Asymmetric synthesis of 1,2-diamines by the addition of allylic zinc and magnesium reagents to N,N'-bis[(S)-1-phenylethyl)]ethanediimine

Article abstract of DOI:10.1055/s-2000-6377

The diimine prepared by condensation of glyoxal trimer dihydrate with (S)-1-phenylethylamine underwent double addition of allylic zinc compounds (2-butenyl-, 2,4-pentadienyl-, 2-methyl-2-propenylzinc bromide) in THF generally at -78 °C, with allylic inversion. The newly formed stereocentres adjacent to the nitrogen atoms had prevalently the R configuration. Removal of the auxiliary from the secondary 1,2-diamines with concomitant hydrogenation of the C=C double bonds afforded the primary 1,2-diamines. The reaction with 3-methyl-2-butenylzinc bromide gave almost exclusively the α- amino imine from which the α-aminoaldehyde was obtained by hydrolysis. On the other hand, 3-methyl-2-butenylmagnesium chloride reacted at 0-20 °C to give the diamine with linear-chain substituents, owing to the reversibility of the organometallic addition.

Full text of DOI:10.1055/s-2000-6377

PAPER
581
Asymmetric Synthesis of 1,2-Diamines by the Addition of Allylic Zinc and
Magnesium Reagents to N,N’-Bis[(S)-1-phenylethyl)]ethanediimine
Giuseppe Alvaro,a Fabrizia Grepioni,b Stefano Grilli,c Lucia Maini,c Gianluca Martelli,c Diego Savoiac,*
a Glaxo-Wellcome S.p.A., Medicines Research Centre, via A. Fleming 4, 37100 Verona, Italy
b Dipartimento di Chimica, Università di Sassari, via Vienna 2, 07100 Sassari, Italy
c Dipartimento di Chimica "G. Ciamician", Università di Bologna, via Selmi 2, 40126 Bologna, Italy
Fax: 39(051)2099456; E-mail: savoia@ciam.unibo.it
Received 23 October 1999; revised 27 November 1999
Abstract: The diimine prepared by condensation of glyoxal trimer
N
N
dihydrate with (S)-1-phenylethylamine underwent double addition
of allylic zinc compounds (2-butenyl-, 2,4-pentadienyl-, 2-methyl-
2-propenylzinc bromide) in THF generally at -78 °C, with allylic
inversion. The newly formed stereocentres adjacent to the nitrogen
atoms had prevalently the R configuration. Removal of the auxiliary
from the secondary 1,2-diamines with concomitant hydrogenation
of the C=C double bonds afforded the primary 1,2-diamines. The
reaction with 3-methyl-2-butenylzinc bromide gave almost exclu-
sively the a-amino imine from which the a-aminoaldehyde was ob-
tained by hydrolysis. On the other hand, 3-methyl-2-
butenylmagnesium chloride reacted at 0-20 °C to give the diamine
with linear-chain substituents, owing to the reversibility of the orga-
nometallic addition.
Ph
Ph
(R,R)-1
R
N
R
N
R
N
R
N
RMgX
R
R
S
S
+
Ph
Ph
H
H
Ph
H
H
Ph
Et2O, -78 °C
ref. 2
(S,S)-2, -3
(R,R)-2, -3
2: R = Ph: (S,S)/(R,R) = 90:10 (1H NMR)
3: R = Me: (S,S)/(R,R) = 70:30 (1H NMR)
N
N
Ph
Ph
(S,S)-1
HCO2NH4
Pd(OH)2/C
t-BuMgCl
Key words: allylations, amines, asymmetric synthesis, Grignard re-
N R
H
N
actions, zinc
R
hexane-Et2O
45 °C, (ref. 3) Ph
EtOH, 80 °C
H
Ph
(R,R)-4, d.r.>99:1
The double addition of organometallic reagents to enanti-
omerically pure 1,2-diimines derived from glyoxal is an
appealing route to C2 symmetric 1,2-diamines.1 The enan-
tiomers of 1-phenylethylamine have been generally used
as the chiral auxiliaries in these reactions,2-5 but the dias-
tereoselective addition of MeLi-CeCl3 reagent to the bis-
SAMP-hydrazone has been reported (yield 50%, d.e.
98%).6 It has been claimed that the addition of Grignard
reagents and alkyllithiums to the diimine (R,R)-1 in tet-
rahydrofuran (THF) gave a complex mixture of products,
and the reaction with phenylmagnesium chloride in dieth-
yl ether afforded only two diastereomers of the 1,2-di-
amine 2 with a diastereomeric ratio (d.r.) = 90:10 (Scheme
1). The S configuration of the newly formed stereocenters
of the main diastereomer 2 was determined by X-ray crys-
tallographic analysis.2 Under the same conditions, meth-
ylmagnesium bromide afforded the diamine 3,
presumably with the same sense of asymmetric induction,
but with lower diastereoselectivity (d.r. = 70:30).2
H2N
NH2
(R,R)-5
Scheme 1
ing, considering the relatively high temperature at which
the reaction was performed and the low diastereoselectiv-
ities generally observed in the additions of tert-butyl orga-
nometallic reagents to chiral bidentate imines derived
from 2-pyridinaldehyde.7
Moreover, it was described that the carefully controlled
addition of allylmagnesium chloride to either (R,R)- or
(S,S)-1 in THF at -78 °C gave mixtures of two diastereo-
meric homoallylic diamines 6 with d.r. = 86:14 (Scheme
2).4 We successively demonstrated that the addition to
(S,S)-1 afforded mainly (R,R)-6 in that reaction, and fur-
thermore improved the diastereoselectivity by using al-
lylzinc bromide. In fact, we obtained the three
diastereomers with d.r. = 93.5:3:3.5, and then prepared
optically pure (R,R)-4,5-diaminooctane ((R,R)-7) by re-
moval of the auxiliary.5 Moreover, we have recently re-
ported the transition metal-catalyzed cyclization reactions
of the diamine (R,R)-6 to give 1,2-diamino-4-cyclohexene
and 1,2-diamino-4,5-dimethylcyclohexane derivatives 88
and 9,9 respectively.
