Chiral polyamino alcohols via hydroaminomethylation: A new class of polyamines for dendritic cores and ligand precursors

Article abstract of DOI:10.1002/adsc.200900267

In this contribution, the synthesis of a new class of chiral polyamino alcohols (PAA) via a two-step hydroaminomethylation/hydrolysis procedure is reported. The chiral polyamines are obtained by hydroaminomethylation of N-olefinic oxazolidinones with diff

Full text of DOI:10.1002/adsc.200900267

FULL PAPERS
DOI: 10.1002/adsc.200900267
Chiral Polyamino Alcohols via Hydroaminomethylation: A New
Class of Polyamines for Dendritic Cores and Ligand Precursors
Muhammad Afzal Subhani,a,b Kai-Sven Mꢀller,a and Peter Eilbrachta,*
a
Organische Chemie Institut, Universitꢁt Dortmund, Otto-Hahn-Str. 6, 44221 Dortmund, Germany
Fax : (+49)-231-755-5363; e-mail: peter.eilbracht@uni-dortmund.de
Present address: School of Chemical and Materials Engineering, National University of Science and Technology,
b
H-12 Islamabad, Pakistan
Received: April 17, 2009; Revised: June 25, 2009; Published online: September 8, 2009
Abstract: In this contribution, the synthesis of a new ciently through a multifold hydroaminomethylation/
class of chiral polyamino alcohols (PAA) via a two- hydrolysis procedure. Furthermore, chiral PAA are
step hydroaminomethylation/hydrolysis procedure is investigated as ligands in ruthenium-catalyzed asym-
reported. The chiral polyamines are obtained by hy- metric hydrogen transfer reduction of acetophenone
droaminomethylation of N-olefinic oxazolidinones to 1-phenyl alcohol.
with different amines in first step followed by hydrol-
ysis of the resulting polyamines to give the chiral Keywords: amino alcohols; hydroaminomethylation;
PAA in the second step. The dendritic chiral PAA hydroformylation; hydrolysis; polyamines; polyami-
(Mw=1300–1400 gmolÀ1) are also synthesized effi- no alcohols
Introduction
In the last decade, hydroaminomethylation has
been used as a powerful tool in the synthesis of many
Chiral amino alcohols are important building blocks organic compounds of great importance.[9,10] Hydro-
of many natural products and an important functional
aminomethylation combines hydroformylation[11] and
ACHTUNGTRENNUNG
feature in the design of a number of enzyme inhibi- reductive amination to a synthetically versatile one-
tors.[1,2] Chiral amino alcohols are also versatile chiral pot procedure for the synthesis of secondary and terti-
auxiliaries and ligands for the introduction of chirality ary amines (Scheme 1). Syntheses of linear and cyclic
in asymmetric catalysis of C C, C O and C H bond- polyfunctionalized amines,[12] azamacro hetrocycles as
forming reactions.[3–5] Asymmetric addition of dialkyl- complexing agents for metal ions,[13] polyamine deriv-
zinc to carbonyl compounds and imines,[6] asymmetric atives of putrescine and spermidine from N-olefinic
cyanosilylation of aldehydes[7] and asymmetric hydro- phthalimide,[14] dendritic polyamine from polyallyl
gen transfer reduction of ketones[8] are some recent ethers[15] and selective synthesis of tertiary amines
examples in the literature where amino alcohols are from olefins and urea[16] via hydroaminomethylation
À
À
À
À
employed as chiral ligands. The presence of N O are some recent examples.
functional groups makes chiral amino alcohols suita-
Herein we report an efficient preparation of chiral
ble for chiral recognition and for a combinatorial ap- polyamino alcohols (PAA) by hydroaminomethyla-
proach to catalysis.
tion of chiral N-olefinic oxazolidinones 1a–c with dif-
Scheme 1. Hydroaminomethylation.
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Scheme 2. Synthesis of chiral amino alcohols via hydroaminomethylation/hydrolysis.
ferent amines (e.g., 2, 5, 8 and 11). In this synthetic methylation were used. As shown in Scheme 3 two-
strategy chiral N-olefinic oxazolidinones are used as fold hydroaminomethylation of 1a–c with piprazine 5
chiral amino alcohol masked functional groups. The gave chiral polyamines 6a–c in high yields. Subse-
carbamate ring of the oxazolidinones can be hydro- quently chiral PAA 7a–c were obtained on hydrolysis
lyzed with KOH (50 wt% in H2O) in ethanol to give of polyamines 6a–c (Scheme 3).
the respective chiral amino alcohols. Subsequently,
Recently, we envisaged urea as an ammonia
chiral PAA are used as ligand in the Ru-catalyzed source,[16,18] since it generates ammonia on hydrolysis
asymmetric hydrogen transfer reduction of acetophe- and simultaneously acts as a scavenger for aldehydes
none.
to protect them against reduction to alcohols. Follow-
ing these lines, tertiary polyamines 9a–c were synthe-
sized starting from 1a–c and urea 8 via hydroamino-
methylation. The desired symmetric polyamines 9a–c
were obtained selectively and in good to excellent
Results and Discussion
In initial studies, chiral N-olefinic oxazolidinones 1a–c yields and subsequently were hydrolyzed to give
were hydroaminomethylated with morpholine 2 as chiral polyamino alcohols 10a–c (Scheme 3).
amine component to give corresponding chiral amines
Polyamines and synthetic analogues have been in-
3a–c in excellent yields (Scheme 2). The optimized vestigated as potential therapeutic agents in various
hydroaminomethylation conditions {CO/H2 (1:1) biological disorders and have attracted considerable
60 bar, [RhACHTUNGTRENNUNG
(COD)Cl)]2 (0.3 mol%), 1208C, 48 h} were attention in organic chemistry.[19–20] The chiral amino
used for all reactions. No hydrogenation product of alcohols 4a–c and chiral PAA 7a–c and 10a–c having
an aldehyde was observed, because primary and sec- a chiral ethylhydroxy functional group at the nitrogen
ondary amines immediately condense with the alde- atom are similar to the derivatives of naturally occur-
hyde generated in situ and the resulting imines and/or ring polyamines such as putrescines and spermidine.
enamines are usually reduced under the harsh condi- Putrescines and spermidine are important biological
tions. The chiral oxazolidinones, also known as Evanꢃs polyamines which are present in all living cells and
auxiliaries, are well known for their use as chiral aux- play important physiological functions.[21] Purescine
iliaries for chiral induction.[17] But in this case, we did derivatives have been used as antimalaria[22] and anti-
not observe any chiral induction during hydroformyla- plasmodic agents.[23] This kind of polyamines has also
tion or reduction of imines. In the following step been found to be important in other fields of current
chiral amines 3a–c were hydrolyzed with KOH (50 research, for example, metabolism[24] and biogene-
wt% in H2O) in ethanol to give the corresponding sis,[25] antibiotics,[26] coagulation inhibitors,[27] antidiar-
chiral amino alcohols 4a–c in good to excellent yield rhoics[28] and cytostatics.[29]
(Scheme 2).
