New chiral amino alcohol ligands for catalytic enantioselective addition of diethylzincs to aldehydes

Article abstract of DOI:10.1039/c8ob00165k

A study aimed at the synthesis and structure optimization of new, efficient, optically active β-amino alcohol ligands with a structure suitable for immobilization on magnetite nanoparticles has been carried out. The optimized homogeneous amino alcohol catalysts 13a and 13b, the chirality of which arises from the Sharpless epoxidation of suitable allyl alcohols, were tested by employing the well-established enantioselective amino alcohol-promoted addition of diethylzinc to benzaldehyde, giving the corresponding benzyl alcohol with nearly quantitative yield and ee = 95%. Then, their broad applicability as chiral catalysts was evaluated by carrying out the same reaction on a family of aldehydes, including variously substituted aromatic ones as well as an aliphatic analogue. The results have confirmed the validity of the fine-tuning process performed on ligands 13a and 13b. In fact, both exhibited excellent catalytic activity as demonstrated by the chemical yields and ee obtained from all the tested aldehydes, almost independent of the position and type of substitution in the aromatic ring.

Full text of DOI:10.1039/c8ob00165k

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New chiral amino alcohol ligands for catalytic enantioselective
addition of diethylzinc to aldehydes
Carla Sappino, a† Alessandra Mari, a† Agnese Mantineo,a Mauro Moliterno,a Matteo Palagri,a Chiara
Received 00th January 20xx,
Accepted 00th January 20xx
Tatangelo,a Lorenza Suber,b Paolo Bovicelli,c Alessandra Ricelli,c and Giuliana Righic†*
DOI: 10.1039/x0xx00000x
E-mail: giuliana.righi@cnr.it
www.rsc.org/
Abstract. A study aimed at the synthesis and structure optimization of new, efficient, optically active β-amino alcohol
ligands with a structure suitable for immobilization on magnetite nanoparticles has been carried out. The optimized
homogeneous amino alcohol catalysts 13a and 13b, the chirality of which arises from the Sharpless epoxidation of suitable
allyl alcohols, were tested by employing the well-established enantioselective amino alcohol-promoted addition of
diethylzinc to benzaldehyde giving the corresponding benzyl alcohol with nearly quantitative yield and ee=95%. Then their
broad applicability as chiral catalysts was evaluated by carrying out the same reaction on a family of aldehydes, including
variously substituted aromatic ones as well as an aliphatic analogue. The results have confirmed the validity of the fine-
tuning process performed on ligands 13a and 13b. In fact, both exhibited excellent catalytic activity as demonstrated by the
chemical yields and ee obtained from all the tested aldehydes, almost independent of the position and type of substitution
in the aromatic ring.
alcohols, and, at the same time, leads to the formation of a new
C-C bond. After the work of Noyori,5 1,2-amino alcohols have
become the preferred choice in the enantioselective addition of
dialkylzincs to aldehydes. This reaction has become a classical
Introduction
In recent decades, research on asymmetric catalysis has grown
considerably, culminating in award of the 2001 Nobel Prize in
Chemistry to Knowles,1 Noyori2 and Sharpless3 “for their work
on chirally catalyzed hydrogenation and oxidation reactions”.
Most of the chiral catalysts developed so far are small, optically
active organic molecules able to form complexes with transition
metals trough heteroatoms incorporated in their structure
(commonly P, O, N, S). Research on new efficient catalysts relies
mostly on trial-and-error, thereby having a consistent number
of structurally correlated molecules, available for testing in the
selected enantioselective reaction becomes a decisive factor.
For this reason, it is important to design a structure which
includes an easily tunable site, in order to access to many
potential catalysts with relatively modest effort.
test in the design of new amino alcohol chiral ligands, and many
new catalysts have been developed. To mention some
examples,
N,N-dialkylnorephedrines6
and
substituted
aminophenylalcohols7,8 led to outstanding results. Due to our
research on stereocontrolled synthesis of amino alcohols,9,10 we
were involved in the development of a novel class of amino
alcohol ligands. Moreover, we focused on the design and
synthesis of ligands that display a functionality suitable for their
covalent anchoring to magnetite nanoparticles (Figure 1).11, 12
The use of magnetic nanoparticles has recently led to the
development of new catalysts that combine the advantages of
both homogeneous and heterogeneous catalysis, leading to
easily recyclable highly efficient systems, and thereby reducing
the process’s economic and environmental effects.13
β
-amino alcohols represent one of the most studied classes of
Herein we report the design and synthesis of a novel, versatile
and easily tunable class of amino alcohol ligands, developed
through the well-established enantioselective addition of
diethylzinc to aldehydes. Moreover, it is a specific feature of
these new ligands that their stucture is enriched with a
functionality for a future immobilization on magnetically
recoverable nanoparticles.
chiral ligands/auxiliaries. They have been used, both in acyclic-
and cyclic-derivative form, since the beginning of asymmetric
synthesis.4 Enantioselective addition of organometallic
reagents to aldehydes affords optically active secondary
a. Dip. Chimica, Sapienza Università di Roma, p.le A. Moro 5, 00185 Roma, Italy
b. CNR-Istituto di Struttura della Materia-Via Salaria km 29,300-00015
Monterotondo Scalo (Roma) Italy.
c. CNR-IBPM- c/o Dip. Chimica, Sapienza Università di Roma, p.le A. Moro 5, 00185
Roma, Italy
† These authors contributed equally to this work.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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Results and Discussion
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DOI: 10.1039/C8OB00165K
Unfunctionalized amino alcohol ligands
First, to understand the influence of regio- and stereochemistry
of the amino alcohol moiety on the catalytic activity, amino
alcohol ligands 1, 2, 3 were prepared (Figure 1).
All the ligands were obtained starting from the optical active
epoxy alcohol 5a carrying out the Sharpless AE on the allylic
alcohol 4a. The epoxy alcohol 5a was transformed into the
corresponding carboxylic acid, and then coupled with allylamine
to afford the amide 6a (Scheme 1).§ The aminolysis of amide 6a
(Scheme 1) afforded the anti stereochemistry of the amino
alcohol moiety in the mixture of regioisomers
1 and 2 (ratio
50:50). In contrast, obtaining the syn stereochemistry in the
amino alcohol system required a two-step process: an initial
oxirane ring opening by means of MgBr2 in diethyl ether at room
temperature followed by a nucleophilic substitution by azide
(Scheme 2). Finally, the azido alcohol
reduction employing PPh3, thereby resulting in the
corresponding amino alcohol ligand (Scheme 2).
At this point, these optically active amino alcohols were tested
in the addition of diethylzinc to benzaldehyde, employing a 6%
molar amount of ligand and performing the reactions at room
temperature in toluene. Unfortunately, these ligands had no
significant catalytic activity: in all cases, reaction yields were
comparable to those obtained in the absence of a ligand (24-
44%) and no asymmetric induction was observed.
8 was subjected to
3
Scheme 1: a) TBHP, Ti(O-iPr)4, L-(+)-DET, CH2Cl2 dry, -20 °C, 12h, 88%
b) NaIO4, RuCl3, CH3CN/CCl4/buffer pH 7, r.t., 12h c) allylamine,
EDC/HOAt, CH2Cl2, r.t., 2h, 53-75% d) NH3/H2O, 65 °C, 12 h, 72%
Scheme 2: a) MgBr2, Et2O, r.t., 8h, 73% b) NaN3, 18-crown-6,
DMSO, 60 °C, 12h, 88% c) PPh3, MeOH/H2O, r.t., 8h, 68%
Figure 1: Structure of amino alcohol ligands 1, 2 and 3
N,N-dialkylated amino alcohol ligand
In light of the disappointing results obtained and considering
the numerous examples of N,N-dialkylated amino alcohol
ligands present in the literature, we decided to functionalize the
nitrogen of
1, 2 and 3, which afforded the corresponding
dipropyl derivatives in moderate yields (Scheme 3).
Amino alcohols 9-11 were then evaluated as ligands in the
reaction test. As shown in Table 1, yields increased significantly
and enantiomeric excesses, albeit modest, were observed. In
particular, these preliminary results seem to indicate that the
amino alcohol regiochemistry has no influence on catalytic
efficiency (entries 1,2), whereas the syn stereochemistry (entry
3) is less efficient than that of the anti one (entries 1,2), in
agreement with some results already reported.14
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DOI: 10.1039/C8OB00165K
NR'2
O
Ti(OiPr)4
O
O
R
N
H
R'2NH
neat
R
N
H
OH
6a R = propyl
6b R = c-hexyl
6c R = phenyl
12a R = propyl NR'2 = dibutylaminyl
12b R = c-hexyl NR'2 = dipropylaminyl
12c R = c-hexyl NR'2 = dibutylaminyl
12d R = c-hexyl NR'2 = piperidinyl
12e R = c-hexyl NR'2 = morpholinyl
12f R = phenyl NR'2 = dibutylaminyl
12g R = phenyl NR'2 = piperidinyl
Scheme 4: 12h, r.t., 85-95%
Table 2: Addition of Et2Zn to benzaldehyde catalyzed by
ligands 12a-g
Scheme 3: a) n-PrI, K2CO3, CH3CN, reflux, 12h, 55-70%
Table 1: Addition of Et2Zn to benzaldehyde catalyzed by
entry
ligand
yield (%)b
ee (%)
ligands
9
,
10 and 11
1
2
3
4
5
6
7
12a
12b
12c
12d
12e
12f
87
88
93
78
80
61
50
25
29
31
16
15
7
Entry
ligand
yield (%)b
ee (%)
28
1
2
3
9
89
86
76
10
11
27
0
a)
All the experiments were performed under identical conditions (6h).
