Synthesis and X-ray Crystal Structure of N,N-Bis-(R,R)-4,5-diamino-1,7-octadiene

Full text of DOI:10.1021/jo962219v

4180
J . Org. Chem. 1997, 62, 4180-4182
Ch a r t 1
Syn th esis a n d X-r a y Cr ysta l Str u ctu r e of
N,N-Bis[(S)-1-p h en yleth yl]-(R,R)-4,5-
d ia m in o-1,7-octa d ien e
Giuseppe Alvaro, Fabrizia Grepioni, and Diego Savoia*
Dipartimento di Chimica “G. Ciamician”, Universita` di
Bologna, via Selmi 2, 40126 Bologna, Italy
Received November 26, 1996
In tr od u ction
The addition of organometallic reagents to the carbon-
nitrogen double bond(s) of 1-aza-4-hetero-1,3-dienes 1-3
(Chart 1), derived from 1-phenylethylamine, is an at-
tractive method for the preparation of optically active 1,2-
diamines,1 1-(2-pyridyl)alkylamines,2 and R-amino acids,3
respectively. Apart from the reactions of allylboron and
-aluminum compounds, which can coordinate only the
imine nitrogen atom, the organometallic reactions likely
proceed through the preliminary formation of a rigid
chelate complex between the 1,4-heterodiene moiety and
the metal center. This provides the activation of both
the imine double bond and the metal-carbon bond and
introduces a constraint that generally improves the
stereocontrol with respect to the corresponding reactions
of simple unactivated imines.
predicted the 4R,5R configuration for the major diaste-
reomer of the diamine 4.1a
However, a clear picture of the asymmetric induction
operating in these reactions has not been achieved yet.
In fact, the addition of allylmagnesium chloride to the
bis-imine (S,S)-1 or (R,R)-1 afforded the N,N-disubsti-
tuted 4,5-diamino-1,7-octadiene 4 (Chart 1) with good
diastereoselectivity, only two of the three diastereomers
being produced with 86:14 ratio.1a The S configuration
of the newly formed stereocenters was assumed when
using the S auxiliary, as shown in (S,S)-4 (for sake of
simplicity, we define only the configuration of the newly
formed stereocenters). This assumption was based on
the results of the addition of allylboron reagents to the
imine prepared from (R)-1-phenylethylamine and isobu-
tyraldehyde, as well as (S)-3a , where the S auxiliary
produced the S chirality (si face addition), and vice
versa.3a,b However, allyltin trichloride attacked the re
face of (S)-3a .3d Moreover, the configuration of the
product obtained through the addition of 2-(alkoxym-
ethyl)allylzinc bromides to 3b was not determined.3c
We have recently reported on allylmetalation reactions
of imines derived from (S)-1-phenylethylamine, including
(S)-2, to give (R)-R-aryl-substituted homoallylic amines.2a
Particularly, we observed that allylzinc bromide added
to the re face of (S)-2 with better diastereoselectivity (dr
87:13) than other allylmetal reagents. Consequently, we
Resu lts a n d Discu ssion
Herein we describe that allylzinc bromide adds to (S)-1
with increased diastereoselectivity with respect to allyl-
magnesium chloride, and in both cases the major dias-
tereomer possesses the R configuration of the newly
formed stereocenters, as shown in (R,R)-4.
Allylzinc bromide was easily prepared from allyl
bromide and zinc powder in THF and was used more
conveniently than allylmagnesium chloride, for which the
diastereoselectivity was dependent on stringent temper-
ature control (-78 °C) and on the addition rate (syringe-
controlled addition). The addition of allylzinc bromide
(3 mol equiv) did not require particular care and afforded
the amine 4 with excellent yield (GC, 98%; isolated yield,
92%) and a diastereomeric ratio (dr) of 93.5:3:3.5, re-
ported in the order of elution determined by GC-MS
analysis of the crude reaction mixture.4 On the other
hand, the addition of allylmagnesium chloride in the
same conditions was unsatisfactory (GC, 4, 92%; dr 65:
17:18; unidentified high-boiling byproducts, 8%).
