Reaction of the lithio-derivative of methoxyallene with hydrazones. Part 1: Synthesis and transformation of α-allenyl hydrazines

Article abstract of DOI:10.1016/S0040-4020(01)00030-8

The lithio-derivative of methoxyallene reacts with aldehyde hydrazones leading to expected α-allenyl hydrazines when ether is the solvent of the reaction. The yields are good as well as the diastereoselectivity observed in the case of SAMP-hydrazones. These hydrazines are cleanly transformed to N-dialkylamino-3-methoxy-3-pyrrolines when they are reacted with n-BuLi in THF. These compounds are sometimes accompanied by the isomeric 4-methyl azetidines. The N-dialkylamino-3-methoxy-3-pyrrolines are transformed to 3-methoxy-3-pyrrolines by hydrogenolysis of the nitrogen-nitrogen bond, to 3-alkoxy-pyrroles by treatment with a peracid and to 3-amino-pyrroles by acidic migration of the dialkylamino group. In the case of SAMP-hydrazines, the obtained 3-methoxy-3-pyrrolines have a high enantiomeric purity. Lastly, attempts to prepare α-hydrazino-esters (and subsequently α-amino-esters) by ozonolysis of the allenyl moiety failed due to the formation of a methyl glyoxylate.

Full text of DOI:10.1016/S0040-4020(01)00030-8

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1939±1950
Reaction of the lithio-derivative of methoxyallene with
hydrazones. Part 1: Synthesis and transformation of
a-allenyl hydrazinesq
Â
Âp
Valerie Breuil-Desvergnes and Jacques Gore
  Ã
Laboratoire de Chimie Organique I, associe au CNRS, Universite Claude Bernard 5622, Bat 308, CPE-Lyon,
43 Bd du 11 novembre 1918, 69622 Villeurbanne, France
Received 2 August 2000; revised 7 December 2000; accepted 4 January 2001
AbstractÐThe lithio-derivative of methoxyallene reacts with aldehyde hydrazones leading to expected a-allenyl hydrazines when ether is
the solvent of the reaction. The yields are good as well as the diastereoselectivity observed in the case of SAMP-hydrazones. These
hydrazines are cleanly transformed to N-dialkylamino-3-methoxy-3-pyrrolines when they are reacted with n-BuLi in THF. These
compounds are sometimes accompanied by the isomeric 4-methyl azetidines. The N-dialkylamino-3-methoxy-3-pyrrolines are transformed
to 3-methoxy-3-pyrrolines by hydrogenolysis of the nitrogen±nitrogen bond, to 3-alkoxy-pyrroles by treatment with a peracid and to
3-amino-pyrroles by acidic migration of the dialkylamino group. In the case of SAMP-hydrazines, the obtained 3-methoxy-3-pyrrolines
have a high enantiomeric purity. Lastly, attempts to prepare a-hydrazino-esters (and subsequently a-amino-esters) by ozonolysis of the
allenyl moiety failed due to the formation of a methyl glyoxylate. q 2001 Elsevier Science Ltd. All rights reserved.
Since the pioneering work of Brandsma et al.,1 who demon-
strated that methoxyallene 1 can be regioselectively metal-
lated at C1 by reaction with n-butyllithium, a lot of work has
been devoted to the use of the so formed a-lithio methoxy-
allene 2 and to its reaction with various electrophiles.
Mainly, the addition of 2 to aldehydes and ketones has
been studied; it gives exclusively the a-allenic alcohol,2
which can be hydrolysed to conjugated ketones or involved
in cyclization processes (Fig. 1).3
Comparatively, only a few studies dealt with the addition
of 2 (or the lithio derivative of 3) on a carbon±nitrogen
double bond in order to prepare a-allenic amines or
derivatives thereof. Very recently this addition was
studied with achiral6 or chiral7 nitrones and with
various imines.8 In our case, we tried to add the lithio-
derivative of enantiopure alkoxyallene 3 to aromatic
silylimines but the reaction, sometimes successful, was
not reproducible and gave tars more often than tractable
products. Consequently, we turned our attention to
hydrazones, which have been used extensively as reagents
for electrophilic amination. In this context, Enders et al.9
described the use of hydrazones bearing an a-methoxy-
methyl pyrrolidinyl group (SAMP- or RAMP-hydrazones)
in various reactions, and particularly in the asymmetric
addition of organometallics; this was the motivation for
this study.
Figure 1.
In our group, we were particularly interested in the stereo-
chemical behaviour of the lithio-derivative of chiral alkoxy-
allene 3 (Rˆenantiopure substituent such as ephedrine
derivatives or diacetoneglucose). They react with aromatic
aldehydes giving a-allenic alcohols in good yield with a
correct stereo differentiation (d.e. up to 85%);4 this reaction
has been used in the multi-step synthesis of the styrryl
lactone (1)-gonodiol.5
1. Results and discussion
1.1. Preparation of the hydrazones
The hydrazones required for this study were prepared as
shown in Scheme 1 by reaction of the aldehydes with
the commercially available hydrazines as previously
reported.10
q For preliminary results, see Refs. 19 and 20.
Keywords: organolithium; allenes; asymmetric synthesis; pyrrolines;
pyrroles.
p
The yields of this reaction are nearly quantitative and
the hydrazones are pure enough to be used without any
Corresponding author. Tel.: 133-04-72-44-81-35; fax: 133-04-72-43-
12-14; e-mail: gore@univ-lyon1.fr
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00030-8

Â
V. Breuil-Desvergnes, J. Gore / Tetrahedron 57 (2001) 1939±1950
1940
1.2. Reaction of lithio methoxyallene with hydrazones;
obtention of a-allenyl hydrazines
We will describe here some results of our study of this
reaction and will present in the following paper11 that the
nature of the product can be dramatically modi®ed by the
type of solvent and by the experimental conditions
(temperature and reaction time). The results listed in
Table 2 are those, in ether, of the reaction of hydrazones
with a-lithio methoxyallene 2 prepared by the reaction at
2308C of 1 equiv. of n-BuLi with 1. The addition of the
organometallic is made at 2788C, the temperature being
raised to 2208C after 2 h, the reaction time then being
16 h. A preliminary study showed that 6 M equiv. of 2 are
Scheme 1.
puri®cation. In any case, they are easily puri®ed by FC on
alumina gel. As anticipated, only one isomer is detected by
1H and 13C NMR, the con®guration being E on the basis of
literature data. In Table 1 are listed the prepared hydra-
zones which differ from each other by the aromatic or
aliphatic nature of R and by the structure of the hydrazine
moiety.
Table 1. Hydrazones prepared for this study
Ph
b-naphthyl
p-MePh
p-MeOPh
Et
isoPr
tBu
4a
4b
4c
4d
4e
4f
4g
5a
6a
7a
5b
6b
7b
5c
6c
7c
5d
6d
7d
5e
6e
7e
5f
6f
7f
5g
6g
7g
Table 2. Reaction of 2 with various hydrazones in ether
Ph
b-naphthyl
p-MePh
p-MeOPh
Et
isoPr
tBu
8a
8b
8c
8e
9e
8f
9f
9a
9b
9c
9d
9g
10a
10b
10c
10d
10e
10f
10g
11a d.e. .99%
11b d.e. .99%
11c d.e. .99%
11d d.e. .99%
11e d.e. 93%
11f d.e. 95%
11g d.e. 98%

Â
V. Breuil-Desvergnes, J. Gore / Tetrahedron 57 (2001) 1939±1950
1941
Figure 2.
Scheme 2.
reduction of the hydrazine to an amine will be discussed
further in this paper. Of course, this two-step sequence
was particularly attractive in the case of SAMP-hydrazines
11, as it could provide a potential access to enantiopure
a-amino acids by a formal asymmetric formation of the
C±CO2H bond.14
necessary to engage completely the hydrazones; sur-
prisingly, no reaction is observed when the reaction is run
with 2 equiv. and a variable amount of hydrazone is
recovered when intermediate quantities of 2 are used.12
The ®rst attempts at ozonolysis were carried out with the
hydrazine 10a in the classical way by using dichloro-
methane as solvent, the ozonolysis being followed by a
supposed reduction of the ozonide by dimethylsul®de.
Surprisingly, this reaction led only to methyl phenyl-
glyoxylate 12 with no trace of the expected a-hydrazino
ester 13 (Scheme 2).
Uniformly, this reaction led to a-allenyl hydrazines 8±11.
These compounds are fairly unstable under chromato-
graphic conditions, either on silica gel or on neutral
1
alumina, but H and 13C NMR spectra showed that the
crude product resulting from the usual work-up has a purity
$95%, this crude product being obtained in almost quanti-
tative yield (Table 2).
It is noteworthy that the crude product contains, besides 12,
the corresponding oxime 14 identi®ed mainly by GC±MS
coupling and that morpholine is also formed in the ozo-
nolysis reaction. Since the saturated hydrazine 15 does not
react with ozone and a-aminoalkoxyallenes give a-amino
esters in the same conditions,7 it appeared that the transfor-
mation of 10a to 12 via 14 could involve the intramolecular
reduction of the ozonide by the hydrazine group as depicted
in Scheme 3.
