Synthesis of amines from alcohols in a nonepimerizing one-pot sequence - Synthesis of bioactive compounds: Cinacalcet and dexoxadrol

Article abstract of DOI:10.1002/ejoc.201200171

A general, mild, and chemoselective one-pot oxidation/imine-iminium formation/nucleophilic addition sequence allowing the N-alkylation of amines by alcohols is described. This metal-free, one-pot sequence produced a wide variety of amines in good yields and diastereoselectivities, without the epimerization of the enantioenriched amines or alcohols involved in the process. This method was applied to the syntheses of the biologically active compounds cinacalcet and dexoxadrol. Copyright

Full text of DOI:10.1002/ejoc.201200171

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FULL PAPER
DOI: 10.1002/ejoc.201200171
Synthesis of Amines from Alcohols in a Nonepimerizing One-Pot Sequence –
Synthesis of Bioactive Compounds: Cinacalcet and Dexoxadrol
Claire Guérin,[a] Véronique Bellosta,[a] Gérard Guillamot,[b] and Janine Cossy*[a]
Keywords: Amines / Amination / Alcohols / Alkylation / Allylation / Green chemistry
A general, mild, and chemoselective one-pot oxidation/im-
ine-iminium formation/nucleophilic addition sequence al-
lowing the N-alkylation of amines by alcohols is described.
This metal-free, one-pot sequence produced a wide variety
of amines in good yields and diastereoselectivities, without
the epimerization of the enantioenriched amines or alcohols
involved in the process. This method was applied to the syn-
theses of the biologically active compounds cinacalcet and
dexoxadrol.
in good yields, the main drawback is the need of harsh con-
ditions such as high temperature, which can be detrimental
when optically active amines or alcohols are involved in the
reaction.[34]
Introduction
Amines are ubiquitous in pharmaceuticals and agro-
chemicals. Because their synthesis can be challenging when
they are highly functionalized, there is a continuing interest
in the development of procedures to access them. One typi-
cal process to synthesize amines is by N-alkylation using
alkyl halides, however, there can be problems due to poly-
alkylation and the toxicity of alkyl halides.[1] As attention
has been drawn to the necessity of developing methods
which are environmentally safe, alternative procedures
using less hazardous reagents have been examined. Thus,
aliphatic amines can be obtained by the reduction of nitriles
and amides,[2,3] by nucleophilic addition to imines and en-
amines, by their reduction, by the reductive amination of
carbonyls,[4–10] by the hydroamination or hydro-
aminomethylation of alkenes and alkynes,[11–15] by C–H
amination,[16,17] and by the N-alkylation of alkylamines
using alcohols.[18–22] Among these reagents, alcohols are of
particular interest because they are stable, nontoxic, and
easily available. Moreover, it is a challenge to use biomass,
which is mostly constituted of polyhydroxylated com-
pounds, instead of petroleum derivatives for the synthesis
of value-added chemicals, and thus, alcohols should be con-
sidered as either the starting materials or the reagents.[23]
The “borrowing hydrogen method”, also called hydrogen
auto-transfer, allows the direct use of alcohols for the alkyl-
ation of amines in the presence of catalysts.[24–33] Although
transition metals allow the alkylation of amines by alcohols
In addition, the development of ecocompatible one-pot
procedures[35–37] for the syntheses of pharmaceuticals[38] is
of importance, as the preparation of fine chemicals and
pharmaceuticals often involves complex multistep syntheses
which require expensive isolation and purification steps for
the intermediates, generating large amounts of waste. One
challenge is to decrease the number of synthetic steps, lead-
ing in most cases to the reduction in the amount of solvent
and purifying agents used, and consequently, to a decrease
in waste. Taylor et al. reported a mild one-pot oxidation/
imine-iminium formation/reduction sequence for the con-
version of benzylic, allylic, or propargylic alcohols to
amines using MnO2 as the oxidant, a polymer-supported
cyanoborohydride as the reducing agent, and acetic acid as
the additive.[39–40] However, the scope of this one-pot se-
quence is limited to activated alcohols.
Recently, we described the N-alkylation of amines by
alcohols using a transition-metal-free one-pot oxidation/
imine-iminium formation/reduction sequence.[41] Here, we
[a] Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS
UMR 7084,
10 Rue Vauquelin, 75231 Paris Cedex 05, France
Fax: +33-1-40794660
E-mail: janine.cossy@espci.fr
[b] PCAS,
23 Rue Bossuet, Z.I. la vigne aux Loups, 91160 Longjumeau,
France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200171.
Scheme 1. One-pot oxidation/imine-iminium formation/nucleo-
philic addition.
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would like to report on the scope and limitation of this one-
pot sequence and its application to the syntheses of biolo-
gically active compounds and, when the nucleophilic hy-
dride is replaced by an allylboronate, of homoallylamines
(see Scheme 1).
Scheme 3. Limit of the oxidation/reductive amination sequence.
To demonstrate the utility of this one-pot sequence, this
Results and Discussion
method was applied to the synthesis of cinacalcet,[43–47]
a
clinically used calcimimetic agent (e.g., Sensipar, Mimpara).
The synthesis would feature the N-alkylation of (R)-
naphthylethylamine [(R)-2b] with alcohol 4 (see Scheme 4).