More recently, the preparation of (R,R)-3,4-diamino-
2,2,5,5-tetramethylhexane ((R,R)-5) has been described,3
involving the addition of the diimine (S,S)-1 to tert-butyl-
magnesium chloride in hexane/ether mixture at 45 °C to
give almost exclusively the secondary diamine (R,R)-4
(for sake of simplicity, only the configuration of the newly
formed stereocentres of the secondary diamines are indi-
cated), and the subsequent hydrogenolysis step (Scheme
1). The diastereoselectivity therein obtained was surpris-
Synthesis 2000, No. 4, 581–587 ISSN 0039-7881 © Thieme Stuttgart · New York

582
G. Allvaro et al.
PAPER
(S,S)-1
omers could be obtained, and all were detected by GC-
MS analysis of the crude reaction mixture. However, two
diastereomers were highly predominant, accounting for
90% of the whole mixture. We separated them by column
chromatography and observed by 1H and 13C NMR spec-
troscopy that the first eluted isomer had C2-symmetry
while the second one had C1-symmetry. For both com-
pounds the (R,R)-configuration of the newly formed ste-
reocentres at C4 and C5 (adjacent to the nitrogen atoms)
was supposed by analogy with the known asymmetric in-
duction observed in the formation of the diamine 6. The
complete assignment of the stereochemistry of the C2-
symmetric diamine (R,R)-10a was achieved by the X-ray
spectroscopic analysis of the corresponding bis-hydro-
chloride (R,R)-10a.2HCl. In fact, the structure depicted in
Figure 1 (see Supporting Material) shows the R configu-
ration of C4 and C5 and the S configuration of C3 and C6.
The structure is analogous to that of (R,R)-6, described in
our previous work.5 The molecular symmetry is C2 with a
staggered arrangement of the phenyl and allyl groups with
respect to the diazaoctane chain.
THF,
-78 °C
M
+
+
R
S
R
S S
N R
N
N
N
N
N
Ph
Ph
Ph
H
H
Ph
H
H
Ph
H
H
Ph
(R,R)-6
(S,R)-6
(S,S)-6
M = MgCl: (R,R)/(S,S) = 86:14 (1H NMR, syringe-controlled addition, ref. 4)
M = ZnBr: (R,R)/(S,R)/(S,S) = 93.5:3:3.5 (GC-MS, ref. 5)
HCO2NH4,
Pd/C
crystallization or
chromatography
(R,R)-6
MeOH,
H2N
NH2
65 °C
(R,R)-7
ref. 7
ref. 8
N
N
Ph
H
H
Ph
TsHN
NHTs
8
9
Scheme 2
ZnBr
(S,S)-1
+
R
N R
H
N
R
N R
H
N
THF, -78 °C
Ph
H
Ph
Ph
H
Ph
(R,R)-10a, 30%
after chromatography
(R,R)-10b, 25%
after chromatography
We did not succeed in further improving the diastereose-
lectivity in the preparation of the diamine 6 by using (al-
lyl)2Zn-MgCl2, (allyl)Et2ZnMgCl,5 allylPbBr-MBrCl,10,11
(allyl)3Al2Br3,10 and (allyl)Bu3Sn-TiCl4. Only with
allylSnCl2I11 we achieved a high diastereoselectivity (d.r.
= 95:5), but only 80% conversion of the diimine was ob-
served by GC-MS analysis despite the use of 5 molar
equivalents of allylmetal compound, and this caused the
difficult purification of the product.
1) HCO2NH4, Pd/C
MeOH, 65 °C, 2 h
2) HCl
R
R
ClH3N R
NH3Cl
ClH3N R
NH3Cl
(R,R)-11b, 85%
(R,R)-11a, 85%
Since allylzinc bromide appeared to be the reagent of
choice, we successively investigated the reactivity, regi-
oselectivity and diastereoselectivity of substituted allylz-
inc bromides, aiming at the same time to prepare novel
1,2-diamines having sterically demanding alkyl substitu-
ents on the chain connecting the nitrogen atoms. Here we
report the outcomes of the addition reactions of the imine
(S,S)-1 with 2-butenylzinc bromide,12 2,4-pentadienylzinc
bromide,13 2-methyl-2-propenylzinc bromide12 and 3-me-
thyl-2-butenylzinc bromide.14 All the reagents were pre-
pared by the direct reaction of the corresponding allylic
bromide with zinc powder in anhydrous THF in nitrogen
atmosphere. Alternatively, since the preparation of 2,4-
pentadienylzinc bromide was not readily reproducible
owing to Wurtz coupling reaction,13c we prepared 2,4-
pentadienylzinc chloride via metallation of 1,4-pentadi-
ene with n-BuLi in hexane/Et2O mixture,15 followed by
transmetallation with the ZnCl2-TMEDA complex.16
Scheme 3
Suitable crystals were not obtained for the other isolated
diastereomer, but we are confident that it has the same R
configuration of C4 and C5, consistent with the degree of
diastereoselectivity demonstrated in the previous and fol-
lowing reactions involving allylic zinc reagents. This im-
plies that the same auxiliary-induced and substrate-
induced diastereoselectivities occurred in the addition of
crotylzinc bromide and only the simple (syn/anti) diaste-
reoselectivity was not controlled, being dependent on the
geometry of the C = C double bond in the organometallic
reagent.17 Hence, we presume that the other diastereomer
has the structure depicted for (R,R)-10b, differing from
(R,R)-10a only for the configuration of the stereocentres
at C3 and C6. After hydrogenolysis and concomitant hy-
drogenation of the C=C double bonds of (R,R)-10a,b, the
bis-hydrochlorides of the saturated primary diamines
(R,R)-11a,b were obtained, both having positive values of
optical activity.
