Study of the regioselectivity and diastereoselectivity in the addition of 3-substituted-2-propenylmetal reagents to N,N′-di[1(S)-phenylethyl]ethanediimine

Article abstract of DOI:10.1016/S0040-4020(02)01094-3

The additions of 3-aryl-2-propenyllithium and -zinc reagents to N,N′-di[1(S)-phenylethyl]ethanediimine in THF occurred by α and γ-addition, affording 4,5-diamino-1,7-dienes with linear and branched allylic substituents, respectively. 3-Phenoxy- and 3-alkoxy-2-propenyllithiums reacted with lack of regioselectivity, whereas the corresponding zinc reagents exclusively followed the γ-addition pathway. The (S)-configuration of the auxiliaries induced the preferential attack to the Re face of the azomethine groups. In the γ-addition route, four new stereocentres were formed and the simple (syn/anti) diastereoselectivity was dependent on the alkene geometry in the allylmetal reagents. C₂-symmetric compounds with syn-syn-syn or anti-syn-anti relative stereochemistry were prevalently obtained. In contrast, when 3-ethoxy-2-propenylzinc chloride was prepared by transmetallation of the corresponding titanium reagent, a C₁-symmetric compound (anti-syn-syn) was mainly formed.

Full text of DOI:10.1016/S0040-4020(02)01094-3

Tetrahedron 58 (2002) 8679–8688
Study of the regioselectivity and diastereoselectivity
in the addition of 3-substituted-2-propenylmetal reagents
to N,N0-di[1(S)-phenylethyl]ethanediimine
*
Claudio Fiorelli, Lucia Maini, Gianluca Martelli, Diego Savoia and Carla Zazzetta
`
Dipartimento di Chimica ‘G. Ciamician’, Universita di Bologna, via Selmi 2, 40126 Bologna, Italy
Dedicated to Professor Gianfranco Cainelli on the occasion of his 70th birthday
Received 28 June 2002; revised 6 August 2002; accepted 29 August 2002
Abstract—The additions of 3-aryl-2-propenyllithium and -zinc reagents to N,N0-di[1(S)-phenylethyl]ethanediimine in THF occurred by a
and g-addition, affording 4,5-diamino-1,7-dienes with linear and branched allylic substituents, respectively. 3-Phenoxy- and 3-alkoxy-2-
propenyllithiums reacted with lack of regioselectivity, whereas the corresponding zinc reagents exclusively followed the g-addition pathway.
The (S)-configuration of the auxiliaries induced the preferential attack to the Re face of the azomethine groups. In the g-addition route, four
new stereocentres were formed and the simple (syn/anti) diastereoselectivity was dependent on the alkene geometry in the allylmetal
reagents. C2-symmetric compounds with syn–syn–syn or anti–syn–anti relative stereochemistry were prevalently obtained. In contrast,
when 3-ethoxy-2-propenylzinc chloride was prepared by transmetallation of the corresponding titanium reagent, a C1-symmetric compound
(anti–syn–syn) was mainly formed. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
problem of regioselectivity, which has been more deeply
studied for the addition to carbonyl compounds, alkyl
halides or other electrophiles.4 – 6 In fact, the a or
g-additions of such reagents to unsaturated electrophiles 1
gives either the linearly substituted (E) and/or (Z)-homo-
allylic alcohols and amines 2, or the branched homoallylic
isomers 3 (Scheme 1).
The synthetic utility of the organometallic addition to
imines is limited, as compared to carbonyl compounds, by
the low reactivity of the imine function towards organo-
metallic reagents,1 and the occurrence of competitive
reaction pathways, such as deprotonation and SET pro-
cesses. Nevertheless, a number of stereoselective synthesis
of amines have been described exploiting the addition of
organometallic reagents to chiral imines, particularly those
bearing a stereogenic N-substituent.1–3 The use of allylme-
tal compounds or allyl carbanions can circumvent the
aforementioned reactivity problems. However, the use of
g-substituted allylmetal compounds raises the additional
The simple (syn/anti) diastereoselectivity7–10 in the for-
mation of branched products 3 is governed by a number of
factors: the nature of both the imine and the allylmetal
reagent, the substitution pattern and the alkene geometry in
the latter compound, the presence of a Lewis acid, which in
turn affects the mechanism and/or the transition state
Scheme 1.
Keywords: allylation; amines; diastereoselection; imines; regioselection.
*
Corresponding author. Tel.: þ39-51-2099571; fax: þ39-51-2099456; e-mail: savoia@ciam.unibo.it
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01094-3

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C. Fiorelli et al. / Tetrahedron 58 (2002) 8679–8688
Scheme 2.
structure. Several reactions of chiral imines with g-sub-
stituted allylmetal reagents have been described previously.