In the case of SAMP-hydrazones, the reaction is highly dia-
stereoselective and the a-allenyl hydrazines 11 are obtained
with a diastereomeric excess, ranging from 93 to $99%
1
determined by GC and H NMR. The S con®guration of
the stereogenic carbon was assigned by reference to the
model proposed by Enders et al. for the diastereoselection
of the addition of organometallics to such hydrazones.13 It
was con®rmed later by X-ray diffraction study of a derived
compound (see below).
In order to avoid this intramolecular reduction by decreasing
the nucleophilicity of nitrogen, attempts to prepare carba-
mates 16a,b or sulfamide 17 were made under different
conditions; they were all unsuccessful (Fig. 2). Also, the
ozonolysis was run in dichloromethane in the presence of
1±5 equiv. of pyridine15 as we expected a different mecha-
nistic pathway. The hydrazino ester 13 was effectively
obtained with a maximum yield of about 10% mixed with
the oxime 14 and morpholine in the crude product and it was
impossible to isolate it in pure form from this mixture.
1.3. Reaction in ether of 2 with various hydrazones.
Attempts to prepare a-amino acids from a-allenyl
hydrazines
In every case studied so far, a-allenyl hydrazines were the
only products formed in the reaction of a-lithio methoxy-
allene 2 with hydrazones 4±7 and the diastereoselection was
high in the case of SAMP-hydrazones 7. These hydrazines
could be the precursors of a-amino acids by a two-step
sequence involving the ozonolysis of the allenic moiety
followed by hydrogenolysis of the N±N bond; both
reactions are known to give good yields: ozonolysis of the
methoxyallene group has been reported previously8 and the
In a last experiment, we ran the same reaction with the
diastereopure SAMP-hydrazine 11a but the result was the
Scheme 3.

Â
V. Breuil-Desvergnes, J. Gore / Tetrahedron 57 (2001) 1939±1950
1942
nature of R, either aromatic or aliphatic. The yields are high
and the diastereomeric excess is retained.
In the case of morpholine hydrazines, the cyclization to
pyrrolines is observed only when R is an aromatic group.
On the contrary, the aliphatic compounds remained
unchanged under the same experimental conditions. Lastly,
in the dimethyl and piperidinyl series, the hydrazines when
R is aliphatic are again inert under these reaction conditions,
while when R is aromatic, cyclization occurs giving a
mixture of the corresponding pyrroline with an azetidine
19; both compounds are dif®cult to separate by ¯ash
chromatography but, in the two series, it was possible to
isolate the azetidine in pure form and to propose its structure
on the basis of MS and NMR spectra. These azetidines are
also obtained, but with better yield, in the reaction of hydra-
zones 4, 5, 6 with a-lithio methoxyallene 2 in THF, where
the cyclized products are obtained directly without stopping
at the a-allenyl hydrazine step.11
Scheme 4.
same, discounting the possibility of preparing enantiopure
a-amino acids by this sequence.
1.4. Formation of N-dialkylamino-3-pyrrolines
As will be shown in the following paper,11 the reaction of
a-lithio-methoxyallene 2 with hydrazones in THF led in
many cases and in good yield to N-dialkylamino-3-pyrro-
lines 18 (Scheme 4); these compounds are also obtained
diastereoselectively in the case of SAMP-hydrazones 7.
As it was probable that compounds 18 came from the cycli-
zation of the a-allenyl lithium hydrazides, we treated some
of the a-allenyl hydrazines 8±11 with n-BuLi in THF to try
to obtain the same cyclization.
Evidently, the most interesting results are those concerning
the SAMP-hydrazines 11 since the cyclization gives exclu-
sively the N-dialkylaminopyrrolines 18 in high yield and
diastereomeric excess. The exact structure of 18a has been
demonstrated by X-ray diffraction at 2508C (Fig. 3). The
asymmetric carbon of the pyrroline has the S con®guration
as expected by the model proposed by Enders et al. for the
addition of organometallics to SAMP-hydrazones.13
First of all, 11a was treated with 1 equiv. of n-BuLi under
the same conditions (time, temperature) as those used in the
direct cyclization depicted in Scheme 4. Effectively, 18a
was then obtained in a 60% yield mixed with the non-
engaged starting material. When 2 equiv. of n-BuLi were
used, 18a was obtained with almost quantitative yield after
puri®cation by ¯ash chromatography over alumina.
1.5. Transformation of N-dialkylamino-3-pyrrolines to
3-pyrrolines and to 3-alkoxy and 3-amino pyrroles
Having in hand N-dialkylamino-3-pyrrolidines in racemic
or in diastereomeric pure form, it was interesting to try to
obtain the parent 3-pyrrolines by reduction of the N±N
bond; although numerous reports have described the syn-
thesis of diversely substituted 3-pyrrolines,16 compounds
such as 20 bearing an enol ether functionality, a potential
precursor of polyfunctionalized pyrrolidines, were never
described. The interest is increased by the diastereomeric
Consequently, the reaction with other hydrazines was run by
using 2 equiv. of base. The results are given in Table 3.
They show marked differences in the behaviour of the
cyclization, which is fairly dependent on the nature of the
substituent R and on those of the terminal nitrogen of
the hydrazine. With SAMP-hydrazines the cyclization to
the corresponding pyrrolines is observed regardless of the
Table 3. Cyclization of a-allenyl lithium hydrazides
Starting hydrazone
Product
Yield (%)
D.e. (%)
11a
11b
11c
11e
11f
18a RˆPh
97
95
96
94
93
.99
.99
.99
98
18b Rˆb-naphthyl
18c Rˆp-CH3Ph
18e RˆEt
18f RˆisoPr
.99
R, R0ˆ±(CH2)5±
9a
9e
RˆPh 18g119a
20 (7/1)
RˆEt no cyclization
R,R0ˆ±(CH2)2±O±(CH2)2±
10a
10b
10e
RˆPh 18h119b
97 (8/1)
96
Rˆb-naphthyl 18i
RˆEt no cyclization
R, R0ˆCH3
8a
8e
RˆPh 18j119c
20 (7/1)
RˆEt no cyclization

Â
V. Breuil-Desvergnes, J. Gore / Tetrahedron 57 (2001) 1939±1950
1943
Fortunately, it was possible to turn the reaction selectively
towards each product by changing the reaction time. In the
case of 2£1024 mol of 18a, the reaction run at 508C in a
stainless steel bomb led preferentially to 20a (75%) when
the reaction time is 24 h and to 21a (82%) when the reaction
time is 48 h. The purity of the obtained compounds is
around 95% since it is almost impossible to separate 20a
and 21a by ¯ash chromatography and the reaction is never
totally selective. At 308C, the reaction gives a mixture of
both compounds, a reaction time of 48 h being necessary to
engage all the starting material.
Having in hand satisfactory results for the hydrogenolysis of
the N±N bond, we extended the method to some homo-
logues of 18a. It was done primarily with compounds 18
of the SAMP series in order to obtain the pyrrolines 20 in
enantioenriched form. For analytical purposes, it was also
necessary to obtain racemic pyrrolines (^)-20. They were
obtained starting with morpholinyl pyrrolines 18h,k. The
results are all listed in Table 4.
Figure 3.
The enantiomeric excess of 20a was dif®cult to determine
due to the instability of this compound. All the attempts
made in GC and HPLC on chiral columns were unsuccess-
ful. Fortunately, it was possible to determine this excess by
1H NMR using Eu(hfc)3 as chiral shift reagent.19 While
racemic 20a exhibited two signals for the vinylic proton,
only one remained for the enantioenriched 20a; conse-
quently its e.e. was estimated $95% showing that no
epimerization occurred in the hydrogenolysis step. The
same observation was also made in the case of 20c, showing
that the entire sequence starting from SAMP-hydrazones
constitutes a good method for the preparation of enantiopure
pyrrolines of type 20. In this sequence, the most dif®cult
step was the breaking of the N±N bond of hydrazines 18.
purity of the starting material and by an expected high
enantiomeric excess for the parent 3-pyrroline coming
from the SAMP series.
Many conditions have been described for the reduction of
the N±N bond of hydrazines but they concern mainly
compounds having a free N±H17 or an N-acyl bond.18
They involve hydrogenolysis catalysed by Raney nickel,
hydroboration or reduction by electron transfer (Li or Na/
NH3, SmI2 with a proton source, Zn/AcOH etc). Most of
these methods were tested using 18a as model compound
but they all proved to be unsuccessful. These repeated failures
were then attributed to the structure of 18a and analogues
where both nitrogens are trisubstituted but without the
presence of an acyl group. Considering that such an acyl
group has a bene®cial effect on the reduction by polarizing
the N±N bond, we treated 18a with methyl- and benzylchloro-
formate to form the ammonium salts 22a or 22b (not isolated).
The hypothesis was good since the hydrogenation of these
compounds in the presence of Raney nickel led to a mixture
of the two possible reaction products 20a and 21a, their ratio
being closely dependent on the experimental conditions
(Scheme 5). 2-Methoxymethyl pyrrolidine is also present
in the crude product and its puri®cation is quite dif®cult
due to the similarity of the physical properties of the three
products. Surprisingly, this crude product is free of the
corresponding carbamates but we have no explanation for
the obvious hydrogenolysis of the N±CO2R bond.
Surprisingly, this operation proved to be very easy in two
other transformations of aromatic N-dialkyl aminopyrro-
lines 18, transformations found in a serendipitous manner
and which convert 18 to valuable pyrroles substituted in
position 3 by an electron donating group.