The two-step hydroaminomethylation/hydrolysis
Next, multi-fold hydroaminomethylation/hydrolysis procedure has been used so far to synthesize chiral
was carried out for the synthesis of dendritic chiral amino alcohols with low Mw (Scheme 2 and
PAA. This was achieved on use of multifunctional Scheme 3). The use of an amine core with a high
polyamine core molecules, for example, piperazine 5 degree of active sites available for hydroaminomethy-
for 2-fold, urea[16] 8 as ammonia equivalent for 3-fold lation will lead to dendritic chiral PAA. The tris(ami-
and tris(aminoethyl)amine 11 for 6-fold hydroamino- noethyl)amine 11 core molecule with three primary
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Chiral Polyamino Alcohols via Hydroaminomethylation
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Scheme 3. Synthesis of chiral PAA via hydroaminomethylation/hydrolysis.
amine groups gives access to a 6-fold hydroaminome- gands in the regioselectivity of hydroformylation is
thylation that leads directly to higher Mw dendritic well known.[31,32] It is also known that the presence of
polyamines in one step. Hydroaminomethylation of amines influences the n/iso selectivity of the hydrofor-
chiral N-methylallyloxazolidinones 1a–c with tris(ami- mylation step because amines compete with phos-
noethyl)amine 11 was carried out under standard hy- phines as ligands for the metal centre and thereby in-
droaminomethylation conditions (vide supra) in diox- fluence the regioselectivity. Therefore, for a highly re-
ane with a reaction time extended from 72 h to 120 h. gioselective hydroaminomethylation, the BIPHE-
The dendritic chiral PAA 12a-c (Mw=1300– PHOS 21 modified RhACTHNURTGNENG(U acac)CO2 catalysts was used
1400 gmolÀ1) were obtained in moderate to good in 1:5 ratio under optimized conditions [CO/H2 (10/10
yields (Scheme 4). Dialysis was used as a membrane bar), 508C, 48 h] for hydroformylation of 1a in the
ultrafiltration method for the purification of these first step. The aldehydes 14 were obtained in an n:iso
chiral polyamines 12a–c due to their higher Mw.[30]
ratio of (87:13) and in full conversion (Scheme 5) that
In our initial studies, N-methylallyloxazolidinone was determined by 1H NMR spectroscopy. To the
had been used as a model system to prove the princi- same pot (autoclave), amine cores 14 and/or 17 were
ple and to avoid the linear (n) to branched (iso) selec- added and set under reductive amination conditions
tivity problem in the initial hydroformylation step. [CO/H2 (10/50 bar)] to get dendritic polyamines 16
But the use of the N-methylallyl system leads to the and 19 that were hydrolyzed to give dendritic PAA 17
generation of an extra stereogenic centre on each and 20, respectively, in excellent yields (Scheme 5).
branch of the dendritic polyamines which is usually
We chose the ruthenium-catalyzed asymmetric hy-
not desired (Scheme 2, Scheme 3, and Scheme 4). drogen transfer reduction of acetophenone to 1-phe-
This problem can be avoided by the use of an N-allyl nylethanol as model reaction to investigate the initial
system instead of N-methylallyl, but regioselectivity is applications of these dendritic chiral polyamino alco-
a major problem in the initial hydroformylation step hols.[3c,8,33] Several ruthenium complexes were pre-
of such terminal olefins when Rh or Rh salts with tri- pared in situ from [RuCl2ACTHUNTRGNEUNG(p-cymene)]2 (2 mol%) and
phenylphosphine are used as catalysts for these reac- chiral PAA (4 mol%) in isopropyl alcohol and were
tions. Generally, the basic requirement to achieve employed in the asymmetric hydrogen transfer reduc-
high selectivity in hydroaminomethylation is to use a tion of acetophenone in the presence of KOH
catalyst with a combination of a phosphine or phos- (10 mol%). The isopropyl alcohol was used as hydro-
phite ligand in the initial hydroformylation step. The gen donor which have favourable properties such that
influence of different phosphine and phosphite li- it is stable, easy to handle (bp 828C), non-toxic, envi-
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Scheme 4. Synthesis of dendritic chiral PAA via hydroaminomethylation/hydrolysis.
ronmentally friendly, inexpensive and dissolves in as 13a–c and 20 have multiple sites available for cata-
many organic compounds. In addition, this reaction is lyst interaction that can be the reason for lower enan-
an attractive route as it avoids the use of pressurized tioselectivities. (Table 1, entries 10–12, 14). Further-
hydrogen and/or use of the hazardous reducing more, the better ees were obtained when chiral amino
agents. Initially, all of the chiral amino alcohol ligands alcohols and chiral PAA derived from 1a were used
were screened in the transfer hydrogenation of aceto- as ligands (Table 1, entries 1, 4, 7, 10 , 13 and 14) as
phenone and results are summarized in Table 1.
compared to the chiral amino alcohols and chiral
In general the catalytic reactions proceeded PAA derived from 1b and 1c, respectively (Table 1).
smoothly at room temperature and good to excellent
conversions (76–91%) and moderate to good ee (22–
71%) were observed (Table 1). The best ee (71%) was Conclusions
obtained when monoamino alcohol 4a was used as
ligand (Table 1, entry 1). However, a small decrease The chiral amino alcohols and chiral PAA were syn-
in enantioselectivity was observed with increased thesized in good to excellent yields via a two step hy-
number of amino alcohol functionalities and increase droaminomethylation/hydrolysis procedure. Our ap-
in Mw of chiral PAA which can be attributed to the proach relies on use of chiral N-olefinic oxazolid-
dendritic effect.[34] The larger polyamino alcohols such
ACHTUNGTRENiNGNU nones which are easily accessible from chiral pool of
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Chiral Polyamino Alcohols via Hydroaminomethylation
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Scheme 5. Regioselective hydroaminomethylation.
amino acids. The chiral oxazolidinone are used as alcohols and chiral PAA have also been employed as
chiral amino alcohol masked functionalities. To the ligands in the Ru-catalyzed asymmetric hydrogen
best of our knowledge, this is a new class of poly- transfer reduction of acetophenone. Good to excellent
amines with terminal chiral amino alcohol groups. conversion (76–91%) and moderate to good enantio-
This method is an efficient tool for the synthesis of selectivity (22–71%) were observed. The best results
new derivatives of highly biological active polyamines were obtained when chiral amino alcohols and chiral
such as putrescines and spermidine. The chiral amino PAA derived from (S)-4-benzyl-3-(2-methylallyl)oxa-
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Table 1. Ruthenium catalyzed asymmetric hydrogen transfer
reduction of acetophenone.
rified by column chromatography or bulb to bulb distillation
if necessary.
General Procedure B: Hydrolysis of Oxazolidinone
Functionalized Amines to Chiral Amino Alcohols
In a typical hydrolysis procedure, the oxazolidinone func-
tionalized amine or polyamine (1 mmol) was dissolved in
20 mL of ethanol. To the reaction mixture 10 mL of aqueous
KOH solution (50 wt%) were added and the mixture re-
fluxed for 20 h. Ethanol was removed under reduced pres-
sure and the aqueous phase was extracted with 15 mL of
ethyl acetate three times. Organic fractions were combined,
dried over MgSO4 and the solvent was removed under re-
duced pressure to get chiral amino alcohol or chiral PAA al-
cohol without any further purification.
