Simple 1,3-diamines and their application as ligands in ruthenium(II) catalysts for asymmetric transfer hydrogenation of aryl ketones

Article abstract of DOI:10.1039/c5nj00110b

In this research work simple unsymmetrical 1,3-diamines were studied. The synthesis of the diamines started from non-commercial available compounds. S-5a and S,S-5c were obtained by biocatalysis with non conventional yeast, Rhodotorula rubra MIM 147, with

Full text of DOI:10.1039/c5nj00110b

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Simple 1,3-diamines and their application as
ligands in ruthenium(II) catalysts for asymmetric
Cite this:DOI: 10.1039/c5nj00110b
transfer hydrogenation of aryl ketones†
Giorgio Facchetti, Raffaella Gandolfi, Marco Fuse, Daniele Zerla, Edoardo Cesarotti,
`
Michela Pellizzoni and Isabella Rimoldi*
In this research work simple unsymmetrical 1,3-diamines were studied. The synthesis of the diamines started
from non-commercial available compounds. S-5a and S,S-5c were obtained by biocatalysis with non
conventional yeast, Rhodotorula rubra MIM 147, with excellent 99% e.e. and d.e. up to 90%. Different
approaches of synthesis were applied to the same backbone to study both the steric and electronic effects
of the ligands. The reactivity of the corresponding ruthenium complexes was evaluated in the asymmetric
hydrogen transfer reduction of acetophenone as a standard substrate and of other different aryl ketones,
highlighting the flexibility of the six membered chelating ring. A screening of the reaction conditions indicated
aqueous media in the presence of HCOONa as a hydrogen donor to be the best system for overcoming the
lack of stereocontrol thus allowing us to obtain 56% e.e. in the reduction of acetophenone with the complex
in which the ligand was diamine 1, revealed as the best in terms of reactivity and stereoselectivity also in the
reduction of the other different aryl ketones, in particular for a-tetralone, i (63% e.e.).
Received (in Montpellier, France)
14th January 2015,
Accepted 27th February 2015
DOI: 10.1039/c5nj00110b
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metal centre. Some examples of symmetric 1,4-diamines and few
examples of 1,3-diamines were reported in the literature,12–17 mainly
Introduction
In the last decade asymmetric transfer hydrogenation (ATH) used as a typical ruthenium complex [(diphosphine)-RuCl2-
has been revealed as a valid alternative to the use of molecular (diamine)] for hydrogenation of simple aromatic and aliphatic
H2 in obtaining enantiomerically pure alcohols which can be ketones, in the catalytic addition of diethylzinc to aldehyde or
applied to the synthesis of many fine chemicals, pharmaceuticals in the Cu-catalyzed enantioselective Henry reaction.18–21
and agrochemical products.1
Considering the wide range of 1,2-diamines used as ligands
It is well known that the performance of the catalytic system and their utility in asymmetric catalysis, this work reported the
is strictly related to a synergistic effect between the solvent synthesis of simple asymmetric monotosylated 1,3-diamines,
nature and the hydrogen donor. In recent years the develop- up to now poorly investigated in ATH (Fig. 1), and the evaluation
ment of ATH in aqueous media has been emerged as a valid of their catalytic performances.
alternative to the use of organic solvents for its non-toxic,
economic and environmental compatible profile.
Results and discussion
Since the pioneering work reported by Noyori and Ikariya
groups in 1995,2,3 the catalysts of choice in ATH reductions of
The starting material for the synthesis of these 1,3-diamines was
ketones have been established to be the ruthenium(II) complexes
the reduction products of benzoylacetonitrile and its ethylated
chelating different substituted 1,2-diamines such as DPEN and
derivative.
its derivatives, among them the monotosylated compounds were
Different approaches using either asymmetric transfer hydro-
revealed as the most efficient ones.3–11
genation for the reduction of benzoylacetonitrile 5 with
iridium(III)22 and/or ruthenium(II) diamines complexes23 or
All these types of catalysts were based on the presence of
ligands forming five membered rings when chelated to the
Dipartimento di Scienze Farmaceutiche, Sez. Chimica Generale e Organica
`
‘‘A. Marchesini’’, Universita degli Studi di Milano, Via Venezian 21, 20133 Milano,
Italy. E-mail: isabella.rimoldi@unimi.it; Fax: +39 02 503 14615;
Tel: +39 02 503 14609
† Electronic Supplementary Information (ESI) available. See DOI: 10.1039/
c5nj00110b
Fig. 1 Monotosylated 1,3-diamines.
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presence of EtOH as a co-substrate this yeast afforded 5a and 5c in
a 50/50 mixture along with a decreasing enantiomeric excess.
Best results were obtained when two similar yeasts were used:
Rhodotorula rubra MIM 146 and Rhodotorula rubra MIM 147. In
both cases 5a was the only product yielded in an excellent 98% e.e.
in S configuration. With the aim of verifying the ability of these two
Fig. 2 Biotransformation of benzoylacetonitrile by yeasts.
whole-cell catalysts24,25 were studied. Recently our group dis- yeasts to reduce and resolve compound 5b, its racemic mixture
played the reduction of the substrate 5 and its corresponding was quantitatively synthesised by Saccharomyces cerevisiae which
ethylated derivative 5b using Carreira’s [Cp*Ir(diamine)(H2O)]SO4 mediated non-stereoselective introduction of the ethyl group.34,35
complexes in which the diamine ligand CAMPY and its derivatives With R. rubra MIM 146 the conversion of racemic 5b in 5c was
were used as a source of chirality26 with good stereoselectivity. achieved in 48 h with 78% d.e. and 499% e.e. in S,S configuration.
Unfortunately it was not enough to use these products as starting The best result was obtained with R. rubra MIM 147 which
materials for the synthesis of enantiomerically pure diamines. produced S,S-5c at the same time with 499% e.e. and with a
Good results were obtained by a biotransformation reaction which d.e. up to 90% thus allowing us to completely separate the two
has been studied especially by Gotor and Dehli27–29 employing the diastereomers using classical chromatographic techniques.
fungus Curvularia lunata. In these studies they underlined the
First of all, starting from linear substrate S-5a, two different
production of the expected side product, 2-(1-hydroxy-1-phenyl- types of diamines were synthesised in which the tosyl-amine
methyl)butanenitrile 5c, during the biotransformation occurring moiety was set either on the aliphatic chain or on the preformed
on benzoylacetonitrile 5.
stereocentre (Scheme 1).
Based on the above results we decided to investigate differ-
After obtaining the corresponding aminoalcohol 6a by reduction
ent yeasts capable of reducing the same substrate 5 and its with LiAlH4, the synthesis proceeded into two different pathways.
derivative 5b. A screening of different genera and species of The cyclisation with CDI in CH2Cl2 gave the corresponding (S)-6-
yeasts available in our laboratory’s library was carried out (data phenyl-1,3-oxazinan-2-one 7a with the retention of configuration.36
not reported) (Fig. 2).
Successively, the reaction with NaH and TsCl provided 6-phenyl-3-
Most of them resulted to produce ethylated keto-compound tosyl-1,3-oxazinan-2-one 10a, with an excellent yield (80% after
5b as the major product while 3-hydroxy-3-phenylpropanenitrile crystallization). In the second pathway, after protecting the amino
5 was produced in a minor amount in the presence of glucose as group with (Boc)2O, substrate 8a reacts with TsCl in the presence of
a co-substrate.