The addition of crotylmetals (M¼MgCl, SnBu3–BF3) to
imines gave low to moderate levels of simple diastereo-
selectivity,11,12 but crotyl-9-BBN gave anti/syn ratios of the
g-addition products ranging from 100:0 to 0:100.11 More-
over, the anti/syn ratio 84:16 was obtained in the addition
of crotyllithium to the benzaldimine derived from
the 2(S)-amino-1(R)-methoxy-1,2-diphenylethane.12 The
additions of crotyl-9-BBN, -MgCl, -ZrCp2Cl and -Ti(i-
PrO)3 to chiral aliphatic imines gave low syn/anti ratios, but
(E)-crotyl-9-BBN added the imine derived from butyl
glyoxylate and 1(S)-phenylethylamine with excellent syn-
as well as Cram-selectivity.13 The same glyoxylate imine
gave better anti-selectivity with 3-phenoxy-, 3-methoxy-
(anti/syn 5:1) and 3-methylthio-2-propenylzinc bromide
(anti/syn 3:1) than with the corresponding titanate, alumi-
nate or boronate reagents.14 In these reactions, the prevalent
formation of the anti-isomer was explained by assuming the
intramolecular coordination of the heteroatom to the metal,
resulting in the (Z)-geometry of the allylic double bond; it
is also noteworthy that the 1,3-asymmetric induction
(auxiliary induced diastereoselectivity) was high for the
methoxy-substituted zinc reagent, but absent for the
phenoxy-substituted reagent.14 A remarkably complete
stereocontrol was observed in the addition of the geo-
metrically stable (Z)-2-ethoxycarbonyl-2-butenylzinc
bromide to ethyl N-benzylidene (R)-phenylglycinate.15
The intramolecular allylation of a chiral aliphatic aldimine
by a terminal (Z)-3-alkoxy-2-alkenyl-tributylstannane
moiety was promoted by different Lewis acids, which
affected also the simple diastereoselectivity: only the
trans(anti)-isomer was obtained in the HCl and ZrCl4
mediated cyclisations.16
perhaps through an open or boat-like six-membered cyclic
transition state. Conversely, the reagent prepared from
acrolein (R,R)-1,2-dicyclohexylethylene acetal reacted with
the opposite regioselectivity (a-addition), so acting as a
chiral homoenolate equivalent.21
We have been mostly active during the last decade in
allylmetalation reactions of imines and 1,2-diimines carry-
ing stereogenic N-substituents.3 Particularly, we have
described that the addition of pentadienyl-, 1-trimethylsilyl-
allyl- and cinnamyllithium to the glyoxal diimine 4 in THF
at 278 to 08C gave regioselectively the linear substituted
1,2-diamines 5b–d with high stereocontrol (Scheme 2).22
This is in direct contrast with the reported exclusive
formation of branched products by the g-addition of
crotyllithium to a chiral benzaldimine.12 We have also
reported that crotyl- and pentadienylzinc halides added to
the same diimine with allylic rearrangement to give the
branched 1,2-diamines 6a,b with high levels of 1,3-
asymmetric induction.23 However, in this case the syn/anti
diastereoselectivity was not controlled, owing to the
geometrical instability of crotylzinc bromide. Conse-
quently, it appeared interesting to us to widen the scope of
the allylmetalation reactions of the diimine 4 investigating
the reactivity and selectivity of differently substituted
allyllithium and-zinc reagents having a stable (E) or (Z)-
geometry. Particularly, the 3-oxy-substituted 2-propenyl-
lithium reagents were expected to behave as homoenolate
equivalents, so allowing the preparation of compounds 5.
On the other hand, the preparation of branched oxy-
substituted 1,2-diamines 6 using the corresponding zinc
reagents would also be interesting. Here we describe the
reactions of 3-aryl- and oxygen-substituted 2-propenyl-
lithium and -zinc reagents to the diimine 4.
Finally, it is noteworthy that substituted allyltitanium
reagents were quite useful for the stereoselective addition
to imines: in fact, the (E)-crotyl17,18 and (E)-cinnamyltita-
nium17 reagents added to N-propylidene-1(R)-phenylethy-
lamine to give the homoallyilc amines with prevalent syn
stereochemistry.† On the other hand, the reaction of
(Z)-cyclooctenyltitanium reagent with N-benzylidenepro-
pylamine gave the anti-adduct.19 Therefore, it is surprising
that the 3-benzyloxy-2-propenyltitanium reagent derived
from acrolein dibenzyl acetal, presumably having (Z)-
geometry, gave the syn-adduct with an aliphatic imine,20
2. Results and discussion
2.1. Preparation of 3-substituted-2-propenylmetal
reagents
The methods we have used to prepare the g-substituted
allylmetal species are described in Scheme 3. Following the
described route to the desired lithium and zinc reagents,24,25
we have carried out the metalation of allyl-substituted
arenes 7 and allyl ethers 10 by nBuLi–TMEDA in THF at
the proper temperatures to give the lithium reagents 8 and
11,24 respectively.‡ Starting from allylarenes 7, the
†
Sato17 prepared reagents having the structure 150 from acrolein acetals
derived from ethylene glycol, (R,R)-2,3-butandiol and (R,R)-1,2-
dicyclohexyl-1,2-ethanediol. In our hands, the titanium reagent
prepared from 14 did not react with a 2-pyridylimine, but added to
benzaldehyde as expected to give the linear homoallylic alcohols, thus
demonstrating the structure 150.
‡
We consider the allylic lithium reagents as highly ionic compounds,
although crotyllithium has been depicted as a covalent compound
reacting with an imine by allylic rearrangement.12

C. Fiorelli et al. / Tetrahedron 58 (2002) 8679–8688
8681
Scheme 3.
Scheme 4.
completeness of the metallation steps was ensured by
raising the temperature from 278 to 08C, and this
temperature was maintained in the subsequent transmetalla-
tion with the ZnCl2–TMEDA complex, which produced the
corresponding zinc reagents 9 and 12. Although it has been
reported that the g-oxygen-substituted allyllithium com-
pounds must be prepared and maintained at a temperature
below 2788C to avoid decomposition by Wittig rearrange-
ment,6,24,25 we have obtained the best results following the
Yamamoto protocol, by which the reagents 11a and 12a
were prepared at 2308C.14 It should be underlined that
different alkene geometries are present in the allylmetal
reagents, i.e. 8, 9 vs 11, 12, depending on the nature of the
allyl substituent. The (Z)-geometry of the cinnamyl reagents
8 and 9 is dictated by the steric properties of the Ph
substituent in the allyl moiety. On the other hand, either the
ionic or covalent oxygen-substituted reagents 11 and 12
have the (Z)-geometry, which is stabilised by internal
coordination.
addition of (h2-propene)-Ti(O-iPr)2, which is generated in
situ from Ti(O-iPr)4 and 2 equiv. of iPrMgCl.18 It is
noteworthy that the branched reagents 150 are formed
from the cyclic acetals derived from 1,2-diols,† e.g. 14,
whereas the (Z)-linear isomers 1500 are produced from the
acyclic acetals, e.g. 13. The reactivity of the titanium
reagents 150 and 1500 towards imines is only moderate, being
almost limited to aliphatic imines.§ Therefore, we have
converted them to the corresponding zinc reagents by a
transmetallation step, as previously described by Normant
to prepare (Z)-3-ethoxy-2-propenylzinc chloride.26 By this
way, we envisioned the preparation of either branched
products exploiting the reagent 160, in turn prepared from
the cyclic acetal 14, or linear products from the alternative
structures 1600 and/or 16000.
§
The allylic titanium reagents 150 and 1500 are poorly reactive towards
aromatic imines. In our hands, 14 reacted unsatisfactorily with the
diimine 4, presumably the second attack being hampered by steric
hindrance.