Entry Ligand
[L*]
Conversion Yield
ee [%][c] (Config-
uration)
[%][a]
[%][b]
1
4a
91
89
90
88
83
76
90
92
78
85
79
81
92
89
85
84
85
84
78
72
85
86
73
81
71
74
85
82
71 (S)
68 (S)
57 (S)
69 (S)
60 (S)
40 (S)
64 (S)
41 (S)
31 (S)
59 (S)
51 (S)
22 (S)
63 (S)
57 (S)
2
4b
3
4c
4
7a
5
7b
6
7c
7
8
9
10
11
12
13
14
10a
10b
10c
13a
13b
13c
17
General Procedure C: Hydroaminomethylation N-
Methylallyloxazolidinones with Urea
A solution of N-methylallyloxazolidinone (10 mmol), urea
(10 mmol) and [RhACHTNURGTNEUNG(COD)Cl]2 (0.3 mol%) in 100 mL of di-
oxane:methanol:glacial acetic acid (90:9:1) solvent mixture
was placed in an pressure vessel (autoclave) and treated
under hydroaminomethylation conditions [40/40 bar (CO/
H2), at 100–1208C for 72 h]. After cooling, the pressure was
removed and the solvent was evaporated to dryness. The re-
sulting mixture was treated with 10 mL of conc. sodium hy-
droxide solution and 10 mL of water. The mixture was ex-
tracted with 200 mL of ethyl acetate, the organic layer was
dried over MgSO4 and the solvent was removed under re-
duced pressure. The crude product was purified by column-
chromatography on alumina (activity III) if necessary.
20
[a]
[b]
[c]
Determined by GC.
Isolated yields.
Determined by chiral GC.
zolidin-2-one (1a) were used as ligands. The chiral
PAA can also be used as potential core molecules for
higher generation dendrimer synthesis.
(S)-4-Benzyl-3-(2-methyl-4-morpholinobutyl)oxazolidin-2-
one (3a): The general procedure A for hydroaminomethyla-
tion was followed with morpholine (189 mg, 2.16 mmol) and
(S)-4-benzyl-3-(2-methylallyl)oxazolidin-2-one 1a (500 mg,
2.16 mmol). The crude product was purified by flash chro-
matography on alumina activity III to get chiral amine 3a as
an oil; yield: 597 mg (83%). 1H NMR (400 MHz, CDCl3):
d=0.81–1.02 (3H, m), 1.24–1.39 (2H, m), 1.84 (1H, m),
2.21–2.38 (6H, m), 2.81–2.94 (1H, m), 3.25–3.39 (1H, m),
3.01–3.11 (2H, m), 3.67–3.88 (4H, m), 4.13 (1H, m), 4.71–
4.89 (2H, m), 7.11–7.27 (5H, m); 13C NMR (400 MHz,
CDCl3): d=17.2, 28.1, 39.3, 48.8, 52.8, 53.2, 56.0, 56.5, 65.8,
Experimental Section
1
All general chemicals were purchased and used as such. H
and 13C NMR spectra were recorded at room temperature
with Bruker DRX 400 and DRX 500 spectrometers using
CDCl3 as solvent and TMS as internal standard. Infrared
spectroscopy was performed on a Nicolet Impact 400 D
spectrometer using KBr palletss or as disks with KBr. GC
analyses were performed on a Chromatograph MFS 800
(column: CHROMPACK DB-1701, 25 mꢄ0.32 mmꢄ1.0 m,
detector: FID) by FISON instruments.
˜
128.6, 130.3, 130.5, 137.0, 159.7. IR (film, KBr): n=708, 739,
768, 1011, 1053, 1135, 1248, 1396, 1462, 1501, 1606, 1741,
2810, 2926, 3026, 3534 cmÀ1; LR-MS (FAB): m/z=333.2
[M+H]+; HR-MS (FAB): m/z=333.215, calcd. for
C19H28N2O3 [M+H]+: 333.21.
General Procedure A: Hydroaminomethylation of N-
(S)-3-(2-Methyl-4-morpholinobutyl)-4-phenyloxazolidin-2-
one (3b): The general procedure A for hydroaminomethyla-
tion was followed with (S)-3-(2-methylallyl)-4-phenyloxazo-
lidin-2-one 1b (500 mg, 2.301 mmol) and morpholine
(200 mg, 2.301 mmol). The crude product was purified by
flash chromatography on alumina activity III to give chiral
amine 3b as an oil; yield: 695 mg (95%, 2.18 mmol).
1H NMR (400 MHz, CDCl3): d=0.78–0.96 (3H, dd, J=
6.53 Hz, 7.03 Hz), 1.19–1.77 (3H, m), 2.17–2.49 (4H, m),
2.55–2.74 (1H, m), 3.19–3.35 (1H, m), 3.64–3.76 (4H, m),
4.13–4.19 (1H, m), 4.61–4.81 (2H, m), 7.26–7.48 (5H, m);
13C NMR (100 MHz, CDCl3): d=17.5, 29.4, 30.6, 47.9, 53.9,
Methylallyloxazolidinones with Amines
In a typical hydroaminomethylation procedure, the N-meth-
ylallyloxazolidinone (10 mmol, 1 equiv.) and amine
(10 mmol, 1 equiv.) were dissolved in 10 mL of dioxane,
[RhACHTUNGTRENNUNG(COD)Cl]2 (15 mg,0.3 mol%) was added and the mix-
ture was placed in an pressure vessel (autoclave) and treated
under typical hydroaminomethylation conditions [CO:H2
(1:1) 60–80 bar, 1008C, 48–72 h]. Caution! CO is highly
toxic. The reaction vessel was cooled down to room temper-
ature and the solvent was removed under reduced pressure.
After evaporation of the solvent, the crude mixture was pu-
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56.5, 60.4, 67.1, 69.8, 127.0, 129.2, 138.0, 158.7; IR (film,
1.08 mmol) and (S)-4-benzyl-3-(2-methylallyl)oxazolidin-2-
one 1a (500 mg, 2.16 mmol). The crude product was purified
by flash chromatography on alumina activity III to get chiral
polyamine 6a as an oil; yield: 519 mg (84%). 1H NMR
(400 MHz, CDCl3): d=0.86–0.90 (6H, m), 1.24 and 1.52
(4H, m), 1.84 (2H, m), 2.52–2.63 (8H, m), 2.88–2.90 (2H,
m), 3.31–3.36 (2H, m), 3.05–3.08 (4H, m), 3.97 (4H, m),
˜
KBr): n=701, 759, 867, 1118, 1454, 1625, 1751, 2809, 2854,
2954, 3390 cmÀ1; ESI-MS: m/z=319.1 [M+H]+; HR-MS
(FAB): m/z=319.1860, calcd. for C18H26N2O3 [M+H]+:
319.1943.
(S)-4-Isopropyl-3-(2-methyl-4-morpholinobutyl)oxazoli-
din-2-one (3c): The general procedure A for hydroaminome-
thylation was followed with (S)-4-isopropyl-3-(2-methyl-
4.13
CDCl3): d=17.7, 30.1, 38.3, 47.8, 48.3, 52.8, 53.2, 56.0, 56.5,
(2H, m), 7.14–7.25 (10H, m); 13C NMR (400 MHz,
ACHTUNGTRENNUNG
ACHTUNGTRENNUNGallyl)oxazolidin-2-one 1c (213 mg, 1.163 mmol) and morpho-
˜
line (104 mg, 1.163 mmol). The crude product was purified
by flash chromatography on alumina activity III to give
chiral amine 3c as an oil; yield: 265 mg (79%, 0.91 mmol).