When compounds 1820 were treated with m-chloroperben-
zoic acid in dichloromethane at 208C, they were cleanly
transformed to 3-alkoxy-2-aryl pyrroles 23. A proposed
mechanism for this transformation is depicted in Scheme
6, the key step being a Cope elimination of the N-oxide
24. Some examples of the alkoxy pyrroles prepared in this
way are given in the same scheme. These compounds,
which can be valuable for the preparation of polypyrroles,21
have been rarely reported in the literature.22
Scheme 5.

Â
V. Breuil-Desvergnes, J. Gore / Tetrahedron 57 (2001) 1939±1950
1944
Table 4. Hydrogenolysis of the N±N bond of N-dialkylamino pyrrolines 18 (in each series, only one diastereomer of 21 was observed to which the cis structure
was attributed, assuming that hydrogenation occurred by the less hindered half space of the double bond)
Starting material
Experimental conditions for hydrogenation
20
21
18a
RˆPh; R0, R0ˆSMPa
2£1024 mol
18b
Rˆb-naphthyl
R0, R0ˆSMPa
4£1024 mol
18db
508C, 24 h, 50 bar
508C, 48 h, 50 bar
(1)-20a
(1)-20b
75%
,5%
(1)-21a
(1)-21b
,5%
82%
508C, 48 h, 50 bar
508C, 72 h, 50 bar
79%
±
±
63%
Rˆp-MeOPh
R0, R0ˆSMPa
4£10£4 mol
18h
508C, 48 h, 50 bar
508C, 72 h, 50 bar
(1)-20c
(^)-20a
(^)-20c
68%
±
(1)-21c
(^)-21a
±
±
57%
RˆPh
508C, 36 h, 30 bar
508C, 36 h, 40 bar
57%
69%
,5%
R0, R0ˆ±(CH2)2O(CH2)2±
2£10£4 mol
18kb
Rˆp-MeOPh
R0, R0ˆ±(CH2)2O(CH2)2±
3£1024 mol
a
(S)-Methoxymethylpyrrolidine.
For preparation, see Ref. 11.
b
Scheme 6.
It is noteworthy that the same reaction gives lower yield
with other amino groups: with Ar being a p-methoxyphenyl
group, the yields are, respectively, 42 and 38% in the
piperidinyl and in the dimethylamino series. Lastly, only
traces of pyrrole were observed when the aromatic sub-
stituent is replaced by an ethyl group in the morpholinyl
series.
Still more surprising was the result of the treatment of
compounds 18 with 0.2N HCl in a mixture THF/H2O 4:1;
3-amino-2-aryl pyrroles 25 were obtained in almost quanti-
tative yields. They arise from a 1,3-migration of the amino
group, the mechanism of which being undetermined for the
moment (Scheme 7).
Scheme 7. 18h: ArˆPh, R, R0ˆdimethyl!25a (95%); 18g: ArˆPh, R,
R0ˆmorpholinyl!25b (95%); 18f: ArˆPh, R, R0ˆpiperidinyl!25c
(90%) (not pure enough to be totally characterized but characteristic signals
of pyrrole skeleton are present on NMR spectra); 18a: ArˆPh, R, R0ˆ(S)-2-
methoxymethylpyrrolidinyl ! 25d (97%); 18c: Arˆp-CH3Ph, R, R0ˆ(S)-
2-methoxymethylpyrrolidinyl!25e (97%).

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V. Breuil-Desvergnes, J. Gore / Tetrahedron 57 (2001) 1939±1950
1945
Again, this reaction does not work when Ar is replaced by
an aliphatic group. In this case, the corresponding 3-aza-
cyclopentanone is obtained in low yield.
2.2.3. 1-N-Piperidinyl-amino-1-phenyl-2-methoxy-buta-
2,3-diene (9a). Rfˆ0.63 (EP/AcOEt 90:10). IR (®lm):
1
nˆ3300, 3060±3020, 2960±2880, 1960, 1610, 1455. H
NMR (CDCl3, 300 MHz): dˆ1.28±1.36 (m, 2H), 1.51±
1.58 (m, 4H), 2.57±2.69 (m, 5H), 3.35 (s, 3H), 4.57 (m,
1H), 5.48 (m, 2H), 7.25±7.41 (m, 5H). 13C NMR
(50 MHz): dˆ23.9 (CH2), 26.0 (CH2), 56.2 (CH3), 57.8
(CH2), 63.8 (CH), 91.9 (CH2), 127.2 (CH), 127.9 (CH),
128.3 (CH), 134.6 (C), 141.1 (C), 199 (C). EI MS m/z
(%): 258 (10), 159 (12), 145 (5), 129 (9), 115 (12), 91
(12), 70 (15), 55 (32), 42 (100). HRMS CI: theoretical:
259.18103; measured: 259.18132.
2. Experimental
2.1. General remarks
All procedures were conducted in oven-dried glassware
under positive nitrogen pressure and using syringe±needle
transfer techniques. THF was distilled from sodium±benzo-
1
phenone and diethyl ether from CaH2. H NMR (200 or
300 MHz) and 13C NMR (50 or 75 MHz) spectra were
recorded on a Bruker AC 200 or AM 300. Chemical shifts
are reported as d value relative to the solvent peak of CHCl3
set to 7.26 for 1H and 77.16 for 13C. IR spectra were carried
out on a Perkin±Elmer 298 spectrophotometer. Melting
points were determined in open capillaries and are uncor-
rected. Optical rotation values were determined using a
Perkin±Elmer 241 polarimeter. Flash chromatography
(FC) was performed using alumina N/UV 254. Mass spec-
trometry was performed on a NERMAG R 10-10 H coupled
with a GC DELSI DI 700 (EIˆ70 eV, column type DB5
30 m, CI gas:ammonia). HRMS spectra were carried out
on a Thermoquest Finnigan (MAT 95 XL) spectrometer
(CI gas:isobutane).
2.2.4. 1-N-Morpholinyl-amino-1-phenyl-2-methoxy-buta-
2,3-diene (10a). Rfˆ0.5 (EP/AcOEt 90:10). IR (®lm):
1
nˆ3300, 2970±2820, 1950, 1610, 1450. H NMR (CDCl3,
300 MHz): dˆ2.63±2.75 (m, 5H), 3.39 (s, 3H), 3.66 (t, 4H),
4.58 (m, 1H), 5.45 (m, 2H), 7.24±7.40 (m, 5H). 13C NMR
(50 MHz): dˆ49.9 (CH2), 56.3 (CH3), 63.3 (CH), 67.0
(CH2), 92.0 (CH2), 127.27 (CH), 127.6 (CH), 128.1 (CH),
157.2 (C), 198.8 (C). EI MS m/z (%): 245 (22), 174 (47),
159 (10), 144 (13), 115 (15), 101 (100), 77 (9), 57 (23),
29 (13). HRMS EI: theoretical: 260.15247; measured:
260.15167.
2.2.5. (1S,2S0)-1-N-[(20-Methoxymethyl)pyrrolidin-10-yl]-
amino-1-phenyl-2-methoxy-buta-2,3-diene (11a). Rfˆ
20
0.38 (EP/AcOEt 97:3). [a]D ˆ226 (cˆ0.53, CHCl3). IR
1
(®lm): nˆ3300, 3080±2820, 1920, 1610, 1450. H NMR
2.2. Preparation of a-allenic hydrazines
(CDCl3, 300 MHz): dˆ1.53 (m,1H), 1.67 (m, 2H), 1.89
(m, 1H), 2.33 (m, 1H), 2.99 (s, 1H), 3.15 (m, 1H), 3.37 (s,
3H), 3.39 (s, 3H), 3.35±3.66 (m, 2H), 4.53 (m, 1H), 5.52 (m,
2H), 7.27±7.42 (m, 5H). 13C NMR (50 MHz): dˆ21.2
(CH2), 36.4 (CH2), 56.2 (CH3), 57.3 (CH2), 59.1 (CH3),
65.5 (CH), 65.9 (CH), 75.7 (CH2), 91.8 (CH2), 127.4
(CH), 127.7 (CH), 128.4 (CH), 135.9 (C), 141.3 (C),
199.2 (C). EI MS m/z (%): 243 (7), 211 (17), 174 (19),
129 (100), 97 (45), 71 (27), 70 (15), 45 (36). HRMS EI:
theoretical: 288.18377; measured: 288.18294.
2.2.1. General procedure. a-Lithio methoxyallene was
synthesized in situ by addition of an equivalent of n-butyl-
lithium (2.5 MHz hexane solution) to a solution of 5 mmol
methoxyallene in ether (5 ml) at 2408C. The solution was
chilled to 2788C, then after 20 min, a solution of hydra-
zones 4±7 (0.833 mmol in 2 ml of ether) was added drop-
wise. The mixture was warmed to 2208C. After 16 h at this
temperature, the mixture was quenched with 5 ml of water
and extracted with ether (2£5 ml). The combined organic
phases were dried (Na2SO4) and concentrated. The crude
product obtained in quantitative yield was not puri®ed
2.2.6. 1-N-Dimethylaminyl-amino-1-b-naphthyl-2-meth-
oxy-buta-2,3-diene (8b). Rfˆ0.42 (EP/AcOEt 97:3). IR
(®lm): nˆ3300, 3060±3020, 2970±2800, 1960, 1660,
1
because of its instability on silica or alumina gel. Its H
and 13C NMR spectra indicate a purity $95% as well as
TLC on neutral alumina (petroleum ether EP/ethyl acetate
AcOEt) using phosphomolybdic acid as chemical tracer.