Acrolein acetals are useful starting materials to prepare
alkoxy-substituted allyltitanium reagents by oxidative

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C. Fiorelli et al. / Tetrahedron 58 (2002) 8679–8688
good level of diastereoselectivity (Scheme 4).{ In both
reaction mixtures, two diastereomers were evidenced
1
by t.l.c. and H NMR spectroscopy. The prevalent ones
180a,b, having C2-symmetry, were isolated pure by crystal-
lisation (180a, 60%; 180b, 33%). The configuration of
180a was determined by X-ray structure analysis, which
showed the R configuration of all the newly formed
stereocentres (Fig. 1). The minor diastereomers 1800a,b
were not isolated pure, but their C1-symmetry was
demonstrated by 1H NMR spectroscopy of enriched
chromatographic fractions.
2.3. Addition of 3-oxygen-substituted 2-propenylmetal
reagents
We first studied the addition of g-phenoxyallyllithium 11a
and observed that a mixture of isomeric and diastereomeric
Figure 1. X-Ray structure of compound 180a; two independent molecules,
which differ very slightly, are present in the crystal, but only one is shown.
Scheme 5.
2.2. Addition of g-arylallylmetal reagents
1,2-diamines were formed. Column chromatography
allowed separation of three main compounds with satis-
factory purity, presumably all of them having the R
configuration of the newly formed stereocentres (a to N).
Two of them, 190 (17%) and 20 (5%), had C2-symmetry, but
differed for having branched or (Z)-linear g-phenoxyallyl
substituents, respectively, and the third one, 21 (23%), had
one (Z)-linear and one branched substituents. This lack of
regioselectivity was rather unexpected, considering the
outcome of the previously described reaction with cinna-
mylithium, although we have found no report on the
regioselective a-addition of alkoxyallyllithiums to imines.
The anti,syn,anti-configuration could be assigned to the
branched diamine 190 when the same compound was
obtained as the major product of the reaction of the diimine
4 with 3-phenoxy-2-propenylzinc chloride 12a (Scheme 5).
The reaction of the diimine 4 with 3 equiv. of the 3,4-di-
methoxyphenylallyllithium reagent 8b was performed in
THF at 2788C and followed the same reaction pathway as
the cinnamyllithium,21 affording exclusively the linear
1,2-diamines 170b and 1700b, coming from the double
a-addition to the CvN groups (Scheme 4). An 80:20 ratio
of diasteromers was determined by 1H NMR analysis of the
crude product. The main (R,R)-diastereomer 170b was
isolated with 42% yield by crystallisation from methanol,
and the R configuration of the newly formed stereocentres
was assumed by analogy with the previously prepared
(R,R)-170a.21 Moreover, the (E)-geometry of the double
bonds was shown from the J value of the vinylic protons.
The minor diastereomer 1700b was not isolated.
Conversely, the cinnamyl- and 3,4-dimethoxyphenylallyl-
zinc chloride 9a,b, obtained by transmetallation of
the corresponding lithium reagents, reacted with the
1,2-diimine 4 exclusively by g-attack, giving the branched
bis-homoallylic 1,2-diamines 18a,b with high yields and a
{
This result is in contrast with the reported formation of the linear
homoallylic amine by addition to N-benzylidene methylamine at room
temperature,27 however, this likely occurred because of the rapid
isomerisation of the initially formed branched homoallylic amine to the
most stable linear isomer.

C. Fiorelli et al. / Tetrahedron 58 (2002) 8679–8688
8683
Figure 3. X-Ray structure of compound 220.
relationship of the hydroxy and amino groups was so
determined (Fig. 3). The anti relationship of the hydroxy
and amino groups could be related to the coupling constant
J¼2.2 Hz measured for the NCHCHOH protons in the H
Figure 2. X-Ray structure of compound 190-2HCl; chloride ions are omitted.
In this case, compound 190 could not be separated from an
isomer by chromatography, as a 4:1 ratio of isomers was
1
1
determined by H NMR analysis, but crystallisation of the
NMR spectrum, whereas the coupling constant J¼6.6 Hz
was assigned to the corresponding proton in the syn-1,2-
aminoalcohol moieties of 190 (Scheme 5). The C1-sym-
metric diastereomer 2200 was also obtained in 12% yield
by column chromatography of the mother liquor coming
from the crystallisation of the crude reaction product.
Surprisingly, the diethoxy-substituted diamine 23 was the
main prod0u00ct obtained by the reaction of 4 with the zinc
reagent 16 a (Scheme 6), which was in turn prepared from
the titanium reagent 150a (Scheme 3). The C1-symmetry of
23, which was isolated pure in 45% yield by chroma-
tography of the crude product, was determined from the 1H
NMR spectrum, where the two coupling constants J¼2.0,
6.6 Hz for the CHCHN protons proved the anti and syn
relationships of the two 1,2-alkoxy-amine moieties. More-
over, the X-ray structure lacking, the S configuration of the
NCHpCHpN stereocentres was inferred in the light of the
outcome of the reaction of 4 with allylzinc bromide
prepared by treatment of (allyl)Ti(iPrO)2Br with ZnBr2: as
a fact the diallylation product was obtained with almost the
same diastereomeric ratio (92:4:4) provided by neat
allylzinc bromide.28 This finding demonstrates that the
presence of the Ti(IV) salt did not affect the sense and the
degree of the asymmetric induction in the allylzincation
reaction.
derived dihydrochlorides mixture from methanol, followed
by basic treatment gave pure 190 in 31% yield. Its structure
was determined by X-ray crystallographic analysis (Fig. 2).
1H NMR analysis of the diastereomeric mixture allowed
assignment of the C2-symmetry of the minor diastereomer,
to which the structure 1900 may be assigned, assuming
the same sense of asymmetric induction in the additions to
the diimine moiety. Aiming to assess the influence of the
O-substituent on the regio- and diastereoselectivity, and
particularly to find a route to 1,8-dialkoxy-4,5-diamino-1,7-
dienes, we carried out the reaction with the THPO-
allyllithium 11b24 and O-ethoxymethyl derivative 11c,
hoping that these reagents would add exclusively by
a-addition. Unfortunately, both the reactions gave a
complex mixture of at least four relevant products. 1H
NMR spectroscopy showed the presence of linear and
branched substituents, although with different ratios in the
two cases. The crude products were not elaborated further.