1H NMR (400 MHz, CDCl3): d=0.79–1.01 (9H, m), 1.14–
1.43 (2H, m), 1.69–1.94 (H, m), 2.02–2.16 (1H, m), 2.29–2.55
(4H, m), 2.78–2.94 (1H, m), 3.31–3.34 (1H, m), 3.62–3.77
(4H, m), 4.07–4.24 (3H, m); 13C NMR (100 MHz, CDCl3):
d=17.5, 18.1, 27.3, 29.5, 30.6, 53.8, 56.7, 58.3, 62.6, 67.1,
66.8, 128.6, 130.3, 130.5, 137.0, 159.7; IR (film, KBr): n=702,
743, 762, 1006, 1059, 1175, 1259, 1380, 1454, 1496, 1603,
1747, 2810, 2926, 3026, 3500 cmÀ1; LR-MS (FAB): m/z=
577.7 [M+H]+; HR-MS (FAB): m/z=576.3734, calcd. for
C34H48N4O4 [M+H]+: 576.3676.
Chiral polyamine (6b): The general procedure A for hy-
droaminomethylation was followed with piperazine (158 mg,
1.84 mmol) and (S)-4-phenyloxazolidin-2-one 1b (800 mg,
3:68 mmol). The crude product was purified by flash chro-
matography on alumina activity III to get chiral polyamine
6b as an oil; yield: 898 mg (91%). 1H NMR (400 MHz,
CDCl3): d=0.80–0.96 (6H, m), 1.21–1.34 (2H, m), 1.64–1.78
(2H, m), 1.36–1.34 (1H, m), 1.50–1.63 (2H, m), 2.13–2.56
(8H, m), 2.56–2.77 (2H, m), 3.20–3.37 (4H, m), 4.11–4.22
(2H, m), 4.59–4.71 (2H, m), 4.73–4.86 (2H, m), 7.25–7.48
(10H, m); 13C NMR (100 MHz, CDCl3): d=17.3, 29.8, 36.0,
47.8, 52.9, 56.1, 59.7, 69.7, 127.0,129.0, 129.2, 137.8; IR (film,
˜
68.6, 159. 8. IR (film, KBr): n=867, 914, 1118, 1286, 1373,
1461, 1621, 1741, 2884, 2956 cmÀ1; ESI-MS: m/z=285.3
[M+H]+ HR-MS (FAB): m/z=285.2025, calcd. for
C15H25N3O2 [M+H]+: 285.21.
(S)-2-(2-Methyl-4-morpholinobutylamino)-3-phenylpro-
pan-1-ol (4a): The general procedure B for hydrolysis was
followed with 3a (300 mg, 0.902 mmol), to get chiral amino
alcohol 4a as an oil; yield: 224 mg (81%). 1H NMR
(400 MHz, CDCl3): d=0.84–0.99 (3H, m), 1.29–1.41 (2H,
˜
m), 1.84–1.87 (1H, m), 2.21–2.31
G
KBr): n=701, 761, 873, 1060, 1120, 1230, 1253, 1417, 1457,
m), 2.79–2.95 (1H, m), 3.21–3.32 (1H, m), 2.99–3.09 (2H,
m), 3.63–3.78 (4H, m), 3.82 (1H, m), 4.31–4.45 (2H, m),
7.11–7.27 (5H, m); 13C NMR (400 MHz, CDCl3): d=18.1,
30.1, 38.3, 50.8, 51.8, 53.5, 56.0, 57.5, 66.8, 128.6, 129.3, 131.5,
1751, 2809, 2925, 2952, 3488 cmÀ1; LR-MS (FAB): m/z=
549.0 [M+H]+; HR-MS (FAB): m/z=548.3390, calcd. for
C32H44N4O4 [M+H]+: 548.3363.
Chiral polyamine (6c): The general procedure A for hy-
droaminomethylation was followed with piperazine (117 mg,
1.36 mmol) and (S)-4-isopropyl-3-(2-methylallyl)oxazolidin-
2-one 1c (500 mg, 2.72 mmol). The crude product was puri-
fied by flash chromatography on alumina activity III to get
chiral polyamine 6c as an oil without any further purifica-
˜
137.0; IR (film, KBr): n=698, 743, 771, 1001, 1044, 1139,
1251, 1389, 1459, 1505, 1611, 2810, 2933, 3042, 3521 cmÀ1
LR-MS (FAB): m/z=307.2 [M+H]+; HR-MS (FAB): m/z=
307.2358, calcd. for C18H30N2O2 [M+H]+: 307.2307.
(S)-2-(2-Methyl-4-morpholinobutylamino)-2-phenyletha-
nol (4b): The general procedure B for hydrolysis was fol-
lowed with (S)-3-(2-methyl-4-morpholinobutyl)-4-phenylox-
azolidin-2-one (700 mg, 2.19 mmol) 3b to get chiral amino
alcohol 4b as an oil; yield: 603 mg (93%, 2.03 mmol).
1H NMR (400 MHz, CDCl3): d=0.90–0.95 (3H, m), 1.26–
1.30 (2H, m), 1.66–1.74 (1H, m), 2.35–2.51 (8H, m), 3.71–
3.75 (6H, m), 7.21–7.39 (5H, m); 13C NMR (100 MHz,
CDCl3): d=18.5, 31.1, 36.6, 53.7, 57.0, 62.1, 66.6, 68.9. 69.7,
1
tion; yield: 590 mg (90%). H NMR (400 MHz, CDCl3): d=
0.79–0.98 (18H, m), 1.20–1.32 (1H, m), 1.34–1.44 (2H, m),
1.46–1.62 (4H, m), 1.74–1.89 and 2.00–2.15 (4H, m), 2.26–
2.61 (8H, m), 2.74–2.94 and 3.26–3.41 (4H, m), 3.71–3.74
(2H, m), 4.05–4.24 (4H, m); 13C NMR (100 MHz, CDCl3):
d=14.0, 17.6, 27.1, 29.7, 31.3, 47.2, 58.6, 59.2, 62.4, 68.3,
˜
158.4; IR (film, KBr): n=769, 873, 1051, 1120, 1253, 1425,
1758, 2807, 2929, 2958, 3311 cmÀ1; HR-MS (ESI-FT-MS):
m/z=481.3735, calcd. for C26H48N4O4 [M+H]+: 481.3676.
Chiral polyamino alcohol (7a):The general procedure B
for hydrolysis was followed with polyamine 6a (350 mg,
0.61 mmol), to get chiral polyamino alcohol 7a as an oil;
127.5, 129.7, 137.0; IR (film, KBr): n=701, 759, 867, 1118,
1454, 1625, 2809, 2854, 2954, 3390 cmÀ1; ESI-MS: m/z=
293.2 [M+H]+; HR-MS (FAB): m/z=292.2226, calcd. for
C17H28N2O2 [M+H]+: 292.2151.