1
1460. H NMR (CDCl3, 300 MHz): dˆ1.82 (s, 1H), 2.52
(s, 6H), 3.40 (s, 3H), 4.74 (s, 1H), 5.54 (m, 2H), 7.44 (s, 3H),
7.79±7.89 (m, 4H). 13C NMR (CDCl3, 50 MHz): dˆ48.1
(CH3), 56.3 (CH3), 64 (CH), 92.3 (CH2), 125.6 (CH), 126.1
(CH), 126.8 (CH), 127.6 (CH), 127.7 (CH), 127.8 (CH),
128.0 (CH), 133.2 (C), 133.4 (C), 135.9 (C), 157.3 (C),
198.7 (C). EI MS m/z (%): 268 (60), 253 (40), 224 (56),
209 (87), 194 (53), 179 (71), 165 (100), 127 (30). HRMS:
theoretical: 268.15756; measured: 268.15734.
As shown in Table 2, 25 homologous a-allenyl hydrazines
have been prepared which differ by the nature of the sub-
stituents of the terminal nitrogen and by that of the starting
aldehydes. We describe below 13 of them which are repre-
sentative of the different substitutions. The spectra of the
others can be deduced from those described.
2.2.7. 1-N-Piperidinyl-amino-1-b-naphthyl-2-methoxy-
buta-2,3-diene (9b). Rfˆ0.70 (EP/AcOEt 90:10). IR
(®lm): nˆ3350, 3030±3010, 2980±2680, 1955, 1650,
1440. 1H NMR (CDCl3, 300 MHz): dˆ1.27±1.39 (m,
2H), 1.47±1.60 (m, 4H), 2.24 (s, 1H), 2.58±2.82 (m, 4H),
3.39 (s, 3H), 4.75 (m, 1H), 5.49 (m, 2H), 7.42 (m, 2H), 7.54
(s, 1H), 7.75±7.83 (m, 4H). 13C NMR (50 MHz): dˆ23.9
(CH2), 25.9 (CH2), 56.3 (CH3), 57.8 (CH2), 63.9 (CH), 92.0
(CH2), 125.5 (CH), 125.6 (CH), 126.0 (CH), 126.1 (CH),
126.7 (CH), 127.8 (CH), 128.1 (CH), 133.0 (C), 133.3 (C),
2.2.2. 1-N-Dimethylaminyl-amino-1-phenyl-2-methoxy-
buta-2,3-diene (8a). Rfˆ0.33 (EP/AcOEt 97:3). IR (®lm):
nˆ3300, 2920±2840, 1950, 1450. 1H NMR (CDCl3,
300 MHz): dˆ1.93 (s, 1H), 2.53 (s, 6H), 3.44 (s, 3H),
4.59 (s, 1H), 5.56 (m, 2H), 7.0±7.5 (m, 5H). 13C NMR
(CDCl3, 50 MHz): dˆ48.1 (CH3), 56.2 (CH3), 64.1 (CH),
92.0 (CH2), 136.0 (C), 136.0 (C), 140.6 (C), 128.3 (CH),
128.4 (CH), 128.6 (CH), 198.7 (C). EI MS m/z (%): 203 (6),
174 (12), 144 (8), 128 (5), 115 (7), 91 (5), 77 (6), 59 (100).
HRMS: theoretical: 218.14191; measured: 218.14193.

Â
V. Breuil-Desvergnes, J. Gore / Tetrahedron 57 (2001) 1939±1950
1946
136.1 (C), 138.7 (C), 198.9 (C). CI MS m/z (%): 309 (100),
239 (88), 209 (15), 99 (34), 81 (28), 71 (38). HRMS CI:
theoretical: 309.196688; measured: 309.19679.
75.7 (CH2), 91.6 (CH2), 127.9 (CH), 128.8 (CH), 136.1 (C),
136.8 (C), 138.4 (C), 199.2 (C). EI MS m/z (%): 302 (4),
287 (5), 257 (8), 233 (6), 225 (9), 211 (5), 188 (17), 173 (8),
129 (100), 115 (10), 97 (24), 85 (13), 70 (20), 55 (7), 45
(15). HRMS EI: theoretical: 302.19942; measured:
302.19788.
2.2.8. 1-N-Piperidinyl-amino-1-(p-methylphenyl)-2-meth-
oxy-buta-2,3-diene (9c). Rfˆ0.58 (EP/AcOEt 90:10). IR
1
(®lm): nˆ3300, 3030, 2980±2780, 1960, 1610, 1450. H
2.2.13. (1S,2S0)-1-N-[(20-Methoxymethyl)pyrrolidin-10-yl]-
amino-1-isopropyl-2-methoxy-buta-2,3-diene (11f). Rfˆ
0.34 (EP/AcOEt 95:5). IR (®lm): nˆ3300, 2980±2810,
1960, 1470. 1H NMR (CDCl3, 300 MHz): dˆ0.99 (d,
Jˆ7.3 Hz, 6H), 1.27 (m, 1H), 1.64 (m, 3H), 2.52; 3.24 (m,
2H), 2.91 (m, 1H), 3.06 (m, 1H), 3.31 (s, 3H), 3.31±3.49 (m,
2H), 3.55 (s, 3H), 3.64 (m, 1H), 5.44 (m, 2H). 13C NMR
(50 MHz): dˆ19.5 (CH3), 19.7 (CH3), 21.3 (CH2), 26.6
(CH2), 30.2 (CH), 55.7 (CH3), 56.5 (CH2), 58.9 (CH),
65.2 (CH3), 67.5 (CH), 75.5 (CH2), 90.1 (CH2), 135.0 (C),
200.0 (C). EI MS m/z (%): HRMS EI: theoretical:
254.19942; measured: 254.19936.
NMR (CDCl3, 300 MHz): dˆ0.83 (m, 2H), 1.45 (m, 4H),
1.76 (s, 3H), 3.10 (m, 4H), 3.36 (s, 3H), 4.75 (m, 1H), 5.44
(m, 2H), 7.34 (m, 2H), 7.69 (m, 2H). 13C NMR (50 MHz):
dˆ21.2 (CH2), 24.2 (CH2), 25.9 (CH2), 52.0 (CH2), 56.8
(CH3), 67.9 (CH), 92.8 (CH2), 128.4 (CH), 130.2 (CH),
136.4 (C), 137.3 (C), 157.5 (C), 199.0 (C). EI MS; m/z
(%): 272 (4), 257 (17), 202 (25), 188 (68), 105 (20), 99
(100), 84 (34), 55 (48), 42 (33). HRMS EI: theoretical:
272.18886; measured: 272.18719.
2.2.9. 1-N-Piperidinyl-amino-1-ethyl-2-methoxy-buta-
2,3-diene (9e). Rfˆ0.65 (EP/AcOEt 90:10). IR (®lm):
nˆ3310, 2980±2790, 1960, 1450. 1H NMR (CDCl3,
300 MHz): dˆ0.85 (m, 5H), 125 (m, 4H), 1.56 (t, Jˆ
4.5 Hz, 4H), 2.58 (m, 2H), 3.22 (t, Jˆ5.8 Hz, 1H), 4.58 (s,
3H), 5.44 (m, 2H). 13C NMR (50 MHz): dˆ10.6 (CH3), 24.0
(CH2), 26.1 (CH2), 32.5 (CH2), 56.0 (CH3), 57.9 (CH2), 61.6
(CH), 90.7 (CH2), 135.1 (C), 198.9 (C). EI MS m/z (%): 195
(32), 181 (11), 99 (100), 84 (20), 69 (13), 55 (88), 41 (49).
HRMS CI: theoretical: 211.18104; measured: 211.18107.
2.2.14. (1S,2S0)-1-N-[(20-Methoxymethyl)pyrrolidin-10-yl]-
amino-1-tert-butyl-2-methoxy-buta-2,3-diene (11g). Rfˆ
0.56 (EP/AcOEt 97:3). IR (®lm): nˆ3400, 2970±2820,
1
1950, 1450. H NMR (CDCl3, 300 MHz): dˆ0.92 (s, 6H),
1.05 (s, 3H), 1.29 (m, 3H), 1.67 (m, 1H), 1.88; 2.42 (m, 2H),
2.96 (s, 1H), 3.33(s, 3H), 3.39 (s, 3H), 3.29±3.55 (m, 2H),
5.43 (m, 2H). 13C NMR (50 MHz): dˆ21.4 (CH2), 26.6
(CH2), 27.3 (2CH3), 28.3 (CH3), 50.0 (CH2), 55.8 (CH3),
59.0 (CH3), 64.7 (CH), 69.2 (CH), 75.5 (CH2), 92.1
(CH2), 147.3 (C), 200.5 (C). EI MS m/z (%): 223 (9), 211
(90), 179 (12), 135 (10), 98 (35), 70 (50), 55 (80), 41 (100).