b) Chemical yields are referred to isolated compounds
12g
4
a) All the experiments were performed under identical conditions
(6h). b) Chemical yields are referred to isolated compounds
Screening on the effect of the R and R’ groups
Optimization of ligand structure
The catalytic effect showed by ligands 9 and 10 prompted us to
synthetize a set of N,N-dialkylated amino alcohols with different
R and R’ groups following a previously reported methodology
(Scheme 4).15
To verify our hypothesis, we introduced a spacer between the
carbonyl group and the amino alcohol moiety; in particular, we
considered use of a double bond, expected to regioselectively
direct the nucleophilic ring opening of the epoxide, to be
The amino alcohols 12a-g were evaluated as chiral ligands in the
reaction test. As shown in Table 2, no significant effects of the
R and R’ groups were observed: yields were generally very good,
even if the level of asymmetric induction remained very
moderate. Lower catalytic activity was registered when
R=phenyl, although the structure of 12f and 12g is very similar
to that of efficient enantioselective ligands reported in
literature.7 The collected data have led us to hypothesize that a
carbonyl group adjacent to the amino alcohol site has an
unfavourable effect on the formation of the chiral complex
responsible for the enantiofacial differentiation.16-17
appropriate. The
α,β-unsaturated amides 13a-f and 14 were
synthesized in satisfactory yields from the corresponding
optically active epoxy alcohol by means of the sequence
described in Scheme 5. It is noteworthy that the final aminolysis
of the epoxy ring, expected to be effortless due to the high
reactivity of the allylic position, required testing of different
reaction conditions to enable achievement of the desired amino
alcohol in good yields.§§ In particular, by employing LiClO4 in
refluxing acetonitrile, the
completely converted into the corresponding amino alcohol
derivatives 13a . Whereas R=propyl and cyclohexyl substrates
led to a single regioisomer, the reaction on substrate with
R=phenyl produced both amino alcohols 13f and 14 §§§
Finally, the new set of amino alcohols 13a and 14 was tested
α,β-unsaturated epoxy amide was
-e
.
-f
in the usual addition of diethylzinc to benzaldehyde. As
reported in Table 3, the results with R=cyclohexyl were
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excellent, especially for R’=morpholine and dibutylamine
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DOI: 10.1039/C8OB00165K
(entries 1 and 2).
a
b
O
O
O
O
O
R
OH
R
H
R
OH
5a R = propyl
5b R = c-hexyl
5c R = phenyl
15a R = propyl
15b R = c-hexyl
15c R = phenyl
16a R = propyl
16b R = c-hexyl
16c R = phenyl
c
O
OH
O
NR'2
O
d
O
R
N
H
R
N
R
N
R= phenyl
H
H
NR'2
OH
13f
14
17a R = propyl
17b R = c-hexyl
17c R = phenyl
R=propyl,
cyclohexyl
d
OH
O
R
N
H
NR'2
13a-e
Scheme 5: a) TEMPO/IBDA, CH2Cl2, r.t., 4h, 72-81% b) diethylphosphonoacetic acid, BuLi, THF, -70°C., 8h c) allylamine, EDC,
HOAt, CH2Cl2, r.t., 8h, 65-72% from 15 d) LiClO4, R’2NH, CH3CN, reflux, 12h, 72-84%
Table 3: Addition of Et2Zn to benzaldehyde catalyzed by ligands 13a-f and 14
Entry
ligand
13a
13b
13c
13d
13e
13f
yield (%)b
>95
>95
84
ee (%)
90
1
2
3
4
5
6
7
95
83
53
10
39
54
70
52
14
71
38
a) All the experiments were performed under identical conditions (6h).
b) Chemical yields are referred to isolated compounds
Scope
catalytic activity as demonstrated by the chemical yields and ee
obtained from all the tested aldehydes, almost independent of
the position and type of substitution in the aromatic ring.
Generally, 13b seems to be a slightly more efficient ligand than
13a, the difference being particularly noticeable with 4-MeO-
benzaldehyde (entry 7). It is noteworthy that the catalytic
efficiency and asymmetric induction remain remarkable also
when the tested aldehyde was aliphatic (entry 4).
At this point, with the optimized ligands 13a and 13b in hand,
we decided to employ them in the addition of diethylzinc to a
family of aldehydes, including variously substituted aromatic
ones as well as an aliphatic analogue. Results shown in Table 4
have confirmed the consistency of the fine-tuning process
performed on ligands. Both 13a and 13b exhibited excellent
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Table 4: Addition of Et2Zn to different aldehydes catalyzed by ligands 13a and 13b
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DOI: 10.1039/C8OB00165K
Yield (%)b
13a
Yield (%)b
13b
ee (%)
13a
ee (%)
13b
entry
Aldehyde
Product
18a
18b
18c
18d
18e
18f
1
2
Benzaldehyde
1-Naphthaldehyde
>95
>95
88
>95
>95
88
90
83
88
92
88
96
92
58
95
93
92
90
91
88
90
89
93
95
97
87
95
80
96
97
97
98
98
97
90
91
88
97
96
92
3
Cinnamaldehyde
4
3-Thiophenecarboxaldehyde
Cyclohexanecarboxaldehyde
2-Methoxybenzaldehyde
3-Methoxybenzaldehyde
4-Methoxybenzaldehyde
2-Methylbenzaldehyde
3-Methylbenzaldehyde
4-Methylbenzaldehyde
2-Fluorobenzaldehyde
2-Chlorobenzaldehyde
3-Bromobenzaldehyde
4-Bromobenzaldehyde
3-Cyanobenzaldehyde
4-Cyanobenzaldehyde
>95
90
>95
88
5
6
>95
60
>95
60
18g
18h
18i
7
8
65
99
9
95
94
18j
10
11
12
13
14
15
16
17
>95
>95
88
>95
>95
88
18k
18l
18m
18n
18o
18p
18q
>95
>95
89
>95
>95
89
90
92
94
93
a) All the experiments were performed under identical conditions (6h). b) Chemical yields are referred to isolated compounds
catalysed by amino alcohols, as well as the immobilization of the
ligands on magnetite nanoparticles.
Conclusions
In conclusion, we have designed and fine-tuned new, efficient,
optically active -amino alcohol ligands, the chirality of which
Experimental Section
β
arises from the Sharpless epoxidation of suitable allyl alcohols.
After optimizing the structures of 13a and 13b by employing the
well-established enantioselective amino alcohol-promoted
addition of diethylzinc to benzaldehyde, their broad
applicability as chiral catalysts was evaluated by carrying out the
same reaction on a family of aldehydes, including variously
substituted aromatic ones as well as an aliphatic analogue. The
results confirmed the validity of the fine-tuning process
performed on ligands 13a and 13b. In fact, both exhibited
excellent catalytic activity as demonstrated by the chemical
yields and ee obtained from all the tested aldehydes, almost
independent of the position and type of substitution in the
aromatic ring.
General methods and materials
All anhydrous reactions were carried out in flame-dried
glassware under argon atmosphere. Unless otherwise stated,
commercial reagents were used without further purification. All
chromatographic purifications were performed on silica gel
(230-400 mesh). Thin layer chromatography (TLC) was
performed on pre-coated silica gel 60 F254 plates and
visualization was achieved by inspection under UV light
(Mineralight UVG 11 254 nm) followed by staining with
phosphomolybdic acid dip [polyphosphomolybdic acid (12 g),
ethanol (250 mL)] or Ninhydrin dip [ninhydrin (5 g), sulfuric acid
(5 mL), n-butanol (100mL)]. Organic solvents used for the
chemical synthesis and for chromatography were of analytical
grade. Benzaldehyde was freshly distilled before use. For all
known compounds the spectral characteristics were in
agreement with those reported in the literature. NMR spectra
In light of the reported results, we are currently investigating
the catalytic efficiency of 13a and 13b in other reactions
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were recorded using a Varian Mercury 300 (1H-NMR 300 MHz 58.7, 42.2, 41.1. Anal. Calcd for C12H13NO2: C, 70.92; H, 6.45; N,
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and 13C-NMR 75 MHz) and chemical shifts are reported in ppm 6.89. Found: C, 71.15; H, 6.48; N, 6.92.
DOI: 10.1039/C8OB00165K
using the residual solvent peak as a reference. Analytical high General procedure for the preparation of compounds 1 and 2
:
performance liquid chromatography (HPLC) was performed In a sealed tube epoxy amide 6a (169 mg, 1 mmol) was placed
using the indicated chiral column. Optical rotations were and treated with aq 33% NH4OH (10 mL). After two days with
measured on a digital polarimeter Jasco DIP-370 with a cell path stirring at 60 °C the reaction mixture was concentrated in vacuo
length of 1 cm at 589 nm; solution concentrations are reported to give a pale yellow oil. The crude material was purified by flash
in grams per 100 ml. Elemental analyses for C, H, and N were chromatography (chloroform/methanol 92:8) giving 1, 65 mg,
performed on an EA 1110 CHNS-O Instrument.
Synthesis of amino alcohol ligands
The following compounds were prepared following already (c=1.6 in CH3OH); H-NMR (300 MHz, CDCl3)
35% and
(2 ,3 )-
2, 69 mg, 37%.
S
S
N
-allyl-2-amino-3-hydroxyhexanamide 1: [α]25D= -7.8
1
δ
: 7.62 (bt, 1H, J=
known procedures§§§§ and all experimental data were 5.6 Hz), 5.83-5.67 (m, 1H), 5.17-5.01 (m, 2H), 3.83-3.70 (m, 3H),
consistent with the ones reported in the literature 5a 18 5b 19
3.31 (d, 1H, J= 5.4 Hz), 2.89-2.71 (bs, 3H), 1.53-1.21 (m, 4H), 0.83
5c 18 12a 15 15a,,20 15b20 (t, J=7.1 Hz); 13C-NMR (75 MHz, CDCl3)
: 173.9, 133.9, 116.2,
,
,
,
,
δ
General procedure for the preparation of compounds 6a, 6b, 72.7, 59.2, 41.4, 34.2, 18.8, 14.0; Anal. Calcd for C9H18N2O2: C,
6c: The epoxy alcohol (5a or 5b or 5c) (1 mmol) was dissolved in 58.04; H, 9.74; N, 15.04. Found: C, 58.25; H, 9.75; N, 15.08.