On the other hand, a good control of the regio- and
diastereoselectivity was obtained using THPO–allylzinc
chloride 12b (Scheme 6). After acidic removal of the
OH-protective groups, followed by basic treatment, a solid
diamino-diol 220 was obtained and purified by crystal-
lisation (48% yield). The crystals of 220 were suitable for
X-ray diffraction analysis, and the relative anti,syn,anti
Finally, we made an attempt to prepare regioselectively a
Scheme 6.

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C. Fiorelli et al. / Tetrahedron 58 (2002) 8679–8688
Ph
Me
Ph
Me
Ph
Me
Ph
Me
H
H
H
H
H
H
Ph
O
H
H
H
H
H
N
N
N
N
N
N
Li
Li
Zn Br
Zn Br
Ar
R
N
N
H
H
H
RO
Me
Ph
Me
Ph
Me
Ph
Me
Ph
H
H
I
II
III
IV
Figure 4.
1,8-dialkoxy-4,5-diamino-1,7-diene by using the zinc
reagent 16b prepared from the cyclic acrolein acetal 14,
through the titanium reagent 150b (Scheme 3); however, a
mixture of branched diastereomers was instead obtained,
which could not be separated by chromatography.
propenyltitanium species to an aliphatic imine.20 Finally,
the observed g-addition of the zinc reagent 16b to 4
indicated that the structures 1600b and 16000b were preferred,
contrary to the precursory titanium reagent 15b, which
assumes the structure 150b.pp
2.4. Origin of the regio- and stereocontrol
The regioselectivity of the allylic lithium compounds was
dependent on the nature of the allylic substituent and is not
easily rationalised. As a matter of fact, the aryl-substituted
reagents 8 exclusively reacted by a-addition to give the
linear homoallylic products 17, preserving the (E)-geometry
of the CvC bond, whereas the behaviour of oxyallyl-
lithiums was affected by the O-substituent. A perfect
regioselectivity was observed with the THP-protected
reagent 11b which gave exclusive a-addition leading to
the (Z,Z)-linear diamine 22, while preserving the double
bond geometry. Instead, the 3-phenoxy-2-propenyllithium
11a gave the products 190 –21 by competitive a and
g-addition processes. If we assume that all the allylic
lithium species are ionic, an acyclic transition state must be
considered for their additions to the diimine–lithium cation
complex. The a-attack of the carbanion, depicted in model
III (Fig. 4), is clearly favoured by the reduced non-bonding
interactions, with respect to the g-attack. So, the lack of
regioselectivity of 3-phenoxy-2-propenyllithium 11a is
surprising. The formation of the diamines 19 and 21, having
at least one branched substituent, is probably favoured by
the (Z)-geometry of the reagent, which makes easier the
g-attack with respect to the (E)-reagent, as depicted in
model IV, which is relative to the first addition step.
Alternatively, it can be assumed that the reagent 11a exists
(reacts) as a covalent species, as in a previous report,12 in
this case a cyclic transition state analogous to II should be
involved.
Both the regioselectivity and the stereoselectivity were
affected by the nature of the organometallic reagent, i.e.
either the metal and the allylic substituent. First of all, it
should be considered that the carbon–metal bond is largely
covalent in allylic zinc compounds, whereas it is borderline
between covalent and ionic in allyllithiums. For the addition
of allylic zinc reagents to imines a six-membered cyclic
transition state is expected for the C–C bond forming step,
which follows the preliminary N–Zn coordination. Conse-
quently, branched homoallylic amines are formed with
g-substituted allylzinc species, and the simple (syn/anti)
diastereoselectivity is dictated by the alkene geometry in the
reagent. The syn-relationship of the phenyl and amino
substituents in the compounds 18a,b stems from the
preferred (E)-geometry of the aryl-substituted reagents
9a,b, which is maintained in the C–C bond forming steps
developing through cyclic transition states, e.g. I, which is
relative to the first organometallic attack to the 1,2-diimine
4 (Fig. 4). Conversely, the anti-stereochemistry of the
hydroxy and amino substituents in the compounds 19, 22
and, in part, 23 is rationalised by assuming the (Z)-geometry
of the zinc reagents 12, which are stabilised by internal
O–Zn coordination and react in the first step through the
transition structure II.k On the other hand, the formation of
the C1-symmetric product 23, where both the syn and anti
diastereoselectivity were operating, may have different
explanations. We suggest that the oxophilicity of the
titanium salt causes the disruption of the intramolecular
O–Zn coordination in 1600a which enter into equilibrium
with the linear structure 16000a (Scheme 3). Alternatively, but
less likely, one can suppose that the Ti–Zn transmetallation,
i.e. 1500a to 1600a, was incomplete and the consecutive
additions of two different organometallic species to the
diimine 4 occurred with opposite simple diastereoselec-
tivity, i.e. by syn addition of the titanium reagent and
anti-addition of the zinc reagent. It is worth reminding
the reported syn-selective addition of a 3-benzyloxy-2-
3. Conclusions
In this work, we have investigated the reactivity of
g-substituted allyllithium and -zinc reagents to the glyoxal
diimine 4, and determined the role of the metal and the
allylic substituent on the regioselectivity and diastereo-
selectivity. Particularly, we have found that the g-aryl-
substituted allyllithium reagents gave exclusively
a-addition products, whereas the g-phenoxy and
g-alkoxy-substituted lithium compounds followed both the
a and g-addition pathways. Moreover, the geometry of
the (E)-aryl- or (Z)-oxy-substituted reagents was preserved
k
Although the stereochemistry of the compounds 190 and 23 was not safely
determined, the depicted configuration of the N–Cp–Cp–N stereocentres
is highly probable, in view of the high level of diastereoselectivity
generally obtained with allylic zinc reagents; consequently, the
configuration of the CHpO stereocentres is determined by the C2 or
C1-symmetry of the compound.
pp
The reagent 150b was not described by Sato.17 In our hands, it did not
react with a chiral 2-pyridylimine but added benzaldehyde to give a
mixture of (E) and (Z)-4-alkoxy-1-phenyl-3-propen-1-ol.