4-DMAP and TEA directly giving 10a with the inversion of configu-
The group of red to pinkish yeasts is one of the most interesting ration at the chiral centre.
biocatalysts30–33 in the reduction of differently substituted aryl-
Indeed, under these specific conditions, the formation of TsO-
ketones and among them Sporobolomyces salmonicolor is the best on the benzylic alcohol and the tosylation of the amido moiety
known for this application. As expected, this yeast was able to allowed by the 4-DMAP drove a SN2 reaction. This methodology
produce the desired product 5a in a quantitative yield with 80% appears to be very appealing considering that starting from only
e.e. in S configuration avoiding the use of any co-substrate. In the one isomer we obtained both the enantiomers of 10a (Scheme 1).
Scheme 1 Synthesis of linear diamines 1.
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Substrate 10a, with the strong nucleophile NaN3 in DMF, protecting group with ZnBr2,37 diamine 4 was obtained in a
underwent SN2 substitution on the chiral centre resulting in quantitative yield.
the opening of the cycle and the decarboxylation. The corre-
The so synthesised diamines were reacted with [Ru( p-
sponding azides were reduced in the presence of Pd/C to cymene)Cl2]2 to give the corresponding ruthenium(II) complexes
monotosylated diamines, N-(3-amino-3-phenylpropyl)-4-methyl- assuming a six membered ring conformation. The synthesis of
benzenesulfonamides 1. For the synthesis of the analogue the ruthenium(II) complexes here reported was realised by reflux-
monotosylated diamine 2, we planned a procedure starting ing in toluene for 3 h and utilised without further purification as
from S-6a. The amino moiety was firstly protected with 1-[2- a pre-catalyst in ATH. Different reaction conditions were evalu-
(trimethylsilyl)ethoxycarbonyloxy]pyrrolidin-2,5-dione (Teoc-OSu). ated using acetophenone as a test substrate. With regard to
Then the classic procedure, by which the alcoholic function was solvents, water was revealed to be the best choice, as when iPrOH
reacted with mesyl chloride in the presence of TEA,16 was or MeOH was employed, the reaction conversion resulted
performed unfortunately giving 9a the corresponding oxazina- significantly decreased.5,38 In the same way the selection of
none R-7a, with inversion of configuration, as observed when hydrogen donors39 (HCOOH, HCOONa, azeotropic mixture
Boc is used as a protecting group for the amino moiety. There- 5 : 2 = TEA:HCOOH and iPrOH) proved HCOONa among others,
fore, an alternative starting material, (R)-(+)-3-chloro-1-phenyl- in a ratio of 10 : 1 with the substrate, as the best in terms of the
1-propanol, for the synthesis of enantiopure diamine S-2, was enantioselectivity achieved. In fact by using a different hydro-
studied. The synthesis proceeded as reported in the following gen donor, a racemic mixture of the product was obtained in all
scheme (Scheme 2).
cases. Conversely the temperature variation (20 1C, 40 1C or
The second type of diamine was synthesised starting from the 60 1C) did not show any significant effect on enantioselectivity.
reduced ethylated product 5c. The synthesis of diamine 3 vs. 1 Results obtained for the four diamine ligands under the set
mirrored each other from the beginning to the end (Scheme 3). reaction conditions: water as a solvent and HCOONa as a
In the case of diamine 4, the methodology was the same as hydrogen donor at 40 1C are reported in Table 1.
that initially thought for diamine 2 but in this case the formation
Unexpectedly the presence of an additional chiral centre in
of oxazinanone 7c did not take place and after removing the Teoc position 2 of the ligands 3 and 4 did not improve the enantio-
selectivity but in contrast it negatively influenced the stereo-
selectivity of the catalysts along with a significant decrease in the
reaction rate (entries 3 and 4 vs. 1 and 2). The results obtained by
changing the position of the tosyl moiety confirmed the impor-
tance of the stereogenic centre to be in proximity of the amine
involved in the catalytic cycle contributing to increase both
the reaction conversion and enantioselectivity through a steric
and/or an electronic effect (entries 1 vs. 2 and 3 vs. 4).
The reactivity and selectivity of the complexes carrying the
linear diamines 1 and 2 were studied in ATH of different aryl
ketones (Table 2).
The best results both in terms of the reaction rate and enantio-
Scheme 2 Synthesis of linear diamines 2.
selectivity were achieved with the catalyst bearing diamine ligand
Scheme 3 Synthesis of ethylated diamines 3 and 4.
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Table 1 ATH of acetophenone using [Ru(p-cymene)(L)Cl] complexes
enlarged when compared to the one obtained by using 1,2
ligands, a lower optical induction was observed due to the
flexibility of the chelating ring as already underlined for
the diphosphine ligands.43 Nevertheless the right combina-
tion between the hydrogen donor and the solvent proved to
drastically influence the catalytic performance of this type of
catalyst as well as the electronic and steric properties of the
Entry
Liganda
Conversionb (%)
e.e.b (%)
1
2
3
4
R-1
S-2
S,R-3
R,S-4
97
68
44
18
56 (S)
33 (R)
22 (R)
4 (R)
a
Reactions were carried out at 40 1C using 0.5 mmol of the substrate
with 0.5 mol% of the ruthenium complex in 3 mL of water in the substrate.
b
presence of 10 equiv. HCOONa as a hydrogen donor. Conversion was
determined by NMR and e.e. was determined by HPLC after 48 h.
Experimental section
General
Table 2 ATH of different aryl ketones
1H and 13C NMR spectra were recorded in CDCl3 or CD3OD on a
Bruker DRX Avance 300 MHz equipped with a non-reverse
probe at 25 1C. Chemical shifts (in ppm) were referenced to
the residual solvent proton/carbon peak. FTIR spectra were
collected by using a Perkin Elmer (MA, USA) FTIR Spectrometer
‘‘Spectrum One’’ in a spectral region between 4000 and 450 cmꢀ1
and analysed using the transmittance technique with 32 scans per
ion and 4 cmꢀ1 resolution. Polarimetry analyses were carried
out on a Perkin Elmer 343 Plus equipped with a Na/Hal lamp.
ESI-MS analyses were performed by using a Thermo Finnigan
(MA, USA) LCQ Advantage system MS spectrometer with an
electronspray ionisation source and an ‘Ion Trap’ mass analyser.
The MS spectra were obtained by direct infusion of a sample
solution in MeOH under ionisation, ESI positive. Catalytic reac-
tions were monitored by gas chromatography analysis using a
chiral stationary phase column (MEGA DMT b, 25 m, internal
diameter 0.25 mm) or by HPLC analysis with Merck-Hitachi
L-7100 equipped with Detector UV6000LP and chiral column
(OD-H Chiralcel or AD Chiralpak) and with JASCO PU-2080 Plus
(OJ-H Chiralcel). Commercially reagent grade solvents were
dried according to standard procedures and freshly distilled
under nitrogen before use.