Crotylzinc bromide quickly reacted at -78 °C in THF to
give the diamine 10 in high yield by a double addition pro-
cess with allylic rearrangement (Scheme 3). Since four
stereocentres were formed in this reaction, nine diastere-
Synthesis 2000, No. 4, 581–587 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of 1,2-Diamines by the Addition of Allylic Zinc
583
It is noteworthy that 2,4-pentadienylzinc bromide or chlo- value of the N1-C1-C2-N2 torsion angle (174.07° and
ride reacted exclusively at C3 of the pentadienyl moiety to 176.55° for the two molecules, respectively). One of the
give the branched amine with high yield and diastereose- two minor diastereomers of the secondary diamine (S,S)-
lectivity (Scheme 4). Only reactions with carbonyl com- 15 was isolated by column chromatography, but was not
pounds were previously described,13 and the ratio of converted to the corresponding primary diamine.
branched to linear addition products was found to be de-
pendent on the steric and electronic factors of the carbonyl
substituent(s) as well as the solvent and the temperature.
(S,S)-1
In our reaction, the main diastereomer (R,R)-12 accounted
for 92% of the mixture (GC-MS analysis) and was easily
THF, 0 ºC
ZnBr
obtained pure with 75% yield by chromatography, or with
70% yield by crystallization from methanol. The second-
ary diamine (R,R)-12 was in part submitted to hydrogen-
ation on Pd/C in MeOH to obtain the saturated secondary
diamine (R,R)-13, and in part converted to the primary di-
amine (R,R)-14 by hydrogenation-hydrogenolysis using
ammonium formate and Pd/C in refluxing MeOH. The
positive sign of the optical rotation power of the dihydro-
chloride of the diamine (R,R)-14 demonstrated the
assigned configuration by comparison with the dihydro-
chloride of (4R,5R)-diaminooctane (R,R)-75 and (R,R)-
11a.
+
+
S
S
S
R
R
R
N
N
N
N
N
N
Ph
Ph
Ph
H
H
Ph
H
H
Ph
H
H
Ph
(S,S)-15
(S,R)-15
(S,S)/(S,R)/(R,R) = 10:11:79 (GC/MS)
chromatography chromatography
(R,R)-15
(S,S)-15, 8%
(R,R)-15, 55%
1) HCO2NH4, Pd/C, MeOH, 65 °C, 2 h
2) HCl
The addition of 2-methyl-2-propenylzinc bromide to
(S,S)-1 occurred only at 0 °C and produced the three dias-
tereomers of the diamine 15 with a ratio 10:11:79, in the
order of elution by GC-MS analysis, suggesting the op-
posite configuration of the newly formed stereocenters
(Scheme 5). Instead, the prevalent diastereomer was sep-
arated by column chromatography and then converted to
the saturated primary diamine, whose dihydrochloride
had a positive value of optical rotation power, and conse-
quently the R configuration of the newly formed stereo-
centers as depicted for (R,R)-16. This compound was then
converted to the ditosylamide (R,R)-17, which crystal-
lized nicely from MeOH. Two independent molecules
are present in the asymmetric unit, differing only in the
TsCl, Et3N
CH2Cl2
ClH3N
NH3Cl
TsHN
NHTs
(R,R)-16, 75%
(R,R)-17, 52%
Scheme 5
The reaction of the diimine (S,S)-1 with one equivalent of
3-methyl-2-butenylzinc bromide occurred even at -78 °C
(Scheme 6) and afforded the mono-addition product, i.e.
the a-amino imine 18, presumably having the R configu-
ration of the newly formed stereocenter in the main dias-
tereomer (d.r. = 90:10 by GC and 1H NMR analysis). On
the other hand, when the reaction was performed with 2.5
equivalents of the reagent, one product coming from a
double addition process was formed in trace amounts. The
yield, however, did not increase by raising the tempera-
ture to 25 °C, as observed by GC-MS analysis of the re-
action mixture. Moreover, by heating the reaction mixture
at reflux a complex mixture of diastereomeric bis-adducts
was formed. The imine function of the product 18 under-
went hydrolysis during the chromatographic purification
on SiO2 column and the optically pure a-amino aldehyde
19 was isolated with 45-50% yield. It should be consid-
ered that imine 18 and aldehyde 19 are promising interme-
diates for the preparation of asymmetrically substituted
1,2-diamines and 1,2-aminoalcohols by nucleophilic ad-
ditions to the unsaturated functional groups.
(S,S)-1
ZnBr or
THF, -78 °C
ZnCl-TMEDA
1) HCO2NH4, Pd/C
MeOH,65 °C, 2 h
H2, Pd/C
R
N R
H
N
MeOH, 25 °C
24h
2) HCl
Ph
H
Ph
(R,R)-12, d.r. 92:2:6;
70%, d.r. >99:1 after
crystallization
Differing from the corresponding zinc reagent, 3-methyl-
2-butenylmagnesium chloride added to the diimine
(S,S)-1 at 0-25 °C to give the double addition product 20
with high diastereoselectivity (d.r. = 91:9 by GC-MS
analysis). Both the diastereomers had linear alkyl substit-
uents, as shown by 1H NMR analysis of the crude product.
R
N R
H
N
ClH3N
NH3Cl
Ph
H
Ph
(R,R)-13, 75%
(R,R)-14, 85%
Scheme 4
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584
G. Allvaro et al.
PAPER
mL). The collected organic layers were dried (Na2SO4) and concen-
trated at reduced pressure. The residue was chromatographed on a
SiO2 column at medium pressure eluting with cyclohexane/Et2O
mixtures. The yields of the pure compounds reported below refer to
chromatographed compounds. Alternatively, the products were iso-
lated with slightly lower yields when the crude reaction products
were extracted with MeOH and allowed to crystallize.