C. Fiorelli et al. / Tetrahedron 58 (2002) 8679–8688
8685
in the linear diamines obtained. Only moderate control of
1,3-asymmetric induction was obtained with the lithium
reagents.
propoxide, glyoxal trimeric dihydrate, (S)-1-phenylethyl-
amine, TMEDA, acrolein, allyl alcohol, 3,4-dihydro-2H-
pyran, 2,3-dimethyl-2,3-butandiol, 7a,b, 10a, 13a. The 1,2-
bis-imine 4 was prepared according to the described
procedure.28 All the organometallic reactions were per-
formed in a flame-dried apparatus under a static atmosphere
of dry N2.
Most importantly, all the g-substituted allylzinc halides
reacted with the diimine 4 with complete regioselectivity
(g-addition) and high stereocontrol. The auxiliary-induced
and simple diastereoselectivity were generally good,
however, the latter was dependent on the nature of the
allylic substituent, which in turn affects the geometry of the
CvC bond. In these reactions ten diastereomers can be
formed, but we generally obtained two main diastereomers,
accounting for 80–90% of the crude product. The prevalent
diastereomer often had C2-symmetry, and could be isolated
as a crystalline compound with satisfactory to good yield.
Only from the g-ethoxyallylzinc reagent which was
prepared from the titanium reagent a C1-symmetric diamine
was mainly obtained, presumably owing to the presence of a
titanium(IV) salt.
4.2. Preparation of the 3-substituted-2-propenylmetal
reagents
4.2.1. Lithium reagents 8a,b and 11a,b. nBuLi (1.6 M in
hexanes, 9.4 mL, 15 mmol) was slowly added to the
solution of TMEDA (2.25 mL, 15 mmol) and the substituted
propene (15 mmol) in THF (25 mL) at the indicated
temperature: allylbenzene 7a and 4-allyl-1,2-dimethoxy-
benzene 7b, 278 to 08C; allyl phenyl ether 10a and allyl
tetrahydropyranyl ether 10b, 2308C. The mixture was then
stirred for further 30 min.
From the synthetic point of view, these reactions widen the
accessibility of 1,2-diamines and especially open a new
route to 2,3-diamino-1,4-diols. Moreover, it is possible to
exploit the presence of the alkene functions in these useful
intermediates. For example, the homoallylic amines are
synthetic equivalents of b-amino-carbonyl compounds and
b-aminoacids and the 1,7-diene skeleton can be converted
to cyclohexene and cyclohexane by transition metal-
catalysed or -promoted cyclisation procedures. For
example, we have described the reductive cyclozircona-
tion29 and the ring-closing metathesis30 reactions of the
unsubstituted compounds 5 or 6 (R¼H) to 1,2-diamino-4,5-
dimethylcyclohexane and -4-cyclohexene with good yield.
Similarly, aza-heterocyclic compounds can be constructed
by electrophile-mediated aminocyclization reactions. For
example, Alexakis has recently reported the synthesis of the
2,20-bis(pyrrolidine) from 6 (R¼H), through a sequence
involving the hydroboration of the CvC double bonds.31
The application of several cyclisation procedures to the
substituted 1,7-octadienes herein described is currently
under investigation in our laboratory.
4.2.2. Zinc reagents 9a,b and 12a–c. These were prepared
by the slow addition of a solution of the ZnCl2–TMEDA
complex (3.80 g, 15 mmol) in THF (15 mL) to the
previously prepared solutions of the corresponding lithium
reagents 8a,b and 11a,b at the same temperature used for the
metallation step, and the mixture was stirred for further
30 min.
4.3. Addition of the allylic organometallic reagents 11
and 12 to the 1,2-diimine (4)
To the solution of the allylic organometallic reagent
(15 mmol), cooled at 2788C under N2, was added the
solution of the 1,2-diimine 4 (1.32 g, 5 mmol) in dry THF
(20 mL) during 30 min. After stirring for 1 h, the mixture
was quenched with de-aerated H2O (10 mL), and the
organic phase was extracted with Et2O (3£20 mL). The
collected ethereal phase was dried (Na2SO4) and concen-
trated to leave the crude 1,2-diamine, generally as an oil.
The pure diastereomers were then obtained by chromatog-
raphy on an SiO2 column eluting with cyclohexane–EtOAc
mixtures.
4.3.1. (E,E)-4(R),5(R)-Di-[1-(S)-phenylethylamino]-1,8-
di-(3,4-dimethoxyphenyl)-1,7-octadiene (170b). This was
obtained by reaction of 4 with 8b; the crude semi-solid
compound was crystallised from methanol to give a white
crystalline solid: 1.30 g (42%); mp 111–1138C; [a]2D0¼
256.4 (c 0.97, CHCl3); nmax (Nujol) 3328, 3050, 2930,
4. Experimental
4.1. General conditions
Melting points are uncorrected. Solvents were distilled over
the appropriate drying agent in N2 atmosphere before use:
THF (sodium benzophenone ketyl, then LiAlH4), Et2O (Na,
then LiAlH4), nhexane (Na), CH2Cl2 (P2O5). Optical
rotations were measured on a digital polarimeter in a 1 dm
1
2841, 1628, 1262, 1010, 902 cm21; H NMR (300 MHz,
CDCl3): d¼1.34 (d, J¼6.3 Hz, 6H, CHMe), 1.40 (broad,
2H, NH), 2.30 (m, 6H, CH2CHCHCH2), 3.84 and 3.87 (2s,
12H, OMe), 3.86 (q, J¼6.3 Hz, 2H, CHMe), 5.62 (dt, J¼
16.0, 5.4 Hz, 2H, CH2CHvCH), 5.82 (d, J¼16.0 Hz, 2H,
CHvCHAr), 6.65–6.79 (m, 6H, Ar), 7.25–7.45 (m, 10H,
Ph); 13C NMR (300 MHz): d 25.4, 34.5, 55.7, 55.9, 56.5,
108.6, 111.0, 118.7, 126.4, 126.7, 127.4, 128.2, 131.01,
146.6, 148.1 and 148.8. Found: C 77.42, H 7.81, N 4.50%;
C40H48N2O4 requires: C 77.38, H 7.79, N 4.51%.
cell and [a]D-values are given in 1021 deg cm3 g21. H
1
NMR spectra were recorded on a Varian Gemini instrument
at 300 or 200 MHz for samples in CDCl3 which was stored
over Mg: 1H chemical shifts are reported in ppm relative to
CHCl3 (dH 7.27) and J-values are given in Hz. MS spectra
were taken at an ionizing voltage of 70 eV on a Hewlett–
Packard 5970 or 5890 spectrometer with GLC injection.