Among the various reagents allowing the oxidation of
alcohols, the mild 2,2,6,6-tetramethyl-1-piperidinyloxyl and
[bis(acetoxy)iodo]benzene (TEMPO-BAIB) system[42] was
selected, as this system releases AcOH into the reaction me-
dium, which is an efficient additive and enhances the ad-
dition of a nucleophile to imine or iminium intermediates.
In most cases, the best reducing agent was found to be
NaBH(OAc)3.[41] Optically active alcohols A possessing a
stereogenic center at the β position as well as optically
active amines E possessing a stereogenic center in the α po-
sition were involved in this one-pot sequence to give sec-
ondary and tertiary amines C and F, respectively, without
racemization (see Scheme 2). Although the resulting op-
tically active amines C and F are accessible by reductive
amination of the corresponding carbonyl compounds, a
benefit of the one-pot oxidation/reductive amination se-
quence is that sensitive carbonyl and imine intermediates
do not require preparation and isolation.
Scheme 4. Retrosynthetic analysis of cinacalcet.
The synthesis of cinacalcet began with the preparation
of alcohol 4 in two steps from commercially available tri-
fluoromethylated cinnamic acid 5 (see Scheme 5). After hy-
drogenation of enoic acid 5 (Pd/C, EtOH, room temp.,
16 h), in quantitative yield, the resulting carboxylic acid 6
was reduced by LiAlH4 [THF (tetrahydrofuran), room
temp., 2 h, 71%] to give desired alcohol 4. Using the one-
pot sequence, that is, oxidation by TEMPO-BAIB followed
by the simultaneous addition of (R)-naphthylethylamine
[(R)-2b, 2 equiv.] and NaBH(OAc)3 (2 equiv.), cinacalcet
was isolated in 84% yield with an excellent enantiomeric
excess (ee Ͼ 96%). A short synthesis of cinacalcet was thus
achieved with an overall yield of 60% in three steps, one of
them being a one-pot sequence.
Scheme 2. N-Alkylation of amines with alcohols without racemiza-
tion of optically active partners.
One limit of this one-pot oxidation/reductive amination
sequence was observed during the preparation of amine 3a,
which was obtained with partial racemization (ee = 48%)
from enantioenriched alcohol (R)-1a (ee Ͼ 96%, see
Scheme 3). The racemization probably occurred because of
Scheme 5. Synthesis of cinacalcet.
To access primary amines from alcohols, the reaction of
the formation of an enol or enamine intermediate stabilized secondary alcohols with ammonium formate was studied.
by the phenyl group at the β position. It is worth noting Because of the low solubility of ammonium formate in
that under these conditions, the alkylation of poor nucleo- CH2Cl2, modifications of the one-pot oxidation/reductive
philic amines such as hexamethyldisilazane, tosylamine, and amination procedure were necessary. The use of Na-
benzyl carbamate could not be achieved.
BH(OAc)3 in MeOH to reduce a carbonyl compound has
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One-Pot Synthesis of Amines from Alcohols
Scheme 6. Synthesis of primary amines.
been reported and resulted in a rapid reduction of the carb-
onyl group instead of a reductive amination.[48] Thus, as the
addition of MeOH was necessary to solubilize the ammo-
nium formate, NaBH3CN was used instead of NaBH-
(OAc)3.[49] Treatment of secondary alcohol 1b with TEMPO
and BAIB was followed by the consecutive addition of am-
monium formate (10 equiv.), MeOH, and NaBH3CN to ob-
tain primary amine 3b (see Scheme 6). For practical
Scheme 7. One-pot oxidation/imine formation/allylation sequence.
reasons, primary amine 3b was not purified, but was iso- (0.2 equiv.)/BAIB (1.15 equiv.) in CH2Cl2 at room temp.,
lated after it was protected as benzyl carbamate 7 in 78% benzylamine (2c) and allylboronic ester 10 were added to
yield. Using the same conditions, primary amine 3c was ob- the reaction mixture at room temp. After 5 h, homoallyl
tained in a one-pot sequence from hexan-3-ol (1c) and amine 11a was isolated in 83% yield. To study the dia-
transformed into tert-butyl carbamate 8 in 89% yield. How- stereoselectivity of the reaction, alcohols possessing a β-chi-
ever, when the primary alcohol solketal (1d) was used, carb- ral stereogenic center were submitted to the oxidation/imine
amate 9 was not obtained. As NaBH3CN can reduce alde- formation/allylation sequence. The results are reported in
hydes, the glyceraldehyde acetonide formed in situ may have Table 1. When alcohol 1a was involved in this one-pot se-
been reduced before the formation of the imine intermedi- quence using benzylamine (2c), homoallylamine 11b was
ate.