CCl4 (2 mL), CH3CN (2 mL) and phosphate buffer (pH = 7, 0.2 M, (2
3 mL) with vigorous stirring. Then NaIO4 (2.8 mmol, 600 mg) and (c=3.3 in CH3OH); H-NMR (300 MHz, CDCl3)
R
,3
R
)-
N
-allyl-3-amino-2-hydroxyhexanamide 2: [α]25D= 31.1
1
δ
: 7.48 (bt, 1H,
RuCl3 (0.05 mmol, 10 mg) were added. After 12 h, CH2Cl2 and J=6.0 Hz), 5.86-.71 (m, 1H), 5.20-5.05 (m, 2H), 4.01 (d, 1H, J=4.1
water were added. The organic layer was separated and the Hz), 3.89-3.80 (m, 2H), 3.50-3.20 (bs, 3H), 3.15-3.06 (m, 1H),
aqueous layer was extracted several times with CH2Cl2. The 1.46-1.14 (m, 4H), 0.86 (t, 3H, J=6.5 Hz); 13C-NMR (75 MHz,
combined organic extracts were dried, concentrated and then CDCl3) δ: 172.7, 134.0, 116.3, 74.2, 53.6, 41.3, 33.6, 19.3, 14.1;
filtered on a celite pad. The solvent was removed in vacuo Anal. Calcd for C9H18N2O2: C, 58.04; H, 9.74; N, 15.04. Found: C,
affording the crude carboxylic acid. The crude product was 58.28; H, 9.85; N, 15.18.
dissolved in CH2Cl2 (5 mL) and allyl amine (1.1 mmol, 0,08 ml) (2S,3R)-N-allyl-3-bromo-2-hydroxyhexanamide 7: To a solution
was added. The solution was added to a solution of 1-Ethyl-3- of compound 6a (169 mg, 1 mmol) in Et2O (15 mL) at -20°C
(3-dimethylaminopropyl)carbodiimide (170 mg, 1.1 mmol) and under argon, MgBr2∙OEt2 (390 mg, 1.5 mmol) was added and the
1-Hydroxy-7-azabenzotriazole (136 mg, 1 mmol) in CH2Cl2 (5 mixture was stirred for 12 h. The mixture was diluted with Et2O
mL) and the reaction was stirred at room temperature for 2 and washed with water and brine. The organic layer was dried
hours. CH2Cl2 and water were added. The organic layer was and concentrated in vacuo. The crude material was purified by
separated and the aqueous layer was extracted three times flash chromatography (hexane/EtOAc 70:30) affording
with CH2Cl2. The combined organic extracts were washed with mg, 73%, yellowish; [α]25D= 51.3 (c=3.6 in CHCl3); 1H-NMR (300
brine, dried and concentrated in vacuo. The crude material was MHz, CDCl3) : 7.06 (bs, 1H), 5.88-5.68 (m, 1H), 5.23-5.03 (m,
purified by flash chromatography using hexane/EtOAc 70:30 as 2H), 4.53-4.30 (m, 2H), 4.05 (d, 1H, J=4.4 Hz), 3.90-3.81 (m, 2H),
eluent. 1.88-1.70 (m, 1H), 1.62-1.45 (m, 2H), 1.44-1.25 (m, 1H), 0.88 (t,
(2 ,3 )- : 169.8, 133.4, 116.7, 76.0,
-allyl-3-propyloxirane-2-carboxamide (6a): obtained J=6.9 Hz); 13C-NMR (75 MHz, CDCl3)
from 5a, 130 mg, 75%, pale yellow oil; 1H-NMR (300 MHz, CDCl3) 59.1, 41.4, 33.9, 21.1, 13.2; Anal. Calcd for C9H16BrNO2: C, 43.22;
: 6.25 (bs, 1H), 5.83-5.66 (m, 1H), 5.16-5.02 (m, 2H), 3.85-3.74 H, 6.45; N, 5.60. Found: C, 43.35; H, 6.45; N, 5.65.
(m, 2H), 3.19 (d, 1H, J = 1.9 Hz), 2.94-2.86 (m, 1H), 1.68-1.36 (m, (2 ,3 )- -allyl-3-azido-2-hydroxyhexanamide 8: A solution of
4H), 0.93 (t, 3H, J=7.0 Hz); 13C-NMR (75 MHz, CDCl3)
: 168.2, compound (250 mg, 1 mmol), NaN3 (260, 4 mmol) and 18-
7. 182
δ
R
S
N
δ
δ
R
S N
δ
7
133.4, 116.1, 59.1, 55.0, 40.8, 33.4, 18.7, 13.4; Anal. Calcd for crown-6 (135 mg, 0.51 mmol) in DMSO (1.0 mL) was stirred at
C9H15NO2: C, 63.88; H, 8.93; N, 8.28. Found: C, 64.03; H, 8.95; N, 65 °C under argon for 12 h. The mixture was diluted with Et2O
8.29.
(2 ,3
and washed several times with water and brine. The organic
layer was then dried and concentrated in vacuo.
R
S
)-
N
-allyl-3-cyclohexyloxirane-2-carboxamide
(6b)
:
obtained from 5b, 154.8 mg, 74%, pale yellow oil; 1H-NMR (300 Chromatographic purification (hexane/EtOAc 70:30) afforded
8
.
1
MHz, CDCl3)
2H), 3.93-3.81 (m, 2H), 3.30 (d, 1H, J = 2.2 Hz), 2.76 (dd, 1H, J = NMR (300 MHz, CDCl3)
6.4, 2.2 Hz), 1.88-1.62 (m, 5H), 1.40-1.05 (m, 6H); 13C-NMR (75 5.08 (m, 2H), 4.70 (d, 1H, J=6.2 Hz), 4.10 (d, 1H, J=3.9 Hz), 3.92-
MHz, CDCl3) : 168.5, 133.6, 116.6, 63.7, 54.3, 41.0, 39.5, 29.0, 3.80 (m, 2H), 3.72-3.64 (m, 1H), 1.77-1,33 (m, 4H), 0.93 (t, 3H,
28.6, 26.1, 25.5, 25.4. Anal. Calcd for C12H19NO2: C, 68.87; H, J= 6.5 Hz); 13C-NMR (75 MHz, CDCl3)
: 172.1, 133.3, 116.3, 73.5,
9.15; N, 6.69. Found: C, 68.91; H, 9.23; N, 6.82. 62.9, 41.5, 32.3, 19.3, 13.6; Anal. Calcd for C9H16N4O2: C, 50.93;
(2 ,3 )- -allyl-3-phenyloxirane-2-carboxamide (6c): obtained H, 7.60; N, 26.40. Found: C, 51.09; H, 7.65; N, 26.48.
from 5c, 107.7 mg, 53%, pale yellow oil; H-NMR (300 MHz, (2R,3S)-N-allyl-3-amino-2-hydroxyhexanamide 3: To a solution
CDCl3) : 7.81-7.68 (d, 1H, J = 7.2 Hz), 7.53-7.09 (m, 4H), 6.35 of (186 mg, 1 mmol) in MeOH (15 ml) H2O (1.5 ml) and PPh3
δ
: 6.20 (bs, 1H), 5.89-5.71 (m, 1H), 5.23-5.09 (m, 187 mg, 88%, pale yellow oil, [α]25D= 24.5 (c=3.6 in CHCl3); H-
δ
: 7.17 (bs, 1H), 5.89-5.70 (m, 1H), 5.25-
δ
δ
R
S N
1
δ
8
(bs, 1H), 6.00-5.72 (m, 1H), 5.30-4.99 (m, 2H), 4.16-3.95 (m, 2H), (393 mg, 1.5 mmol) were added and allowed to stirred at room
3.95-3.77 (m, 1H), 3.55-3.40 (m, 1H); 13C-NMR (75 MHz, CDCl3) temperature for 12 h. Methanol was then evaporated and the
δ
: 167.2, 133.3, 131.2, 128.8, 128.4, 128.2, 126.8, 125.6, 116.5, aqueous layer extracted with CHCl3. The organic layer was dried
6 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
and concentrated in vacuo. The crude product was purified by (2
ARTICLE
R,3R)-N-allyl-3-cyclohexyl-3-(dibutylamino)-2-
View Article Online
, 126.6 mg, hydroxypropanamide 12c: obtained fromDO6I:b10a.1n03d9/BCu82ONBH0,0136252K
flash chromatography (CHCl3/MeOH 98:2) giving
3
68%, pale yellow oil; [α]25D= 12.5 (c=2.6 in CHCl3); 1H-NMR (300 mg, >95%, colorless oil; H-NMR (300 MHz, CDCl3)
δ
: 7.33 (bs,
1
MHz, CDCl3)
2H), 3.96 (m, 3H), 3.28-3.15 (m, 1H), 1.64-1.15 (m, 4H), 0,88 (t, 4.06 (m, 1H), 3.93-3.71 (m, 2H), 2.70-2.42 (m, 4H), 2.23-2.14 (m,
3H, J= 7.3 Hz); 13C-NMR (75 MHz, CDCl3) : 173.4, 136.9, 115.8, 1H), 1.84-1.13 (m, 19H), 0.87 (t, 6H, J = 7.5 Hz); 13C-NMR (75
73.4, 52.7, 41.1, 35.5, 19.3, 13.8; Anal. Calcd for C9H18N2O2: C, MHz, CDCl3) :173.3, 133.9, 116.7, 70.9, 67.5, 53.0, 41.5, 37.4,
58.04; H, 9.74; N, 15.04. Found: C, 58.18; H, 9.81; N, 15.15. 32.7, 30.8, 26.5, 26.2, 25.9, 20.4, 14.0; Anal. Calcd for
General procedure for the preparation of compounds 9, 10, 11: C20H38N2O2: C, 70.96; H, 11.31; N, 8.28. Found: C, 71.21; H,
A mixture of the substrate ( or or ) (1.0 mmol), n-propyl 11.37; N, 8.30.
iodide (0,194 ml, 2.0 mmol), K2CO3 (276 mg, 2.0 mmol) and (2 ,3 )- -allyl-3-cyclohexyl-2-hydroxy-3-(piperidin-1-
δ: 7.01 (bs, 1H), 5.90-5.67 (m, 1H), 5.24-5.01 (m, 1H), 5.87-5.71 (m, 1H), 5.23-5.06 (m, 2H), 4.83 (bs, 1H), 4.16-
δ
δ
1
2
3
R
R N
CH3CN (5 mL) was refluxed for 48 h. The reaction mixture was yl)propanamide 12d: obtained from 6b and piperidine, 280 mg,
1
cooled to room temperature and filtered. The filtrate was >95%, colorless oil; H-NMR (300 MHz, CDCl3)
δ
: 7.67 (bs, 1H),
concentrated in vacuo and the residue was purified by flash 5.84-5.68 (m, 1H), 5.20-5.00 (m, 2H), 4.58 (bs, 1H), 4.04 (d, 1H,
chromatography (CHCl3/MeOH 98:2).