Chromatographic separations were performed on columns
of SiO2 (Merck, 230–400 mesh) at medium pressure. The
following compounds were purchased from Aldrich: nBuLi,
zinc, zinc dichloride–TMEDA complex, titanium tetraiso-
4.3.2. 4(R),5(R)-Di-[1(S)-phenylethylamino]-3(R),6(R)-
diphenyl-1,7-octadiene (180a). This was obtained by the
reaction of 4 with 9a; the crude solid product was

8686
C. Fiorelli et al. / Tetrahedron 58 (2002) 8679–8688
crystallised from MeOH to give a white crystalline solid:
1.50 g (60%); mp 135–1368C; [a]2D0¼249.1 (c 0.42,
CHCl3); nmax (Nujol) 3358, 3061, 3022, 1599, 1491,
(MeOH) and basic treatment: yellowish oil, 0.82 g (31%);
[a]2D0¼225.4 (c 0.52, CHCl3); nmax (liquid film) 3346,
3026, 2959, 1596, 1494, 1239, 1110, 1002 cm21; 1H NMR
(200 MHz, CDCl3): d¼1.29 (d, J¼6.6 Hz, 6H, CHMe), 1.87
(broad, 2H, NH), 2.89 (d, J¼5.2 Hz, 2H, NCHCHN), 3.91
(q, J¼6.6 Hz, 2H, CHMe), 4.62 (t, J¼3.4 Hz, 2H, CHO),
5.14 (dt, J¼7.6, 1.4 Hz, 2H, CHvCH2), 5.21 (broad s,
2H, CHvCH2), 5.79 (ddd, J¼5.4, 11.1, 16.8 Hz, 2H,
CHvCH2), 6.65–6.76 (m, 4H, OPh), 6.85–6.98 (m, 2H,
OPh), 7.12–7.35 (m, 14H, Ph and OPh). Found: C 81.18, H
7.56, N 5.25%; C36H40N2O2 requires: C 81.16, H 7.57, N
5.26%.
1
1101, 992 cm21; H NMR (300 MHz, CDCl3): d¼1.05 (d,
J¼6.6 Hz, 6H, CHMe), 1.56 (broad, 2H, NH), 2.53 (d, J¼
7.2 Hz, 2H, NCHCHN), 3.25 (m and q, J¼6.6 Hz, 4H,
CHCHPh and NCHMe), 4.39 (dd, J¼1.8, 17.1 Hz, 2H,
CHvCH2), 4.86 (dd, J¼1.8, 10.2 Hz, 2H, CHvCH2), 5.89
(dt, J¼17.1, 10.2 Hz, 2H, CHvCH2), 6.57–6.68 (m, 4H,
Ph), 6.98–7.08 (m, 6H, Ph), 7.22–7.42 (m, 10H, Ph).
Found: C 86.37; H 8.06, N 5.59%; C36H40N2 requires: C
86.35; H 8.05, N 5.60%.
4.3.3. 4(R),5(R)-Di-[1(S)-phenylethylamino]-3(R),6(S)-
diphenyl-1,7-octadiene (1800a). This compound was not
obtained pure. The mother liquor from the crystallisation of
180a were concentrated and the residue was chromato-
graphed on a SiO2 column (cyclohexane–ethyl acetate
20:1); a fraction containing a 1:3 mixture of 180a/1800a was
obtained and analysed by 1H NMR, from which the signals
of the C1-isomer 1800a were identified: d¼0.87 and 1.34 (2d,
J¼6.6 Hz, 6H, CHMe), 1.56 (broad, 2H, NH), 2.08 and 2.66
(2d, J¼8.4, 9.6 Hz, 2H, NCHCHN), 2.88 and 3.78 (2 q,
J¼6.6 Hz, 2H, NCHMe), 3.01 (m, 2H, CHPh), 3.87 (dd,
J¼1.8, 17.1 Hz, 1H, CHvCH2), 4.58 (dd, J¼1.8, 10.2 Hz,
1H, CHvCH2), 4.95 (dd, J¼1.8, 10.2 Hz, 1H, CHvCH2),
5.04 (dd, J¼1.8, 17.1 Hz, 1H, CHvCH2), 5.32 (dt, J¼17.1,
10.2 Hz, 1H, CHvCH2), 6.10 (dt, J¼17.1, 10.2 Hz, 1H,
CHvCH2), 6.16–6.24 and 6.65–6.89 (2m, 4H, Ph), 7.0–
7.40 (m, 16H, Ph).
190-2HCl: mp 211–2128C (dec.); [a]2D0¼þ59.8 (c 0.54,
1
CHCl3); H NMR (200 MHz, CDCl3): d 1.65 (broad, NH),
1.96 (d, J¼7.0 Hz, 6H, CHMe), 3.50 (d, J¼8.4 Hz, 2H,
NCHCHN), 4.67 (q, J¼7.0 Hz, 2H, CHMe), 5.32 (dd,
J¼4.8, 8.2 Hz, 2H, CHvCH2), 5.67 (dd, J¼3.0, 8.2 Hz, 2H,
CHvCH2), 5.94 (m, 4H, OCHCHvCH2), 6.58 (d,
J¼8.2 Hz, 8H, OPh), 6.79–7.35 (m, 12H, OPh and Ph),
7.52 (d, J¼7.4 Hz, 4H, Ph), 10.5 and 11.3 (2 broad s, 2H,
NH).
A C2-symmetric isomer, presumably 1900, was present in the
product prior to crystallisation; the 1H NMR signals differed
from those of 190 only for NCHCHN (d¼3.06: d, J¼6.6 Hz)
and two ortho-phenol protons (d¼6.80: d, J¼7.0 Hz).