obtained in low yield and in a modest diastereomeric ratio
Because of the success of the oxidation/reductive amin- of 4:1 in favor of the expected anti isomer (Table 1, En-
ation sequences, the addition of other nucleophiles to try 2). The low yield may be because of the formation of an
imines formed in situ from alcohols was examined. All- enol or enamine intermediate, which is favored as alcohol
ylmetals can successfully be added to C=N bonds.[50–51] 1a is substituted by a phenyl group at the β position. Better
Among allylmetals, organoboron reagents were selected be- diastereoselectivities were observed when a polar group was
cause of their functional group tolerance and stability, present at the β position of the primary alcohol. When (Ϯ)-
which are key properties for the development of a one-pot solketal (1d) and diol 1f were used, the corresponding 1,2-
process.[52] One-pot three-component reactions allowing the amino alcohols 11c and 11d were formed in 70% and 82%
synthesis of homoallylamines from aldehydes have been yield with diastereomeric ratios of 9:1 and 11:1, respectively,
achieved.[53–77] However, to the best of our knowledge, the in favor of the anti isomer (Table 1, Entries 3 and 4). 1,2-
direct aminoallylation of alcohols has not been reported. Diamino compound 11e was isolated as a single dia-
Hence, the preparation of homoallylamines of type G was stereomer in 60% yield from 1g (Table 1, Entry 5). Because
envisaged using a one-pot process involving the oxidation of the presence of the carbamate functionality in diamino
of an alcohol followed by imine formation and allylboration compound 11e, the diastereomeric ratio could not be deter-
1
(see Scheme 7).
mined by examining the H and 13C NMR spectroscopic
1
At first, the in situ allylboration of the imine generated data of the crude material. However, at 395 K, the H and
from octanol (1e) and benzylamine (2c) was studied 13C NMR spectra of purified product 11e clearly showed
(Table 1, Entry 1). After oxidation of octanol by TEMPO the presence of only one diastereomer.
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C. Guérin, V. Bellosta, G. Guillamot, J. Cossy
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Table 1. Direct synthesis of homoallylamines from alcohols.
When possible, the relative configuration of the ste-
reogenic centers was determined by comparison with the
NMR spectroscopic data reported in the literature,[78,79]
and for amines 11d and 11e by the formation of their cyclic
derivatives (see Scheme 8). Thus, 1,2-amino alcohol 11d was
transformed into the corresponding known cis-oxazolidi-
none 11dЈ in 72% yield. Compound 11e was treated with
ethylmagnesium bromide, and bicyclic compound 11eЈ was
formed as a single diastereomer. The existence of a strong
nOe between the protons of imidazolidone 11eЈ (H-3 and
H-4) showed that they have a cis relationship. This was con-
firmed by a strong nOe between H-8 and H-1b. Thus, the
carbamate and amine moieties in 11e are in an anti relation-
ship. The predominant formation of the anti isomer in the
one-pot oxidation/imine formation/allylation sequence can
be explained with the model proposed by Yamamoto et al.
for the addition of organoboranes to imines.[79–82]
The one-pot sequence was applied to the synthesis of
dexoxadrol, a dissociative anaesthetic drug which was
found to be an N-methyl-d-aspartate (NMDA) antagonist
producing similar effects to those obtained with phencycl
idine on animals (Scheme 9).[83–85] To the best of our
Scheme 8. Determination of the relative configuration of stereo-
knowledge, only one diastereoselective synthesis of dexox- genic centers for compounds 11d and 11e.
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One-Pot Synthesis of Amines from Alcohols
adrol has been reported, and the most biologically active anti isomer was isolated after chromatography in 34% over-
anti diastereomer was obtained in seven steps from d-man- all yield. To obtain the piperidine ring present in dexoxad-
nitol.[86] Using our method, the diastereoselective access to rol, amine 14 was protected as a benzyl carbamate [CbzCl,
dexoxadrol was planned from the renewable starting mate- N,N-diisopropylethylamine (DIPEA), CH2Cl2, 90%], and
rial glycerol[87–89] in five steps, one of them being a one-pot the resulting carbamate 15 was transformed into unsatu-
sequence. The construction of the piperidine framework of rated piperidine 16 in 91% yield using Grubbs second-gen-
dexoxadrol was envisaged by a ring-closing metathesis eration catalyst [G-II (10 mol-%), CH2Cl2, room temp., 4 h].
(RCM) applied to unsaturated amine H. This amine would After hydrogenation under 1 atm of H2 (Pd/C, 10%,
be obtained from protected glycerol 12 and allylamine using EtOH), (Ϯ)-dexoxadrol was isolated in 46% yield. As this
the one-pot process discussed previously.
synthetic pathway is flexible, various analogues of dexoxad-
rol could potentially be obtained either by using different
amines or allylboranes as well as by the functionalization
of intermediate 16.
Conclusions
The TEMPO-BAIB system for the oxidation of alcohols
proved to be compatible with reducing agents as well as
Scheme 9. Retrosynthetic analysis of (Ϯ)-dexoxadrol.
The synthesis of (Ϯ)-dexoxadrol started from glycerol with allylboronic esters. Thus, a one-pot oxidation/imine-
(13), which was transformed to ketal 12 using benzo- iminium formation/nucleophilic addition sequence allowed
phenone under acidic conditions [p-toluenesulfonic acid the alkylation of amines with alcohols in good yields and
(PTSA) (0.05 equiv.), toluene, 93%] (Scheme 10). Alcohol with good diastereoselectivities, affording the introduction
12 was then submitted to the one-pot oxidation/imine for- of structural diversity. Under these conditions, a variety of
mation/allylboration sequence using allylamine, which af- amines were obtained at room temp. without the racemiza-
forded the corresponding homoallylamine 14 in 54% yield tion of the substrates or reagents and without the use of
in a diastereomeric anti/syn ratio of 3.4:1. The desired pure any transition metal, which is of importance for the prepa-
Scheme 10. Synthesis of (Ϯ)-dexoxadrol.