Entrya
Ligand
Substrate
Conversionb (%)
e.e.b (%)
1
2
3
4
5
6
7
8
9
R-1
a
b
c
d
e
f
g
h
i
40
70
95
46
43
50
—
—
70
0
41 (S)
40 (S)
18 (S)
23 (S)
35 (S)
—
—
63 (S)
10
11
12
13
14
15
16
17
18
S-2
a
b
c
d
e
f
g
h
i
5
15
35
8
—
15
—
—
10
0
34 (R)
24 (R)
15 (R)
—
5 (R)
—
Enzymatic synthesis of rac-2-benzoylbutanenitrile 5b
—
0
Commercial Baker’s yeast (50 g Lꢀ1) was suspended in a
phosphate buffer (200 mL, 0.1 M, pH 7) containing 50 g Lꢀ1
of glucose and 5 g Lꢀ1 of substrate 5. The biotransformation
system was shaken using a mechanic stirrer at 28 1C. When
the total conversion was achieved, the cells were separated by
centrifugation. Both the aqueous phases and the cell mixture
were extracted with diethyl ether (3 ꢁ 50 mL), dried with
Na2SO4 and the solvent was removed in vacuo. The crude
product was purified by flash chromatography (CH2Cl2/hexane/
ethyl acetate = 4 : 1 : 1) to give 860 mg of 5b (86% yield). 1H NMR
(300 MHz, CDCl3): d = 1.16 (t, J = 7.7 Hz, 3H, –CH3), 2.02–2.15
(m, 2H, –CH2–), 4.30 (dd, J = 6.2, 4.3 Hz, 1H, –CH–), 7.49–7.56
a
Reactions were carried out at 40 1C using 0.5 mmol of the substrate
with 0.5 mol% of the ruthenium complex in 3 mL of water in the
presence of 10 equiv. HCOONa as a hydrogen donor. Conversion was
determined by NMR and e.e. was determined by HPLC after 48 h.
b
R-1 when compared to catalyst carrying S-2 diamine (entries 1–9 vs.
10–18). In particular in the reduction of a-tetralone, an appreciable
63% e.e. was achieved with a yield of 70% in 48 h (entry 9).40–42
Conclusions
Easily prepared 1,3-diamines were developed starting from (m, 2H, arom), 7.65 (d, J = 7.6 Hz, 1H, arom), 7.95 (d, J = 6.7 Hz,
chiral substrates. The production of the starting material was 2H, arom) ppm; 13C NMR (75 MHz, CDCl3): d = 190.88, 170.91,
realised by a biocatalytic approach using a non-conventional 134.63, 133.93, 130.38, 129.31, 128.92, 128.68, 41.38, 23.77, 11.89
yeast, Rhodotorula rubra MIM 147, achieving very good results ppm; IR n = 3467, 2975, 2936, 2249, 1694, 1597, 1449, 1265, 1233,
in terms of stereoselectivity, yield and recovery.
1208, 1000, 696 cmꢀ1; elemental analysis for C11H11NO: C, 76.28;
The catalytic data showed that when a six membered ring H, 6.40; N, 8.09; found: C, 76.13; H, 6.34; N, 7.98; MS (ESI) of
was formed by employing 1,3-diamines as a source of chirality, C11H11NO m/z 196.1 ([M + Na]+).
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General procedure of biotransformation with Rhodotorula
rubra MIM 147
(1S,2S)-2-(Aminomethyl)-1-phenylbutan-1-ol S,S-6c. Yellow
oil (215 mg, 84% yield). [a]2D0 = ꢀ18.3 (c = 2.0, CHCl3);
1H NMR (300 MHz, CDCl3): d = 0.88 (m, 3H, –CH3); 1.26–1.30
(m, 2H, –CH2–); 2.87–2.91 (m, 2H, –CH2–); 2.95–2.97 (m, 1H,
–CH–); 3.09 (br, 2H, NH2); 4.71(d, J = 6.59 Hz, 1H, –CH–); 5.2
(s, 1H, OH); 7.23–7.38 (m, 5H, arom) ppm; 13C NMR (75 MHz,
CDCl3): d = 145.05, 128.31, 128.07, 127.14, 126.73, 126.55, 79.45,
47.11, 43.42, 22.36, 11.79 ppm; IR n = 3367, 3305, 2960, 2929,
2874, 1601, 1493, 1453, 1043, 1026, 701 cmꢀ1; MS (ESI) of
Rhodotorula rubra MIM 147 was routinely maintained on malt
extract slants (8 g Lꢀ1, yeast extract 5 g Lꢀ1, agar 15 g Lꢀ1, pH 5.6).
The strain, grown on malt extract slants for 72 h at 28 1C, was
inoculated into 1000 mL Erlenmeyer flasks containing 150 mL of
the same liquid medium and incubated on a reciprocal shaker
(100 spm) for 48 h at 28 1C. Cells obtained by centrifugation
(4000ꢁ g for 15 min at 4 1C) of the culture broth (1 L) were washed
with deionised water (3 ꢁ 200 mL). After lyophilisation 20 g Lꢀ1 of
yeast was suspended in 500 mL of 0.1 M phosphate buffer pH = 7
containing 50 g Lꢀ1 of glucose. The substrates dissolved in DMSO
were added to the biotransformation system in 2 g Lꢀ1 (5) or
1 g Lꢀ1 (rac-5b) of substrate concentration and 1% of the solvent.
The biotransformation system was shaken using a mechanic
stirrer at 28 1C for 48 h. The cells were separated by centrifugation
and broth were extracted with diethyl ether (3 ꢁ 150 mL), dried
with Na2SO4 and the solvent was removed in vacuo. The crude
product was purified by flash chromatography (ethyl acetate/
cyclohexane = 7 : 3) to give 786 mg of S-5a (78% yield) or 287 mg
of S,S-5c (57% yield).
C
11H17NO m/z 180.1 ([M + H]+).
General synthesis of oxazinanones 7a or S,S-7c
N,N0-Carbonyldiimidazole (204 mg, 1.35 mmol) was added to a
solution of 6a or S,S-6c in CH2Cl2 at room temperature and the
resulting mixture was stirred for 12 h. Then, the solvent was
evaporated and the residue solved in ethylacetate and washed
with aqueous HCl (0.1 M) and water. After drying and elimina-
tion of the solvent, crystallization by diffusion of hexane into
the acetone solution afforded the product.
(S)-6-Phenyl-1,3-oxazinan-2-one S-7a. White solid (179 mg,
1
75% yield). [a]2D0 = ꢀ37.4 (c = 0.7, CHCl3); H NMR (300 MHz,
CDCl3): d = 2.14–2.17 (m, 2H, –CH2–), 3.39–2.44 (m, 2H, –CH2–),
5.34 (dd, J = 2.93, 9.53 Hz, 1H, –CH–), 5.81 (s, 1H, NH), 7.26–
7.39 (m, 5H, arom) ppm; 13C NMR (75 MHz, CDCl3): d = 154.61,
138.67, 128.85, 128.59, 125.85, 78.83, 39.17, 28.91 ppm; IR
S-5a. All characterization data are in agreement with the
previously reported literature.22,23,44,45 [a]D20 = ꢀ63.8 (c = 1,
CHCl3); HPLC data: HPLC data for 5a: OJ-H Chiralcel, eluent:
hexane : 2-propanol = 90 : 10, flow = 1.0 mL minꢀ1, l = 216 nm;
rt: (S) = 24.5 min, (R) = 30.8 min.