J = 5.7 Hz), 3.89-3.67 (m, 2H), 2.75-2.46 (m, 4H), 2.41 (dd, 1H, J
9: = 8.5, 6.4 Hz), 2.08-1.97 (m, 1H), 1.83-0.94 (m, 16H); 13C-NMR
(2
S
,3S
)-
N
-allyl-2-(dipropylamino)-3-hydroxyhexanamide
1
obtained from
MHz, CDCl3)
1
, 175.7 mg, 65%, pale yellow oil; H-NMR (300 (75 MHz, CDCl3)
δ
: 173.4, 133.9, 116.2, 73.5, 67.1, 51.4, 51.3,
δ
: 7.53 (bt, 1H, J = 5.6 Hz), 5.18-4.99 (m, 2H), 3.91- 41.2, 36.6, 32.7, 30.2, 26.9, 26.3, 26.1, 25.8, 24.3; Anal. Calcd for
3.71 (m, 4H), 3.06 (d, 1H, J = 4.6 Hz), 2.90-2.79 (m, 1H) 2.52-2.34 C17H30N2O2: C, 69.35; H, 10.27; N, 9.51. Found: C, 69.60; H,
(m, 4H), 1.59-1.13 (m, 8H), 0.93-0.73 (m, 9H); 13C-NMR (75 MHz, 10.30; N, 9.55.
CDCl3) δ: 173.0, 134.0, 116.1, 71.7, 67.5, 51.1, 41.3, 34.5, 23.3, (2R,3R)-N-allyl-3-cyclohexyl-2-hydroxy-3-
19.1, 13.9, 11.6; Anal. Calcd for C15H30N2O2: C, 66.62; H, 11.18; morpholinopropanamide 12e: obtained from 6b and
1
N, 10.36. Found: C, 66.85; H, 11.20; N, 10.42.
(2 ,3 )- -allyl-3-(dipropylamino)-2-hydroxyhexanamide 10: CDCl3)
obtained from
, 189.3 mg, 70%, pale yellow oil; 1H-NMR (300 (m, 2H), 4.15 (d, 1H, J = 4.4 Hz), 3.90-3.75 (m, 2H), 3.65-3.52 (m,
MHz, CDCl3) : 7.75 (bs, 1H), 5.85-5.66 (m, 1H), 5.20-5.02 (m, 4H), 2.78-2.57 (m, 4H), 2.53 (dd, 1H, J = 9.0, 4.4 Hz), 2.08-1.82
2H), 4.53 (bs, 1H), 3.90 (d, 1H, J = 7.4 Hz), 3.84-3.75 (m, 2H), (m, 3H), 1.72-1.55 (m, 3H), 1.30-0.92 (m, 5H); 13C-NMR (75 MHz,
2.82-2.73 (m, 1H) 2.36-2.28 (m, 4H), 1.60-1.19 (m, 8H), 0.87 (t, CDCl3) : 173.4, 133.8, 116.5, 72.7, 67.6, 50.5, 41.3, 36.1, 32.2,
3H, J =7.4 Hz), 0.77 (t, 6H, J = 7.3 Hz); 13C-NMR (75 MHz, CDCl3) 30.2, 26.3, 26.0, 25.9; Anal. Calcd for C16H28N2O3: C, 64.83; H,
: 173.5, 133.9, 116.6, 68.8, 63.8, 53.3, 41.6, 27.5, 22.3, 21.2, 9.52; N, 9.45. Found: C, 65.05; H, 9.56; N, 9.48.
morpholine, 257.8 mg, 87%, colorless oil; H-NMR (300 MHz,
R
R
N
δ: 7.48 (bt, 1H, J = 5.3 Hz), 5.84-5.67 (m, 1H), 5.20-5.05
2
δ
δ
δ
14.4, 11.7; Anal. Calcd for C15H30N2O2: C, 66.62; H, 11.18; N, (2R,3R)-N-allyl-3-(dibutylamino)-2-hydroxy-3-
10.36. Found: C, 66.83; H, 11.22; N, 10.44.
phenylpropanamide 12f: obtained from 6c and Bu2NH, 315 mg,
1
(2
obtained from
CDCl3) : 7.49 (bs, 1H), 5.90-5.70 (m, 1H), 5.23-5.01 (m, 2H), 3.96 1H, J = 7.1 Hz), 3.91 (d, 1H, J = 7.1 Hz), 3.70 (ddt, 2H, J = 15.7,
R
,3S
)-
N
-allyl-3-(dipropylamino)-2-hydroxyhexanamide 11
:
>95%, colorless oil; H-NMR (300 MHz, CDCl3)
δ
: 7.57 (bs, 1H),
3
, 148.7, 55%, pale yellow oil; 1H-NMR (300 MHz, 7.30-7.15 (m, 5H), 5.55-5.39 (m, 1H), 5.00-4.83 (m, 2H), 4.44 (d,
δ
(d, 1H, J = 2.6 Hz), 3.91-3.80 (m, 2H), 3.15-3.04 (m, 2H) 2.73-2.49 6.0, 1.3, Hz), 3.55 (ddt, 2H, J = 15.7, 5.5, 0.3 Hz), 2.61-2.47 (m,
(m, 4H), 1.78-1.32 (m, 8H), 0.96-0.81 (m, 9H); 13C-NMR (75 MHz, 2H), 2.36-2.22 (m, 2H), 1.44-1.31 (m, 4H), 1.28-1.08 (m, 4H),
CDCl3)
19.4, 13.8, 11.3; Anal. Calcd for C15H30N2O2: C, 66.62; H, 11.18; 133.9, 129.6, 127.8, 127.6, 116.3, 69.3, 67.4, 49.8, 41.4, 28.9,
N, 10.36. Found: C, 66.85; H, 11.21; N, 10.40. 20.6, 13.9; Anal. Calcd for C20H32N2O2: C, 72.25; H, 9.70; N, 8.43.
General procedure for the preparation of compounds 12a-g: A Found: C, 72.54; H, 9.74; N, 8.46.
mixture of the epoxy amide (6a or 6b or 6c) (1.0 mmol), amine (2 ,3 )- -allyl-2-hydroxy-3-phenyl-3-(piperidin-1-
δ δ: 172.1, 135.4,
: 173.5, 133.7, 116.2, 69.6, 59.3, 49.6, 41.2, 33.5, 22.8, 0.81 (t, 6H, J = 7.3 Hz); 13C-NMR (75 MHz, CDCl3)
R
R N
(excess, 1 mL) and Ti(O-iPr)4 (1.5 mmol, 0,448 ml) was stirred at yl)propanamide 12g: obtained from 6c and piperidine, 275 mg,
1
room temperature for 12 h. After this time, EtOAc was added >95%, colorless oil; H-NMR (300 MHz, CDCl3)
δ
: 7.89 (bs, 1H),
and the organic layer was washed with an aqueous tartaric acid 7.38-6.96 (m, 5H), 5.66-5.40 (m, 1H), 5.05-4.80 (m, 2H), 4.58 (d,
solution (0.5 M), dried and concentrated in vacuo. The crude 1H, J = 7.3 Hz), 4.10 (bs, 1H), 3.76-3.56 (m, 2H), 3.66 (d, 1H, J =
product was purified by flash chromatography (CH2Cl2/MeOH, 7.3 Hz), 2.60-2.20 (m, 4H), 1.63-1.21 (m, 6H); 13C-NMR (75 MHz,
95:5, 0.2% NH4OH).
(2 ,3 )- -allyl-3-cyclohexyl-3-(dipropylamino)-2-
CDCl3)
δ: 172.3, 133.9, 129.3, 127.8, 127.6, 116.2, 71.6, 68.3,
R
R N
51.4, 41.3, 26.3, 26.2, 24.2; Anal. Calcd for C17H24N2O2: C, 70.80;
hydroxypropanamide 12b: obtained from 6b and Pr2NH, 279.2, H, 8.39; N, 9.71. Found: C, 71.07; H, 8.42; N, 9.75.