The crude product 4 obtained by the allylzincation
reaction was chromatographed to obtain the prevalent
diastereomer (>99% pure) with 76% yield. Fortunately,
in an alternative attempt for purification, 4 crystallized
from diethyl ether in crystals (57% yield) suitable for
X-ray structure analysis. The molecular structure in the
* Corresponding author: tel, (051)259571; fax, (051)259456; e-mail,
savoia@ciam.unibo.it.
X Abstract published in Advance ACS Abstracts, May 15, 1997.
(1) (a) Neumann, W.; Rogic, M. M.; Dunn, T. J . Tetrahedron Lett.
1991, 32, 5865. (b) Bambridge, K.; Begley, M. J .; Simpkins, N. S.
Tetrahedron Lett. 1994, 35, 3391.
(2) (a) Alvaro, G.; Boga, C.; Savoia, D.; Umani-Ronchi, A. J . Chem.
Soc., Perkin Trans. 1 1996, 875. (b) Alvaro, G.; Savoia, D.; Valentinetti,
M. R. Tetrahedron 1996, 52, 12571.
(3) (a) Yamamoto, Y.; Nishii, S.; Maruyama, K.; Komatsu, T.; Ito,
W. J . Am. Chem. Soc. 1986, 108, 7778. (b) Yamamoto, Y.; Ito, W.
Tetrahedron 1988, 44, 5415. (c) van der Heide, T. A. J .; van der Baan,
J . L.; de Kimpe, V.; Bickelhaupt, F.; Klumpp, G. W. Tetrahedron Lett.
1993, 34, 3309. (d) Hallet, D. J .; Thomas, E. J . J . Chem. Soc., Chem.
Commun. 1995, 657.
(4) A minor product (<2% yield) was formed in all the reaction
mixtures produced with allylzinc and -magnesium halides in different
conditions. GC-MS analysis showed a retention time falling within
the range of the three expected diastereomeric products 4 and,
surprisingly, the identical mass spectral fragmentation. We suppose
that it is a diastereomer of 4 resulting from the diallylation of (R,S)-1,
most likely present in addition to (S,S)-1, due to the ascertained
presence of small amounts of the R enantiomer in the starting (S)-1-
phenylethylamine.
S0022-3263(96)02219-0 CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 12, 1997 4181
1
bromide to (S,S)-1 was assessed by GC-MS and H-NMR
analysis and pointed against the occurrence of the radical
mechanism in the first allylation step.
As in our previous reports on the addition of allyl- and
methylmetal reagents to bi- and tridentate imines de-
rived from (S)-1-phenylethylamine2 and methyl (S)-
valinate,7 we assume that the 1:1 complex 7a (Chart 1)
is preliminarily formed between (S,S)-1 and allylzinc
bromide and that the intramolecular nucleophilic transfer
of the allyl group to one of the two CdN double bonds
occurs through a six-membered cyclic transition state.
By analogy with previous observations on (S,S)-2,2b we
demonstrated by 1H-NMR spectroscopy and NOE experi-
ments that the most stable conformation of the imine 1
is that in which the two azomethine groups are oriented
anti to each other, as depicted in Chart 1, but with the
H-CdN bond almost eclipsed with the H-C* bond of
the auxiliary. In fact, irradiation of the azomethine
proton gave a positive NOE response on the H-C* (15%)
and Ph (3%) absorptions of the auxiliary. The orientation
of the auxiliary was slightly modified by complexing the
imine with anhydrous zinc bromide, i.e., in 7b, as the
same NOE experiment gave similar responses on the
H-C* (9%) and Ph (6%) absorptions. This suggested that
Ph was more inclined toward H-CdN to the detriment
of H-C*; therefore, we postulate that in 7b, and conse-
quently in the organometallic complex 7a , the methyl in
the auxiliary group is approximately anti to H-CdN.
The two azomethine groups in 7a are not equally
leaned toward the intramolecular nucleophilic attack;
however, they become equivalent by simple interchange
of the allyl and bromide substituents at zinc. Consider-
ing the different steric properties of the H and Ph
substituents of the auxiliary, the transfer of the allyl
group will occur to the more accessible azomethine group.