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3 H), 0.98 (d, J = 6.3 Hz, 3 H) ppm. 13C NMR (CDCl3): δ = 145.4
(s), 128.6 (d, 2 CH), 127.2 (d, 2 CH), 126.4 (d), 54.6 (t), 48.5 (d),
40.0 (d), 22.9 (q), 22.7 (q), 20.3 (q) ppm. MS (EI, 70 eV): m/z (%)
= 177 (1) [M]+·, 162 (1) [M – Me]+, 91 (10) [C7H7]+, 77 (5) [Ph]+,
73 (5), 72 (100) [iPrNH=CH2]+. HRMS (ESI): calcd. for C12H20N
[M + H]+ 178.1590; found 178.1591. The enantiomeric excess was
determined by the formation of a salt with (S)-(+)-O-acetylman-
delic acid. (R)-N-isopropyl-2-phenylpropan-1-amine (3a) (21.5 mg,
0.12 mmol) and (S)-(+)-O-acetylmandelic acid (23.6 mg,
0.12 mmol) were dissolved in CDCl3. The analysis of the 1H NMR
spectroscopic data of this salt in comparison to the data obtained
for the salt prepared from the racemic product showed the presence
of a mixture of diastereomers (de = 48%).
ration of amines for biological testing. This sequence of re-
actions has been used to synthesize biologically active com-
pounds in a limited number of steps, avoiding the isolation
of potentially sensitive carbonyl and imine intermediates.
Experimental Section
General Methods: Infrared (IR) spectra were recorded with a
Bruker TENSORTM 27 (IRFT) on an ATR (attenuated total re-
flectance) plate, and wavenumbers are indicated in cm–1. The NMR
spectroscopic data were recorded with a Bruker Avance-1 400 in-
strument. The 1H NMR spectroscopic data were recorded at
400 MHz in CDCl3 or deuterated DMSO (dimethyl sulfoxide), and
the data are reported as follows: (1) chemical shift in ppm from
tetramethylsilane as an internal standard, (2) multiplicity (s = sing-
let, d = doublet, t = triplet, q = quartet, quint = quintuplet, m =
multiplet or overlap of nonequivalent resonances, and br. = broad),
and (3) integration. The 13C NMR spectroscopic data were re-
corded at 100 MHz in CDCl3 or deuterated DMSO, and the data
are reported as follows: (1) chemical shift in ppm from tetramethyl-
silane with the solvent as an internal indicator (CDCl3, 77.16 ppm
or DMSO, 39.52 ppm) and (2) multiplicity, with respect to proton
(deduced from DEPT experiments, s = quaternary C, d = CH, t =
CH2, and q = CH3). The high resolution mass spectrometry was
performed by the Groupe de Spectrométrie de Masse de l’Univer-
sité Pierre et Marie Curie (Paris, France). The optical rotations
were measured with a Perkin–Elmer model 343 polarimeter with a
1 dm path length. TLC was performed on Merck 60F254 silica gel
plates with UV and Hanessian or ninhydrin stain for the visualiza-
tion methods. CH2Cl2 was distilled from CaH2. Alcohols 1f,[90]
1g,[91] and 12[92] were obtained by following existing procedures.
Other reagents were obtained from commercial suppliers and used
as received. Flash chromatography was performed on silica gel
(230–400 mesh). The diastereomeric ratios were measured by exam-
3-[3-(Trifluoromethyl)phenyl]propan-1-ol (4):[47] Pd/C (10%,
100 mg) was added to a solution of 3-(trifluoromethyl)cinnamic
acid (5, 3 g, 13.9 mmol, 1 equiv.) in ethanol (50 mL). After 16 h of
stirring at room temp. under 1 atm of H2, the reaction mixture was
filtered through Celite and concentrated under reduced pressure.
The crude residue 6 (3.03 g, 13.9 mmol) was dissolved in THF
(20 mL), and the resulting solution was added to a suspension of
LiAlH4 (405 mg, 27.8 mmol, 2 equiv.) in THF (80 mL). After stir-
ring at room temp. for 2 h, water (405 μL), NaOH (15% aqueous
solution, 405 μL), and then water (1.2 mL) again were successively
and carefully added to the mixture. After around 30 min, the white
solid was removed by filtration through Celite. The filtrate was con-
centrated under reduced pressure followed by purification by
chromatography on silica gel (CH2Cl2/MeOH, 99:1) to give com-
pound 4 (2.02 g, 9.9 mmol, 71% over 2 steps). The physical and
spectroscopic data were in agreement with the data reported in the
1
literature.[94] Rf = 0.39 (PE/EtOAc, 70:30). H NMR (CDCl3): δ =
7.48–7.32 (m, 4 H), 3.67 (t, 3J = 6.4 Hz, 2 H), 2.78 (tapp 3J =
,
7.7 Hz, 2 H), 2.45 (br. s, 1 H), 1.95–1.84 (m, 3J = 7.4 Hz, 2 H) ppm.
2
13C NMR (CDCl3): δ = 142.9 (s), 131.9 (d), 130.7 (s, JC,F
=
31.8 Hz, CCF3), 128.9 (d), 125.2 (d, 3JC,F = 3.7 Hz), 124.4 (s, JC,F
= 272.0 Hz, CF3), 122.8 (d, JC,F = 3.5 Hz), 61.8 (t), 34.0 (t), 31.9
1
3
1
ining the H NMR spectroscopic data of the crude material.