n = 3389, 2966, 2878, 1797, 1682, 1494, 1456, 800, 702 cmꢀ1
;
S,S-5c. 1H NMR (CDCl3, 300 MHz): d = 1.09 (t, J = 7.7 Hz, 3H,
–CH3), 1.51–1.69 (m, 2H, –CH2–), 2.76–2.83 (m, 1H, –CH–), 4.79
(d, J = 6.2 Hz, 1H, –CH–), 7.33–7.56 (m, 5H) ppm; 13C NMR
(CDCl3, 75 MHz): d = 140.71, 128.69, 128.05, 127.04, 76.57,
24.85, 10.38 ppm; IR n = 3390, 2964, 1494, 1453, 160, 1103,
1038, 702 cmꢀ1; elemental analysis for C11H13NO: C, 75.40; H,
7.48; N, 7.99; found: C, 75.23; H, 7.32; N, 7.89; MS (ESI) of
elemental analysis for C10H11NO2: C, 67.78; H, 6.26; N, 7.90;
found: C, 67.68; H, 6.24; N, 7.88; MS (ESI) of C10H11NO2 m/z
200.1 ([M + Na]+).
(5S,6S)-5-Ethyl-6-phenyl-1,3-oxazinan-2-one S,S-7c. White
1
solid (177 mg, 72% yield). [a]2D0 = ꢀ7.0 (c = 0.7, CHCl3); H NMR
(300 MHz, CDCl3): d = 0.84 (t, J = 7.33 Hz, 3H, –CH3), 1.21–1.25
(m, 2H, –CH2–), 2.02–2.05 (m, 1H, –CH–), 3.12 (t, J = 9.89 Hz, 1H,
–CHH–), 3.43–3.49 (m, 1H, –CHH–), 4.97 (d, J = 8.79 Hz, 1H, –CH–),
5.27 (s, 1H, NH), 7.29–7.36 (m, 5H, arom) ppm; 13C NMR (75 MHz,
CDCl3): d = 155.38, 138.14, 128.86, 128.75, 128.55, 127.15, 126.05,
84.04, 43.81, 38.79, 22.31, 11.09 ppm; IR n = 3435, 2961, 2925,
2854, 1698, 1457, 1355, 802, 761 cmꢀ1; elemental analysis for
C
11H13NO m/z 198.3 ([M + Na]+). [a]D20 = ꢀ46.4 (c = 0.5, CHCl3).
HPLC data: Chiralcel OD-H, eluent: hexane : 2-propanol = 95 : 5,
flow = 0.8 mL minꢀ1, l = 216 nm; rt: (R,S) = 26.9 min, (S,S) =
28.6 min, (S,R) = 34.2 min, (R,R) = 36.4 min.
C
12H15NO2: C, 70.22; H, 7.37; N, 6.82; found: C, 70.13; H, 7.33;
N, 6.79; MS (ESI) of C12H15NO2 m/z 206.1 ([M + H]+).
General synthesis of aminoalcohol 6a or S,S-6c
To a solution of 5a or S,S-5c (1.72 mmol) in anhydrous THF (10 mL),
LiAlH4 was added (100 mg, 2.6 mmol) and the resulting mixture was
General synthesis of tosyl-oxazinanones S-10a or S,S-9c
stirred under a nitrogen atmosphere at 0 1C. After 1 hour, some To a solution of S-7a or S,S-7c (1.69 mmol) in anhydrous THF at
water was carefully added in order to quench the excess LiAlH4 and 0 1C the stoichiometric amount of NaH was added (68 mg,
the solution was then reduced in volume and extracted with 1.69 mmol). After thirty minutes the solution of tosyl chloride
dichloromethane (3 ꢁ 15 mL). The organic layers were dried on in THF (387 mg, 2.03 mmol) was dropped into the former
Na2SO4, filtered and evaporated to give the product.
solution and stirred at room temperature overnight. The resulting
(S)-3-Ammino-1-phenylpropan-1-ol S-6a. Pale yellow oil solution was quenched with water and extracted with trichloro-
1
(200 mg, 77% yield). [a]2D0 = ꢀ44.38 (c = 0.3, CHCl3); H NMR methane (3 ꢁ 10 mL). The collected organic layers were dried
(300 MHz, CDCl3): d = 1.78–1.82 (m, 2H, –CH2–), 2.48–2.52 (br, on Na2SO4, filtered and evaporated to give a yellow oil then
2H, NH2) 2.95–2.98 (m, 2H, –CH2–), 4.92 (dd, J = 4.03, 8.06 Hz, purified by crystallization in dichloromethane–hexane to pro-
1H, –CH–), 7.21–7.38 (m, 5H, arom) ppm; 13C NMR (75 MHz, vide the product.
CDCl3): d = 145.16, 128.43, 128.14, 127.20, 125.85, 125.54, 75.44,
(S)-6-Phenyl-3-tosyl-1,3-oxazinan-2-one S-10a. White solid
40.57, 39.87 ppm; IR n = 3360, 2917, 2874, 1601, 1492, 1453, (440 mg, 80% yield). [a]2D0 = ꢀ24.7 (c = 0.5, CHCl3); 1H NMR
1337, 1062 cmꢀ1; MS (ESI) of C9H13NO m/z 152.0 ([M + H]+), (300 MHz, CDCl3): d = 2.25–2.29 (m, 2H, –CH2–), 2.45 (s, 3H, –CH3),
174.1 ([M + Na]+).
4.00–4.08 (m, 2H, –CH2–), 5.34 (dd, J = 2.93, 9.53 Hz, 1H, –CH–),
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7.23–7.37 (m, 7H, arom), 7.94 (d, J = 8.43 Hz, 2H, arom) ppm;
N-((S)-2-((R)-Azido(phenyl)methyl)butyl)-4-methylbenzene-
13C NMR (75 MHz, CDCl3): d = 148.82, 145.44, 137.61, 135.37, sulfonamide S,R-10c. Pale yellow oil (73 mg, 68% yield). [a]2D0
=
1
129.68, 129.16, 129.06, 129.03, 125.75, 79.67, 44.22, 29.89, 21.93 +103.5 (c = 0.4, CHCl3); H NMR (300 MHz, CDCl3): d = 0.81–
ppm; IR n = 3436, 2976, 2923, 1709, 1354, 1174, 1148 cmꢀ1
;
0.86 (m, 3H, –CH3), 1.24–1.29 (m, 2H, –CH2–), 1.73–1.79 (m, 1H,
elemental analysis for C17H17NO4S: C, 61.62; H, 5.17; N, 4.23; –CH–), 2.44 (s, 3H, –CH3), 2.89 (t, J = 6.23 Hz, 2H, –CH2–), 4.59–
found: C, 61.57; H, 5.13; N, 4.20; MS (ESI) of C17H17NO4S m/z 4.63 (m, 2H, –CH– + NH), 7.13–7.36 (m, 7H, arom), 7.69
354.1 ([M + Na]+).