The bridged bicyclic transition state 8 (Chart 1) is then
proposed for the first carbon-carbon bond-forming step.
A polar mechanism is reasonably assumed in the
second allylation step, which is chelation-controlled, since
the azomethine group has an R-zincioamido-substituted
stereocenter. The syn relative configuration of the newly
formed stereocenters is expected according to the Cram
rule (1,2-asymmetric induction), and the stereocontrol is
enforced by the 1,3-asymmetric induction of the auxiliary.
In our opinion, (R,R)-4 is produced through the bicyclic
transition state 9 (Chart 1).
The higher degree of stereocontrol provided by allylzinc
bromide with respect to allylmagnesium chloride in this
reaction can be attributed to the lower reactivity of the
zinc reagent, resulting in a later transition state, and to
its higher Lewis acidity. Similarly, allylzinc halides and
diallylzinc were preferred to Grignard reagents for the
diastereoselective addition to CdO,8 CdN,2a,3c,7,9 and CdC
groups.10
The cleavage of the auxiliary groups of (R,R)-4 with
concomitant hydrogenation of the CdC double bonds was
accomplished by treatment with ammonium formate in
the presence of palladium on carbon in methanol to afford
the C2-symmetric diamine (R,R)-10 (Chart 1), which was
isolated as the dihydrochloride salt in 85% yield.
The synthetic utility of the allylation reaction of the
bis-imine 1 is increased by the possibility, only in part
explored,1a to functionalize the CdC double bonds prior
to removing the auxiliary. Moreover, substituted allylic
F igu r e 1. Molecular structure of (R,R)-4 in the solid state,
showing the labeling scheme. The crystallographic 2-fold axis
passes through the C1-C1′ bond and is perpendicular to the
plane of the picture. Relevant bond distances (in Å): N1-C1,
1.453(3); N1-C5, 1.460(3); C1-C1′, 1.531(4); C1-C2, 1.537(3); C2-
C3, 1.446(6); C3-C4, 1.158(6) (see the Experimental Section);
C5-C6, 1.528(6);C5-C7 1.502(4).
solid state is depicted in Figure 1, which shows the R
configuration of the newly created stereocenters.
The diazaoctane chain in between the two methyl
carbons C6 and C6′ of the auxiliary groups can be seen as
constituted by two equivalent W-type fragments related
by a crystallographic 2-fold axis passing through the
C1-C1′ bond. The atoms of the chain are almost coplanar
(maximum elevation from the average plane 0.28 Å), this
resulting in a staggered arrangement of the substituents,
i.e., the allyl groups at C1 and C1′ and the phenyl groups
at C5 and C5′.
The R,R configuration of the C1 and C1′ carbon atoms
is in agreement with the asymmetric induction observed
in the addition of phenylmagnesium chloride to (R,R)-1
in Et2O at -78 °C (si face addition), which afforded 5
(Chart 1) with dr 90:10.1b The configuration of 5 was
established by X-ray structure analysis, and its molecular
features are similar to those of (R,R)-4; by analogy, the
same stereochemical outcome was reasonably supposed
for the preparation of 6 by the addition of methylmag-
nesium bromide to (R,R)-1 (dr 70:30).1b Moreover, meth-
yllithium added to the re face of (S)-2, although the si
face addition mainly occurred with monodentate aromatic
imines.2b Consequently, at the moment this sense of
asymmetric induction (re face addition to the (S)-imine,
and vice versa) appears to be general for the reactions of
the bidentate imines derived from 1-phenylethylamine,
as represented by 1-3, with organometallic reagents
capable of chelation.
The same asymmetric induction was also observed in
the addition of the zinc enolates of esters and R-amino
esters to the imines (R,R)-1 and (R)-2, where the azeti-
dinones were produced with the S configuration at C4.5
Notably, the reaction of the lithium enolate of methyl
phenylacetate with (R,R)-1 gave exclusively the N-
alkylation product (1,2-diaminoethene) by a SET radical
process5b that was also operating in the reaction of
dialkylzinc compounds with 1,4-diazadienes.6 The ab-
sence of the N-monoallylated product in the crude reac-
tion mixture resulting from the addition of allylzinc
(5) (a) van der Steen, F. H.; Kleijn, H.; Britovsek, G. P.; J astrzebski,
J . T. B. H.; van Koten, G. J . Org. Chem. 1992, 57, 3906. (b) Kleijn,
H.; van Maanen, L.; J astrzebski, J . T. B. H.; van Koten, G. Recl. Trav.