1
(S)-2-(2-Methyl-4-morpholinobutylamino)-3-methylbutan-
1-ol (4c): The general procedure B for hydrolysis was fol-
lowed with (S)-4-isopropyl-3-(2-methyl-4-morpholinobutyl)-
oxazolidin-2-one 3c (200 mg, 0.703 mmol) to get chiral
amino alcohol 4c as an oil; yield: 163 mg (89%, 0.62 mmol).
1H NMR: (400 MHz, CDCl3): d=0.87–1.01 (9H, m), 1.21–
1.41 (2H, m), 1.56–1.73 (1H, m), 2.25.2.76 (8H, m),3.67–
3.78 (6H, m); 13C NMR: (100 MHz, CDCl3): d=18.7, 20.0,
29.2, 31.9, 33.0, 53.8, 54.2, 57.4, 60.7, 62.1, 67.3; IR: (film,
yield: 259 mg (80%). H NMR (400 MHz, CDCl3): d=0.88–
1.02 (6H, m), 1.31–1.49 (4H, m), 1.84 (2H, m), 2.52–2.63
(8H, m), 2.88–2.90 (2H, m), 3.31–3.36 (2H, m), 3.11–3.19
(4H, m), 3.86–4.01 (4H, m), 4.31ACTHUNTGRNEUNG(2H, m), 7.14–7.25 (10H,
m); 13C NMR (400 MHz, CDCl3): d=17.7, 29.1, 39.8, 50.0,
51.2, 52.6, 55.2, 56.0, 57.3, 69.1, 128.6, 130.3, 130.5, 135.0; IR
˜
(film, KBr): n=705, 743, 762, 1011, 1059, 1175, 1259, 1380,
1454, 1496, 1603, 2810, 2956, 3026, 3506 cmÀ1; LR-MS
(FAB): m/z=525.4 [M+H]+; HR-MS (FAB): m/z=525.415,
calcd. for C32H52N4O2 [M+H]+: 525.409.
˜
KBr): n=867, 914, 1118, 1286, 1373, 1461, 1621, 2884, 2956,
3380 cmÀ1; ESI-MS: m/z=259.3 [M+H]+; HR-MS (FAB):
m/z=258.2218, calcd. for C14H30N2O2 [M+H]+: 258.2307.
Chiral polyamine (6a): The general procedure A for hy-
droaminomethylation was followed with piperazine (93 mg,
2-(4-{4-[4-(2-Hydroxy-1-phenylethylamino)-3-methylbu-
tyl]-piperazin-1-yl}-2-methylbutylamino)-2-phenylethanol
(7b): The general procedure B for hydrolysis was followed
with polyamine 6b (347 mg, 0.265 mmol), to get chiral polya-
Adv. Synth. Catal. 2009, 351, 2113 – 2123
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2119

Muhammad Afzal Subhani et al.
FULL PAPERS
1
˜
mino alcohol 7b as an oil; yield: 271 mg (88%); H NMR
(500 MHz, CDCl3): d=0.86–0.88 (6H, m), 1.20–1.24 (4H,
m), 1.45 (2H, m), 2.27–2.33 (16H, m), 3.39–3.66 (6H, m,),
7.24–7.30 (10H, m); 13C NMR (100 MHz, CDCl3): d=18.6,
31.8, 32.4, 53.3, 53.9, 56.6, 62.1, 66.7, 127.2, 127.6, 128.6,
159.1; IR (film, KBr): n=766, 873, 1051, 1120, 1258, 1425,
1758, 2807, 2933, 2958, 3324 cmÀ1; HR-MS (FAB): m/z=
609.4 [M+H]+; HR-MS (FAB): m/z=609.4526, calcd. for
C33H60N4O6 [M+H]+: 609.4513.
2-(4-{Bis-[4-(1-benzyl-2-hydroxyethylamino)-3-methylbu-
tyl]-amino}-2-methylbutylamino)-3-phenylpropan-1-ol (10a):
The general procedure B for hydrolysis was followed with
polyamine 9a (200 mg, 0.265 mmol), to get chiral polyamino
alcohol 10a as an oil; yield: 168 mg (94%). 1H NMR
(400 MHz, CDCl3): d=0.79–0.98 (9H, m), 1.10–1.37 (6H,
m), 1.43–1.63 (3H, m), 2.25–2.62 (12H, m), 2.70–3.00 (9H,
m), 3.31–3.34 (3H, m), 3.60–363 (3H, m), 7.19–7.33 (15H,
m); 13C NMR (100 MHz, CDCl3): d=18.4, 30.8, 48.6, 52.7,
˜
141.0; IR (film, KBr): n=761, 802, 1099, 1260, 1406, 1453,
1563, 1727, 2871, 2928, 2961, 3389 cmÀ1; LR-MS (FAB):
m/z=497.5 [M+H]+; HR-MS (FAB): m/z=497.3787, calcd.
for C26H48N4O4 [M+H]+: 497.3777.
2-(4-{4-[4-(1-Hydroxymethyl-2-methylpropylamino)-3-
methylbutyl]-piperazin-1-yl}-2-methylbutylamino)-3-methyl-
butan-1-ol (61): The general procedure B for hydrolysis was
followed with polyamine 6c (347 mg, 0.265 mmol), to get
chiral polyamino alcohol 7c as an oil; yield: 271 mg (88%).
1H NMR (400 MHz, CDCl3): d=0.84–1.03 (8H, m), 1.25–
1.41 (4H, m), 1.59–1.61 (2H, m), 1.79–1.81 (2H, m), 2.33–
2.37 (8H, m), 2.43–2.54 (8H, m), 3.24–3.35 (2H, m), 3.56–
3.61 (18H, m); 13C NMR (100 MHz, CDCl3): d=18.7, 20.0,
˜
57.2, 67.3, 127.8, 129.6, 129.8, 136.3; IR (film, KBr): n=744,
1041, 1114, 1376, 1454, 1621, 2867, 2925, 3372 cmÀ1; ESI-
MS: m/z=675.6 [M+H]+; HR-MS (ESI): m/z=675.5156,
calcd. for C42H66N4O3 [M+H]+: 675.5166.
2-(4-{Bis-[4-(2-hydroxy-1-phenylethylamino)-3-methylbu-
tyl]-amino}-2-methylbutylamino)-2-phenyl-ethanol
˜
29.4, 32.2, 33.7, 53.7, 57.0, 64.9; IR (film, KBr): n=754, 815,
(10b):
1014, 1110, 1371, 1763, 1644, 2809, 2950, 3372 cmÀ1; ESI-
The general procedure B for hydrolysis was followed with
polyamine 9b (347 mg, 0.265 mmol), to get chiral polyamino
alcohol 10b as an oil; yield: 271 mg (88%). 1H NMR
(500 MHz, CDCl3): d=0.90–0.92 (9H, m), 1.26–1.30 (3H,
m), 1.60–1.70 (6H, m), 2.36–2.48 (12H, m), 3.55–3.62 (3H,
m), 3.70–3.78 (6H, m), 7.28–7.37 (15H, m); 13C NMR
(500 MHz, CDCl3): d=19.0, 31.8, 32.3, 51.8, 54.3, 65.7, 67.1,
MS: m/z=429.5 [M+H]+; HR-MS (ESI-FT-MS): m/z=
429.4152, calcd. for C24H52N4O2ACTHUNTRGNEUNG
[M+H]+: 429.4163.
