0 Hz, 1H), 1.37 (s, 3H), 1.46–1.65 (m, 2H), 1.85 (m, 1H),
1.96–2.12 (m, 2H), 2.39 (ddd, J¼11.5, 9.0, 7.0 Hz, 1H), 2.87–2.99 (m,
2H), 3.15 (ddd, J¼11.5, 9.5, 7.5 Hz, 1H), 3.25 (m, 1H), 3.45 (t,
J¼7.0 Hz, 2H), 4.48 (s, 2H), 6.97 (d, J¼2.0 Hz, 1H), 7.06–7.21 (m,
2H), 7.21–7.35 (m, 6H), 7.61 (d, J¼7.5 Hz, 1H), 8.35 (br s, 1H, NH).
1. Chaplinski, V.; de Meijere, A. Angew. Chem. 1996, 108, 491–492; Angew. Chem.,
Int. Ed. Engl. 1996, 35, 413–414.
2. Kulinkovich, O. G.; de Meijere, A. Chem. Rev. 2000, 100, 2789–2834.
3. de Meijere, A.; Kozhushkov, S. I.; Savchenko, A. I. In Titanium and Zirconium in
Organic Synthesis; Marek, I., Ed.; Wiley-VCH: Weinheim, 2002; pp 390–434.
4. de Meijere, A.; Kozhushkov, S. I.; Savchenko, A. I. J. Organomet. Chem. 2004, 689,
2033–2055.
13C NMR (75.5 MHz, CDCl3):
d 15.0, 15.4, 25.0, 26.4, 28.2, 29.5, 49.6,
5. Lee, J.; Cha, J. K. J. Org. Chem. 1997, 62, 1584–1585.
50.1, 52.6, 70.4, 72.9, 111.1, 114.6, 118.8, 119.1, 121.5, 121.8, 127.4,
127.5, 127.5, 128.3, 136.2, 138.5. MS (ESþ) m/z 244, 375 (MHþ), 376.
HRMS (ESþ) m/z calcd for C25H31N2O (MHþ) 375.2436, found
375.2439.
6. The group of Kulinkovich was the first to demonstrate the possibility of ligand
exchange in reactions of this type: Kulinkovich, O. G.; Savchenko, A. I.; Sviridov,
S. V.; Vasilevski, D. A. Mendeleev Commun. 1993, 230–231.
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4.9.3. Tetrahydrocarboline (11)
A
solution of aminocyclopropane (trans)-10 (1.0 equiv,
0.11 mmol, 41 mg) in chlorobenzene (2 mL) was heated at reflux
for 8 h. The reaction being incomplete according to TLC analysis,
11. Ouhamou, N.; Six, Y. Org. Biomol. Chem. 2003, 1, 3007–3009.
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by-products owing to the comparable polarities of the N-phenylacetamide and
the hydroxyl moieties. However, silylation or benzylation of the mixture
yielded readily isolable ethers 1d and 1e, and deprotection of isolated 1d
cleanly gave 1c.
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para-toluenesulfonic acid (10% equiv, 11 mmol, 1.9 mg) was added
and the mixture was stirred at reflux for a further 24 h under
a static atmosphere of Ar. After cooling, the solvent was removed
under reduced pressure to afford a viscous black oil (44 mg).
Analysis of this crude product by 13C NMR spectroscopy revealed
a z40:60 ratio for the cis and trans diastereoisomers, defined
according to the relative configurations of the methyl and 2-
benzyloxyethyl groups, and assigned by comparison with
diastereoisomers of a similar carboline.33 Purification by flash
column chromatography (NH4OH saturated aq solution/EtOAc
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gradient from 0% to 5%) yielded pure cis-11 (9.2 mg, 25
a 47:53 mixture of cis and trans diastereoisomers of 11 (14 mg,
37 mol, 34%), and pure trans-11 (10 mg, 27 mol, 24%). Less polar
cis-11: brown oil. IR (neat): 3295, 2924, 2854, 1453, 1095, 907, 727,
697 cmꢁ1. 1H NMR (500 MHz, CDCl3):
1.41 (s, 3H), 1.47–1.64 (m,
mmol, 22%),
m
m
21. Savchenko, A. I.; Kulinkovich, O. G. Zh. Org. Khim. 1997, 33, 913–915; Russ. J. Org.
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d
3H), 1.82 (m, 1H), 1.86–2.00 (m, 2H), 2.14 (m, 1H), 2.57 (m,
J¼16.0 Hz, 1H), 2.87 (td, J¼9.5, 6.0 Hz, 1H), 2.92 (ddd, J¼16.0, 11.0,
5.5 Hz, 1H), 3.02 (m, 1H), 3.16–3.33 (m, 2H), 3.51–3.59 (m, 2H),
4.54 (AB system, dA¼4.53 ppm, dB¼4.55 ppm, JAB¼12.0 Hz, 2H),
7.08 (t, J¼7.5 Hz, 1H), 7.12 (t, J¼7.5 Hz, 1H), 7.23 (d, J¼7.5 Hz, 1H),
7.28–7.39 (m, 5H), 7.47 (d, J¼7.5 Hz, 1H), 7.77 (br s, 1H, NH). 13C
22. Epstein, O. L.; Kulinkovich, O. G. Tetrahedron Lett. 2001, 42, 3757–3758.
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Angew. Chem., Int. Ed. 2002, 41, 2160–2162.
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26. This effect was favourable in these reactions, dramatically increasing their di-
astereoselectivities. Urabe, H.; Sato, F. Tetrahedron Lett. 1998, 39, 7329–7332.
27. Lee, J.; Cha, J. K. Tetrahedron Lett. 1996, 37, 3663–3666.
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31. Eisch, J. J.; Adeosun, A. A.; Gitua, J. N. Eur. J. Org. Chem. 2003, 4721–4727.
NMR (125.8 MHz, CDCl3):
d 16.6, 22.6, 28.4, 28.5, 30.3, 43.4, 47.3,
48.5, 61.0, 70.0, 73.0, 106.0, 110.7, 118.2, 119.4, 121.5, 127.0, 127.7,
127.7, 128.5, 135.8, 135.8, 138.4. MS (ESþ) m/z 375 (MHþ), 376.
HRMS (ESþ) m/z calcd for C25H31N2O (MHþ) 375.2436, found
375.2446. More polar trans-11: brown oil. IR (neat): 3313, 2927,
32. Garnier, J.-M.; Lecornue, F.; Charnay-Pouget, F.; Ollivier, J. Synlett 2007,
´
2827–2828.
2860, 1668, 1620, 1453, 1093, 907, 726, 697 cmꢁ1
.
1H NMR
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4654–4662.
34. Madelaine, C.; Six, Y.; Buriez, O. Angew. Chem. 2007, 119, 8192–8195; Angew.
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(500 MHz, CDCl3):
d 1.23 (m, 1H), 1.50 (m, 1H), 1.68–1.83 (m, 2H),
1.93–2.02 (m, 2H), 2.01 (s, 3H), 2.10 (m, 1H), 2.51 (dd, J¼15.5,
3.5 Hz, 1H), 2.99–3.23 (m, 5H), 3.51 (m, 1H), 3.59 (m, 1H), 4.56 (s,
2H), 7.05–7.14 (m, 2H), 7.19 (m, 1H), 7.28–7.38 (m, 5H), 7.48 (d,
J¼7.5 Hz, 1H), 7.93 (br s, 1H, NH). 13C NMR (125.8 MHz, CDCl3):
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