Chim. Pay-Bas 1992, 111, 497. (c) van Maanen, H. L.; Kleijn, H.;
J astrzebski, J . T. B. H.; Lakin, M. T.; Spek, A. L.; van Koten, G. J .
Org. Chem. 1994, 59, 7839.
(6) Wissing, E.; Kleijn, H.; Boersma, J .; van Koten, G. Recl. Trav.
Chim. Pay-Bas 1993, 112, 618. In this paper it was asserted that
alkylzinc halides instead form stable complexes with 1,4-diazadienes.
(7) (a) Bocoum, A.; Savoia, D.; Umani-Ronchi, A. J . Chem. Soc.,
Chem. Commun. 1993, 1542. (b) Basile, T.; Bocoum, A.; Savoia, D.;
Umani-Ronchi, A. J . Org. Chem. 1994, 59, 7766. (c) Alvaro, G.; Savoia,
D. Tetrahedron: Asymmetry 1996, 7, 2083.

4182 J . Org. Chem., Vol. 62, No. 12, 1997
Notes
126.7, 116.3, 56.6, 56.0, 35.0, 25.1; GC-MS m/z (relative
intensity) 105 (100), 174 (97), 70 (60), 307 (6). (R,R)-4
corresponds to the previously prepared diastereomer of 4,
zinc reagents, e.g., bearing functional groups that are
incompatible with Grignard reagents, can be presumably
exploited aiming to prepare structurally more complex
molecules.
having [R]19.5 ) -120 (c 0.023, CH2Cl2), to which the wrong
D
configuration was assigned.1a
Cr ysta l Str u ctu r e Deter m in a tion of (R,R)-4. Diffraction
intensities for compound (R,R)-4 were collected at room
temperature on an Enraf-Nonius CAD-4 diffractometer equipped
with a graphite monochromator (Mo KR radiation, l ) 0.710 73
Å). The intensities were reduced to Fo2, and the structure was
solved by direct methods followed by difference Fourier and
subsequent full-matrix least-squares refinement using the
computer programs SHELX8612a and SHELXL92.12b All non-H
atoms were allowed to vibrate anisotropically. The H atoms
were added in calculated positions and refined riding on their
respective carbon atoms. Results of thermal motion analysis12c
showed that, on top of rigid-body libration of the whole
molecule around an axis almost parallel to the cell R-axis, the
C3-C4 group (numbering according to Figure 1) experiences a
very large additional librational motion around the C1-C2
bond, both facts being responsible for the poorly resolved C3-
C4 double-bond distance. SCHAKAL912d was used for the
graphical representation of the results. Crystal data and
details of measurement: monoclinic, C2; a ) 21.870(4), b )
6.675(4), c ) 7.726(4) Å; â ) 97.68(3)°, Z ) 2, V ) 1117.7(9)
Å3; Fcalcd ) 1.036 mg m-3, 2θ-range ) 2.5-25.0°; 2062 measured
reflections, 1822 independent reflections used in the refine-
ment, 119 refined parameters; R1 [I > 2σ(I)] ) 0.0598, R2w
(all data) ) 0.1819. Tables of crystal data, atomic coordinates,
and bond distances and angles have been deposited with the
Cambridge Crystallographic Data Centre.14
Exp er im en ta l Section
Gen er a l. General methods were described previously.2a
N,N-Bis-[(S)-1-ph en yleth yl]eth an ediim in e [(S,S)-1]. The
previously reported procedure starting from 40% aq glyoxal
can be followed;11 however, the following method is more
convenient. In a dry apparatus, the mixture of glyoxal trimer
dihydrate (Aldrich; 1.05 g, 15 mmol), MgSO4 (7 g), and (S)-1-
phenylethylamine (Fluka; ee g 99%,4 3.63 g, 30 mmol) in
anhydrous CH2Cl2 (30 mL) was stirred in N2 atmosphere for
5 h and then filtered, and the solution was concentrated at
reduced pressure to leave (S,S)-1 as an oil: 3.96 g, 100% yield;
1
[R]20 ) -152 (c 2.26, CHCl3); H NMR (CDCl3, 300 MHz) δ
D
8.07 (s, 2), 7.38-7.24 (m, 10), 4.53 (q, J ) 6.7 Hz, 2), 1.60 (d,
J ) 6.7 Hz, 6); by irradiating at δ 8.07 (CHdN) positive NOE
on the absorption at δ 7.35 (Ph, 3%) and 4.53 (CHMe, 15%)
were observed; 13C NMR (CDCl3, 200 MHz) δ 160.6, 143.5,
128.5, 127.2, 126.6, 69.6, 23.9.