ZnBr
HCl 2N
Et2O
(S,S)-1
CHO
N
N
N
THF, -78 ºC, 2 h
Ph
Ph
H
Ph
H
MgCl
18, 90% (crude),
d.z. 90:10
19, 50%
THF, 0-25 ºC
3,6-Dimethyl-4(R),5(R)-di-[1(S)-phenylethylamino]octa-1,7-di-
ene [(R,R)-10a,b]
These compounds were isolated by column chromatography on
SiO2 column eluting with cyclohexane/Et2O (95:5), in the following
order of elution.
H2, Pd/C, MeOH
HCl
(R,R)-10a (1.50 g, 30%, 10a:10b = 93:7); [a]20 -57.4 (c 1.32,
N
N
D
ClH3N
NH3Cl
Ph
H
Ph
H
CHCl3).
1H NMR (CDCl3, 200 MHz): d = 7.40-7.20 (m, 10H, Ph), 5.65-
5.45 (m, 2H, CH = CH2), 4.85-4.60 (m, 4H, CH = CH2), 3.76 (q,
2H, PhCHMe), 2.30-2.15 (m, 4H, NCHCHMe), 1.5 (broad, 2H,
NH), 1.25 (d, 6H, J = 7.0 Hz, PhCHMe), 0.71 (d, 6H, J = 7.0 Hz,
CHCHMe).
20, 90% (crude), d.r. 91:9;
after chromatography: 66%, d.r. 99:1
(R,R)-21, 70%
Scheme 6
MS: m/z (%) = 105 (100) [PhCHMe], 188 (60) [M+/2], 84 (45), 321
However, the course of the reaction performed in the tem-
perature range -78 to 25 °C could be followed by GC-
MS analysis. In this way, we demonstrated the intermedi-
acy of the branched a-amino imine 18 and a number of in-
termediate double addition products, one of which had the
same retention time as that of the minor product previous-
ly detected in the organozinc reaction. We can reasonably
assume that the linear double addition product 20 was
formed through a series of retro-addition and re-addition
processes. The secondary diamine 20 was then converted
to the bis-hydrochloride of the primary diamine (R,R)-21
by routine procedure. In this case H2 rather than
HCO2NH4 was used as the reducing agent, and the expect-
ed R configuration was confirmed by the positive value of
the optical rotation power.
(11) [M+-C4H7], 79 (11), 77 (8), 161 (7), 266 (3, M+-2 C4H7).
The diamine (R,R)-10a was converted to the bis-hydrochloride
(R,R)-10a.2HCl, which nicely crystallized from MeOH): mp
208 °C (dec.); [a]20D -6 (c 0.35, CHCl3).
1H NMR (CDCl3, 300 MHz): d = 11.1, 9.9 and 1.6 (br, 4H, NH2),
7.78 (m, 4H, Ph), 7.48 (m, 6H, Ph), 4.88 (m, 2H, CH = CH2), 4.53
(d, 2H, J = 10.2 Hz, CH = CH2), 4.43 (q, 2H, NCHMe), 3.51 (d, 2H,
J = 17.4 Hz, CH = CH2), 2.76 (m, 4H, NCHCHMe), 2.04 (d, 6H,
J = 6.6 Hz, NCHMe), 1.33 (d, 6H, J = 5.1 Hz, NCHCHMe).
20
(R,R)-10b (1.25 g, 25%, 10b:10a 93:7); [a]D -44.8 (c 1.23,
CH2Cl2).
1H NMR (CDCl3, 200 MHz): d = 7.35-7.15 (m, 10H, Ph), 5.65-
5.43 (m, 2H, CH = CH2), 4.85-4.50 (m, 4H, CH = CH2), 3.76 and
3.68 (2 q, 2H, PhCHMe), 2.25-2.10 (m, 4H, NCHCHMe), 1.50 (br,
2H, NH), 1.25 and 1.22 (2 d, 6H, J = 7.0 Hz, PhCHMe), 0.75 and
0.63 (2 d, 6H, J = 7.0 Hz, CHCHMe).
General methods and the procedure for the preparation of the imine
were described previously.5 The allylic zinc reagents were prepared
from the corresponding allylic bromides according to the described
procedures,12-14 and the clear solutions were taken by a syringe after
decantation of unreacted zinc powder.
3,6-Diethenyl-4(R),5(R)-di-[1(S)-phenylethylamino]octa-1,7-di-
ene [(R,R)-12]
Yield: 2.80 g (70%) after crystallization from MeOH; mp 59 °C;
[a]20D -2.5 (c 2.24, CHCl3).
1H NMR (CDCl3, 200 MHz): d = 7.30-7.13 (m, 10H, Ph), 5.69-
5.55 (m, 2H, CH = CH2), 5.40-5.27 (m, 2H, CH = CH2), 4.88-4.68
(m, 6H, CH = CH2), 4.27-4.18 (m, 2H, CH = CH2), 3.67 (q, 2H,
CHMe), 2.70 (q, 2H, NCHCH), 2.19 (d, 2H, J = 6.8 Hz, NCHCH),
1.48 (br, 2H, NH), 1.22 (d, 6H, J = 6.6 Hz, CHMe).
13C NMR (300 MHz, CDCl3): d = 146.1, 139.6, 139.1, 128.0, 127.8,
126.8, 115.5, 114.6, 57.5, 56.2, 52.3, 24.2.
MS: m/z (%) = 105 (100) [PhCHMe], 200 (26) [M+/2], 266 (18), 79
(17), 161 (16), 77 (12), 106 (11), 96 (9), 103 (8), 333 (8) [M+-
C5H7).