(t) ppm.
General Procedure for the One-Pot Oxidation/Imine-Iminium
Synthesis of Cinacalcet:[43] The general procedure for the one-pot
oxidation/imine-iminium formation/reduction was applied to
alcohol 4 (204 mg, 1 mmol) and (R)-naphthylethylamine [(R)-2b,
0.32 mL, 2 mmol]. Purification by flash chromatography on silica
gel (PE/EtOAc, from 90:10 to 70:30) gave cinacalcet (300 mg,
0.84 mmol, 84%) as a brownish oil. The physical and spectroscopic
data matched with those described in the literature.[43] Rf = 0.33
Formation/Reduction:[40]
2,2,6,6-Tetramethyl-1-piperidinyloxyl
(TEMPO, 30 mg, 0.2 mmol, 0.2 equiv.) and [bis(acetoxy)iodo]-
benzene (BAIB, 370 mg, 1.15 mmol, 1.15 equiv.) were added to a
stirred solution of an alcohol (1 mmol) in CH2Cl2 (4 mL), and the
mixture was stirred at room temp. until there was complete conver-
sion of the alcohol (2–20 h), as confirmed by TLC or GC–MS.
When the oxidation was incomplete after 16 h, additional amounts
of BAIB (up to 240 mg, 0.75 mmol) were added to the reaction
mixture. Then, an amine (2 mmol, 2 equiv.) and NaBH(OAc)3
(414 mg, 2 mmol, 2 equiv.) were both added to the reaction mix-
ture. After 2–20 h, the mixture was carefully quenched with aque-
ous NaOH (1 m solution, 10 mL), and the resulting mixture was
extracted with Et2O (3ϫ20 mL). The combined organic layers were
dried with MgSO4, filtered, and concentrated under reduced pres-
sure. Purification was achieved by flash chromatography on silica
gel.
1
(PE/EtOAc, 50:50). H NMR (CDCl3): δ = 8.19 (d, J = 8.0 Hz, 1
H), 7.86 (m, 1 H), 7.74 (d, J = 8.3 Hz, 1 H), 7.63 (d, J = 7.2 Hz, 1
H), 7.53–7.39 (m, 5 H), 7.36–7.26 (m, 2 H), 4.61 (q, J = 6.5 Hz, 1
H), 2.76–2.53 (m, 4 H), 1.82 (quintapp, J = 7.4 Hz, 2 H), 1.48 (d, J
= 6.8 Hz, 3 H), 1.40 (br. s, 1 H) ppm. 13C NMR (CDCl3): δ = 143.2
(s), 141.3 (s), 134.1 (s), 131.9 (d), 131.4 (s), 130.7 (s, 2JC,F = 31.6 Hz,
CCF3), 129.1 (d), 128.8 (d), 127.3 (d), 125.9 (d), 125.8 (d), 125.5
3
1
(d), 125.2 (d, JC,F = 3.4 Hz, CHarom), 124.4 (s, JC,F = 264 Hz,
3
CF3), 123.1 (d), 122.8 (d), 122.7 (d, JC,F = 3.9 Hz, CHarom), 53.9
(d), 47.4 (t), 33.6 (t), 32.0 (t), 23.8 (q) ppm. The enantiomeric excess
was determined by the formation of a salt with (S)-(+)-O-acetyl-
mandelic acid. Cinacalcet (20.0 mg, 0.06 mmol) and (S)-(+)-O-
acetylmandelic acid (11 mg, 0.06 mmol) were dissolved in CDCl3.
The analysis of the 1H NMR spectroscopic data of this salt in com-
parison to the data obtained for the salt prepared from the racemic
product showed the presence of one diastereomer (de Ͼ 96%).
(R)-N-Isopropyl-2-phenylpropan-1-amine (3a):[93] The general pro-
cedure for the one-pot oxidation/imine-iminium formation/re-
duction was applied to (R)-phenyl-1-propanol (1a, 123 mg,
0.9 mmol) and isopropylamine (2a, 0.15 mL, 1.8 mmol). Purifica-
tion by flash chromatography on silica gel [PE/EtOAc/(MeOH +
0.1% NH4OH), from 60:40:0 to 0:90:10] gave 3a (153 mg,
0.86 mmol, 96%) as a yellow oil. IR: ν = 3028, 2962, 2928, 1494,
˜
1471, 1452, 1379, 1337, 1174, 1136, 1080, 1018 cm–1. 1H NMR General Procedure to Access Primary Amines: 2,2,6,6-Tetramethyl-
(CDCl3): δ = 7.34–7.18 (m, 5 H), 2.92 (m, 1 H), 2.69–2.82 (m, 3 1-piperidinyloxyl (30 mg, 0.2 mmol, 0.2 equiv.) and [bis(acetoxy)-
H), 1.70 (br. s, 1 H), 1.26 (d, J = 7.0 Hz, 3 H), 1.01 (d, J = 6.3 Hz, iodo]benzene (370 mg, 1.15 mmol, 1.15 equiv.) were added to a
6
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stirred solution of an alcohol (1 mmol) in CH2Cl2 (4 mL), and the
mixture was stirred at room temp. until there was complete conver-
sion of alcohol (2–20 h), as confirmed by TLC or GC–MS. When
the oxidation was not complete after 16 h, additional amounts of
BAIB (up to 240 mg, 0.75 mmol) were added to the reaction mix-
ture. Then, HCO2NH4 (631 mg, 10 mmol, 10 equiv.), MeOH
(2 mL), and NaBH3CN (125.7 mg, 2 mmol, 2 equiv.) were added
to the reaction mixture. After 16–72 h, the mixture was carefully
quenched with aqueous NaOH (1 m solution, 10 mL), and the re-
sulting mixture was extracted with Et2O (3ϫ20 mL). The com-
bined organic layers were dried with K2CO3, filtered, and concen-
trated under atmospheric pressure.