1
90%, colorless oil; H-NMR (300 MHz, CDCl3)
δ
: 7.31 (bs, 1H), (2
R
,3
S
)-3-phenyloxirane-2-carbaldehyde 15c: To a stirred
5.89-5.68 (m, 1H), 5.26-5.03 (m, 2H), 4.12 (d, 1H, J = 4.9 Hz), solution of epoxy alcohol 5c (150 mg, 1 mmol) in CH2Cl2 (8 ml)
3.94-3.73 (m, 2H), 2.72-2.39 (m, 5H), ), 2.31-2.12 (m, 1H), 1.93- at 0°C, Et3N (0.56 ml, 3.8 mmol) and PySO3 (478 mg, 3 mmol) in
0.87 (m, 15H), 0.82 (t, 6H, J = 7.4 Hz); 13C-NMR (75 MHz, CDCl3) DMSO (3 ml) were added. The mixture was stirred at room
δ
: 173.3, 134.0, 116.7, 71.2, 67.5, 55.2, 41.5, 37.4, 32.7, 30.8, temperature for 12 h. Then the mixture was diluted with 20 ml
26.5, 26.2, 25.9, 23.7, 11.5; Anal. Calcd for C18H34N2O2: C, 69.63; of Et2O and 40 ml of hexane, washed with NaHCO3 s.s.; the
H, 11.04; N, 9.02. Found: C, 69.81; H, 11.09; N, 9.06.
aqueous layer was extracted with a mixture 1:2.8 Et2O/hexane
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Organic & Biomolecular Chemistry
Page 8 of 11
ARTICLE
Journal Name
and the organic layer washed with NaHPO4 1 M, and brine then 128.6, 128.5, 125.7, 125.4, 116.6, 61.2, 60.7, 42.0V;iewAnAratilc.leCOanllcinde
DOI: 10.1039/C8OB00165K
dried and concentrated in vacuo. The crude material was for C14H15NO2: C, 73.34; H, 6.59; N, 6.11. Found: C, 73.60; H,
purified by flash chromatography (hexane/EtOAc 85:25) giving 6.62; N, 6.15.
1
15c , 120 mg, 81%, colorless oil; H-NMR (300MHz, CDCl3) δ: General procedure for the preparation of compounds 13a-f, 14
:
9.20 (d, 1H, J = 6.0 Hz), 7.48-7.18 (m, 5H), 4.16 (d, 1H, J = 1.5 Hz), The epoxy amide (17a or 17b or 17c) (1 mmol), LiClO4 (1.59 g,
3.44 (dd, 1H, J = 6.0, 1.5 Hz). 13C-NMR (75 MHz, CDCl3) δ: 196.7, 15 mmol), and the selected amine (10 mmol, excess) in
134.1, 129.1, 128.7, 125.6, 62.8, 56.6. Anal. Calcd for C9H8O2: C, acetonitrile (3 mL) were stirred at 55 °C for 24 h. Then H2O was
72.96; H, 5.44. Found: C, 72.99; H, 5.47.
added, and the aqueous layer was extracted with CH2Cl2. The
General procedure for the preparation of compounds 17a-c:
A
combined organic extracts were dried, concentrated in vacuo
solution of aldehyde (15a or 15b or 15c) (1 mmol) in THF dry and purified by flash chromatography (CH2Cl2/MeOH 95:5).
(8.0 ml) was added dropwise to a stirred solution of n-BuLi (1.5 ,4 ,5 )- -allyl-5-cyclohexyl-4-(dibutylamino)-5-
(
E R S N
mL of
a
1.6
M
hexane solution, 2.4 mmol) and hydroxypent-2-enamide 13a: obtained from 17b and Bu2NH,
1
diethylphosphonoacetic acid (0.2 mL, 1.1 mmol) in THF dry (1.5 262.5 mg, 72%, colorless oil; [α]25D= -16.5 (c=3.6 in CHCl3); H-
mL) under an argon atmosphere at -70°C. After 2 hours the NMR (300 MHz, CDCl3) δ: 6.70 (dd, 1H, J = 15.4, 9.5 Hz), 6.38 (bs,
reaction mixture was allowed to reach the room temperature 1H), 5.91 (d, 1H, J = 15.4 Hz), 5.87-5.70 (m, 1H), 5.13 (bd, 1H, J
and then stirred for 12 hours. 0.1 M HCl aqueous solution was = 17.2 Hz), 5.06 (bd, 1H, J = 10.9 Hz), 3.87 (bt, 2H, J = 4.8 Hz),
added until pH 2 and the aqueous layer was extracted several 3.39 (bt, 1H, J = 6.2 Hz), 3.09 (dd, 1H, J = 9.5, 6.2 Hz), 3.00 (bs,
times with Et2O. The combined organic extracts were dried and 1H), 2.52-2.26 (m, 4H), 1.82-1.40 (m, 6H), 1.40-0.90 (m, 13H),
concentrated in vacuo affording the crude carboxylic acid 16a- 0.83 (t, 6H, J = 7.1 Hz); 13C-NMR (300 MHz, CDCl3)
. The crude product was dissolved in CH2Cl2 (5 mL) and allyl 140.3, 134.0, 127.3, 116.2, 74.4, 64.5, 50.3, 41.8, 38.8, 29.8,
amine (1.1 mmol, 0,08 ml) was added. The solution was added 29.3, 27.3, 26.4, 26.1, 25.8, 20.3, 13.9; Anal. Calcd for
to solution of 1-Ethyl-3-(3-dimethylaminopropyl)- C22H40N2O2: C, 72.48; H, 11.06; N, 7.68. Found: C, 72.73; H,
carbodiimide (170 mg, 1.1 mmol) and 1-Hydroxy-7- 11.09; N, 7.70.
azabenzotriazole (136 mg, 1 mmol) in CH2Cl2 (5 mL) and the ,4 ,5 )- -allyl-5-cyclohexyl-5-hydroxy-4-morpholinopent-2-
δ: 165.2,
c
a
(
E R S N
reaction was stirred at room temperature for 2 hours. CH2Cl2 enamide 13b: obtained from 17b and morpholine, 251.5 mg,
1
and water were added. The organic layer was separated and the 78%, colorless oil; [α]25D = - 27.2 (c 3.2, CHCl3); H-NMR (300
aqueous layer was extracted three times with CH2Cl2. The MHz, CDCl3) δ: 6.74 (dd, J = 15.7, 9.9 Hz, 1H), 5.96 (d, J = 15.7
combined organic extracts were washed with brine, dried and Hz, 1H), 5.92-5.78 (m, 1H), 5.72 (bs, 1H), 5.26-5.11 (m, 2H), 3.96
concentrated in vacuo. The crude material was purified by flash (bt, 2H, J = 5.7 Hz), 3.69 (bt, 4H, J = 4.4 Hz), 3.53 (dd, 1H, J = 8.5,
chromatography (hexane/EtOAc 70:30).
E, ,3 )- -allyl-3-(3-propyloxiran-2-yl)acrylamide
obtained from 16a, 130.8 mg, 67% from 15a, colorless oil; H- 6H); 13C-NMR (75 MHz, CDCl3) δ: 164.6, 139.2, 133.9, 127.9,
NMR (300 MHz, CDCl3): δ 6.58 (dd, 1H, J = 15.3, 6.7 Hz), 6.44 (bs, 116.8, 72.3, 68.9, 67.0, 51.6, 42.0, 39.4, 29.5, 27.9, 26.4, 25.6,
1H), 6.14 (d, 1H, J = 15.3 Hz), 5.86-5.72 (m, 1H), 5.14-4.98 (m, 25.5; Anal. Calcd for C18H30N2O3: C, 67.05; H, 9.38; N, 8.69.
2H), 3.88 (bt, 2H, J=5.7 Hz), 3.16 (dd, 1H, J = 6.7, 1.8 Hz), 2.81 Found: C, 67.30; H, 9.40; N, 8.70.
3.0 Hz), 3.20 (bs, 1H), 2.89 (dd, 1H, J = 9.8, 3.0 Hz), 2.65-2.41 (m,
17a: 4H), 2.03 (bd, 1H, J = 11.9 Hz), 1.78-1.48 (m, 4H), 1.41-0.76 (m,
(
2S
S
N
1
(ddd, 1H, J1=J2=5.2, 1.9 Hz), 1.59-1.37 (m, 4H), 0.91 (t, J = 7.2 Hz,
(E,4R,5S)-N-allyl-5-cyclohexyl-5-hydroxy-4-(piperidin-1-
3H); 13C-NMR (75 MHz, CDCl3): δ 164.8, 140.4, 133.8, 125.5, yl)pent-2-enamide 13c: obtained from 17b and piperidine, 247
116.3, 61.4, 56.4, 41.9, 33.8, 19.0, 13.7; Anal. Calcd for mg, 77%,colorless oil; [α]25D = - 27.3 (c 3.1, CHCl3); 1H-NMR (300
C11H17NO2: C, 67.66; H, 8.78; N, 7.17. Found: C, 67.91; H, 8.80; MHz, CDCl3) δ: 6.71 (dd, J = 15.3, 9.5 Hz, 1H), 6.09 (s, 1H), 5.92
N, 7.18.
E, ,3
(d, 1H, J = 15.3 Hz), 5.92-5.75 (m, 1H), 5.23-5.05 (m, 2H), 3.92
-allyl-3-(3-cyclohexyloxiran-2-yl)acrylamide 17b: (bt, 2H, J = 5.0 Hz), 3.48 (bd, 1H, J = 7.9 Hz), 3.20 (bs, 1H), 2.82
(
2S
S
)-
N
1
obtained from 16b, 97.4 mg, 72% from 15b, colorless oil; H- (bd, 1H, J = 9.5 Hz), 2.54-2.24 (m, 4H), 1.96 (bd, 1H, J = 12.4 Hz),
NMR (300 MHz, CDCl3) δ
: 6.71 (bs, 1H), 6.54 (dd, 1H, J = 15.2, 1.80-0.75 (m, 16H); 13C-NMR (75 MHz, CDCl3) δ: 165.0, 140.1,
6.6 Hz), 6.14 (d, 1H, J = 15.2 Hz), 5.83-5.68 (m, 1H), 5.10 (bd, 1H, 134.0, 127.1, 116.5, 72.9, 68.9, 52.1, 42.0, 39.3, 29.2, 28.0, 26.4,
J = 17.2 Hz), 5.04 (bd, 1H, J = 10.3 Hz), 3.84 (bt, 2H, J = 4.9 Hz), 26.2, 25.7, 25.6, 24.4; Anal. Calcd for C19H32N2O2: C, 71.21; H,
3.23 (bd, 1H, J = 6.6 Hz), 2.60 (bd, 1H, J = 6.5 Hz), 1.81-1.53 (m, 10.06; N, 8.74. Found: C, 71.50; H, 10.12; N, 8.77.