Preparation of 2,4-Pentadienylzinc Chloride-TMEDA Complex
from Penta-1,4-diene
Penta-2,4-dienyllithium was prepared according to the reported
procedure.15 Penta-1,4-diene (3.6 mL, 3.5 mmol), pre cooled at 0 °C
owing to its volatility, was added slowly to a solution of BuLi (1.6
M in hexane, 18.8 mL, 30 mmol) in THF (10 mL) at -78 °C. The
temperature was allowed to rise to 0 °C and two phases were
formed. THF (3 mL) and ZnCl2-TMEDA complex (7.57 g,
30 mmol) were added at the same temperature, and the mixture was
stirred by a magnetic bar for 1 h. The orange colour of the organic
phase became yellow and a white precipitate was formed. The clear
solution was taken up by a syringe after decantation.
2,7-Dimethyl-4,5-di-[1(S)-phenylethylamino]octa-1,7-diene
[(R,R)-15 and (S,S)-15)]
The crude reaction product, obtained as a yellowish solid, was chro-
matographed to obtain pure diastereomers as oily compounds, in the
following order of elution:
(S,S)-15: 0.300 g (8%); [a]20D -90.1 (c 0.56, CHCl3).
1H NMR (CDCl3, 300 MHz): d = 7.40-7.20 (m, 6H, Ph), 7.10 (m,
4H, Ph), 4.85 (s, 2H, C = CH2), 4.73 (s, 2H, C = CH2), 3.54 (q, 2H,
CHMe), 2.74 and 2.43 (2 d, 4H, J = 10.7, 14.2 Hz, CHCH2), 1.81 (t,
Reactions of the Imine (S,S)-1 with Allylic Zinc Reagents. Prep-
aration of Secondary 1,2-Diamines
A solution of the allylic zinc reagent (30 mmol) was added slowly
(15 min) to a solution of the imine (2.65 g, 10 mmol) in THF
(30 mL) at -78 °C (0 °C for 15). The mixture was stirred for 1.5-3
h, during which the progress of the reaction was followed by TLC
or GC-MS analysis. Then the mixture was quenched with 20 mL of
a 1:1 mixture of 1 M NH4Cl and 30% NaOH. The organic phase was
separated and the aqueous phase was extracted with Et2O (3 ¥ 20
Synthesis 2000, No. 4, 581–587 ISSN 0039-7881 © Thieme Stuttgart · New York

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Asymmetric Synthesis of 1,2-Diamines by the Addition of Allylic Zinc
585
2H, NCHCHN), 1.47 (s, 6H, CH2 = CMe), 1.44 (s, 2H, NH), 1.21 (d,
6H, J = 6.7 Hz, CHMe).
Anal. Calcd for C10H26Cl2N2: C, 48.98, H, 10.69, N, 11.42. Found:
C, 48.77, H, 10.71, N, 11.39.
MS: m/z (%) = 105 (100), 188 (72) [M+/2], 84 (40), 79 (15), 77 (11),
321 (4) [M+- C4H7].
4(R),5(R)-Diamino-3,6-diethyloctane Dihydrochloride (R,R)-14
Yield: 0.70 g (85%); mp 228 °C (dec.); [a]20D +29.1 (c 1.90, H2O).
The free amine had [a]20D +18.9 (c 2.06, CHCl3).
1H NMR (CDCl3, 300 MHz, 20 °C): d = 8.2 and 2.6 (br, NH3), 4.2
(m, 2H, CHN), 1.6-1.4 (m, 2H, NCHCH), 1.55-1.10 (m, 8H), 0.92
(m, 12H, Me).
(R,R)-15: 2.08 g (55%); [a]20D -107.2 (c 0.724, CHCl3).
1H NMR (300 MHz, CDCl3-D2O): d = 7.40-7.20 (m, 10H, Ph),
4.43 (s, 2H, C = CH2), 3.95 (s, 2H, C = CH2), 3.67 (q, 2H, CHMe),
2.25, 2.10 and 1.95 (3 m, 6H, NCHCH2), 1.39 (s, 6H, CH2 = CMe),
1.27 (d, 6H, J = 6.6 Hz, CHMe).
Anal. Calcd for C12H30Cl2N2: C, 52.74, H, 11.06, N, 10.25. Found:
C, 52.70, H, 11.08, N, 10.23.
3,6-Diethyl-4(R),5(R)-di-[1(S)-phenylethylamino]octane [(R,R)-
13)]
10% Pd/C (30 mg) was added to a solution of the diamine (R,R)-12
(0.400 g, 1 mmol) in MeOH (15 mL) and the mixture was stirred in
H2 atm (1 atm) for 24 h. The solution was filtered through Celite,
then concentrated at reduced pressure, and the residue was chro-
matographed on an SiO2 column eluting with cyclohexane/EtOAc
(95:5) to obtain the diamine (R,R)-13 as an oil.
4(R),5(R)-Diamino-2,7-dimethyloctane Dihydrochloride [(R,R)-
16]
Yield: 0.54 g (75%); mp 218 °C (dec.); [a]20 +29.1 (c 1.80,
D
MeOH).
1H NMR (D2O, 300 MHz, 20 °C): d = 3.74 (m, 2H, CHN), 1.72 (m,
4H, NCHCH2), 1.48 (m, 2H, CHMe2), 1.0 and 0.96 (2 d, 12H,
J = 6.3 Hz, CHMe2).
Yield: 0.300 g (75%); [a]20D -26 (c 1.33, CHCl3).
1H NMR (CDCl3, 200 MHz,): d = 7.35-7.15 (m, 10H, Ph), 3.85 (q,
2H CHMe), 2.25 (s, 2H, NCHCHN), 1.58 (br, 2H, NH), 1.29 (d, 6H,
J = 6.6 Hz, CHMe), 1.40-0.90 (m, 10H, CH2CHCH2), 0.82 and
0.73 (2 t, 12H, CH2Me).
Anal. Calcd for C10H26Cl2N2: C, 48.98, H, 10.69, N, 11.42. Found:
C, 48.91, H, 10.71, N, 11.39.