(d, J = 6.59 Hz, 2H, arom) ppm; 13C NMR (75 MHz, CDCl3):
(5S,6S)-5-Ethyl-6-phenyl-3-tosyl-1,3-oxazinan-2-one S,S-9c. White d = 146.76, 138.25, 136.95, 131.09, 130.71, 130.55, 130.40, 128.32,
1
solid (351 mg, 58% yield). [a]2D0 = ꢀ5.8 (c = 0.6, CHCl3); H NMR 86.06, 49.84, 41.75, 23.82, 21.43, 12.49 ppm; IR n = 3282, 2964,
(300 MHz, CDCl3): d = 0.85–0.89 (m, 3H, –CH3), 1.31–1.35 (m, 2H, 2933, 2101, 1711, 1666, 1328, 1160, 1093, 911 cmꢀ1; MS (ESI) of
–CH2–), 2.05–2.12 (m, 1H, –CH–), 2.46 (s, 3H, –CH3), 3.65 (dd, J = C18H22N4O2S m/z 359.3 ([M + H]+).
2.19, 9.53 Hz, 1H, –CHH–), 4.11 (dd, J = 5.13, 6.59 Hz, 1H, –CHH–),
General synthesis of amino benzensulfonamides R-1, S-1 or S,R-3
4.96 (d, J = 8.43 Hz, 1H, –CH–), 7.19–7.43 (m, 7H, arom), 7.91–7.97
(m, 2H, arom) ppm; 13C NMR (75 MHz, CDCl3): d = 148.89, 145.33, In a stainless steel autoclave (20 mL), equipped with tempera-
136.82, 135.52, 129.66, 129.28, 129.12, 128.97, 126.89, 84.63, 48.41, ture control and a magnetic stirrer, purged five times with
40.31, 22.39, 21.85, 11.06 ppm; IR n = 3426, 2964, 2882, 2101, 1719, hydrogen, a solution of 11a or S,R-10c (0.15 mmol) in methanol
1353, 1175, 1158, 885, 700 cmꢀ1; elemental analysis for with 1% of Pd/C was transferred. The autoclave was pressurised
C
19H21NO4S: C, 63.49; H, 5.89; N, 3.90; found: C, 63.52; H, at 20 atm and kept under stirring at room temperature for four
5.93; N, 3.94; MS (ESI) of C19H21NO4S m/z 360.2 ([M + H]+).
hours. The mixture was then filtered on Celite and the solvent
was evaporated in vacuo to give the product.
Synthesis of (R)-6-phenyl-3-tosyl-1,3-oxazinan-2-one R-10a
(R)-N-(3-Amino-3-phenylpropyl)-4-methylbenzenesulfonamide
To a solution of 8a (270 mg, 1.08 mmol) in fresh-distilled R-1. Yellow oil, without any further purification step (43 mg,
dichloromethane, 4-dimethylaminopyridine (99 mg, 0.81 mmol) 95% yield). [a]2D0 = +8.0 (c = 0.4, CHCl3); 1H NMR (300 MHz,
and triethylamine (2 mL, 14.04 mmol) were added. The reaction CDCl3): d = 1.89 (dd, J = 5.87, 12.09 Hz, 2H, –CH2–), 2.42 (s, 3H,
mixture was then cooled to ꢀ10 1C and stirred for half an hour. –CH3), 2.91–2.95 (m, 2H, –CH2–), 4.04 (t, J = 5.87 Hz, 1H, –CH–),
A solution of tosyl chloride (267 mg, 1.4 mmol) in dichloro- 4.25–4.54 (br, 2H, NH2), 7.17–7.29 (m, 7H, arom), 7.72 (d, J =
methane was then dropped into the former solution and stirred 8.07 Hz, 2H, arom) ppm; 13C NMR (75 MHz, CDCl3): d = 143.10,
overnight allowing the reaction mixture to reach room tempera- 142.74, 136.82, 129.60, 128.73, 127.64, 127.05, 126.29, 54.34,
ture. The reaction was monitored by TLC using dichloromethane/ 40.71, 36.43, 21.42 ppm; IR n = 3350, 3293, 2917, 2099, 1650,
diethyl ether 1 : 1 as an eluent. After 24 h the reaction is com- 1598, 1454, 1323, 1156, 1094, 951, 815 cmꢀ1; MS (ESI) of
pleted. The desired product was obtained as a white solid by slow
diffusion of hexane into the acetone solution (152 mg, 43% yield).
C
16H20N2O2S m/z 305.2 ([M + H]+).
(S)-N-(3-Amino-3-phenylpropyl)-4-methylbenzenesulfonamide
[a]D20 = +24.7 (c = 0.25, CHCl3). All characterization data are in S-1. Pale yellow oil (45 mg, quantitative yield). [a]D20 = ꢀ7.6
agreement with that previously reported for S-10a.
(c = 0.24, CHCl3). All characterization data are in agreement
with that previously reported for R-1.
General synthesis of azido benzenesulfonamides 11a or S,R-10c
N-((S)-2-((R)-Amino(phenyl)methyl)butyl)-4-methylbenzene-
To a solution of 10a or S,S-9c in anhydrous DMF (0.30 mmol), sulfonamide S,R-3. White solid (44.3 mg, 89% yield). [a]2D0 = +4
NaN3 was added (98.2 mg, 1.51 mmol). The solution was refluxed (c = 0.3, CH3OH); 1H NMR (300 MHz, CD3OD): d = 0.85–0.87 (m,
at 120 1C for 3.5 h under a N2 atmosphere. After cooling to room 3H, –CH3), 1.19–1.22 (m, 2H, –CH2–), 1.73–1.76 (m, 1H, –CH–),
temperature, water was added and the solution was extracted with 2.45 (s, 3H, –CH3), 2.86–2.91 (m, 2H, –CH2–), 4.15 (d, J = 3.29 Hz,
diethyl ether (3 ꢁ 10 mL). The collected organic layers were dried 1H, –CH–), 7.05–7.33 (m, 7H, arom), 7.75 (d, J = 8.06 Hz, 2H,
on Na2SO4, filtered and evaporated to give the product.
arom) ppm; 13C NMR (75 MHz, CD3OD): d = 143.51, 140.92,
(R)-N-(3-Azido-3-phenylpropyl)-4-methylbenzenesulfonamide 136.64, 129.53, 128.54, 127.68, 126.96, 55.94, 45.51, 42.45, 20.27,
R-11a. Orange oil (49 mg, 50% yield). [a]2D0 = +61.2 (c = 0.5, 19.18, 9.75 ppm; IR n = 3436, 3292, 2963, 2925, 1631, 1320, 1151,
CHCl3); 1H NMR (300 MHz, CDCl3): d = 1.86–1.90 (m, 2H, –CH2–), 1093, 803, 704 cmꢀ1; elemental analysis for C18H24N2O2S: C,
2.42 (s, 3H, –CH3), 3.00–3.05 (m, 2H, –CH2–), 4.52 (t, J = 7.33 Hz, 65.03; H, 7.28; N, 8.43; found: C, 64.97; H, 7.23; N, 8.39; MS
1H, –CH–), 5.16 (t, J = 7.12 Hz, 1H, NH) 7.19–7.37 (m, 7H, arom) (ESI) of C18H24N2O2S m/z 333.0 ([M + H]+).