5H),1.30-0.91 (m, 6H); 13C-NMR (300 MHz, CDCl3)
δ
: 164.8,
(E,4R,5S)-N-allyl-4-(dibutylamino)-5-hydroxyoct-2-enamide
140.5, 133.8, 125.4, 116.1, 65.7, 55.1, 41.8, 39.8, 29.3, 28.6, 13d: obtained from 17a and Bu2NH, 237 mg, 73%, colorless oil;
1
26.0, 25.4, 25.3; Anal. Calcd for C14H21NO2: C, 71.46; H, 8.99; N, [α]25D = - 13.5 (c 2.7, CHCl3); H-NMR (300 MHz, CDCl3) δ: 6.79
5.95. Found: C, 71.73; H, 9.00; N, 5.97.
E, ,3 )- -allyl-3-(3-phenyloxiran-2-yl)acrylamide
(dd, 1H, J = 15.5, 9.7 Hz), 5.91 (d, 1H, J = 15.5 Hz), 5.92-5.76 (m,
17c: 2H), 5.24-5.11 (m, 2H), 3.95 (bt, 2H, J = 5.7 Hz), 3.75-3.64 (m,
(
2S
S
N
obtained from 16c,149 mg, 65% from 15c, colorless oil; 1H-NMR 1H), 3.03 (dd, 1H, J = 9.6, 5.6 Hz), 2.81 (bs, 1H), 2.61-2.32 (m,
(300 MHz, CDCl3) δ: 7.41-7.23 (m, 5H), 6.78 (dd, 1H, J = 15.3, 6.3 4H), 1.59-1.05 (m, 12 H), 0.89 (t, 9H, J = 7.1 Hz); 13C-NMR (75
Hz), 6.19 (d, 1H, J = 15.3 Hz), 5.97 (bs, 1H), 5.93-5.79 (m, 1H), MHz, CDCl3): δ 164.9, 140.2, 134.0, 127.6, 116.7, 70.4, 67.6,
5.19 (dd, 1H, J = 17.3, 1.3 Hz), 5.14 (dd, 1H, J = 10.3, 1.3 Hz), 3.95 50.9, 42.0, 35.9, 29.9, 20.4, 19.2, 14.1, 14.0; Anal. Calcd for
(bt, 2H, J = 5.7 Hz), 3.78 (d, 1H, J = 1.5 Hz), 3.46 (dd, 1H, J = 6.3, C19H36N2O2: C, 70.32; H, 11.18; N, 8.63. Found: C, 70.58; H,
1.5 Hz). 13C-NMR (75 MHz, CDCl3) δ: 164.5, 139.7, 136.2, 133.8, 11.20; N, 8.65.
8 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
(
E R S N
,4 ,5 )- -allyl-5-hydroxy-4-morpholinooct-2-enamide 13e: Chiralpack IA, hexane/i-PrOH 95:5, 1 mL/min, 220 nm, major 8.8
View Article Online
DOI: 10.1039/C8OB00165K
1
obtained from 17a and morpholine, 237 mg, 84%, colorless oil; min and minor 9.7 min); H-NMR (300 MHz, CDCl3) δ: 8.11-8.00
[α]25D = - 38.0 (c 2.9, CHCl3); H-NMR (300 MHz, CDCl3) δ: 6.72 (m, 1H), 7.88-7.78 (m, 1H), 7.78-7.68 (m, 1H), 7.61-7.52 (m, 1H),
1
(dd, 1H, J = 15.5, 9.9 Hz), 6.01 (bs, 1H), 5.94 (d, 1H, J = 15.5 Hz), 7.52-7.35 (m, 3H), 5.32 (dd, 1H, J = 7.2, 5.2 Hz), 2.19 (bs, 1H),
5.90-5.76 (m, 1H), 5.24-5.09 (m, 2H), 3.99-3.82 (m, 3H), 3.69 (t, 2.05-1.78 (m, 2H), 0.98 (t, 3H, J = 7.4 Hz); 13C-NMR (75 MHz,
4H, J = 4.5 Hz), 3.11 (bs, 1H), 2.70 (dd, 1H, J = 9.8, 3.3 Hz), 2.64- CDCl3) δ: 140.1, 133.7, 130.4, 128.8, 127.7, 125.8, 125.3, 125.3,
2.42 (m, 4H), 1.57-1.19 (m, 4H), 0.89 (t, 3H, J = 6.8 Hz); 13C-NMR 123.1, 122.8, 72.4, 31.0, 10.4.
(75 MHz, CDCl3) δ: 164.6, 139.2, 133.9, 128.3, 116.7, 71.6, 68.4,
67.0, 51.5, 42.0, 35.8, 19.1, 14.0; Anal. Calcd for C15H26N2O3: C, oil; [α]25D = -10.1 (c 2.5, CHCl3); ee = 87.5% (HPLC: Chiralpack IC,
( : 142.7 mg, 88%; colorless
E,S)-1-phenylpent-1-en-3-ol 18c 21
63.80; H, 9.28; N, 9.92. Found: C, 64.02; H, 9.30; N, 9.95.
(4 ,5 )- -allyl-5-hydroxy-4-morpholino-5-phenylpent-2-
hexane/i-PrOH 98:2, 1 mL/min, 254 nm, minor 13.0 min and
major 14.9 min); 1H-NMR (300 MHz, CDCl3) δ: 7.43-7.17 (m, 5H),
R
S,E N
enamide 13f: obtained from 17c and morpholine, 66,4 mg, 21%, 6.57 (d, 1H, J = 15.9 Hz), 6.22 (dd, 1H, J = 15.9, 6.7 Hz), 4.21 (dd,
1
pale yellow oil; [α]25D = 35.0 (c 1.8, CHCl3); H-NMR (300 MHz, 1H, J = 12.3, 6.2 Hz), 1.88 (bs, 1H), 1.74-1.55 (m, 2H), 0.97 (t, 3H,
CDCl3) δ: 7.33-7.20 (m, 5H), 6.68 (dd, 1H, J = 15.5, 9.8 Hz), 5.85- J = 7.4 Hz); 13C-NMR (75 MHz, CDCl3) δ: 136.7, 132.2, 130.3,
5.71 (m, 1H), 5.46 (d, 1H, J = 15.5 Hz), 5.39 (bt, 1H, J = 5.2 Hz), 128.5, 127.5, 126.4, 74.3, 30.2, 9.7.
5.20-5.06 (m, 3H), 3.85 (bt, 2H, J = 5.7 Hz), 3.75 (t, 4H, J = 4.6
(S : 135.7 mg, >95%;
)-1-(thiophen-3-yl)propan-1-ol 18d 23
Hz), 3.03 (dd, 1H, J = 9.8, 3.3 Hz), 2.77-2.60 (m, 4H); 13C-NMR colorless oil; [α]25 = -33.0 (c 2.5, CHCl3); ee = 94.7% (HPLC:
D
(75 MHz, CDCl3) δ: 164.3, 133.8, 130.1, 128.7, 128.1, 127.4, Chiralpack IB, hexane/EtOH 99.6:0.4, 1.8 mL/min, 220 nm,
126.1, 116.5, 73.4, 71.4, 66.8, 51.6, 41.8; Anal. Calcd for minor 15.03 min and major 15.9 min); 1H-NMR (300 MHz, CDCl3)
C18H24N2O3: C, 68.33; H, 7.65; N, 8.85. Found: C, 68.65; H, 7.67; δ: 7.24 (dd, 1H, J = 4.9, 3.0 Hz), 7.12-7.05 (m, 1H), 7.02 (dd, 1H,
N, 8.86.
J = 4.9, 1.2 Hz), 4.57 (t, 1H, J = 6.5 Hz), 3.18 (s, 1H), 1.80-1.63 (m,
2H), 0.88 (t, 3H, J = 7.4 Hz); 13C-NMR (75 MHz, CDCl3) δ: 145.9,
(4S,5R,E)-N-allyl-4-hydroxy-5-morpholino-5-phenylpent-2-
enamide 14: obtained from 17c and morpholine, 196 mg, 62%, 125.6, 125.5, 120.5, 71.5, 30.9, 9.8.
pale yellow oil; [α]25D = -18.8 (c 2.8, CHCl3); 1H-NMR (300 MHz, )-1-cyclohexylpropan-1-ol 18e 24
125.2 mg, 88%; colorless oil;
(
S
:
CDCl3) δ: 7.33- 7.25 (m, 5H), 6.65 (dd, 1H, J = 15.2, 3.7 Hz), 5.89 [α]25D = -8.6 (c 1.9, CHCl3); ee = 80.3% (HPLC on the o-bromo
(d, 1H, J = 15.2 Hz), 5.85-5.71 (m, 1H), 5.53 (bs, 1H), 5.15-5.04 benzoyl ester derivative: Chiralpack IA, hexane/EtOH 99:1, 0.8
(m, 2H), 4.93 (bs, 1H), 3.86 (bt, 2H, J = 5.5 Hz), 3.82-3.72 (m, 4H), mL/min, 220 nm, minor 5.5 min and major 5.9 min); 1H-NMR
3.46 (bs, 1H), 2.74-2.49 (m, 4H); 13C-NMR (75 MHz, CDCl3) δ: (300 MHz, CDCl3) δ: 3.26 (ddd, 1H, J = 8.7, 5.4, 3.9 Hz), 1.87-0.98
165.1, 142.7, 135.2, 134.0, 129.3, 128.2, 128.1, 123.2, 116.2, (m, 16H), 0.94 (t, 3H, J = 7.4 Hz); 13C-NMR (75 MHz, CDCl3) δ:
74.1, 68.6, 66.9, 51.6, 41.8; Anal. Calcd for C18H24N2O3: C, 68.33; 77.6, 43.1, 29.3, 27.7, 26.8, 26.5, 26.4, 26.2, 10.2.