Com p lex 7b. To the solution of (S,S)-1 (0.264 g, 1 mmol)
in CDCl3 (2 mL) was added anhydrous ZnBr2 (0.225 g, 1 mmol),
and the mixture was stirred until complete dissolution.
A
1
sample was analyzed by H-NMR spectroscopy (200 MHz): δ
8.03 (s, 2), 7.40-7.23 (m, 10), 5.14 (q, J ) 7 Hz, 2), 1.92 (d, J
) 7 Hz, 6); by irradiating at δ 8.03 (CH)N) positive NOE at
δ 7.37 (Ph, 6%) and 5.14 (CHMe, 9%) were observed; 13C NMR
(CDCl3, 200 MHz) δ 157.1, 138.2, 129.2, 128.9, 128.0, 66.3,
22.2.
(R,R)-4,5-Dia m in oocta n e [(R,R)-10]. To the solution of
the diamine (R,R)-4 (1.05 g, 3 mmol) in anhydrous methanol
(60 mL) were added Pd/C (0.06 g) and ammonium formate
(1.14 g, 18 mmol). The mixture was magnetically stirred at
reflux temperature for 2 h. After cooling, the reaction mixture
was filtered and the solvent evaporated at reduced pressure
to leave an oil (0.500 g), containing the diamine (R,R)-10 and
some ethylbenzene. To the mixture were added methanol (5
mL) and 37% hydrochloric acid (0.5 mL, 6 mmol). Benzene
(10 mL) and methanol (10 mL) were added, then the solvents
were removed at reduced pressure, and the operation was
repeated twice. The residue was recrystallized from chloro-
N,N-Bis[(S)-1-p h en yleth yl]-(R,R)-4,5-d ia m in o-1,7-octa -
d ien e [(R,R)-4]. Zinc powder (1.30 g, 20 mmol, previously
heated for 5 min at 150 °C while stirring with a magnetic bar
in N2 atmosphere and then cooled to room temperature) was
covered with anhydrous THF (15 mL). Freshly distilled allyl
bromide (1.81 g, 15 mmol) was added, and the mixture was
stirred for 2 h. Stirring was stopped, and excess zinc powder
was allowed to deposit on the bottom of the flask; then the
clear solution of allylzinc bromide was taken by a syringe and
poured slowly (10 min) onto the stirred solution of (S,S)-1 (1.32
g, 5 mmol) in anhydrous THF (15 mL) cooled at -78 °C. The
mixture was stirred for a further 1.5 h; then the reaction was
quenched with a solution obtained by mixing 1 M NH4Cl (5
mL) and 30% NH4OH (5 mL). The organic phase was
separated, and the aqueous phase was extracted with Et2O
(20 mL × 3); the collected organic layers were dried over
Na2SO4, filtered, and concentrated to leave 4 as a crystalline
form to give (R,R)-10‚2HCl (0.550 g, 85%): mp 194-5 °C (lit.13
1
mp 218-220 °C) (d,l); [R]20 ) +31.4 (c 2.04, H2O); H NMR
D
(300 MHz, D2O) δ 3.46 (m, 2), 1.50 (m, 4), 1.39-1.14 (m, 8),
0.78 (t, 6); 13C NMR (300 MHz, D2O, MeOH as internal
standard) δ 52.2, 28.9, 18.3, 12.9.