2.2.10. 1-N-Morpholinyl-amino-1-(p-methoxyphenyl)-2-
methoxy-buta-2,3-diene (10d). Rfˆ0.57 (EP/AcOEt
80:20). IR (®lm): nˆ3300, 3020, 2970±2770, 1960, 1610,
1
1460. H NMR (CDCl3, 300 MHz): dˆ1.61 (s, 1H), 2.70
(m, 4H), 3.39 (s, 3H), 3.67 (t, Jˆ4.8 Hz, 4H), 3.79 (s, 3H),
4.53 (m, 1H), 5.51 (m, 2H), 6.83±6.85 (m, 2H), 7.30±7.33
(m, 2H). 13C NMR (50 MHz): dˆ55.2 (CH3), 56.3 (CH3),
57.0 (CH2), 63.0 (CH), 67.0 (CH2), 91.9 (CH2), 113.5 (CH),
129.0 (CH), 132.8 (C), 135.9 (C), 158.9 (C), 198.9 (C). EI
MS; m/z (%): 275 (8), 204 (23), 189 (100), 174 (40), 158
(18), 115 (25), 101 (43), 77 (13), 57 (19), 29 (15).
C16H22N2O3 (290.3): calcd C 66.18, H 7.63, N 9.64; found
C 65.59, H 7.62, N 9.30.
2.3. Preparation of N-dialkyl-amino-3-pyrrolines 18
2.3.1. General procedure. 0.83 mmol of compound 8±11
were put in solution with 5 ml of THF, the mixture was
chilled to 2788C, and 2 equiv. of n-BuLi (2.5 M hexane
solution) were added dropwise. Then, the mixture was
warmed to 2208C. After 16 h at this temperature, the
mixture was quenched with 5 ml of water and extracted
with ether (2£5 ml). The combined organic phases were
dried (Na2SO4) and concentrated. The crude product was
puri®ed by FC on neutral alumina (Merck 90 type II±III:
0.063±0.20 mm) using a petroleum ether EP/ethyl acetate
mixture as a solvent to give 18 as an oil. The purity of 18
was veri®ed by TLC on neutral alumina using phosphomo-
lybdic acid as chemical tracer.
2.2.11. 1-N-Morpholinyl-amino-1-isopropyl-2-methoxy-
buta-2,3-diene (10f). Rfˆ0.68 (EP/AcOEt 90:10). IR
(®lm): nˆ3300, 2980±2840, 1905, 1450. 1H NMR
(CDCl3, 300 MHz): dˆ0.84 (d, Jˆ6.6 Hz,, 3H), 0.91 (d,
3H), 1.72 (m, 1H), 2.58 (m, 4H), 3.06 (d, Jˆ7.35 Hz, 1H),
3.35 (s, 3H), 3.64 (t, 4H), 5.39 (m, 2H). 13C NMR (50 MHz):
dˆ19.5 (CH3), 19.6 (CH3), 30.5 (CH), 55.9 (CH3), 57.1
(CH2), 66.6 (CH), 67.1 (CH2), 90.4 (CH2), 134.8 (C),
199.2 (C). EI MS m/z (%): 226 (8), 211 (100), 183 (26),
139 (6), 112 (21), 101 (34), 86 (4). HRMS EI: theoretical:
226.16812; measured: 226.16810.
2.3.2. N-(2)-(S)-2-Methoxymethylpyrrolidinyl-(S)-2-
phenyl-3-methoxy-2,5-dihydropyrrole (18a). Yield:
20
97%. Rfˆ0.22 (95:5 EP/AcOEt). [a]D ˆ1113 (cˆ1.55,
CHCl3). IR (®lm): nˆ3080±3020, 2980±2820, 1660,
1450. 1H NMR (CDCl3, 300 MHz): dˆ1.27 (m, 1H),
1.67±1.73 (m, 3H), 2.62 (m, 1H), 2.92 (m, 2H), 3.18 (s,
3H), 3.32 (m, 2H), 3.53 (s, 3H), 3.77±3.93 (m, 2H), 4.61
(m, 1H), 4.98 (m, 1H), 7.26±7.31 (m, 5H). 13C NMR
(50 MHz): dˆ21.0 (CH2), 26.08 (CH2), 43.8 (CH2), 55.2
(CH3), 59.0 (CH3), 64.2 (CH), 64.3 (CH), 74.3 (CH2),
90.2 (CH), 127.3 (CH), 128.1 (CH), 128.2 (CH), 142.9
(C), 157.3 (C). EI MS m/z (%): 288 (48), 243 (88), 174
(11), 159 (62), 129 (31), 115 (28), 91 (31), 71 (100), 45
(72), 27 (20). C17H24N2O2 (288.4): calcd C 70.8, H 8.38,
N 9.71; found C 70.62, H 8.41, N 9.56.
2.2.12. (1S,2S0)-1-N-[(20-Methoxymethyl)pyrrolidin-10-yl]-
amino-1-(p-methylphenyl)-2-methoxy-buta-2,3-diene
(11c). Rfˆ0.42 (EP/AcOEt 95:5). IR (®lm): nˆ3300, 3030±
2810, 1960, 1610, 1460. 1H NMR (CDCl3, 300 MHz):
dˆ1.26±1.86 (m, 2H), 1.64 (m, 2H), 2.23; 3.18 (m, 2H),
2.93 (m, 1H), 3.32 (s, 3H), 3.38 (s, 3H), 3.45±3.64 (m, 2H),
4.48 (s, 1H), 5.52 (m, 2H), 7.07 (m, 2H), 7.28 (m, 2H). 13C
NMR (50 MHz): dˆ21.12 (CH3), 21.22 (CH2), 26.4 (CH2),
56.2 (CH3), 57.3 (CH2), 59.0 (CH3), 65.3 (CH), 65.9 (CH),

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V. Breuil-Desvergnes, J. Gore / Tetrahedron 57 (2001) 1939±1950
1947
2.3.3. N-(2)-(S)-2-Methoxymethylpyrrolidinyl-(S)-2-b-
naphthyl-3-methoxy-2,5-dihydropyrrole (18b). Yield:
95%. Rfˆ0.26 (97:3 EP/AcOEt). [a]D ˆ164.3 (cˆ1.15,
(60), 82 (18), 70 (41), 55 (24), 45 (53), 41 (54). HRMS EI:
theoretical: 254.199428; measured: 254.20021.
20
CHCl3). IR (®lm): nˆ3030, 2990±2920, 1660, 1640,
1450. 1H NMR (CDCl3, 300 MHz): dˆ1.24 (m, 1H),
1.54±1.58 (m, 1H), 1.61±1.71 (m, 2H), 2.64 (m, 1H),
2.92±3.03 (m, 2H), 3.16 (s, 3H), 3.32 (m, 2H), 3.52 (s,
3H), 3.82±4.02 (m, 2H), 4.66 (m, 1H), 5.20 (m, 1H),
7.42±7.47 (m, 3H), 7.81±7.86 (m, 4H). 13C NMR
(50 MHz): dˆ20.9 (CH2), 25.8 (CH2), 43.8 (CH2), 55.4
(CH2), 56.4 (CH3), 58.8 (CH3), 59.6 (CH), 64.2 (CH),
74.1 (CH2), 90.2 (CH), 125.4 (CH), 125.7 (CH), 126.1
(CH), 126.8 (CH), 126.9 (CH), 127.6 (CH), 128.0 (CH),
133.1 (C), 133.2 (C), 140.4 (C), 157.1 (C). EI MS m/z
(%): 338 (75), 293 (100), 209 (35), 179 (38), 152 (16),
127 (13), 71 (65). C21H26N2O2 (338.4): calcd C 74.52, H
7.74, N 8.27; found C 74.75, H 7.95, N 7.97.
2.3.7.
N-Piperidino-2-phenyl-3-methoxy-2,5-dihydro-
pyrrole (18g). Yield: 17%. Rfˆ0.29 (90:10 EP/AcOEt).
IR (®lm): nˆ3020, 2970±2790, 1650, 1450. 1H NMR
(CDCl3, 300 MHz): dˆ1.53 (m, 2H), 2.59 (m, 4H), 2.81
(t, Jˆ5.5 Hz, 4H), 3.51 (s, 3H), 3.77±3.94 (m, 2H), 4.57
(m, 1H), 4.98 (m, 1H), 7.27±7.34 (m, 4H), 7.44 (m, 1H). 13C
NMR (50 MHz): dˆ24.4 (CH2), 26.4 (CH2), 51.3 (CH2),
56.2 (CH2), 56.6 (CH3), 58.4 (CH), 89.9 (CH), 127.0
(CH), 128.0 (CH), 128.1 (CH), 143.2 (C), 157.4 (C). EI
MS m/z (%): 258 (100), 243 (14), 189 (5), 174 (56), 159
(31), 144 (9), 129 (23), 115 (18), 98 (15), 91 (22), 84 (12),
70 (21), 55 (34). HRMS EI: theoretical: 258.173213;
measured: 258.173207.
2.3.8. N-Morpholino-2-phenyl-3-methoxy-2,5-dihydro-
pyrrole (18h). Yield: 86%. Rfˆ0.22 (97:3 EP/AcOEt).