H, 7.65; N, 8.85. Found: C, 68.67; H, 7.69; N, 8.85.
General procedure for the addition of diethylzinc to aldehydes
(
S
)-1-(2-methoxyphenyl)propan-1-ol 18f 22
colorless oil; [α]25 = -22.1 (c 4.0, CHCl3); ee = 95.7%
:
160 mg, >95%;
:
D
To a solution of the chiral amino alcohol (0.06 mmol, 6 mol%) (HPLC:Chiralpack IB, hexane/i-PrOH 97:3, 0.8 mL/min, 280 nm,
toluene (2 mL) the aldehyde (1 mmol) was added at room major 10.9 min and minor 11.7 min); 1H-NMR (300 MHz, CDCl3)
temperature. The mixture was stirred for 20 min and then δ: 7.45 (d, 1H, J = 7.4 Hz), 7.23 (dd, 1H, J1=J2 = 7.7 Hz), 6.95 (dd,
cooled to 0 °C. Diethylzinc (2.5 mL of a 1.0 M hexanes solution, 1H, J1=J2 7.4 Hz), 6.86 (d, 1H, J = 8.1 Hz), 4.82 (t, 1H, J = 6.5 Hz),
2.5 mmol) was added dropwise. Then the reaction mixture was 3.80 (s, 1H), 3.01 (bs, 1H), 1.80 (dq, 2H, J1=J2 7.2 Hz), 0.96 (t, 3H,
allowed to reach the room temperature and stirred for the J = 7.3 Hz, CH3). 13C-NMR (75 MHz, CDCl3) δ 156.3, 132.3, 127.9,
corresponding reaction time under argon. The reaction was 126.8, 120.5, 110.2, 71.8, 55.0, 30.0, 10.3.
quenched by the addition of a saturated NH4Cl solution (10 mL).
(S : 100 mg, 60%;
)-1-(3-methoxyphenyl)propan-1-ol 18g 25
The mixture was then extracted with CH2Cl2. The combined colorless oil; [α]25 = -30.9 (c 2.5, CHCl3); ee = 97.4% (HPLC:
D
organic extracts were dried and concentrated in vacuo. The Chiralpack IA, hexane/i-PrOH 95:5, 1 mL/min, 220 nm, minor 9.9
1
crude product was purified by flash chromatography min and major 10.5 min; H-NMR (300 MHz, CDCl3) δ: 7.25 (t,
(hexane/EtOAc 90:10). Enantiomeric excesses were determined 1H, J = 7.9 Hz), 6.89 (s, 1H), 6.81 (d, 2H, J = 7.5 Hz), 6.86 (d, 1H,
by HPLC analysis. Absolute configurations of the final alcohols J = 8.1 Hz), 4.55 (t, 1H, J = 6.5 Hz), 3.80 (s, 1H), 2.08 (bs, 1H),
were assigned by comparing the sign of the optical rotation or 1.86-1.65 (m, 2H), 0.91 (t, 3H, J = 7.4 Hz); 13C-NMR (75 MHz,
the retention time on HPLC with the literature value. The CDCl3) δ 159.6, 146.3, 129.3, 118.3, 112.8, 111.3, 75.8, 55.1,
following data are related to the use of ligand 13b.
)-1-phenylpropan-1-ol 18a 21
42 mg, > 95%; colorless oil;
[α]25 = -47.2 (c 3.3, CHCl3); ee=95% (HPLC: Chiralpack IB, colorless oil; [α]25 = -45.1 (c 3.3, CHCl3); ee = 97% (HPLC:
31.8, 10.1.
(
S
:
(
S
)-1-(4-methoxyphenyl)propan-1-ol 18h 22
:
159 mg, >95%;
D
D
hexane/i-PrOH 98:2, 0.9 mL/min, 258 nm, minor 12.1 min and Chiralpack IA, hexane/i-PrOH 99.5:0.5, 1 mL/min, 274 nm,
1
major 12.4 min). H-NMR (300 MHz, CDCl3) δ: 7.65 - 7.21 (m, minor 54.6 min and major 61.0 min). 1H-NMR (300 MHz, CDCl3)
5H), 4.54 (t, 1H, J = 6.6 Hz), 2.73 (bs, 1H), 1.86-1.67 (m, 2H), 0.91 δ: 7.22 (d, 2H, J = 8.5 Hz), 6.85 (d, 2H, J = 8.5 Hz), 4.47 (t, 1H, J =
(t, 3H, J = 7.4 Hz); 13C-NMR (75 MHz, CDCl3) δ: 144.6, 128.4, 6.7 Hz), 3.77 (s, 3H), 2.46 (bs, 1H), 1.85-1.60 (m, 2H), 0.86 (t, 3H,
127.4, 126.0, 75.9, 31.9, 10.1.
J = 7.3 Hz); 13C-NMR (75 MHz, CDCl3) δ: 158.7, 136.7, 127.1,
95%; 113.6, 75.4, 55.1, 31.6, 10.1.
(
S
)-1-(naphthalen-1-yl)propan-1-ol 18b 22
:
178mg,
>
colorless oil; [α]25 = -62.0 (c 2.7, CHCl3); ee = 97% (HPLC:
D
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
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Organic & Biomolecular Chemistry
Page 10 of 11
ARTICLE
-tolyl)propan-1-ol 18i 22
[α]25D = -54.5 (c 4.4, CHCl3); ee = 97.8% (HPLC: Chiralpack IA, mL/min, 220 nm, minor 13.06 min and DmOaI:jo10r.11043.92/C28mOBin0)0;16H5K-
hexane/i-PrOH 95:5, 0.8 mL/min, 220 nm, minor 7.6 min and NMR (300 MHz, CDCl3) δ: 7.54-7.30 (m, 4H), 4.52 (t, 1H, J = 6.6
major 8.3 min); 1H-NMR (300 MHz, CDCl3) δ: 7.46 (d, 1H, J = 7.4 Hz), 2.41 (bs, 1H), 1.73-1.54 (m, 2H), 0.82 (t, 3H, J = 7.3 Hz); 13C-
Hz), 7.27-7.08 (m, 3H), 4.86 (t, 1H, J = 6.3 Hz), 2.34 (s, 3H), 1.82- NMR (75 MHz, CDCl3) δ: 146.0, 130.6, 130.4, 129.3, 128.8,
1.68 (m, 3H), 0.98 (t, 3H, J = 7.3 Hz); 13C-NMR (75 MHz, CDCl3) δ: 118.7, 111.6, 74.2, 31.7, 9.6.
Journal Name
(
S
)-1-(o
:
142 mg, 95%; colorless oil; CHCl3); ee = 96% (HPLC: Chiralpack IA, hexane/i-PrOH 95/5, 1.
View Article Online
1
142.7, 134.6, 130.3, 127.1, 126.2, 125.2, 72.0, 30.9, 19.1, 10.4.
(S : 150 mg, 93%;
)-4-(1-hydroxypropyl)benzonitrile 18q 29
(S)-1-(m :
-tolyl)propan-1-ol 18j 26 144 mg, >95%; colorless oil; colorless oil; [α]25 = -37.7 (c 2.8, CHCl3); ee = 92% (HPLC:
D
[α]25D = -43.7 (c 3.3, CHCl3); ee = 98.6% (HPLC: Chiralpack IA, Chiralpack IA, hexane/i-PrOH 95/5, 0.8 mL/min, 220 nm, minor
hexane/i-PrOH 99.5/0.5, 1.5 mL/min, 220 nm, minor 29.7 min 17.3 min and major 18.8 min); 1H-NMR (300 MHz, CDCl3) δ: 7.58
1
and major 31.21 min); H-NMR (300 MHz, CDCl3) δ: 7.29-7.20 (d, 2H, J = 8.2 Hz), 7.42 (d, 2H, J = 8.2 Hz), 4.63 (t, 1H, J = 6.4 Hz),
(m, 1H), 7.20-7.04 (m, 3H), 4.49 (t, 1H, J = 6.6 Hz), 2.92 (s, 1H), 2.57 (bs, 1H), 1.79-1.66 (m, 2H), 0.89 (t, 3H, J = 7.4 Hz); 13C-NMR
2.40 (s, 3H), 1.88-1.66 (m, 2H), 0.94 (t, 3H, J = 7.4 Hz); 13C-NMR (75 MHz, CDCl3) δ: 150.1, 131.8, 126.4, 118.6, 110.2, 74.4, 31.6,
(75 MHz, CDCl3) δ: 144.5, 137.6, 128.0, 127.9, 126.5, 122.9, 9.5.
75.6, 31.6, 21.2, 10.0.
26
(
S
)-1-(
p
-tolyl)propan-1-ol 18k
:
144 mg, >95%; colorless oil;
[α]25 = -41.0 (c 3.4, CHCl3); ee = 97% (HPLC: Chiralpack IA,
D
Conflicts of interest
There are no conflicts to declare.
hexane/i-PrOH 98/2, 1 mL/min, 262 nm, minor 13.9 min and
major 15.6 min); 1H-NMR (300 MHz, CDCl3) δ: 7.23 (d, 2H, J = 8.2
Hz), 7.17 (d, 2H, J = 8.2 Hz), 4.50 (t, 1H, J = 6.6 Hz), 2.73 (bs, 1H),
2.39 (s, 3H), 1.88-1.66 (m, 2H), 0.92 (t, 3H, J = 7.4 Hz); 13C-NMR
(75 MHz, CDCl3) δ: 141.5, 136.7, 128.8, 125.8, 75.5, 31.6, 20.9,
10.0.