7.73 (d, J = 8.43 Hz, 2H, arom) ppm; 13C NMR (75 MHz, CDCl3): d =
Synthesis of tert-butyl-(S)-(3-hydroxy-3-phenylpropyl)
carbamate S-8a
2876, 2099, 1663, 1598, 1454, 1326, 1160, 1093, 909, 815 cmꢀ1; MS To a solution of 6a (520 mg, 2.94 mmol) in a mixture of THF/
143.79, 138.96, 137.02, 130.01, 129.15, 128.74, 127.34, 127.03,
63.78, 40.47, 36.24, 21.73 ppm; IR n = 3283, 3063, 3032, 2927,
(ESI) of C16H18N4O2S m/z 353.2 ([M + Na]+).
water 1 : 1, Na2CO3 was added (720 mg, 6.76 mmol). The
S)-N-(3-Azido-3-phenylpropyl)-4-methylbenzenesulfonamide
solution was then cooled to 0 1C and a solution of di-tert-
S-11a. Orange oil (50 mg, 51% yield). [a]2D0 = ꢀ75.0 (c = 0.25, butyl dicarbonate (770 mg, 3.53 mmol) in 5 mL THF was added
CHCl3). All characterization data are in agreement with that dropwise. After 1 h stirring at 0 1C, the solution was warmed to
previously reported for R-11a.
room temperature and stirred for further 3 h. The reaction was
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monitored by TLC using dichloromethane/diethyl ether 1 : 1 as 1 mmol) was added. After stirring for 12 h at room temperature,
an eluent. After 4 h the reaction was complete and water was water (2 mL) was added and the solution was extracted with diethyl
added to the mixture and extracted with diethyl ether (3 ꢁ 10 mL) ether (3 ꢁ 10 mL). The collected organic layers were washed with
to give the product as a yellow oil (575 mg, 78% yield). [a]D20
=
an aqueous solution of NaHCO3, dried on Na2SO4, filtered and
ꢀ18.9 (c = 0.4, CHCl3); 1H NMR (300 MHz, CDCl3): d = 1.41 (s, 9H, evaporated to give the azido compound. In a stainless steel
–C(CH3)3), 1.75–1.79 (m, 2H, –CH2–), 3.16–3.20 (m, 1H, –CHH–), autoclave (20 mL), equipped with temperature control and a
3.37–3.63 (m, 2H, –CHH– + OH), 4.64 (m, 1H, –CH–), 5.23 (br, magnetic stirrer, purged five times with hydrogen, a solution of
1H, NH), 7.25–7.31 (m, 5H, arom) ppm; 13C NMR (75 MHz, CDCl3): the azido intermediate (0.67 mmol) in methanol with 1% of
d = 157.05, 144.54, 128.65, 127.59, 125.87, 79.76, 71.95, 39.77, 37.83, Pd/C was transferred. The autoclave was pressurised at 20 atm
28.63 ppm; IR n = 3363, 3274, 2975, 1677, 1546, 1291, 1180, 1025, and kept under stirring at room temperature for four hours.
981 cmꢀ1; MS (ESI) of C14H21NO3 m/z 274.10 ([M + Na]+).
The mixture was then filtered on Celite and the solvent was
evaporated in vacuo to give the product.
General synthesis of Teoc-amino alcohols S-9a or S,S-8c
Intermediate (1-azido-3-chloropropyl)benzene. (130 mg, 97%
The synthesis proceeded according to methodology reported in yield). [a]2D0 = ꢀ123.8 (c = 0.5, CHCl3); 1H NMR (300 MHz, CDCl3):
the literature.46
d = 1.99–2.45 (m, 2H, –CH2–), 3.35–3.54 (m, 1H, –CHH–), 3.56–3.82
2-(Trimethylsilyl)ethyl (S)-(3-hydroxy-3-phenylpropyl)carbamate (m, 1H, –CHH–), 4.75 (dd, J = 8.4, 6.0 Hz, 1H, –CH–), 6.99–7.81 (m,
S-9a. Colourless oil (405 mg, 93% yield). [a]2D0 = ꢀ12.3 (c = 1.5, 5H, arom); 13C NMR (75 MHz, CDCl3): d = 138.80, 129.24, 128.86,
CHCl3); 1H NMR (300 MHz, CDCl3): d = 0.02 (s, 9H, –C(CH3)3), 0.89 127.15, 63.33, 41.57, 39.16. ppm; IR n = 3032, 2964, 2919, 2098,
(t, J = 8.43 Hz, 2H, –CH2–), 1.75 (q, J = 6.6 Hz, 2H, –CH2–), 3.11–3.27 1678, 1454, 1244, 760, 700 cmꢀ1; MS (ESI) of C9H10ClN3 m/z 196.7
(m, 2H, –CH2–), 4.05 (t, J = 8.43 Hz, 2H, –CH2–), 4.60–4.66 (q, J = ([M + H]+).
5.50 Hz, 1H, –CH–), 5.42 (br, 1H, NH), 7.14–7.26 (m, 5H, arom)
(S)-3-Chloro-1-phenylpropan-1-amine S-12a. Yellow pale oil
ppm; 13C NMR (75 MHz, CDCl3): d = 169.19, 157.58, 144.78, 128.60, (100 mg, 89% yield). [a]D20 = +5.4 (c = 1.0, CH3OH); 1H NMR
127.67, 127.43, 125.98, 125.88, 71.97, 70.66, 63.14, 39.32, 25.60, (300 MHz, CDCl3): d = 2.12 (dd, J = 13.5, 7.0, 3.1 Hz, 2H, –CH2–),
17.95, ꢀ1.27 ppm; IR n = 3403, 2953, 1743, 1694, 1525, 1251, 1062, 3.01 (br, 2H, NH2), 3.35–3.48 (m, 1H, –CHH–), 3.52–3.65 (m, 1H,
860, 838 cmꢀ1; MS (ESI) of C15H25NO3Si m/z 318.2 ([M + Na]+).
–CHH–), 4.15 (t, J = 7.0 Hz, 1H, –CH–), 7.21–7.39 (m, 5H, arom)
2-(Trimethylsilyl)ethyl ((S)-2-((S)-hydroxy(phenyl)methyl) butyl)- ppm; 13C NMR (75 MHz, CD3OD): d = 143.80, 128.64, 127.82,
carbamate S,S-8c. White oil (374 mg, 82% yield). [a]2D0 = ꢀ9.5 (c = 127.49, 126.78, 126.48, 126.24, 57.51, 53.38, 41.56, 41.15, 30.01,
0.5, CHCl3); 1H NMR (300 MHz, CDCl3): d = 0.09 (s, 9H, –C(CH3)3), 9.77 ppm; IR n = 3352, 3270, 2933, 1602, 1453, 1348, 1072 cmꢀ1
0.93 (t, J = 4.03 Hz, 3H, –CH3), 0.97–1.02 (m, 2H, –CH2–), 1.17–1.28 MS (ESI) of C9H12ClN m/z 170 ([M + H]+).