IR (®lm): nˆ3020, 2980±2820, 1660, 1450. 1H NMR
(CDCl3, 300 MHz): dˆ2.64±2.77 (m, 4H), 3.53 (s, 3H),
3.63±3.70 (m, 4H), 4.59 (m, 1H), 4.93 (m, 1H), 7.25±7.32
(m, 5H). 13C NMR (50 MHz): dˆ49.9 (CH2), 56.6 (CH3),
57.0 (CH2), 65.2 (CH), 67.3 (CH2), 89.8 (CH), 127.9 (CH),
128.0 (CH), 128.1 (CH), 135.7 (C), 142.4 (C). EI MS; m/z
(%): 260 (10), 159 (30), 129 (18), 115 (16), 91 (13), 77 (10),
45 (30), 43 (100). C15H20N2O2 (260.3): calcd C 69.2, H 7.74,
N 10.76; found C 68.8, H 7.65, N 10.74.
2.3.4. N-(2)-(S)-2-Methoxymethylpyrrolidinyl-(S)-2-(p-
methylphenyl)-3-methoxy-2,5-dihydropyrrole
(18c).
20
Yield: 96%. Rfˆ0.25 (97:3 EP/AcOEt). [a]D ˆ1137.5
(cˆ0.52, CHCl3). IR (®lm): nˆ3050, 2980±2820, 1660,
1
1510, 1450. H NMR (CDCl3, 300 MHz): dˆ1.27±1.70
(m, 2H), 1.66 (m, 2H), 2.64 (m, 1H), 2.35 (s, 3H), 2.67
(m, 1H), 2.92 (m, 2H), 3.23 (s, 3H), 3.36 (m, 2H), 3.53 (s,
3H), 3.72±4.02 (m, 2H), 4.61 (m, 1H), 4.97 (m, 1H), 7.11±
7.15 (m, 2H), 7.31±7.35 (m, 2H). 13C NMR (50 MHz):
dˆ21.1 (CH2), 21.3 (CH3), 26.0 (CH2), 43.8 (CH2), 55.2
(CH2), 56.6 (CH3), 59.0 (CH3), 59.6 (CH), 64.0 (CH),
74.4 (CH2), 90.4 (CH), 128.1 (CH), 128.9 (CH), 136.9
(C), 139.8 (C), 157.5 (C). EI MS m/z (%): 302 (19), 257
(84), 173 (31), 159 (60), 143 (18), 91 (4), 71 (16).
C18H26N2O2 (302.4): calcd C 71.39, H 8.77, N 9.18; found
C 71.44, H 8.65, N 9.25.
2.3.9. N-Morpholino-2-naphthyl-3-methoxy-2,5-dihydro-
pyrrole (18i). Yield: 96%. Rfˆ0.25 (90:10 EP/AcOEt). IR
(®lm): nˆ3025, 2980±2810, 1660, 1450. 1H NMR (CDCl3,
300 MHz): dˆ2.66 (m, 4H), 3.54 (s, 3H), 3.61 (m, 4H), 3.88
(m, 2H), 4.64 (m, 1H), 5.13 (m, 1H), 7.45 (m, 2H), 7.63 (s,
1H), 7.83 (m, 4H). 13C NMR (50 MHz): dˆ50.09 (CH2),
50.6 (CH2), 56.7 (CH3), 65.3 (CH), 67.3 (CH2), 90.0 (CH),
125.5 (CH), 125.8 (CH), 126.3 (CH), 127.3 (CH), 127.7
(CH), 127.8 (CH), 128.0 (CH), 133.2 (C), 133.4 (C),
140.1 (C), 157.2 (C). EI MS m/z (%): 310 (100), 295 (7),
241 (6), 240 (15), 224 (6), 211 (13), 210 (99), 180 (13), 179
(50), 165 (18), 152 (12), 127 (12), 107 (11), 86 (15), 84 (24),
56 (8), 43 (14). HRMS EI: theoretical: 310.16813;
measured: 310.16827.
2.3.5. N-(2)-(S)-2-Methoxymethylpyrrolidinyl-(S)-2-
(ethyl)-3-methoxy-2,5-dihydropyrrole (18e). Yield: 94%.
20
[a]D ˆ227 (cˆ0.45, CHCl3). IR (®lm): nˆ3020, 2980±
2840, 1660, 1450. 1H NMR (CDCl3, 300 MHz): dˆ0.86 (t,
Jˆ7.7 Hz, 3H), 1.33±1.40, 1.62±1.81 (m, 2H), 1.51±1.60
(m, 2H), 2.65±2.73, 2.88±2.95 (m, 2H), 3.08 (m, 1H), 3.26±
3.29 (m, 2H), 3.33 (s, 3H), 3.54, 3.69±3.86 (m, 2H), 3.61 (s,
3H), 3.84 (m, 1H), 4.49 (m, 1H). 13C NMR (50 MHz):
dˆ8.8 (CH3), 21.4 (CH2), 27.0 (CH2), 29.7 (CH2), 46.2
(CH2), 53.4 (CH2), 56.4 (CH3), 59.2 (CH3), 59.8 (CH),
62.8 (CH), 75.6 (CH2), 90.0 (CH), 158.0 (C). EI MS m/z
(%): 240 (61), 211 (28), 195 (82), 126 (10), 111 (16), 97
(42), 71 (100), 45 (94). C13H24N2O2 (240.3): calcd C 64.9, H
10.0, N 11.6; found C 64.6, H 9.84, N 11.43.
2.3.10. N-Dimethylamino-2-phenyl-3-methoxy-2,5-dihydro-
pyrrole (18j). Yield: 17%. Rfˆ0.27 (96:4 EP/AcOEt). IR
1
(®lm): nˆ3040±3010, 2990±2780, 1660, 1450. H NMR
(CDCl3, 300 MHz): dˆ2.39 (s, 6H), 3.52 (s, 3H), 3.77 (m,
2H), 4.54 (m, 1H), 4.81 (m, 1H), 7.23 (m, 1H), 7.31 (M,
2H), 7.43 (m, 2H). 13C NMR (50 MHz): dˆ40.8 (CH3), 48.1
(CH2), 56.6 (CH3), 65.9 (CH), 89.5 (CH), 127.2 (CH), 128.0
(CH), 128.1 (CH), 142.5 (CH), 157.4 (C). EI MS; m/z (%):
218 (100), 203 (6), 160 (34), 145 (8), 129 (19), 115 (9), 91
(10), 77 (6), 58 (14), 43 (44). HRMS EI: theoretical:
218.141913; measured: 218.141907.
2.3.6. N-(2)-(S)-2-Methoxymethylpyrrolidinyl-(S)-2-(iso-
propyl)-3-methoxy-2,5-dihydropyrrole (18f). Yield:
20
93%. Rfˆ0.60 (95:5 EP/AcOEt). [a]D ˆ241.6 (cˆ0.48,
1
CHCl3). IR (®lm): nˆ3040, 2980±2810, 1655, 1460. H
NMR (CDCl3, 300 MHz): dˆ0.89 (t, Jˆ7.3 Hz, 6H),
1.61±1.78 (m, 2H), 1.66 (m, 2H), 1.83 (m, 1H), 2.63±2.91
(m, 2H), 3.03 (m, 1H), 3.24±3.52 (m, 2H), 3.33 (s, 3H),
3.48±3.58, 3.68±3.78 (m, 1H), 3.65 (m, 1H), 4.51 (m,
1H). 13C NMR (50 MHz): dˆ18.0 (CH3), 18.1 (CH3),
21.3 (CH2), 27.2 (CH2), 31.3 (CH), 46.8 (CH2), 53.8
(CH), 56.4 (CH3), 58.5 (CH), 59.1 (CH3), 68.3 (CH), 75.7
(CH2), 91.0 (CH), 158.2 (C). EI MS m/z (%): 254 (18), 211
(100), 209 (18), 179 (22), 138 (18), 129 (19), 114 (40), 98
2.3.11. N-Piperidino-2-phenyl-3-methoxy-4-methyl-aza-
cyclobut-3-ene (19a). That compound was always
obtained with 18g in a mixture. It was identi®ed and
characterized by use of 2D NMR: COSY, HSQC and
1
HMBC. Yield: 3%. Rfˆ0.31 (90:10 EP/AcOEt). H NMR
(CDCl3, 300 MHz): dˆ1.30 (m, 2H), 1.73 (m, 4H), 2.16 (s,
1H), 2.66 (m, 4H), 3.70 (s, 3H), 6.20 (s, 1H), 7.27±7.34 (m,

Â
V. Breuil-Desvergnes, J. Gore / Tetrahedron 57 (2001) 1939±1950
1948
4H), 7.70 (d, Jˆ7 Hz, 1H). 13C NMR (50 MHz): dˆ15.0
(CH3), 24.0 (CH2), 25.6 (CH2), 50.8 (CH2), 64.8 (CH3),
116.7 (CH), 127.3 (CH), 128.8 (CH), 129.4 (CH), 135.2
(C), 154.9 (C), 159.4 (C). EI MS m/z (%): 258 (4), 243
(3), 174 (100), 118 (10), 91 (18), 42 (22). HRMS EI: theo-
retical: 258.173213; measured: 258.173207.
2H), 3.91 (m, 1H), 4.15 (m, 1H), 7.08±7.53 (m, 7H). 13C
NMR (75 MHz): dˆ44.0 (CH2), 57.6 (CH3), 66.9 (CH),
82.5 (CH), 125.4 ((CH), 126.4 (CH), 126.7 (CH), 127.4
(CH), 128.0 (CH), 128.4 (CH), 129.5 (CH), 133.2 (C),
133.6 (C), 137.2 (C), 152.3 (C).