4.3.7. (Z,Z)-1,8-Diphenoxy-4(R),5(R)-di-[1(S)-phenyl-
ethylamino]-1,7-octadiene (20). This was obtained by
chromatography, being eluted after 19, and was ca. 90%
1
4.3.4. 4(R),5(R)-Di-[1(S)-phenylethylamino]-3(R),6(R)-
di-(3,4-dimethoxyphenyl)-1,7-octadiene (180b). This was
obtained by reaction of 4 with 9b and chromatography of the
crude product on a SiO2 column (cyclohexane–ethyl acetate
15:1), followed by crystallisation of the main semi-solid
product from methanol: white crystalline solid, 1.02 g
(33%); mp 118–1198C; [a]2D0¼251.3 (c 0.83, CHCl3);
nmax (Nujol) 3313, 3072, 2922, 1592, 1516, 1464,
pure by H NMR analysis, which revealed an unidentified
impurity: yellowish oil, 0.132 g (5%); 1H NMR (300 MHz,
CDCl3): d¼1.29 (d, J¼6.6 Hz, 6H, CHMe), 1.62 (broad,
2H, NH), 2.22–2.45 (m, 6H, CHCH2), 3.88 (q, J¼6.6 Hz,
2H, CHMe), 4.39–4.50 (m, 2H, CH2CHvCH), 6.26 (d,
J¼6.0 Hz, 2H, CHvCHO), 6.87–6.98 (m, 4H, OPh), 7.0–
7,09 (m, 2H, OPh), 7.13–7.37 (m, 14H, OPh and Ph).
1228 cm21
;
1H NMR (300 MHz, CDCl3): d¼1.15 (d,
4.3.8. (Z)-1,6(R)-Diphenoxy-4(R),5(S)-di-[1(S)-phenyl-
ethylamino]-1,7-octadiene (21). This was eluted after 20:
J¼6.6 Hz, 6H, CHMe), 1.57 (broad, 2H, NH), 2.49 (d,
J¼6.0 Hz, 2H, NCHCHN), 3.30 (dd, J¼6.0, 9.6 Hz, 2H,
NCHCHAr), 3.51 (q, J¼6.6 Hz, 2H, CHMe), 3.60 and 3.78
(2s, 12H, OMe), 4.60 (dd, J¼1.5, 17.1 Hz, 2H, CHvCH2),
4.92 (dd, J¼2.1, 10.2 Hz, 2H, CHvCH2), 5.84 (dt, J¼10.2,
17.1 Hz, 2H, CHCH2), 5.97 (d, J¼8.1 Hz, 2H, Ar), 6.04 (s,
2H, Ar), 6.41 (d, J¼8.1 Hz, 2H, Ar), 7.18–7.42 (m, 10H,
Ph). Found: C 77.40, H 7.80, N 4.50%; C40H48N2O4
requires: C 77.38, H 7.79, N 4.51%.
1
yellowish oil, 0.61 g (23%), ca. 85% pure by H NMR
1
analysis; H NMR (300 MHz, CDCl3): d¼1.24, 1.28 (2d,
J¼6.6 Hz, 6H, CHMe), 1.76 (broad, 2H, NH), 2.22–2.35
and 2.41–2.60 (2m, 2H, CHCH2), 2.85–2.96 (m, 2H,
NCHCHN), 3.82 and 3.88 (2 q, J¼6.6 Hz, 2H, CHMe),
4.58–4.68 (m, 1H, CH2CHvCHO), 4.72–4.81 (m, 1H,
CH2vCHCHO), 5.11–5.28 (m, 2H, CHvCH2), 5.71–5.93
(m, 1H, CHvCH2), 6.41 (d, J¼6.0 Hz, 1H, CHvCHOPh),
6.71 (d, J¼8.4 Hz, 2H, OPh), 6.81–6.98 (m, 4H, OPh),
7.11–7.42 (m, 14H, OPh and Ph).
4.3.5. 4(R),5(R)-Di-[1(S)-phenylethylamino]-3(R),6(S)-
di-(3,4-dimethoxyphenyl)-1,7-octadiene (1800b). This
1
compound was not obtained pure; the H NMR spectrum
4.3.9. 3(R),6(R)-Dihydroxy-4(S),5(S)-di-[1(S)-phenyl-
ethylamino]-1,7-octadiene (220). This was obtained by
reaction of 4 with 12b and crystallisation of the crude
product from methanol: white crystalline solid, 0.91 g
(48%); mp 153–1558C; [a]2D0¼2184.3 (c 0.73, CHCl3);
nmax (Nujol) 3500–3100 (broad), 3324, 2923, 1616, 1456,
1121, 1077 cm21; 1H NMR (200 MHz, CDCl3): d¼1.47 (d,
J¼6.6 Hz, 6H, CHMe), 2.51 (d, J¼2.2 Hz, 2H, NCHCHN),
3.96 (q, J¼6.6 Hz, 2H, CHMe), 4.40–4.50 (m, 2H, CHO),
4.65–4.88 (3m, 4H, CHvCH2), 5.09 (ddd, J¼3.6, 10.2,
14.6 Hz, 2H, CHvCH2), 7.15–7.42 (m, 10H, Ph); 13C
of a chromatographic fraction containing a 1:2 mixture of
180b and 1800b showed the following signals attributed to
1800b: d¼0.94 and 1.33 (2d, J¼6.6 Hz, CHMe), 2.12 and
2.64 (2 d, J¼8.5 Hz).
4.3.6. 3(R),6(R)-Diphenoxy-4(S),5(S)-di-[1(S)-phenyl-
ethylamino]-1,7-octadiene (190). This was obtained by
reaction of 4 with 12a, chromatography of the crude product
(SiO2 column, cyclohexane–ethyl acetate 40:1), formation
of the dihydrochloride (gaseous HCl, Et2O), crystallisation

C. Fiorelli et al. / Tetrahedron 58 (2002) 8679–8688
8687
NMR (200 MHz, CDCl3): d¼24.2, 54.6, 55.9, 71.9, 114.8,
127.7, 128.5, 138.8, 142.6. Uncoloured crystals suitable for
X-ray analysis were obtained by slow re-crystallisation from
MeOH. Found: C 75.23, H 8.50, N 7.35%; C24H23N2O2
requires: C 75.25, H 8.48, N 7.36%.
(excluding structure factors) for the structures reported in
this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
CCDC no. 186718–186720. Copies of the data can be
obtained free of charge on application to CCDC, 12 Union
Road, Cambridge CB21EZ, UK (fax: (þ44)1223-336-033;
e-mail: deposit@ccdc.cam.ac.uk).