;
(m, 2H, –CH2–), 1.69–1.75 (m, 1H, –CH–), 3.18–3.25 (m, 1H,
Intermediate 2-(trimethylsilyl)ethyl((S)-2-((R)-azido(phenyl)
+51.8 (c 1.2, CHCl3);
–CHH–), 3.49–3.63 (m, 1H, –CHH–), 4.15 (t, J = 9.16 Hz, 2H, methyl)butyl)carbamate. [a]D20
=
=
–CH2–), 4.48 (d, J = 7.7 Hz, 1H, –CH–), 5.10 (br, 1H, NH), 7.24– 1H NMR (300 MHz, CDCl3): d = 0.07 (s, 9H, –C(CH3)3), 0.92
7.34 (m, 5H, arom) ppm; 13C NMR (75 MHz, CDCl3): d = 157.93, (t, J = 7.70 Hz, 3H, –CH3), 1.25–1.39 (m, 2H, –CH2–), 1.43–1.50
143.54, 129.25, 128.60, 127.79, 126.77, 74.23, 63.44, 63.39, (m, 2H, –CH2–), 1.83–1.86 (m, 1H, –CH–), 3.08–3.14 (t, J = 6.23 Hz,
47.73, 41.74, 21.61, 19.16, 17.99, 12.13, 1.24 ppm; IR n = 3391, 2H, –CH2–), 4.13 (t, J = 9.89 Hz, 2H, –CH2–), 4.54 (d, J = 6.6 Hz,
2958, 1694, 1519, 1251, 1064, 1041, 860, 837 cmꢀ1; MS (ESI) of 1H, –CH–), 7.28–7.40 (m, 5H, arom) ppm; 13C NMR (75 MHz,
C
17H29NO3Si m/z 346.3 ([M + Na]+).
CDCl3): d = 156.98, 138.29, 129.03, 128.72, 128.48, 128.25,
127.44, 126.65, 77.89, 77.26, 76.62, 68.22, 63.25, 45.93, 41.33,
20.67, 17.98, 11.36, ꢀ1.25 ppm; IR n = 3339, 2956, 2100, 1704,
Synthesis of (R)-6-phenyl-1,3-oxazinan-2-one R-7a
A solution of S-9a (405 mg, 1.37 mmol) and triethylamine (380 mL, 1524, 1250, 1176, 860, 838 cmꢀ1; MS (ESI) of C17H28N4O2Si m/z
2.74 mmol) in anhydrous THF (10 ml) was cooled to 0 1C. Mesyl 374.3 ([M + Na]+).
chloride (130 mL, 1.64 mmol) in THF (2 mL) was added dropwise.
2-(Trimethylsilyl)ethyl ((S)-2-((R)-amino(phenyl) methyl) butyl)-
The reaction was stirred for 2 h, filtrated and the solvent evapo- carbamate S,R-11c. Colourless oil (76 mg, 35% total yield for three
1
rated in vacuo. R-7a was obtained as a white solid (179 mg, 74% steps) [a]2D0 = +6.46 (c = 1.3, CHCl3); H NMR (300 MHz, CDCl3):
yield). [a]2D0 = +40.0 (c = 0.5, CHCl3). All characterization data are in d = 0.08 (s, 9H, –C(CH3)3), 0.95 (t, J = 8.03 Hz, 3H, –CH3), 1.15–1.42
agreement with that previously reported for S-7a.
(m, 4H, 2ꢁ –CH2–), 1.63–1.74 (m, 1H, –CH–), 2.85 (br, 2H, NH2),
3.08–3.21 (m, 2H, –CH2–), 4.09–4.13 (m, 3H, –CH2– + –CH–), 5.85
(br, 1H, NH), 7.21–7.38 (m, 5H, arom) ppm; 13C NMR (75 MHz,
CDCl3): d = 157.19, 143.25, 128.60, 128.25, 127.41, 127.03, 126.65,
General synthesis for insertion of the amino group in 1 position
S-12a or S,R-11c
A solution of (R)-(+)-3-chloro-1-phenyl-1-propanol or S,S-8c 126.17, 62.99, 57.91, 45.98, 41.94, 20.10, 17.99, 11.90, ꢀ1.25 ppm;
(0.68 mmol) and triethylamine (190 mL, 1.36 mmol) in anhydrous IR n = 3339, 2596, 1704, 1519, 1250, 860, 837 cmꢀ1; MS (ESI) of
THF (5 mL) was cooled to 0 1C. Mesyl chloride (65 ml, 0.81 mmol) C17H30N2O2Si m/z 323.2 ([M + H]+).
in THF (1 mL) was added dropwise. The reaction was stirred for
General synthesis for sulphonamides in 1 position S-13a or S,R-12c
2 h, filtrated and the solvent evaporated in vacuo. The mesylated
intermediate was used without any other purification step. The To a solution of S-12a or S,R-11c (0.53 mmol) in fresh-distilled
compound was dissolved in dry DMF (5 mL) and NaN3 (65 mg, dichloromethane, triethylamine (112 mL, 0.79 mmol) was added.
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The reaction mixture was then cooled to 4 1C and stirred for Synthesis of (S)-N-(3-amino-1-phenylpropyl)-4-methylbenzenesulfon-
half an hour. A solution of tosyl chloride (126 mg, 0.66 mmol) amide S-2
in dichloromethane was then dropped into the former solution
and stirred overnight allowing the reaction mixture to reach
control and a magnetic stirrer, purged five times with hydrogen, a
room temperature. The reaction was monitored by TLC using
In a stainless steel autoclave (20 mL) equipped with temperature
solution of 14a (40 mg, 0.121 mmol) in methanol with 1% of Pd/C
was transferred. The autoclave was pressurised at 20 atm and kept
EtOAc/hexane 1 : 1 as an eluent.
under stirring at room temperature for four hours. The mixture
was then filtered on Celite and the solvent was evaporated
(S)-N-(3-Chloro-1-phenylpropyl)-4-methylbenzenesulfonamide S-13a
The product was obtained as a white solid by slow diffusion of
in vacuo to give the product S-2 as a yellow pale oil (35 mg,
hexane into the chloroform solution. (80 mg, 50% yield). [a]D20
=
1
95% yield). [a]2D0 = +5.4 (c = 1.5, CH3OH); H NMR (300 MHz,
ꢀ6.5 (c = 0.25, CHCl3); 1H NMR (300 MHz, CDCl3): d = 1.92–2.57
(m, 2H, –CH2–), 2.35 (s, 3H, –CH3), 3.19–3.27 (m, 1H, –CHH–),
3.32–3.51 (m, 1H, –CHH–), 4.52 (q, J = 7.4 Hz, 1H, –CH–),
5.55 (d, J = 7.6 Hz, 1H, NH), 7.00–7.16 (m, 7H, arom), 7.57
(d, J = 8.2 Hz, 2H, arom) ppm; 13C NMR (75 MHz, CDCl3):
d = 143.39, 139.81, 137.62, 129.95, 129.47, 128.88, 128.56,
127.96, 127.30, 126.79, 126.36, 55.98, 41.31, 40.16, 21.64 ppm;
IR n = 3436, 3265, 2965, 1600, 1458, 1325, 1161 cmꢀ1; elemental
analysis for C16H18ClNO2S: C, 59.34; H, 5.60; N, 4.33; found:
C, 58.98; H, 5.52; N, 4.21; MS (ESI) of C16H18ClNO2S m/z 346.3
([M + Na]+).