(20 mL), and the resulting mixture was washed with HCl (10%
aqueous solution, 10 mL) and then with a saturated aqueous solu-
tion of NaHCO3 (10 mL). The organic layer was dried with
MgSO4, filtered, and concentrated under reduced pressure. The 1H
NMR spectroscopic data for the crude material showed no traces
of the desired carbamate 9.
General Procedure for the One-Pot Oxidation/Imine Formation/
Allylation: 2,2,6,6-Tetramethyl-1-piperidinyloxyl (30 mg, 0.2 mmol,
0.2 equiv.) and [bis(acetoxy)iodo]benzene (370 mg, 1.15 mmol,
1.15 equiv.) were added to a stirred solution of an alcohol (1 mmol)
in CH2Cl2 (4 mL), and the mixture was stirred at room temp. until
there was complete conversion of the alcohol (2–20 h), as con-
firmed by TLC or GC–MS. When the oxidation was not completed
after 16 h, additional amounts of BAIB (up to 240 mg, 0.75 mmol)
were added to the reaction mixture. Then, benzylamine 2c
(0.22 mL, 2 mmol, 2 equiv.) and allyl pinacol boronate (10, 205 μL,
1.2 mmol, 1.2 equiv.) were added to the reaction mixture. After 3–
20 h, the mixture was carefully quenched with aqueous NaOH (1 m
solution, 10 mL), and the resulting mixture was extracted with
Et2O (3ϫ20 mL). The combined organic layers were dried with
MgSO4, filtered, and concentrated under reduced pressure. Purifi-
cation was achieved by flash chromatography.
N-(Benzyloxycarbonyl)-1-decen-5-amine (7):[95] The general pro-
cedure to access primary amines was applied to decen-5-ol (1b,
156 mg, 1 mmol). The residue was treated with Et3N (0.29 mL,
2 mmol, 2 equiv.), and the temperature was lowered to 0 °C. Benzyl
chloroformate (0.15 mL, 1.1 mmol, 1.1 equiv.) was added, and the
mixture was warmed to room temp. After stirring for 18 h, the
mixture was treated with citric acid (10% aqueous solution,
10 mL), and the resulting mixture was extracted with CH2Cl2
(20 mL). Then, the organic layer was washed with a saturated aque-
ous solution of NaHCO3 (10 mL), dried with MgSO4, filtered, and
concentrated under reduced pressure. Purification by flash
chromatography on silica gel (PE/EtOAc, from 99:1 to 95:5) gave
7 (225 mg, 0.78 mmol, 78% over 2 steps) as a white solid. The
physical and spectroscopic data were in agreement with the data
reported in the literature.[95] Rf = 0.16 (PE/EtOAc, 95:5). 1H NMR
(CDCl3): δ = 7.39–7.28 (m, 5 H), 5.81 (m, 1 H), 5.09 (s, 2 H), 5.05–
N-Benzylundec-1-en-4-amine (11a):[98] The general procedure for
the one-pot oxidation/imine formation/allylation was applied to oc-
tanol (1e, 157 μL, 1 mmol). Purification by flash chromatography
on silica gel (PE/EtOAc, from 95:5 to 50:50) gave 11a (216 mg,
0.83 mmol, 83%) as an orange oil; Rf = 0.23 (PE/EtOAc, 70:30).
IR: ν = 2924, 2854, 1639, 1495, 1454, 995, 911 cm–1. 1H NMR
˜
3
(CDCl3): δ = 7.34–7.20 (m, 5 H), 5.78 (ddt, J = 17.2, 10.0, and
7.1 Hz, 1 H), 5.13–5.04 (m, 2 H), 3.77 (s, 2 H), 2.61 (quintapp, J =
6.0 Hz, 1 H), 2.26 (m, 1 H), 2.17 (m, 1 H), 1.50–1.36 (m, 3 H),
1.36–1.20 (m, 10 H), 0.88 (t, J = 6.6 Hz, 3 H) ppm. 13C NMR
(CDCl3): δ = 141.0 (s), 136.0 (d), 128.5 (d, 2 CH), 128.3 (d, 2 CH),
126.9 (d), 117.2 (t), 56.3 (d), 51.3 (t), 38.5 (t), 34.0 (t), 32.0 (t), 30.0
(t), 29.4 (t), 25.9 (t), 22.8 (t), 14.3 (q) ppm. MS (EI, 70 eV): m/z
(%) = 218 (39) [M – allyl]+, 91 (100) [C7H7]+. HRMS (ESI): calcd.
for C18H30N [M + H]+ 260.2373; found 260.2373.
4.92 (m, 2 H), 4.51 (br. d, J = 6.9 Hz, 1 H), 3.65 (m, 1 H), 2.18–
2.00 (m, 2 H), 1.65–1.19 (m, 10 H), 0.87 (t, 3J = 7.3 Hz, 3 H) ppm.