Chiral polyamine (9a): The general procedure C for hy-
droaminomethylation was followed with urea and (S)-4-
benzyl-3-(2-methylallyl)oxazolidin-2-one
1a
(1.05 g,
4.54 mmol). The crude product was purified by flash chro-
matography on alumina activity III to give chiral polyamine
9a as an oil; yield: 1.08 g (95%). 1H NMR (400 MHz,
CDCl3): d=0.94 (18H, m), 1.27 and 1.55 (12H, m), 1.87
(6H, m), 2.56 (12H, m), 2.66–2.68 (12H, m), 2.91–2.93 and
3.27–3.41 (12H, m), 3.09–3.14 (12H, m), 3.98–34.16 (18H,
m), 7.18–7.32 (30H, m); 13C NMR (100 MHz, CDCl3): d
[ppm]=18.4, 30.8, 48.6, 52.7, 57.2, 67.3, 127.8, 129.6, 129.8,
˜
127.6, 129.0, 141.0; IR (film, KBr): n=624, 701, 800, 1025,
1089, 1261, 1454, 2809, 2869, 2923, 2960, 3355 cmÀ1; LR-MS
(FAB): m/z=631.7 [M+H]+; HR-MS (FAB): m/z=
633.4679, calcd. for C39H60N4O3 [M+H]: 633.4665.
2-(4-{Bis-[4-(1-hydroxymethyl-2-methylpropylamino)-3-
methylbutyl]-amino}-2-methyl-butylamino)-3-methyl-butan-
1-ol (10c): The general procedure B for hydrolysis was fol-
lowed with polyamine 9c (347 mg, 0.265 mmol), to get chiral
polyamino alcohol 10c as an oil; yield: 271 mg (88%).
1H NMR (500 MHz, CDCl3): d=0.90–0.98 (27H, m), 1.26–
1.28 (6H, m), 1.61–1.63 (3H, m), 1.81–1.84 (3H, m), 2.36–
2.51 (12H, m), 2.55–2.63 (3H, m), 3.33–3.36 and 3.60–3.64
(6H, m); 13C NMR (100 MHz, CDCl3): d=18.8, 20.1, 29.2,
˜
136.3, 159.1; IR (film, KBr): n=505, 593, 664, 702, 761, 842,
937, 1061, 1255, 1380, 1453, 1525, 1603, 1731, 1954, 2454,
2832, 2882, 2972, 3060, 3478 cmÀ1; LR-MS (FAB): m/z=
753.8 [M+ +H+]; HR-MS (FAB): m/z=753.4586, calcd. for
C45H60N4O6 [M+H]+: 753.4513.
Chiral Polyamine (9b): The general procedure C for hy-
droaminomethylation was followed with urea and (S)-3-(2-
˜
32.8, 35.0, 52.0, 53.8, 60.8, 64.8; IR (film, KBr): n=752,
methylallyl)-4-phenyloxazolidin-2-one
1b
(500 mg,
1045, 1105, 1232, 1380, 1463, 1621, 2869, 2960, 3372 cmÀ1
;
2.301 mmol). The crude product was purified by flash chro-
matography on alumina activity III to give chiral polyamine
9b as an oil; yield: 449 mg (83%). 1H NMR (400 MHz,
CDCl3): d=0.75–0.89 (9H, m,) 1.08–1.44 (6H, m), 1.62 (3H,
m), 2.09–2.29 (6H, m), 2.52–2.65 and 3.17–3.32 (6H, m),
4.10–4.15 (3H, m), 4.60–4.65 and 4.72–4.84 (6H, m), 7.23–
7.42 (15H, m); 13C NMR: (100 MHz, CDCl3): d=17.7, 29.2,
31.2, 47.7, 51.3, 60.0, 69.6, 126.8, 128.9, 129.1, 137.7, 158.3;IR
LR-MS (FAB): m/z=531.6 [M+H]+; HR-MS (FAB): m/z=
531.5231, calcd. for C30H66N4O3 [M+H]+: 531.5135.
Chiral polyamine (12a): The general procedure A for hy-
droaminomethylation was followed with tris(2-aminoethyl)-
amine 11 (200 mg, 1.36 mmol, 1 equiv.), (S)-4-benzyl-3-(2-
methylallyl)oxazolidin-2-one 1a (1.9 g, 8.3 mmol, 6.1 equiv.)
and [RhACTHNUTRGENUG(N COD)Cl2] (14 mg, 0.3 mol%). The crude product
was purified by dialysis in chloroform. The solvent was re-
moved under reduced pressure to get polyamine 12a as an
oil; yield: 1.02 g (65%); 1H NMR (400 MHz, CDCl3): d=
0.94 (18H, m), 1.27 & 1.55 (12H, m), 1.87 (6H, m), 2.56
(12H, m), 2.66–2.68 (12H, m), 2.91–2.93 & 3.27–3.41 (12H,
m), 3.09–3.14 (12H, m), 3.98–34.16 (18H, m), 7.18–7.32
(30H, m); 13C NMR (400 MHz, CDCl3): d=18.4, 30.8, 48.6,
52.7, 57.2, 67.3, 127.8, 129.6, 129.8, 136.3, 159.1; IR (Film,
˜
(flm, KBr): n=735, 899, 1056, 1221, 1352, 1411, 1602, 1740,
2922, 2955, 3356 cmÀ1
; HR-MS (FAB): m/z=711.4159,
calcd. for C42H54N4O6 [M+H]+: 711.4143.
Chiral polyamine (9c): The general procedure C for hy-
droaminomethylation was followed with urea and (S)-4-iso-
propyl-3-(2-methylallyl)oxazolidin-2-one
1c
(500 mg,
2.723 mmol), The crude product was purified by flash chro-
matography on alumina activity III to give chiral polyamine
9c as an oil; yield: 508 mg (92%). 1H NMR: (400 MHz,
CDCl3): d=0.83–0.92 (27H, m), 1.22 (6H, m), 1.40 (6H, m),
1.48 (6H, m), 2.42 (6H, m), 2.73–2.87 & 3.29–3.24 (6H, m),
3.71 (3H, m), 4.06–4.22 (6H, m); 13C NMR: (100 MHz,
CDCl3): d=14.6, 18.0, 27.6,29.9, 47.9, 51.6, 59.8, 62.9, 68.8,
˜
KBrl): n=505, 593, 664, 702, 761, 842, 937, 1061, 1255, 1380,
1453, 1525, 1603, 1731, 1954, 2454, 2832, 2882, 2972, 3060,
3478 cmÀ1; LR-MS (FAB): m/z=1619.16 [M+ +H+]; HR-
MS (ESI): m/z=1618.99872, calcd. for C96H132N10O12 [M+
H]+: 1618.00990.
2120
asc.wiley-vch.de
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 2113 – 2123

Chiral Polyamino Alcohols via Hydroaminomethylation
FULL PAPERS
˜
29.8, 47.5, 52.1, 58.9, 62.6, 68.2; IR (Film, KBr): n=723,
Chiral polyamine (12b): The general procedure A for hy-
droaminomethylation was followed with tris(2-aminoethyl)-
amine 11 (67 mg, 0.46 mmol, 1 equiv.), (S)-4-phenyl-3-(2-
methylallyl)oxazolidin-2-one 1b (1 g, 4.6 mmol, 10 equiv.)