4(R),5(R)-Diamino-2,7-dimethyloctane di-(4-methylbenzene-
sulfonamide) [(R,R)-17]
MS: m/z (%) = 204 (100) [M+/2], 105 (88) [PhCHMe], 100 (40),
205 (17), 106 (9), 79 (9), 103 (6), 77 (6), 337 (5, M+-C5H11).
4-Toluenesulfonyl chloride (0.152 g, 0.80 mmol) was added to the
stirred suspension of salt (R,R)-16 (0.090 g, 0.37 mmol) and Et3N
(0.56 mL, 4.0 mmol) in CH2Cl2 (6 mL) at 0 °C. The mixture was
stirred overnight at r.t., filtered, washed with 2 N HCl (3 mL), then
with brine. The organic phase was dried (Na2SO4) and concentrated
to leave a solid, which was washed with Et2O until a white solid was
obtained, which was recrystallized from MeOH.
Anal. Calcd for C28H44N2: C, 82.29, H, 10.85, N, 6.85. Found: C,
82.34, H, 10.87, N, 6.82.
Hydrogenation/Hydrogenolysis of the Unsaturated Secondary
1,2-Diamines; Preparation of the Saturated Primary 1,2-Di-
amines
Yield: 0.090 g, 52%; mp 198-200 °C; [a]25D +84.5 (c 0.44, CHCl3).
To a solution of the diamine (3 mmol) in MeOH (60 mL) was added
Pd/C (0.06 g) and HCO2NH4 (1.14 g, 18 mmol), and the mixture
was heated at the reflux temperature with stirring for 2 h. After cool-
ing, the solution was filtered off and concentrated at reduced pres-
sure to leave an oil containing some ethylbenzene. MeOH (15 mL),
10 N HCl (0.5 mL, 6 mmol) and benzene (10 mL) were added, and
the mixture was concentrated at reduced pressure. This operation
was repeated another two times and finally the residues (the di-hy-
drochlorides of the diamines) were thoroughly washed with CHCl3
until a white powder was obtained.
1H NMR (CDCl3+D2O, 300 MHz): d = 7.78 and 7.36 (2 d, 8H,
J = 7.8 8.1 Hz, SO2C6H4Me), 3.32 (t, 2H, NCHCHN), 2.40 (s, 6H,
SO2C6H4Me), 1.33 (m, 4H, CHCH2CH), 0.82 (m, 2H, CHMe2),
0.67 and 0.54 (2 d, 12H, J = 6.3, 6.0 Hz, CHMe2).
Anal. Calcd for C24H36N2O4S2: C, 59.98, H, 7.55, N, 5.83, Found:
C, 59.94, H, 7.57, N, 5.81.
N-[1(S)-Phenylethyl]-3,3-dimethyl-2(R)-[1(S)-phenylethylami-
no]-4-penteneimine (18)
The solution of the zinc reagent (8 mmol) in THF (40 mL) was
cooled to -78 °C, then the diimine (S,S)-1 (0.53 g, 2 mmol) dis-
solved in THF (2 mL) was added during 15 min. The reaction mix-
ture was stirred for 2 h, then quenched with 1 M HCl (6 mL) and
further stirred for 20 min at 20 °C. After cooling to 0 °C, KOH pel-
lets were added until the aq phase reached pH 11, the organic phase
was separated, and the aq phase extracted with Et2O (3 ¥ 20 mL).
The collected ethereal layers were dried (Na2SO4) and concentrated
at reduced pressure to leave the crude imine 18 as a reddish oil.
4(R),5(R)-Diamino-3(R),6(R)-dimethyloctane Dihydrochloride
[(R,R)-11a]
Yield: 0.63 g (85%); mp 230 °C (dec.); [a]20D +7.5 (c 0.77, MeOH).
1H NMR (D2O, 300 MHz, 20 °C, MeOH as internal standard):
d = 3.57 (m, 2H, CHN), 2.0 (m, 2H, CHMe), 1.43 (m, 4H, CH2Me),
0.95 (m, 12 H, Me).
13C NMR (D2O, 300 MHz, MeOH as internal standard): d = 55.4,
33.1, 25.8, 12.2, 10.4.
Yield: 0.60 g, 1.8 mmol, 90%; [a]D25 -101.8 (c 0.82, CHCl3).
IR (neat): n = 3304 (NH), 1666 (C = N) cm-1.
Anal. Calcd for C10H26Cl2N2: C, 48.98, H, 10.69, N, 11.42. Found:
C, 48.82, H, 10.73, N, 11.38.
1H NMR (CDCl3, 300 MHz): d = 7.48 (d, 1H, J = 5.7 Hz, CH = N),
7.38-7.15 (m, 10H, Ph), 5.95-5.83 (m, 1H, CH = CH2), 5.06-4.95
(m, 2H, CH = CH2), 4.25 (q, 1H, CH = NCHMe), 3.65 (q, 1H,
CHNHCHMe), 2.99 (d, 1H, J = 5.1 Hz, CHNH), 1.95 (br, 1H, NH),
1.47 (d, 3H, J = 6.6 Hz, C = NCHMePh), 1.29 (d, 3H, J = 6.6 Hz,
CHNHCHMePh), 1.1 and 1.05 (2 s, 6H, CMe2).
4(R),5(R)-Diamino-3(R),6(S)-dimethyloctane Dihydrochloride
[(R,R)-11b]
Yield: 0.63 g (85%); mp 232 °C (dec.); [a]20D +2.6 (c 0.39, MeOH).
1H NMR (D2O, 200 MHz, 20 °C, MeOH as internal standard):
d = 3.65-3.40 (m, 2H, CHN), 2.05-1.85 (m, 2H,CHMe), 1.60-
1.30 (m, 4H, CH2Me), 1.10-0.80 (m, 12H, Me).
13C NMR (D2O, 300 MHz, MeOH as internal standard): d = 56.6,
55.2, 33.4, 33.2, 25.7, 22.7, 15.0, 12.9, 10.4, 10.0.