1
solid (1.60 g, 92%); high purity was assessed by H NMR and
GC-MS analysis, the latter indicating dr 93.5:3:3.5. The main
diastereomer (R,R)-4 was obtained pure with 76% yield by
chromatography on a SiO2 column (cyclohexane/ethyl acetate,
85:15) or by crystallization of the crude product from Et2O.
The latter procedure allowed to obtain with 57% yield crystals
Ack n ow led gm en t. These investigations were sup-
ported by The University of Bologna: Funds for Selected
Research Topics.
suitable for X-ray structure analysis: mp 68-70 °C; [R]20
)
Su p p or tin g In for m a tion Ava ila ble: Crystal data and
details of measurement, ORTEP drawing, tables of atomic
coordinates, bond angles and distances, and anisotropic ther-
mal parameters for (R,R)-4 (6 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
D
1
-126.8 (c 2.04, CH2Cl2); H NMR (300 MHz, CDCl3) δ 7.40-
7.20 (m, 10), 5.46-5.35 (m, 2), 4.84-4.67 (m, 4), 3.74 (q, J )
6.6 Hz, 2), 2.22-2.03 (m, 6), 1.50 (br, 2), 1.26 (d, J ) 6.6 Hz,
6); 13C NMR (300 MHz, CDCl3) δ 146.4, 136.4, 128.2, 127.1,
(8) (a) Nagaoka, H.; Kishi, Y. Tetrahedron 1981, 37, 3873. (b)
Fronza, G.; Fuganti, C.; Grasselli, P.; Pedrocchi-Fantoni, G.; Zirotti,
C. Tetrahedron Lett. 1982, 23, 4143. (c) Mulzer, J .; Angermann, A.
Tetrahedron Lett. 1983, 24, 2843. (d) Fuganti, C.; Servi, S.; Zirotti, C.
Tetrahedron Lett. 1983, 24, 5285. (e) Tamao, K.; Nakajo, E.; Ito, Y. J .
Org. Chem. 1987, 52, 957. (f) Overly, K. R.; Williams, J . M.; McGarvey,
G. J . Tetrahedron Lett. 1990, 31, 4573. (g) Taniguchi, M.; Oshima,
K.; Utimoto, K. Bull. Chem. Soc. J pn. 1995, 68, 645.
(9) (a) Dembe´le´, Y. A.; Belaud, C.; Hitchcock, P.; Villie´ras, J .
Tetrahedron: Asymmetry 1992, 3, 351. (b) Dembe´le´, Y. A.; Belaud, C.;
Villie´ras, J . Tetrahedron: Asymmetry 1992, 3, 511.
(10) (a) Kubota, K.; Nakamura, M.; Isaka, M.; Nakamura, E. J . Am.
Chem. Soc. 1993, 115, 5867. (b) Nakamura, M.; Arai, M.; Nakamura,
E. J . Am. Chem. Soc. 1995, 117, 1179. (c) Beruben, D.; Marek, I.;
Normant, J .-F.; Platzer, N. J . Org. Chem. 1995, 60, 2488. (d) van der
Baan, J . L.; van der Heide, T. A. J . ; van der Louw, J .; Klumpp, G. W.
Synlett 1995, 1.
J O962219V
(12) (a) Sheldrick, G. M. Acta Crystallogr. 1990, A46, 467. (b)
Sheldrick, G. M. SHELXL92, Program for Crystal Structure Determi-
nation; University of Go¨ttingen: Go¨ttingen, Germany, 1993. (c)
Trueblood, K. N. THMA11, Thermal motion analysis computer pro-
gram; University of California: Los Angeles, CA, 1990. (d) Keller, E.
SCHAKAL92, Graphical Representation of Molecular Models; Univer-
sity of Freiburg: Germany, 1992.
(13) J ung, S.-H.; Kohn, H. J . Am. Chem. Soc. 1985, 107, 2931.
(14) The author has deposited atomic coordinates for this structure
with the Cambridge Crystallographic Data Centre. The coordinates
can be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.
(11) tom Dieck, H.; Dietrich, J . Chem. Ber. 1984, 117, 694.