1005, 1049, 1185, 1243, 1406, 1456, 2821, 2986, 3363 cmÀ1
;
ESI-MS: m/z=1174.1 [M+H]+; HR-MS (ESI): m/z=
1174.1293, calcd. for C66H144N10O6 [M+H]+: 1174.1270.
and [RhACHTUNGTRENNUNG(COD)Cl2] (7 mg, 0.3 mol%). The crude product
was purified by dialysis in chloroform. The solvent was re-
Chiral Polyamine via n-Selective
HydroaminoACTHNUTRGNEmNUG ethylation (16)
moved under reduced pressure to get polyamine 12b as an
1
oil; yield: 0.705 g (77%). H NMR (400 MHz, CDCl3): d=
0.79–0.86 (18H, m), 1.12–1.66 (18H, m), 2.26–2.96 (36H,
m), 4.09 (6H, m), 4.62–4.76 (12H, m), 7.26–7.37 (30H, m);
13C NMR (100 MHz, CDCl3): d=17.5, 27.9, 29.5, 51.9, 59.9,
(S)-4-Benzyl-3-(2-methylallyl)oxazolidin-2-one 1a (500 mg,
2.31 mmol), Rh(acac)(CO)2 (1 mol%) and BIPHEPHOS
AHCTUNGTRENNUNG
(4 mol%) were dissolved in 7–8 mL of dioxane in a glass
vessel. This glass vessel was placed in an autoclave. The au-
toclave was pressurized with CO/H2 (10/10 bar) and the re-
action was run for 48 h at 508C. Solvent was removed under
reduced pressure and the linear (n) to branch (iso) ratio
(n:iso=87:13) was determined by 1H NMR spectroscopy.
Then piperazine was dissolved in 5–8 mL of dioxane and
added to the reaction vessel and autoclave was pressurized
with CO/H2 (10/40 bar) and the reaction was run for 48 h at
1008C. The autoclave was cool down to room temperature
and solvent was removed under reduce pressure to get poly-
amine 16 without any further purification; yield: 95%.
Note! The reductive amination is done without separation
of regoisomers. So the final product also contains 17%
branched isomers. 1H NMR (500 MHz, CDCl3): d=1.47–
1.61 (8H, m), 2.32–2.35 (4H, t, J=7.53 Hz), 2.46 (8H, m),
2.62–2.68 and 3.52–3.58 (4H, m), 3.07–3.12 (4H, dd, J=
3.51 Hz), 3.51–4.02 and 4.12–4.16 (6H, m), 7.14–7.33 (10H,
m); 13C NMR (100 MHz, CDCl3): d=23.6, 25.0, 38.2, 41.7,
52.9, 55.6, 57.7, 66.5, 126.9, 128.7, 128.8, 135.3, 157.8; IR
˜
69.9, 127.4, 129.3, 138.0, 158.8; IR (film, KBr): n=730, 910,
1062, 1133, 1234, 1382, 1382, 1417, 1747, 2825, 2958,
3475 cmÀ1; ESI-MS: m/z=1534.1 [M+H]+; MS (MALDI-
TOF): m/z=1534.253 [M+H]+.
Chiral polyamine (12c): The general procedure A for hy-
droaminomethylation was followed with tris(2-aminoethyl)-
amine 11 (80 mg, 0.46 mmol, 1 equiv.), (S)-4-isopropyl-3-(2-
methylallyl)oxazolidin-2-one 1c (1 g, 5.45 mmol, 10 equiv.)
and [RhACHTUNGTRENNUNG(COD)Cl2] (8 mg, 0.3 mol%). The crude product
was purified by dialysis in chloroform. The solvent was re-
moved under reduced pressure to get polyamine 12c as an
1
oil; yield: 0.751 g (90%); H NMR (400 MHz, CDCl3): d=
0.73–0.97 (54H, m), 1.12–1.34 (6H, m), 1.36–1.62 (6H, m),
1.67–1.87 (6H, m), 1.93–2.13 (6H, m), 2.28–2.93 (24H, m),
3.16–3.41 (6H, m), 3.60–3.85 (6H, m), 3.93–4.09 (6H, m),
4.12–4.32 (6H, m); 13C NMR (100 MHz, CDCl3): d=
14.2,17.7, 27.2, 29.8, 47.5, 52.1, 58.9, 62.6, 66.5, 160.1; IR
˜
(film, KBr): n=755, 977, 1049, 1185, 1243, 1384, 1438, 2873,
2958, 3363 cmÀ1; ES- MS: m/z=1330.2 [M+H]+.
˜
(film, KBr): n=701, 761, 873, 1060, 1120, 1230, 1253, 1417,
Chiral polyamino alcohol (13a): The general procedure B
for hydrolysis was followed with polyamine 12a (200 mg,
0.123 mmol), to get chiral PAA 13a as a colourless oil;
1457, 1751, 2809, 2925, 2952, 3488 cmÀ1; LR-MS (FAB):
m/z=549.2 [M+H]+; HR-MS (FAB): m/z=549.3410, calcd.
for C32H44N4O4 [M+H]+: 549.3363.
1
yield: 120 mg (67%). H NMR (400 MHz, CDCl3): d=0.81–
0.95 (18H, m), 1.12–1.28 (6H, m), 1.43–1.65 (6H, m), 1.95–
2.15 (6H, m), 2.26–2.96 (48H, m), 3.24–3.44 (6H, m), 3.51–
3.61 (6H, m), 7.07–7.38 (30H, m); 13C NMR (100 MHz,
CDCl3): d=18.3, 23.5, 32.2, 38.1, 52.3, 60.3, 62.6, 126.4,
2-(4-{4-[4-(1-Benzyl-2-hydroxyethylamino)-butyl]-
piperazin-1-yl}-butylamino)-3-phenylpropan-1-ol (17)
The general procedure B for hydrolysis was followed with
polyamine 16 (120 mg, 0.216 mmol), to get 2-(4-{4-[4-(1-
benzyl-2-hydroxyethylamino)butyl]piperazin-1-yl}-butyl-
˜
128.5, 129.2, 138.8; IR (film, KBr): n=700, 744, 804, 1039,
1251, 1454, 1602, 2867, 2923, 3363 cmÀ1 (m); ESI MS: m/z=
1462.1 [M+H]+; LR-MS (FAB): m/z=1462.4 [M]+; HR-MS
(ESI): m/z=1462.1343, calcd. for C90H144N10O6 [M+H]+:
1462.1270.