4.3.10. 3(R),6(S)-Dihydroxy-4(S),5(S)-di-[1(S)-phenyl-
ethylamino]-1,7-octadiene (2200). This was obtained from
the mother liquor coming from the crystallisation of 220, by
solvent evaporation and chromatography (SiO2, cyclohex-
ane–ethyl acetate 10:1): yellowish oil, 0.24 g (12%); ca.
95% pure by 1H NMR analysis; 1H NMR (200 MHz,
CDCl3): d¼1.32, 1.42 (2d, J¼6.6 Hz, 6H, CHMe), 2.18 and
2.80 (2m, 2H, NCHCHN), 3.79–3.84 and 4.22–4.33 (2m,
2H, CHO), 4.0 and 4.07 (2q, J¼6.6 Hz, 2H, CHMe), 4.54–
4.68 (m, 2H, CHvCH2), 4.86 (ddd, J¼5.6, 11.2, 16.4 Hz,
1H, CHvCH2), 5.11 (dt, J¼10.6, 2.2 Hz, 1H, CHvCH2),
5.37 (dt, J¼17.2, 1.8 Hz, 1H, CHvCH2), 5.93 (ddd, J¼4.0,
Crystal data for 180a: C36H40N2, T¼293(2) K, M¼500.70,
Monoclinic, P21, a¼12.0298(8), b¼15.0517(10), c¼
3
˚
˚
17.4652(9) A, b¼104.899(2)8, V¼3056.1(3) A , Z¼4,
m(Mo Ka)¼0.063 mm21
,
Dc¼1.088 Mg m23
, 19,676
reflections collected, 12,134 independent refections, R1
(I.2s(I))¼0.0695, wR2 (F 2, all refls.)¼0.2230, 587
parameters.
Crystal data for 190-2HCl: C36H42Cl2N2O2, T¼293(2) K,
M¼380.52, Monoclinic, P21, a¼10.117(4), b¼9.554(4),
10.6, 17.2 Hz, 1H, CHvCH2), 7.16–7.42 (m, 10H, Ph); 13
C
c¼17.591(6) A, b¼95.99(3)8, V¼1691(1) A , Z¼2,
m(Mo Ka)¼0.225 mm21, Dc¼1.189 g cm23, 3240 reflec-
tions collected, 3136 independent refections, R1
(I.2s(I))¼0.0648, wR2 (F 2, all refls.)¼0.2976, 332
parameters.
3
˚
˚
NMR (200 MHz, CDCl3): d¼23.4, 24.5, 54.7, 56.2, 56.3,
61.7, 72.0, 75.5, 126.9, 127.4, 127.5, 127.6, 127.9, 128.1,
128.3, 128.6, 138.8, 139.5, 143.0, 143.4.
4.3.11. Preparation of 3(R),6(R)-diethoxy-4(S),5(S)-di-
[1(S)-phenylethylamino]-1,7-octadiene (23). iPrMgCl
(2 M in Et2O, 15 mL, 30 mmol) was slowly added to the
stirred solution of acrolein diethyl acetal (1.95 g, 15 mmol)
and titanium(IV) isopropoxide (4.16 g, 15 mmol) at 2608C.
The mixture was further stirred for 2 h at 2508C, then a
solution of anhydrous ZnBr2 (5.06 g, 22.5 mmol) in THF
(30 mL) was added. After stirring for 1 h at 2508C, the
mixture was cooled to 2788C and the diimine 4 (1.32 g,
5 mmol), dissolved in THF (10 mL) was slowly added. The
temperature was allowed to reach 08C during 2 h, then the
mixture was quenched with 30% NH4OH and 1 M NH4Cl
(1:1, 30 mL). After usual work-up, column chromatography
of the crude oily product eluting with cyclohexane–ethyl
acetate (20:1) gave 23 as a yellowish oil: 1.00 g (45%);
[a]2D0¼246.3 (c 0.76, CHCl3); nmax (liquid film) 3330,
Crystal data for 220: C24H32N2O2, T¼293(2) K, M¼380.52,
˚
monoclinic, C2, a¼22.035(6), b¼6.767(4), c¼7.636(9) A,
3
˚
b¼97.09(3)8, V¼1129.9(9) A , Z¼2, m(Mo Ka)¼0.071
mm21, Dc¼1.118 Mg m23, 1157 reflections collected,
1073 independent reflections, R1 (I.2s(I))¼0.0615, wR2
(F 2, all refls.)¼0.2166, 125 parameters.
Acknowledgements
`
Financial support from the Ministero dell’Universita e della
Ricerca Scientifica e Tecnologica, Roma, and The Uni-
versity of Bologna (National Project ‘Stereoselezione in
Sintesi Organica. Metodologie e Applicazioni’) is greatly
acknowledged.
1
2972, 1610, 1452, 1368, 1115 cm21; H NMR (300 MHz,
CDCl3): d¼0.92 and 1.17 (2 t, J¼6.9 Hz, 6H, CH2CH3),
1.23 and 1.32 (2d, J¼6.6 Hz, 6H, CHCH3), 1.69 (broad s,
2H, NH), 2.22 (dd, J¼2.0, 6.6 Hz, 1H, NCHCHN), 2.52 (m,
2H, OCH and NCHCHN), 3.20 (m, 2H, OCH2), 3.44 (m,
3H, OCH and OCH2), 3.80 and 4.07 (2q, J¼6.6 Hz, 2H,
CHMe), 4.36 (dd, J¼1.3, 17.1 Hz, 1H, CHvCH2), 4.86
(dd, J¼1.3, 10.2 Hz, 1H, CHvCH2), 5.02–5.20 (m, 2H,
CHvCH2), 5.40 and 5.62 (2ddd, J¼7.1, 10.2, 17.1 Hz, 2H,
CHvCH2), 7.08–7.43 (m, 10H, Ph); MS m/z (relative
intensity) 105 (100), 218 (Mþ/2, 63), 57 (33), 161 (31), 351
(29), 114 (25), 266 (21). Found: C 77.0, H 9.25, N 7.32%;
C28H40N2O2 requires: C 77.02, H 9.23, N 7.33%.
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