Notes and references
(S : 135 mg, 88%; colorless
)-1-(2-fluorophenyl)propan-1-ol 18l 27
§ The allyl group was chosen as it could eventually be converted
through a Pt-catalyzed hydrosilylation into a trialcoxysilane,
anchorable on magnetite nanoparticles.
oil; [α]25D = -32.3 (c 2.8, CHCl3); ee = 90% (HPLC: Chiralpack IA,
hexane/i-PrOH 98/2, 0.9 mL/min, 267 nm, minor 13.6 min and
major 14.2 min); 1H-NMR (300 MHz, CDCl3) δ: 7.42 (t, 1H, J = 7.4
Hz), 7.26-7.16 (m, 1H), 7.12 (t, 1H, J = 7.4 Hz), 6.99 (t, 1H, J = 9.1
Hz), 4 .89 (t, 1H, J = 6.5 Hz), 2.70 (bs, 1H), 1.83-1.66 (m, 2H), 0.91
(t, 3H, J = 7.3 Hz); 13C-NMR (75 MHz, CDCl3) δ: 159.7 (J = 245.1
Hz), 131.4 (J = 13.3 Hz), 128.5 (J = 8.3 Hz), 127.3 (J = 4.6 Hz),
124.1 (J = 3.5 Hz), 115.0 (J = 22.0 Hz), 69.3, 30.8, 9.8.
§§ Using as Lewis acid Al2O3 (M. Noguchi, M. Yoshioka, S.
Kakimoto, S. Kajigaeshi Bull. Chem. Soc. Jpn. 1987, 60, 3261-3267)
Ti(Oi-Pr)4 or ZnCl2 the starting substrate was completely
recovered even at high temperature and long reaction time.
§§§ Unfortunately, 13f and 14 were chromatographically
inseparable and the compounds’ separation and identification
was achieved by an acetylation of the hydroxyl group; a following
(S : 163 mg, >95%;
)-1-(2-chlorophenyl)propan-1-ol 18m 26
colorless oil; [α]25 = -48.6; ee = 91% (HPLC: Chiralpack IA,
D
hydrolysis allowed to obtain 13f and 14
.
hexane/i-PrOH 99.5/0.5, 1 mL/min, 225 nm, minor 29.6 min and
1
major 32.4 min). H-NMR (300 MHz, CDCl3) δ: 7.49 (dd, 2H, J =
§§§§ All the substrates were prepared starting from the
corresponding allylic alcohols. For the substrate with
R=cyclohexyl the appropriate alcohol is not commercially
7.6, 1.7 Hz), 7.32-7.20 (m, 2H), 7.16 (dd, 2H, J = 7.7, 1.7 Hz), 5.02
(dd, 1H, J = 7.5, 4.9 Hz), 2.86 (bs, 1H), 1.85-1.60 (m, 2H), 0.95 (t,
3H, J = 7.3 Hz); 13C-NMR (75 MHz, CDCl3) δ: 141.9, 131.8, 129.1,
128.1, 127.1, 126.8, 71.6, 30.4, 9.9.
available
and
it
was
synthesized
from
the
cyclohexanecarboxaldehyde, by
a
Horner-Emmons reaction
followed by a reduction of the ester using DIBAL (A. G. M. Barrett,
W. W. Doubleday, G. J. Tustin, Tetrahedron 1996, 52, 48, 15325-
15338).
(S : 205 mg, >95%;
)-1-(3-bromophenyl)propan-1-ol 18n 28
colorless oil; [α]25 = -26.2 (c 2.8, CHCl3); ee = 88% (HPLC:
D
Chiralpack IA, hexane/i-PrOH 98/2, 0.9 mL/min, 267 nm, minor
1
1
2
3
4
W.S. Knowles, Angew. Chem. Int. Ed. 2002, 41, 1998-2007
R. Noyori, Angew Chem Int Ed. 2002, 41, 2008-2022.
15.6 min and major 16.4 min); H-NMR (300 MHz, CDCl3) δ:
7.47-7.29 (m, 2H), 7.21-7.11 (m, 2H), 4.46 (t, 1H, J = 6.5 Hz), 2.90
(bs, 1H), 1.75-1.57 (m, 2H), 0.86 (t, 3H, J = 7.3 Hz); 13C-NMR (75
MHz, CDCl3) δ: 146.7, 130.2, 129.7, 128.9, 124.5, 122.3, 74.9,
31.7, 9.8.
K.B. Sharpless, Angew. Chem. Int. Ed. 2002, 41, 2024-2032
a) D. Ager, I. Prakash, D. R. Schaad, Chem Rev. 1996, 96, 835-
876. b) J. Vicario, D. Badia, L. Carrillo, E. Reyes, J. Etxebarria,
Current Organic Chemistry 2005, 9, 219-235
(S : 191.4 mg, 89%;
)-1-(4-bromophenyl)propan-1-ol 18o 28
5
6
7
M. Kitamura, S. Suga, K. Kawai, R. Noyori, J. Am. Chem. Soc.
1986, 108, 6071-6072.
K. Soai, S. Yokoyama, T. Hayasaka, J. Org. Chem. 1991, 56,
4264-4268
A. Vidal-Ferran, A. Moyano, M. A. Pericàs, A. Riera J. Org.
Chem. 1997, 62, 4970-4982
colorless oil; [α]25 = -35.5 (c 3.8, CHCl3); ee = 96.6% (HPLC:
D
Chiralpack IC, hexane/i-PrOH 99/1, 1.5 mL/min, 220 nm, minor
7.4 min and major 8.6 min); 1H-NMR (300 MHz, CDCl3) δ: 7.44
(d, 2H, J = 8.4 Hz), 7.17 (d, 2H, J = 8.4 Hz), 4.51 (t, 1H, J = 6.5 Hz),
2.33 (bs, 1H), 1.81-1.57 (m, 2H), 0.87 (t, 3H, J = 7.4 Hz); 13C-NMR
(75 MHz, CDCl3) δ: 143.4, 131.2, 127.6, 120.9, 75.0, 31.7, 9.9.
3-(1-hydroxypropyl)benzonitrile 18p: absolute configuration
not available, 155 mg, >95%; colorless oil; [α]25D = -38.4 (c 4.4,
8
9
W. A. Nugent Org. Lett. 2002, 4, 2133-2136
G. Righi and S. Ciambrone, Tetrahedron Lett. 2004, 45, 2103-
2106.
10 G. Righi, P. Bovicelli and I. Tirotta, Tetrahedron Lett. 2013, 54
,
6439-6442.
10 | J. Name., 2012, 00, 1-3
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Page 11 of 11
Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
11 Review: L. M. Rossi, N. J. S. Costa, F. P. Silva, R. Wojcieszak,
Green Chem. 2014, 16, 2906-2933.
View Article Online
DOI: 10.1039/C8OB00165K
12 R. De Palma, S. Peeters, M. J. Van Bael, H. Van den Rul, K.
Bonroy, W. Laureyn, J. Mullens, G. Borghs, G. Maes, Chem.
Mater. 2007, 19, 1821-1831.
13 Review: S. Shylesh, V. Schuneman and W. R Thiel, Angew.
Chem., Int. Ed. 2010, 49, 3428-3459.
14 R. Noyori, M. Kitamura, Angew. Chem., Int. Ed. Engl. 1991, 30
,
49-69.
15 G. Righi, A. Mantineo, L. Suber, A. Mari, Synlett 2012, 23
,
1947-1949.
16 M.Yamakawa, R. Noyori, J. Am. Chem. Soc. 1995, 117, 6327-
6335.
17 M. Yamakawa, R. Noyori, Organometallics 1999, 18, 128-133.
18 Y. Gao, R. M. Hanson, J. M. Klunder, S. Y. Ko, H. Masamune, K.
B. Sharpless, J. Am. Chem. Soc. 1987, 109, 5765-5780.
19 R. Nishizawa, T. Nishiyama, K. Hisaichi, C. Minamoto, M.
Murota, Y. Takaoka, H. Nakai, H. Tada, K. Sagawa, S.
Shibayama, D. Fukushima, K. Maeda, H. Mitsuya, Bioorg. Med.
Chem. 2011, 19, 4028–4042.
20 G Righi, A Chionne, C. Bonini, Eur. J. Org. Chem. 2000, 3127-
3131.
21 M. Asami, S. Inoue, Bull. Chem. Soc. Jpn. 1997, 70, 1687–1690.
22 C. Andres, R. Infante, J. Nieto, Tetrahedron: Asymmetry 2010,
21, 2230–2237.
23 M. A. Aga, B. Kumar, A. Rouf, B. A. Shah, S. C. Taneja,
Tetrahedron Lett. 2014, 55, 2639-2641
24 Z.-L. Wu, H.-L. Wu, P.-Y. Wu, B.-J. Uang, Tetrahedron:
Asymmetry 2009, 20, 1556–1560.
25 W.-X. Zhao, N. Liu, G.-W. Li, D.-L. Chen, A.-A. Zhang, M.-C.
Wang, L. Liu, Green Chemistry 2015, 17, 2924-2930.
26 X.-F. Yang, T. Hirose, G.-Y. Zhang, Tetrahedron: Asymmetry
2008, 19, 1670–1675.
27 A. Kokura, S. Tanaka, T. Ikeno, T. Yamada, Organic Letters
2006, 8, 3025-3027.
28 K. R. Prasad, O. Revu, Tetrahedron 2013, 69, 8422-8428.
29 Y.-S. Shih, R. Boobalan, C. Chen, G.-H. Lee, Tetrahedron
Asymmetry 2014, 25, 327-333
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