AHCTUNGTERGaNNNU mino)-3-phenylpropan-1-ol 17 as dark brown oil; yield:
1
100 mg (92%). H NMR: (400 MHz, CDCl3): d=1.45 1.46-
(8H, m), 2.30 (4H, m), 2.45 (8H, m), 2.57–2.63 and 2.86–
AHCTUNGTRENNUNG
Chiral polyamino alcohol (13b): The general procedure B
for hydrolysis was followed with polyamine 12b (500 mg,
0.325 mmol), to get chiral PAA 13b as a dark brown oil;
2.90 (4H, m), 2.72–2.79 (4H, m), 3.31–3.35 (2H, dd, J=
5.52 Hz), 3.48–3.53 (2H, m), 3.59–3.63 (2H, dd, J=4.02 Hz),
7.17–7.32 (10H, m); 13C NMR: (100 MHz, CDCl3): d=24.3,
27.9, 37.7, 46.6, 52.9, 58.2, 60.1, 62.1, 126.3, 128.4, 129.0,
1
yield: 310 mg (69%). H NMR (400 MHz, CDCl3): d=0.81–
1.01 (18H, m), 1.11–1.38 (6H, m), 1.46–1.83 (12H, m), 2.13–
2.86 (36H, m), 3.40–3.86 (18H, m), 7.15–7.53 (30H, m);
13C NMR (100 MHz, CDCl3): d=18.5, 29.9, 32.0, 52.0, 53.9,
˜
138.4; IR: (film, KBr) n=701, 734, 803, 910, 1031, 1094,
1261, 1454, 1601, 2819, 2933, 3363 cmÀ1 (s); LR-MS (FAB):
m/z=497.1 [M+H]+. HR-MS (FAB): m/z=497.3865, calcd.
for C30H48N4O2 [M+H]+: 497.3777.
˜
60.4, 62.6, 127.4, 128.6, 141.0; IR (film, KBr): n=700, 744,
804, 1039, 1251, 1454, 1602, 2867, 2923, 3363 cmÀ1 (m); ESI-
MS: m/z=1379.4 [M+H]+; HR-MS (ESI): m/z=1377.0389,
calcd. for C84H132N10O6 [M+H]+: 1377.0331.
2-{4-[4-(3,5-Bis-{4-[4-(2-hydroxy-1-
Chiral polyamino alcohol (13c): The general procedure B
for hydrolysis was followed with polyamine 12c (300 mg,
0.225 mmol), to get chiral PAA 13c as a brown oil; yield:
162 mg (61%); 1H NMR (400 MHz, CDCl3): d=0.73–1.07
(54H, m), 1.19–1.33 (6H, m), 1.39–1.59 (6H, m), 1.67–1.79
(6H, m), 2.01–2.13 (6H, m), 2.31–2.93 (30H, m), 3.21–3.39
(6H, m), 3.56–3.91 (6H, m), 3.90–4.11 (6H, m), 4.06–4.29
(6H, m);13C NMR (100 MHz, CDCl3): d=14.2,17.7, 27.2,
phenylethylACTHUNTGRNEUNGamino)-3-methyl-butyl]-piperazin-1-
ylmethyl}-benzyl)-piperazin-1-yl]-2-
methylbutylamino}-2-phenylethanol (19)
(S)-4-Benzyl-3-(2-methylallyl)oxazolidin-2-one 1a (500 mg,
2.31 mmol), RhACHTUNGRTNE(NUG acac)(CO)2 (1 mol%) and BIPHEPHOS
(4 mol%) were dissolved in 7–8 mL of dioxane in a glass
vessel. This glass vessel was placed in an autoclave and then
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Muhammad Afzal Subhani et al.
FULL PAPERS
pressurized with CO/H2 (10/10 bar) and the reaction was References
run for 48 h at 508C. Solvent was removed under reduced
pressure and linear (n) to branch (iso) ratio (n:iso=87:13)
was determined by H NMR spectroscopy. Then amine core
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1
1-(3,5-bis((piperazin-1-yl)methyl)benzyl)piperazine was dis-
solved in 5–8 mL of dioxane and added to the reaction
vessel and autoclave was pressurized with CO/H2 (10/40 bar)
and the reaction was run for 48 h at 1008C. The autoclave
was cooled down to room temperature and thesolvent was
removed under reduced pressure. The crude product was
purified by running dialysis in cholorform overnight to get
polyamine 19 without any further purification; yield: 66%.
Note! Reductive amination is done without separation of
regoisomers. So the final product also contains 17%
branched isomers.1H NMR (500 MHz, CDCl3): d=1.52–1.65
(6H, m), 1.75–1.84 (6H, m), 2.64–2.68 (6H, m), 2.80–3.00
(12H, m), 3.05–3.20 (12H, m), 3.36–3.52 (6H, m), 3.58–3.72
(6H, m), 3.90–4.25 (9H, m), 7.11–7.35 (15H, m); 13C NMR
(100 MHz, CDCl3): d=20.4, 25.2, 30.6, 38.8, 41.5, 56.2, 56.4,
67.3, 127.6, 129.3, 129.4, 130.1, 135.7, 158.7; IR (film, KBr):
˜
n=703, 742, 968, 1029, 1178, 1249, 1361, 1454, 1648, 1741,
2462, 2582, 2933, 3426 cmÀ1; LR-MS (FAB): m/z=1066.10
[M+H]+.
2-{4-[4-(3,5-Bis-{4-[4-(1-benzyl-2-hydroxyethylamino)-
butyl]-piperazin-1-ylmethyl}-benzyl)-piperazin-1-yl]-
butylamino}-3-phenylpropan-1-ol (20)
The general procedure for hydrolysis was followed with
polyamine 19 (190 mg, 0.178 mmol), to get 20 as an oil;
1
yield: 140 mg (80%). H NMR (500 MHz, CDCl3): d=1.49–
1.52 (12H, m), 2.30–2.33 (6H, m), 2.44–2.48 (12H, m), 2.64–
2.68 (12H, m), 2.72–2.79 (6H, m), 2.83–2.91 (6H, m), 3.51
(6H, s), 3.32–3.36 (6H, m), 3.51 (6H, s), 3.62–3.67 (3H, m),
7.15–7.32 (15H, m); 13C NMR (100 MHz, CDCl3): d=23.9,
31.6, 38.1, 47.0, 49.7, 53.2, 53.5, 58.7, 60.0, 63.2, 126.8, 128.8,
˜
128.9, 129.5, 138.7; IR (film, KBr): n=700, 746, 804, 1029,
1095, 1261, 1373, 1454, 1602, 2809, 2871, 2933, 3378 cmÀ1
;
LR-MS (FAB): m/z=988.2 [M+H]+.
General Procedure for Hydrogen Transfer Reduction
of Acetophenone
To a solution of [RuCl2ACTHNUTRGNE(NUG p-cymene)]2 (2 mol%) in 2 mL of
dry isopropyl alcohol, chiral polyamino alcohol ligand
(4 mol%) was added under an inert atmosphere. The sus-
pension was stirred and heated at 808C for 30 min. Then re-
action mixture was allowed to cool down to room tempera-
ture and 2 mL of KOH (0.1M in isopropyl alcohol) solution
was added followed by the addition of acetophenone
(1 mmol). The conversion of acetophenone to 1-phenyletha-
nol and ee were determined by gas chromatography. GC
conditions; carrier gas 50 kPa He, temperature program of
1008C for 5 min, then 48CminÀ1 to 1608C and 208CminÀ1 to
2008C; retention times: 11.30 min for (S)-1-phenylethanol
and 11.50 min for (R)-1-phenylethanol. The major enantio-
mer was (S)-1-phenylethanol.
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