MS: m/z (%) 105 (100) [PhCHMe], 265 (25) [M+-C5H9], 78 (13),
161 (10), 215 (10), 57 (5), 69 (2).
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586
G. Allvaro et al.
PAPER
3,3-Dimethyl-2-[1(S)-phenylethylamino]pent-4-enal (19)
Compound 18 (0.50, g, 1.5 mmol) dissolved in Et2O (4 mL) with
2 N HCl (4 mL) was stirred for 12 h, followed by treatment with
NaOH to reach pH 11. Extraction (Et2O, 2 ¥ 5 mL) and chromatog-
raphy on SiO2 column eluting with cyclohexane/EtOAc mixture
(95:5) gave the aldehyde 19 as an oil.
Yield: 0.174 g (50%); [a]25D -70.6 (c 0.51, CHCl3).
IR (neat): n = 3317 (NH), 1726 (C = O) cm-1.
1H NMR (CDCl3, 300 MHz): d = 9.47 (d, 1H, J = 2.4 Hz, CHO),
7.35-7.10 (m, 5H, Ph), 6.0-5.8 (m, 1H, CH = CH2), 5.15-5.0 (m,
2H, CH = CH2), 3.68 (q, 1H, CHMe), 2.89 (d, 1H, J = 2.4 Hz,
CHNH), 2.0 (br, 1H, NH), 1.33 (d, 3H, J = 6.6 Hz, CHMe), 1.15 and
1.07 (2 s, 6H, Me).
Fourier and subsequent full-matrix least-squares refinement using
the computer programs SHELXL97.18a Fractional atomic coordi-
nates and anisotropic displacement parameters are available as Sup-
porting Information. SCHAKAL9718b was used for the graphical
representation of the results. Common to all compounds: MoKa ra-
diation, l = 0.71069 Å, monochromator graphite, temperature
293 K. All non-H atoms were refined anisotropically. The position
of the N-H hydrogen atoms in both (R,R)-10a.2HCl and (R,R)-17
were observed in the Fourier maps and not refined, while the C-H
hydrogen atoms were added in the calculated positions.
(R,R)-10a.2HCl: C26H36Cl2N2, M = 447.47, tetragonal, P 41212;
a = 13.160(5), b = 13,160(10), c = 31,28(2) Å, Z = 8, V = 5417(6)
Å3; rcalc = 1.097 Mg/m-3, Q-range = 3.0-23.0°, 4187 measured re-
flections, 3753 independent reflections used in the refinement, 247
refined parameters; R1[I>2s(I)] = 0.0822, Rw2(all data) = 0.3174.
MS: m/z (%) = 105 (100), 98 (26), 202 (13) [M+-CHO], 77 (12), 79
(11), 162 (7), [M+-C5H9].
(R,R)-17: C24H36N2O4S2, M = 480.67, monoclinic, P21,
a = 10.333(3), b = 15.061(5), c = 17.252(5) Å, b = 98.36(2)°,
Z = 2, V = 2656.3(14) Å3; rcalc = 1.202 Mg/m-3, Q-range = 3.0-
5.0°; 5019 measured reflections, 4853 independent reflections used
in the refinement, 529 refined parameters; R1[I>2s(I)] = 0.0471,
Rw2(all data) = 0.1385.
Anal. Calcd for C15H21NO: C, 77.88, H, 9.15, N, 6.05. Found: C,
77.49, H, 9.18, N, 6.03.
2,9-Dimethyl-5(R),6(R)-di-[1(S)-phenylethylamino]deca-2,8-di-
ene [(R,R)-20)]
To an approx 1 M soluion of 3,3-dimethyl-2-propenylmagnesium
chloride in THF (22 mL, 22 mmol) (prepared according to the liter-
ature), cooled at 0 °C, was added the imine (S,S)-1 (1.85, 7 mmol)
dissolved in THF (10 mL). The reaction mixture was stirred at
25 °C for 90 min, then quenched with aq NaHCO3, and the organic
phase was extracted with Et2O (3 x 20 mL). The collected ethereal
phases were dried (Na2SO4) and concentrated to leave crude 20
(90 %, d.r. =99:1) which was then chromatographed on a SiO2 col-
umn eluting with cyclohexane/EtOAc mixture (90:10) to give the
pure diamine 20 as an oil.
Tables of crystallographic data, atomic coordinates, bond distances,
and angles have been deposited with the Cambridge Crystallo-
graphic Data Centre.19
Acknowledgement
Financial support from the Ministero dell'Università e della Ricerca
Scientifica e Tecnologica, Roma, and The University of Bologna
(National Project "Stereoselezione in Sintesi Organica. Metodolo-
gie ed Applicazioni") is gratefully acknowledged.
Yield: 1.85 g (66%); [a]20D -116.9 (c 1.4, CHCl3).
1H NMR (200 MHz, CDCl3) d 7.40-7.15 (m, 10H, Ph), 4.68 (t, 2H,
CH = C), 3.76 (q, 2H, CHMe), 2.18-1.95 (m, 6H, NCHCH2), 1.55
and 1.46 (2 s, 12H, CMe2), 1.4 (s, 2H, NH), 1.23 (d, 6H, J = 6.9 Hz,
CHMe).
References
(1) The chemistry of vicinal 1,2-diamine has been recently
reviewed:
MS: m/z (%) = 105 (100) [PhCHMe], 202 (56) [M+/2], 98 (22), 81
Bennani, Y. L.; Hanessian, S. Chem. Rev. 1997, 97, 3161.
Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed.
Engl. 1998, 37, 2580.
(14), 335 (10) [M+-C5H9].
(2) Bambridge, K.; Begley, M. J.; Simpkins, N. S. Tetrahedron
Lett. 1994, 35, 3391.
(3) Roland, S.; Mangeney, P.; Alexakis, A. Synthesis 1999, 228.
(4) Neumann, W.; Rogic, M. M.; Dunn, T. J. Tetrahedron Lett.