CDCl3): d = 1.85–2.05 (m, 2H, –CH2–), 2.30 (s, 3H, –CH3),
2.77–2.9 (m, 2H, –CH2–), 4.46 (t, J = 6.5 Hz, 1H, –CH–),
6.97–7.16 (m, 7H, arom), 7.46 (d, J = 7.8 Hz, 2H, arom) ppm;
13C NMR (75 MHz, CDCl3): d = 142.82, 141.22, 138.12, 129.89,
129.36, 128.45, 127.21, 126.77, 126.56, 57.69, 38.89, 38.47,
21.57 ppm; IR n = 3352, 3270, 2933, 2103, 1652, 1453, 1328,
1152, 1091, 953, 817 cmꢀ1; MS (ESI) of C16H20N2O2S m/z 305.4
([M + H]+).
Synthesis of N-((1R,2S)-2-(aminomethyl)-1-phenylbutyl)-4-methyl-
benzenesulfonamide R,S-4
2-(Trimethylsilyl)ethyl ((S)-2-((R)-((4-methylphenyl)sulfon-
amido)(phenyl)methyl) butyl)carbamate S,R-12c:. Colourless The synthesis proceeded as reported in the literature.37 The
oil (100 mg, 40% yield). [a]2D0 = +20.4 (c = 0.9, CHCl3); product was recovered as colourless oil (58 mg, 87% yield).
1H NMR (300 MHz, CDCl3): d = 0.05 (s, 9H, –C(CH3)3), 0.88 (t, [a]2D0 = +6.5 (c = 1.3, CHCl3); 1H NMR (300 MHz, CD3OD):
J = 8.06 Hz, 3H, –CH3), 0.96 (t, J = 8.06 Hz, 2H, –CH2–), 1.34–1.48 d = 0.86 (t, J = 7.33 Hz, 3H, –CH3), 1.37–1.43 (m, 2H, –CH2–),
(m, 2H, –CH2–),1.81–1.93 (m, 1H, –CH–), 2.30 (s, 3H, –CH3), 2.25 (s, 3H, –CH3), 2.46 (d, J = 6.97 Hz, 1H, –CH–), 3.73–3.82
3.18–3.24 (m, 2H, –CH2–), 4.18 (t, J = 6.78 Hz, 2H, –CH2–), 4.49– (m, 2H, –CH2–), 4.50 (d, J = 5.50 Hz, 1H, –CH–), 7.01–7.10
4.56 (m, 1H, –CH–), 5.29 (br, 1H, NH), 5.49–5.53 (br, 1H, NH), (m, 5H, arom), 7.43–7.51 (m, 4H, arom) ppm; 13C NMR (75 MHz,
6.89–6.98 (m, 2H, arom), 7.04–7.14 (m, 5H, arom), 7.53 (d, J = CD3OD): d = 143.16, 138.47, 138.03, 129.02, 128.21, 127.12, 126.84,
8.43, 2H, arom) ppm; 13C NMR (75 MHz, CDCl3): d = 157.13, 126.76, 65.67, 58.19, 44.69, 20.10, 19.71, 10.32 ppm; IR n = 3252,
143.34, 139.22, 137.52, 129.49, 128.44, 127.17, 126.56, 63.26, 3063, 2968, 2353, 1661, 1598, 1455, 1325, 1159, 1091, 969, 814
58.20, 47.04, 41.22, 29.90, 21.63, 18.00, 11.82, ꢀ1.23 ppm; IR n = cmꢀ1; MS (ESI) of C18H24N2O2S m/z 333.4 ([M + H]+).
3382, 2597, 1694, 1532, 1251, 1160, 860, 838, 702 cmꢀ1; MS
Typical procedure for asymmetric transfer hydrogenation
(ATH). A 10 mL Schlenk tube was loaded with [RuCl2( p-cymene)]2
(1 mmol), the diamine ligand (2.2 mmol) and charged with
distilled toluene (3 mL). The solution was refluxed at 110 1C for
3 h. The solvent was removed in vacuo. To a solution of the keto-
(ESI) of C24H36N2O4SSi m/z 477.3 ([M + H]+).
Synthesis of (S)-N-(3-azido-1-phenylpropyl)-4-methylbenzenesulfon-
amide S-14a
Compound 13a (40 mg, 0.124 mmol) was dissolved in dry substrate (0.5 mmol) in water (2 mL), [Ru( p-cymene)(diamine)Cl]
DMSO (5 mL) and NaN3 (80 mg, 1.24 mmol) was added. After (0.0025 mmol) in 20 mL DMSO and HCOONa as a hydrogen donor
24 h at 100 1C, the solution was cooled to room temperature, (5 mmol, 10 eq.) were added. The reaction mixture was stirred at
water (2 mL) was added and the mixture was extracted with 40 1C for 48 h and extracted with ethyl acetate (2 ꢁ 5 mL). The
diethyl ether (3 ꢁ 5 mL). The collected organic layers were combined organic layers were dried with Na2SO4 and analysed
washed with an aqueous solution of NaHCO3, dried on Na2SO4, by HPLC.
filtered and evaporated to give the product S-14a as a white
Analytical HPLC conditions: Chiralcel OD-H, eluent:
solid (40 mg, 97% yield). [a]2D0 = ꢀ14.3 (c = 0.4, CHCl3); 1H NMR hexane : ethanol = 95 : 5, flow = 0.8 mL minꢀ1, l = 216 nm:
(300 MHz, CDCl3): d = 1.8–2.10 (m, 2H, –CH2–), 2.57 (s, 3H,
1-Phenylethan-1-ol: rt: substrate 4.8 min, (R) = 5.4 min,
–CH3), 3.01–3.33 (m, 2H, –CH2–), 4.31 (dd, J = 8.1, 14.8 Hz, 1H, (S) = 6.0 min.
–CH–), 6.65 (d, J = 8.2 Hz, 1H, NH), 6.98–7.16 (m, 7H, arom),
1-(o-Tolyl)ethan-1-ol: rt: substrate 6.3 min, (R) = 8.4 min,
7.46 (d, J = 7.8, 2H, arom) ppm; 13C NMR (75 MHz, CDCl3): d = (S) = 9.0 min.
143.43, 140.02, 137.72, 129.60, 129.45, 128.90, 128.57, 127.95,
1-(3-Methoxyphenyl)ethan-1-ol: rt: substrate 7.5 min, (R) =
127.28, 126.77, 126.56, 126.29, 56.12, 48.28, 36.59, 21.59 ppm; 12.6 min, (S) = 15.8 min.
IR n = 3232, 2963, 2091, 1599, 1455, 1323, 1156, 1088 cmꢀ1
;
1-(4-(Trifluoromethyl)phenyl)ethan-1-ol: rt: substrate 6.3 min,
elemental analysis for C16H18N4O2S: C, 58.16; H, 5.49; N, 16.96; (S) = 8.1 min, (R) = 8.4 min.
found: C, 58.26; H, 5.51; N, 17.08; MS (ESI) of C16H18N4O2S m/z
1-Phenylpropan-1-ol: rt: substrate 7.1 min, (R) = 9.9 min,
(S) = 10.9 min.
353.3 ([M + Na]+).
New J. Chem.
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NJC
Ethyl 4-hydroxy-4-phenylbutanoate: rt: substrate 12.8 min,
(R) = 13.9 min, (S) = 14.6 min.
Ethyl 3-hydroxy-3-phenylpropanoate: rt: substrate 7.7 min,
(S) = 11.6 min, (R) = 14.6 min.
Paper
23 T. Touge, T. Hakamata, H. Nara, T. Kobayashi, N. Sayo,
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