2.4.3. H-2-(S)-p-Methoxyphenyl-3-methoxy-2.5-dihydro-
pyrrole ((1)-20c). Yield: 68%. Rfˆ0.31 (80:20 CH2Cl2/
2.3.12. N-Morpholino-2-(p-methoxyphenyl)-3-methoxy-
4-methyl-azacyclobut-3-ene (19b). Same remark as for
19a. Yield: 11%. Rfˆ0.24 (97:3 EP/AcOEt). IR (®lm):
20
MeOH). [a]D ˆ12.4 (cˆ0.85, CHCl3). IR (®lm):
1
nˆ3400, 3030, 2970±2800, 1600, 1450. H NMR (CDCl3,
1
nˆ3020, 2960±2810, 1610, 1510, 1440. H NMR (CDCl3,
300 MHz): dˆ2.68 (s, 1H), 3.10 (s, 3H), 3.15±3.51 (m, 2H),
3.77 (s, 3H), 3.90 (m, 1H), 4.36 (m, 1H), 6.84 (m, 2H), 7.46
(m, 2H). 13C NMR (50 MHz): dˆ55.2 (CH3), 57.5 (CH3),
60.4 (CH2), 66.0 (CH), 81.3 (CH), 113.9 (CH), 123.0 (C),
130.7 (CH), 160.0 (C), 171.1 (C).
300 MHz): dˆ2.18 (s, 3H), 2.88 (t, Jˆ4.4 Hz, 4H), 3.69 (s,
3H), 3.85 (t, Jˆ4.4 Hz, 4H), 6.24 (s, 1H), 7.30 (m, 3H), 7.68
(m, 2H). 13C NMR (50 MHz): dˆ15 (CH3), 55.2 (CH2),
58.5 (CH3), 66.4 (CH2), 117.4 (CH), 127.5 (CH), 128.4
(CH), 134.9 (C), 154.5 (C), 160.6 (C). EI MS m/z (%):
260 (12), 145 (6), 201 (4), 188 (5), 176 (100), 118 (25),
90 (23), 77 (3), 56 (17), 28 (13). HRMS CI: theoretical:
261.160303; measured: 261.161252.
2.4.4. H-2-(S)-Phenyl-3-methoxy-pyrrolidine ((1)-21a).
20
Yield: 82%. Rfˆ0.21 (90:10 CH2Cl2/MeOH). [a]D ˆ11.86
(cˆ0.8, CHCl3). IR (®lm): nˆ3300, 3020, 2970±2830,
1
1450. H NMR (CDCl3, 300 MHz): dˆ2.04 (m, 2H), 2.84
2.3.13. N-Dimethylamino-2-phenyl-3-methoxy-4-methyl-
azacyclobut-3-ene (19c). Same remark as for 19a. Yield:
3%. Rfˆ0.35 (94:6 EP/AcOEt). IR (®lm): nˆ3030, 2990±
2780, 1620, 1450. 1H NMR (CDCl3, 300 MHz): dˆ2.15 (s,
3H), 2.61 (s, 6H), 3.68 (s, 3H), 6.18 (s, 1H), 7.24 (m, 1H),
7.31 (m, 2H), 7.70 (m, 2H). 13C NMR (50 MHz): dˆ14.9
(CH3), 47.3 (CH3), 58.4 (CH3), 116.6 (CH), 127.3 (CH),
128.3 (CH), 129.3 (CH), 135.1 (C), 154.7 (C), 159.0 (C).
EI MS; m/z (%): 218 (9), 203 (18), 134 (100), 118 (14), 90
(22), 44 (15), 42 (19). HRMS EI: theoretical: 218.141913;
measured: 218.14151.
(s, 1H), 3.02 (s, 3H), 3.03±3.30 (m, 2H), 3.92 (m, 1H), 4.05
(m, 1H), 7.26 (m, 1H), 7.33 (m, 2H), 7.40 (m, 2H). 13C NMR
(50 MHz): dˆ32.1 (CH2), 44.7 (CH2), 57.5 (CH3), 67.5
(CH), 83.4 (CH), 127.5 (CH), 128.3 (CH), 128.4 (CH),
138.6 (C). EI MS m/z (%): 177 (4), 162 (4), 118 (100),
104 (6), 91 (25), 77 (12), 57 (7), 41 (11), 28 (13).
2.4.5. H-2-(S)-b-Naphthyl-3-methoxy-pyrrolidine ((1)-
21b). Yield: 63%. Rfˆ0.18 (90:10 CH2Cl2/MeOH).
20
[a]D ˆ21.6 (cˆ0.15, CHCl3). IR (®lm): nˆ3300, 3050±
3020, 2970±2830, 1450. 1H NMR (CDCl3, 300 MHz):
dˆ2.08 (m, 2H), 2.74 (s, 1H), 3.01 (s, 3H), 3.39±3.85 (m,
2H), 4.02 (m, 1H), 4.22 (m, 1H), 7.45 (m, 3H), 7.81 (m, 2H).
13C NMR (50 MHz): dˆ32.2 (CH2), 44.8 (CH2), 57.5
(CH3), 67.6 (CH), 83.5 (CH), 125.9 (CH), 126.2 (CH),
126.7 (CH), 126.8 (CH), 127.8 (CH), 127.9 (CH), 128.3
(CH), 133.0 (C), 133.6 (C), 136.3 (C). EI MS m/z (%):
227 (9), 212 (4), 183 (4), 169 (59), 168 (100), 155 (8),
141 (19), 123 (16), 115 (5), 99 (41), 83 (6), 69 (5), 57
(13), 41 (7). HRMS EI: theoretical: 227.13101; measured:
227.13100.
2.4. Formation of 1H-3-pyrrolines 20 and pyrrolidines 21
The ammonium derivative salt of 18 was formed in situ by
addition of 1.2 equiv. of chloroformate to a solution of
N-dialkylamino-3-pyrrolines in 500 ml of THF. After
30 min, the mixture was placed into an autoclave with
5 ml of MeOH and 10% of Raney Ni under a 50 bar pressure
of hydrogen. The mixture was then warmed at 508C during
12 h by 0.1 mmol of starting product. After cooling, the
mixture was ®ltered on celite and puri®ed by FC on silica
gel (Kieselgel Si 60, 40±63 mm): 100% CH2Cl2 then 90%
CH2Cl2/10% MeOH; the purity was then controlled by TLC
using iodine as chemical tracer. Compounds 20 are unstable
compounds which degrade rapidly at room temperature and
under SM spectra conditions.
2.5. Preparation of 3-methoxypyrroles (23)
2.5.1. General procedure. 1.5 equiv. of meta-perbenzoic
acid chloride (m-CPBA) was added dropwise to a solution
of 18 in 5 ml of methylene chloride (CH2Cl2). The mixture
was stirred under room atmosphere during 4 h, controlling
the reaction advance by TLC. Then, 200 mg of Na2CO3
were added and the mixture was stirred during 15 min.
10 ml of water were added and the mixture was extracted
with CH2Cl2 (2£5 ml) and then washed with brine
(3£10 ml). The combined organic phases were dried
(Na2SO4) and concentrated. The crude product was puri®ed
by FC on alumina gel (Merck 90 type II±III: 0.063±
0.20 mm), using a petroleum/AcOEt mixture as solvent, to
give pure 23 as a coloured oil. The purity was controlled by
TLC on alumina using phosphomolybdic acid as chemical
tracer.
2.4.1.
H-2-(S)-Phenyl-3-methoxy-2.5-dihydropyrrole
((1) 20a). Yield: 75%. Rfˆ0.26 (80:20 CH2Cl2/MeOH).
20
[a]D ˆ11.8 (cˆ0.7, CHCl3). IR (®lm): nˆ3400, 3020,
2970±2830, 1610, 1450. 1H NMR (CDCl3, 300 MHz):
dˆ2.82 (s, 1H), 3.19±3.58 (m, 2H), 3.34 (s, 3H), 3.99 (s,
1H), 4.48 (m, 1H), 7.34 (m, 3H), 7.56 (m, 2H). 13C NMR
(50 MHz): dˆ47.7 (CH2), 57.5 (CH3), 66.7 (CH), 81.2
(CH), 128.2 (CH), 128.9 (CH), 129.6 (CH), 130.9 (C),
152.4 (C).
2.4.2. H-2-(S)-b-Naphthyl-3-methoxy-2.5-dihydropyrrole
((1) 20b). Yield: 79%. Rfˆ0.22 (90:10 CH2Cl2/MeOH).
20
[a]D ˆ11.95 (cˆ0.25, CHCl3). IR (®lm): nˆ3400,
2.5.2. 1H-2-Phenyl-3-methoxy pyrrole (23a). Yield: 69%.