13C NMR (CDCl3): δ = 156.1 (s), 138.1 (d), 136.7 (s), 128.5 (d, 2
C), 128.1 (d, 3 C), 114.8 (t), 66.5 (t), 51.0 (t), 35.4 (t), 34.7 (t), 31.7
(t), 30.2 (t), 25.5 (t), 22.6 (t), 14.0 (q) ppm.
tert-Butyl Hexan-3-yl-carbamate (8):[96] The general procedure to
access primary amines was applied to hexan-3-ol (1c, 125 μL,
1 mmol). The residue was dissolved in CH2Cl2 (2 mL). After the
addition of Et3N (0.29 mL, 2 mmol, 2 equiv.), the temperature was
lowered to 0 °C. Boc2O (240 mg, 1.1 mmol, 1.1 equiv.) was added,
and the mixture was warmed to room temp. After stirring for 16 h,
the mixture was diluted with CH2Cl2 (20 mL), and the resulting
mixture was washed with HCl (10% solution, 10 mL) and then
with a saturated aqueous solution of NaHCO3 (10 mL). The or-
ganic layer was dried with MgSO4, filtered, and concentrated under
reduced pressure. Purification by flash chromatography on silica
gel (PE/EtOAc, from 99:1 to 80:20) gave 8 (179 mg, 0.89 mmol,
89% over 2 steps) as a white solid. M.p. 47 °C; ref.[96] m.p. 47 °C.
(2R*,3R*)-N-Benzyl-2-phenylhex-5-en-3-amine (11b): The general
procedure for the one-pot oxidation/imine formation/allylation was
applied to 2-phenylpropanol (1a, 136 mg, 1 mmol). The analysis of
the 1H NMR spectroscopic data of the crude material indicated
that 11b was a mixture of two diastereomers in a ratio of 4:1. Purifi-
cation by flash chromatography on silica gel (PE/EtOAc, 95:5) gave
11b (67 mg, 0.25 mmol, 25%) as a yellow oil. IR: ν = 3062, 3027,
˜
2973, 1494, 1452, 1027, 996, 910 cm–1. 1H NMR (CDCl3, major
anti diastereomer): δ = 7.33–7.10 (m, 10 H), 5.77 (ddt, J = 17.1,
3
10.1 Hz, J = 7.2 Hz, 1 H), 5.07–4.97 (m, 2 H), 3.78 (dAB syst, J =
IR: ν = 3319, 2960, 2927, 2873, 1679, 1531, 1456, 1365, 1281, 1245,
˜
13.0 Hz, 1 H), 3.70 (dAB syst, J = 13.0 Hz, 1 H), 2.90 (quintapp, J =
6.9 Hz, 1 H), 2.76 (dt, J = 5.0, 6.9 Hz, 1 H), 2.19 (m, 1 H), 1.97
(m, 1 H), 1.46 (br. s, 1 H), 1.33 (d, J = 7.0 Hz, 3 H) ppm. 13C
NMR (CDCl3, major anti diastereomer): δ = 145.3 (s), 140.9 (s),
136.0 (d), 128.4, 128.2, 128.0, 126.9, 126.2 (d, 10 CH), 117.2 (t),
62.0 (d), 51.7 (t), 42.6 (d), 36.1 (t), 17.2 (q) ppm. MS (EI, 70 eV):
m/z (%) = 224 (5) [M – allyl]+, 160 (37) [BnNH=CH–(C3H5)]+, 91
(100) [C7H7]+, 65 (10). HRMS (ESI): calcd. for C19H24N
1175, 1163, 1097, 1060, 970, 665 cm–1. 1H NMR ([D6]-
DMSO): δ = 6.50 (br. d, 1 H), 3.27 (m, 1 H), 1.38 (s, 9 H), 1.43–
1.19 (m, 6 H), 0.85 (t, 3J = 6.9 Hz, 3 H), 0.80 (t, 3J = 7.4 Hz, 3
H) ppm. 13C NMR ([D6]DMSO): δ = 155.5 (s), 77.0 (s), 51.0 (d),
36.5 (t), 28.3 (q, 3 C), 27.6 (t), 18.8 (t), 13.9 (q), 10.4 (q) ppm. MS
(EI, 70 eV): m/z (%) = 172 (3) [M – Et]+, 116 (13), 102 (14), 72
(37), 59 (28), 58 (53), 57 (100) [tBu]+, 56 (13). HRMS (ESI): calcd.
for C11H23NO2Na [M + Na]+ 224.1621; found 224.1620.