1991, 32, 5865.
(5) Alvaro, G.; Grepioni, F.; Savoia, D. J. Org. Chem. 1997, 62,
4180.
(6) Enders, D.; Meiers, M. Angew. Chem., Int. Ed. Engl. 1996, 35,
2261.
(7) Alvaro, G.; Pacioni, P.; Savoia, D. Chem. Eur. J. 1997, 3, 726.
Alvaro, G.; Martelli, G.; Savoia, D. J. Chem. Soc., Perkin
Trans. 1 1998, 775.
(8) Alvaro, G.; Grilli, S.; Martelli, G.; Savoia, D. Eur. J. Org.
Chem. 1999, 3, 1523.
(9) Grepioni, F.; Grilli, S.; Martelli, G.; Savoia, D. J. Org. Chem.
1999, 64, 3679.
(10) Basile, T.; Bocoum, A.; Savoia, D.; Umani-Ronchi, A. J. Org.
Chem. 1994, 59, 7766.
(R,R)-2,9-Dimethyl-5,6-diaminodecane Dihydrochloride
[(R,R)-21]
A Parr apparatus was filled with the diamine (R,R)-20 (1.01 g,
2.5 mmol), MeOH (40 mL) and Pd/C (100 mg), then submitted to a
pressure of 45 psi H2 for 24 h. The solution was filtered through a
small pad of Celite, then concentrated to a volume of 10 mL, and
37% HCl (0.5 mL) was added. The mixture was concentrated at re-
duced pressure, and benzene (5 mL) and MeOH (5 mL) were added.
The mixture was concentrated, and the operation was repeated. The
solid residue was treated with CH2Cl2 (5 mL), filtered and washed
with CH2Cl2 (5 mL), then dried at reduced pressure to give pure
(R,R)-21.
Yield: 0.476 g, 70%; mp 204 °C (dec.); [a]20 +25.1 (c 0.94,
D
MeOH).
1H NMR (300 MHz, D2O) d = 3.46 (m, 2H, CHN), 1.56 (m, 4H,
NCHCH2), 1.45 (m, 2H, CHMe2), 1.16 (m, 4H, CH2CHMe2), 0.75
and 0.73 (2 d, 12H, J = 6.6 Hz, CHMe2).
(11) Alvaro, G.; Savoia, D. Tetrahedron: Asymmetry 1996, 7,
2083.
Anal. Calcd for C12H30Cl2N2: C, 52.74, H, 11.06, N, 10.25. Found:
C, 52.53, H, 11.10, N, 10.23.
(12) Frangin, Y.; Gaudemar, M. Bull. Soc. Chim. Fr. 1975, 1173.
(13) (a) Gerard, F.; Miginiac, P. Bull. Soc. Chim. Fr. 1974, 1924.
(b) Gerard, F.; Miginiac, P. Bull. Soc. Chim. Fr. 1974, 2527.
(c) The successful addition of pentadienylzinc bromide to an
aldehyde by a Barbier procedure with ultrasonic activation of
Crystal Structure Characterisation of (R,R)-10a.2HCl and
(R,R)-17
All X-ray diffraction data collections were carried out on a NON-
IUS CAD-4 diffractometer. The intensities were reduced to F2, and
the structures were solved by direct methods followed by difference
Synthesis 2000, No. 4, 581–587 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of 1,2-Diamines by the Addition of Allylic Zinc
587
zinc has been described: Chen, L.-Y; Ghosez, L. Tetrahedron:
Asymmetry 1991, 2, 1181.
Yamamoto, Y.; Komatsu, T.; Maruyama, K. J. Organomet.
Chem. 1985, 285, 31.
(14) Miginiac, P.; Zamlouty, G. J. Organomet. Chem. 1975, 96,
163.
Yamamoto, Y.; Nishii, S.; Maruyama, K.; Komatsu, T.; Ito,
W. J. Am. Chem. Soc. 1986, 108, 7778.
Barbot, F.; Miginiac, P. Bull. Soc. Chim. Fr. 1977, 113.
Yanagisawa, A.; Habaue, S.; Yamamoto, H. J. Org. Chem.
1989, 54, 5198.
Taniguchi, M.; Oshima, K.; Utimoto, K. Chem. Lett. 1992,
2135.
Taniguchi, M.; Oshima, K.; Utimoto, K. Chem. Lett. 1992,
2135.
(18) (a) Sheldrick, G. M. SHELXL97, Program for Crystal
Structure Determination; University of Göttingen; Göttingen,
Germany, 1997.
(15) Bates, R. B.; Gosselink, D. W.; Kaczynski, J. A. Tetrahedron
Lett. 1967, 199.
(b) Keller, E. SCHAKAL97, Graphical Representation of
Molecular Models; University of Freiburg, Germany, 1997.
(19) The author has deposited atomic coordinates for these
structures at the Cambridge Crystallographic Data Centre.
The coordinates can be obtained, on request, from the
Director, Cambridge Crystallographic data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK.
Bates, R. B.; Gosselink, D. W.; Kaczynski, J. A. Tetrahedron
Lett. 1967, 205.
(16) The preparation of 2,4-pentadienylzinc bromide from
pentadienyl potassium was previously described:
Yasuda, H.; Ohnuma, Y.; Nakamura, A.; Kai, Y.; Yasuoka,
N.; Kasai, N. Bull. Chem. Soc. Jpn. 1980, 53, 1101.
(17) The addition of 3-butenylzinc bromide to aldehyde and imines
gave mixtures of syn- and anti-diastereomers:
Courtois, G.; Miginiac, L. J. Organomet. Chem. 1974, 69, 1.
Article Identifier:
1437-210X,E;2000,0,04,0581,0587,ftx,en;Z07899SS.pdf
Synthesis 2000, No. 4, 581–587 ISSN 0039-7881 © Thieme Stuttgart · New York