Rfˆ0.21 (85:15 EP/AcOAEt). lmaxˆ577 nm (e 541),
612 nm (e 527). IR (®lm): nˆ3450, 3030, 2980, 1540,
1
3050±3020, 2960±2750, 1610, 1450. H NMR (CDCl3,
300 MHz): dˆ2.74 (s, 1H), 3.12 (s, 3H), 3.27±3.43 (m,

Â
V. Breuil-Desvergnes, J. Gore / Tetrahedron 57 (2001) 1939±1950
1949
1450. 1H NMR (CDCl3, 300 MHz): dˆ2.9 (m, 1H), 3.86 (s,
3H), 6.09 (t, Jˆ2.9 Hz, 1H), 6.64 (t, Jˆ2.9 Hz, 1H), 7.14
(m, 1H), 7.36 (m, 2H), 7.62 (m, 2H). 13C NMR (50 MHz):
dˆ58.4 (CH3), 97.9 (CH), 114.8 (C), 115.8 (CH), 123.6
(CH), 124.9 (CH), 128.7 (CH), 132.2 (C), 145.9 (C). EI
MS m/z (%): 173 (100), 159 (10), 158 (88), 130 (45), 104
(10), 77 (13), 43 (7). HRMS EI: theoretical: 173.0840;
measured: 173.0849.
(CDCl3, 300 MHz): dˆ2.45 (s, 6H), 2.78 (s, 1H), 5.86 (t,
Jˆ2.9 Hz, 1H), 6.52 (t, Jˆ2.9 Hz, 1H), 7.33 (m, 5H). 13C
NMR (50 MHz): dˆ37.8 (CH3), 101.3 (CH), 114.6 (C),
115.9 (CH), 123.6 (CH), 124.5 (CH), 128.7 (CH), 132.8
(C), 141.7 (C). EI MS m/z (%): 186 (8), 159 (100), 130
(37), 118 (9), 104 (24), 77 (14), 43 (7). HRMS EI: theor-
etical: 186.115698; measured: 186.116553.
2.6.3. 1H-3-Morpholino-2-phenyl-pyrrole (25b). Yield:
95%. Rfˆ0.26 (90:10 EP/AcOAEt). IR (®lm): nˆ3400,
2.5.3. 1H-2-b-Naphthyl-3-methoxy pyrrole (23b). Yield:
64%. Rfˆ0.40 (90:10 EP/AcOAEt). lmaxˆ638 nm (e 1308),
595 nm (e 1208). IR (®lm): nˆ3550, 3030, 2990, 1560,
1
3040±3010, 2970±2820, 1650, 1610. H NMR (CDCl3,
300 MHz): dˆ3.15 (m, 4H), 3.66 (m, 4H), 5.90 (t, Jˆ
2.9 Hz, 1H), 6.57 (t, Jˆ2.9 Hz, 1H), 7.56±7.64 (m, 5H).
13C NMR (50 MHz): dˆ15.3 (CH2), 65.9 (CH2), 101.2
(CH), 115.8 (CH), 127.3 (C), 128.7 (CH), 128.8 (CH),
132.3 (C), 140.7 (C), 153.2 (C). EI MS m/z (%): 228 (5),
176 (58), 145 (20), 133 (26), 131 (30), 129 (20), 105 (65), 89
(27), 77 (39), 63 (13), 51 (22), 43 (100). HRMS EI: theor-
etical: 228.12626; measured: 228.12591.
1
1420. H NMR (CDCl3, 300 MHz): dˆ2.85 (m, 1H), 3.91
(s, 3H), 6.12 (t, Jˆ2.9 Hz, 1H), 6 (t, Jˆ2.9 Hz, 1H), 7.41
(m, 2H), 7.82 (m, 4H), 7.95 (s, 1H). 13C NMR (50 MHz):
dˆ58.8 (CH3), 98.3 (CH), 115.1 (C), 116.6 (CH), 120.8
(CH), 123.0 (CH), 124.9 (CH), 126.1 (CH), 127.00 (CH),
127.6 (CH), 128.2 (CH), 130.1 (C), 131.3 (C), 135.7 (C),
146.2 (C). EI MS m/z (%): 223 (60), 208 (79), 180 (58), 153
(31), 127 (35), 87 (14), 57 (53), 43 (89), 29 (100). HRMS
CI: theoretical: 224.107539; measured: 224.107450.
2.6.4. 1H-3-((S)-2-Methoxymethylpyrrolidinyl)-2-phenyl-
pyrrole (25d). Yield: 97%. Rfˆ0.33 (95:5 EP/AcOAEt). IR
(®lm): nˆ3300, 3050±3010, 2980±2800, 1660, 1610, 1450.
1H NMR (CDCl3, 300 MHz): dˆ1.38±1.76 (m, 2H), 1.70
(m, 2H), 2.67±3.03 (m, 2H), 3.23±3.35 (m, 2H), 3.34 (s,
3H), 5.89 (s, 1H), 6.55 (s, 1H), 7.31±7.38 (m, 3H), 7.63±
7.66 (m, 2H). 13C NMR (50 MHz): dˆ25.0 (CH2), 27.6
(CH2), 46.0 (CH2), 57.7 (CH), 58.8 (CH3), 74.7 (CH2),
101.4 (CH), 114.6 (C), 115.8 (CH), 123.5 (CH), 124.4
(CH), 125.1 (CH), 132.7 (C), 141.6 (C).
2.5.4. 1H-2-(p-Methyl)-phenyl-3-methoxy pyrrole (23c).
Yield: 76%. Rfˆ0.27 (90:10 EP/AcOAEt). lmaxˆ553 nm (e
438). IR (®lm): nˆ3450, 3030, 2980, 1540, 1450. 1H NMR
(CDCl3, 300 MHz): dˆ2.17 (m, 1H), 2.34 (s, 3H), 3.84 (s,
3H), 6.09 (t, Jˆ2.9 Hz, 1H), 6.61 (t, Jˆ2.9 Hz, 1H), 7.10
(m, 2H), 7.48 (m, 2H). 13C NMR (50 MHz): dˆ21.5 (CH3),
58.8 (CH3), 98.3 (CH), 115.4 (C), 115.6 (CH), 124.0 (CH),
129.5 (C), 129.7 (CH), 134.9 (C), 145.7 (C). EI MS m/z (%):
187 (56), 172 (100), 144 (34), 131 (12), 118 (45), 104 (9), 91
(34), 89 (11), 69 (38), 51 (14), 43 (6). HRMS EI: theoretical:
187.0997; measured: 187.10014.
2.6.5. 1H-3-((S)-2-Methoxymethylpyrrolidinyl)-2-p-methyl-
phenyl-pyrrole (25e). Yield: 97%. Rfˆ0.22 (97:3 EP/
AcOAEt). IR (®lm): nˆ3300, 3050, 2980±2760, 1660,
1610, 1450. 1H NMR (CDCl3, 300 MHz): dˆ1.42 (m,
1H),1.67±1.73 (m, 2H), 1.75±1.86 (m, 1H), 2.31 (s, 3H),
2.77±2.98 (m, 3H), 3.24 (m, 1H), 3.27±3.38 (m, 2H), 3.30
(s, 3H), 5.85 (s, 1H), 6.47 (s, 1H), 7.12 (m, 2H), 7.53 (m,
2H). 13C NMR (50 MHz): dˆ21.1 (CH3), 24.6 (CH2), 27.7
(CH2), 46.0 (CH2), 57.7 (CH3), 58.9 (CH), 75.0 (CH2), 101.4
(CH), 114.8 (C), 115.4 (CH), 123.6 (CH), 129.3 (CH), 130.1
(C), 133.9 (C), 141.2 (C). EI MS m/z (%): 270 (6), 225 (25),
186 (11), 173 (100), 168 (11), 158 (13), 144 (18), 119 (27),
91 (16), 70 (34), 43 (10). HRMS EI: theoretical: 270.1732;
measured: 270.1704.
2.5.5. 1H-2-(p-Methoxy)-phenyl-3-methoxy pyrrole
(23d). Yield: 73%. Rfˆ0.15 (80:20 EP/AcOAEt). lmax
ˆ
587 nm (e 705). IR (®lm): nˆ3480, 3025, 2990, 1520,
1
1420. H NMR (CDCl3, 300 MHz): dˆ2.57 (m, 1H), 3.81
(s, 3H), 3.84 (s, 3H), 6.07 (t, Jˆ2.9 Hz, 1H), 6.60 (t,
Jˆ2.9 Hz, 1H), 6.08 (m, 2H), 7.53 (m, 2H). 13C NMR
(50 MHz): dˆ55.3 (CH3), 58.8 (CH3), 98.0 (CH), 113.6
(C), 114.2 (CH), 114.9 (CH), 125.1 (CH), 129.1 (C),
132.3 (C), 144.7 (C). EI MS m/z (%): 203 (15), 169 (5),
155 (7), 147 (15), 135 (52), 111 (18), 97 (29), 85 (36), 71
(45), 57 (100), 43 (76). HRMS EI: theoretical: 203.0946;
measured: 203.0960.
Acknowledgements
2.6. Preparation of 3-amino-2-aryl pyrroles (25)
The ef®cient help of Dr Philippe Compain at the beginning
of this study was greatly appreciated. V. B. D. thanks
MENSR for a scholarship.
2.6.1. General procedure. N-Amino-3-pyrroline was stir-
red during several hours in a mixture of THF and HCl (4 ml/
1 ml). The progress of the reaction was followed by TLC.
The mixture was quenched with a saturated solution of
NaHCO3 until neutrality and extracted with Et2O (3£5 ml).
The combined organic phases were dried (Na2SO4) and
concentrated. The crude product was obtained as a highly
coloured oil and did not require any puri®cation; its purity
was shown by TLC (EP/AcOEt as solvent and phosphomo-
lybdic acid as chemical tracer) as well as by NMR spectra.
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