1
[M + H]+ 266.1903; found 266.1898. H NMR (CDCl3, minor syn
tert-Butyl (2,2-Dimethyl-1,3-dioxolan-4-yl)methylcarbamate (9):[97]
The general procedure to access primary amines was applied to
solketal (1d, 132 mg, 1 mmol). The residue was dissolved in CH2Cl2
(2 mL). After the addition of Et3N (0.29 mL, 2 mmol, 2 equiv.),
diastereomer): δ = 7.33–7.10 (m, 10 H), 5.84 (m, 1 H), 5.14–5.01
(m, 2 H), 3.74 (dAB syst, J = 13.2 Hz, 1 H), 3.64 (dAB syst, J =
13.2 Hz, 1 H), 2.90 (m, 1 H), 2.75 (m, 1 H), 2.34–2.10 (m, 2 H),
1.46 (br. s, 1 H), 1.26 (d, J = 7.0 Hz, 3 H) ppm. 13C NMR (CDCl3,
the temperature was lowered to 0 °C. Boc2O (240 mg, 1.1 mmol, minor syn diastereomer): δ = 144.8 (s), 140.7 (s), 136.0 (d), 128.4,
1.1 equiv.) was added, and the mixture was warmed to room temp. 128.2, 128.1, 126.9, 126.4 (d, 10 CH), 117.1 (t), 61.5 (d), 51.7 (t),
After stirring for 16 h, the mixture was diluted with CH2Cl2 42.4 (d), 34.8 (t), 17.1 (q) ppm.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20171
/KAP1
Date: 04-04-12 16:36:12
Pages: 12
C. Guérin, V. Bellosta, G. Guillamot, J. Cossy
FULL PAPER
(S*)-N-Benzyl-1-{(S*)-2,2-dimethyl-1,3-dioxolan-4-yl}but-3-en-
1-amine (11c):[78] The general procedure for the one-pot oxidation/
(CDCl3): δ = 7.38–7.19 (m, 10 H), 4.62 (dAB syst, J = 10.1 Hz, 1 H),
4.57 (dAB syst, J = 10.0 Hz, 1 H), 3.89 (m, 1 H), 2.68 (m, 1 H), 2.42
imine formation/allylation was applied to solketal (1d, 132 mg, (m, 1 H), 2.12 (m, 1 H), 1.32 (d, J = 7.2 Hz, 3 H) ppm. 13C NMR
1 mmol). The analysis of the 1H NMR spectroscopic data of the
crude material indicated that 11c was a mixture of two dia-
stereomers in a ratio of 9:1. Purification by flash chromatography
on silica gel (PE/EtOAc, from 70:30 to 50:50) gave anti- and syn-
11c (182 mg, 0.7 mmol, 70%) as a yellow oil. Under these condi-
tions, a sample of pure anti-11c (90 mg, 0.34 mmol) was obtained.
(CDCl3): δ = 135.8 (d), 116.7 (t), 79.2 (d), 70.7 (t), 60.3 (d), 34.1
(t), 15.2 (q) ppm.
(4R*,5S*)-5-Methyl-4-propyloxazolidin-2-one (11dЈ):[100] A solution
of 11d (100 mg, 0.34 mmol) in EtOH (13.5 mL) was hydrogenated
in a flow manner using the H-Cube (Thales Nanotechnology Inc.)
operating at 10–15 bars of in situ generated H2 at 40 °C with a flow
rate of 1 mL/min. The catalyst bed (Cat-Cart) Pd(OH)2/C (10%)
used was available from Thales. Upon concentration under reduced
pressure, the residue (65 mg, 0.31 mmol, 1 equiv.) was dissolved in
CH2Cl2 (1 mL). After the addition of Et3N (87 μL, 0.62 mmol,
2 equiv.), the temperature was lowered to 0 °C. Boc2O (74 mg,
0.34 mmol, 1.1 equiv.) was added, and the mixture was warmed to
room temp. After stirring for 16 h, the mixture was diluted with
CH2Cl2 (20 mL), and the resulting mixture was washed with HCl
(10% solution, 10 mL) and then with a saturated aqueous solution
of NaHCO3 (10 mL). The organic layer was dried with MgSO4,
filtered, and concentrated under reduced pressure. Purification by
flash chromatography on silica gel (PE/EtOAc, 95:5) gave tert-bu-
Data for anti diastereomer: R = 0.70 (PE/EtOAc, 60:40). IR: ν =
˜
f
3064, 3028, 2984, 2932, 1454, 1379, 1369, 1249, 1210, 1158, 1062,
914, 858 cm–1. 1H NMR (CDCl3): δ = 7.35–7.21 (m, 5 H), 5.81 (m,
1 H), 5.13 (m, 1 H), 5.10 (m, 1 H), 4.08–4.00 (m, 2 H), 3.89 (m, 1
H), 3.85 (dAB syst, J = 13.0 Hz, 1 H), 3.77 (dAB syst, J = 13.1 Hz, 1
H), 2.80 (qapp, J = 5.7 Hz, 1 H), 2.37–2.24 (m, 2 H), 1.53 (br. s, 1
H), 1.41 (s, 3 H), 1.35 (s, 3 H) ppm. 13C NMR (CDCl3): δ = 140.7
(s), 134.9 (d), 128.5 (d, 2 CH), 128.2 (d, 2 CH), 127.1 (d, CH),
118.0 (t), 108.9 (s), 77.9 (d), 66.9 (t), 58.3 (d), 52.0 (t), 35.2 (t), 26.8
(q), 25.4 (q) ppm. MS (EI, 70 eV): m/z (%) = 246 (1) [M – Me]+,
220 (3) [M – allyl]+, 160 (44) [BnNH=CH–(C3H5)]+, 91 (100)
[C7H7]+. HRMS (ESI): calcd. for C16H24NO2 [M + H]+ 262.1802;
found 262.1806. Data for syn diastereomer: Rf = 0.48 (PE/EtOAc,
1
tyl[(2S*,3R*)-2-benzyloxyhexan-3-yl]carbamate
(84 mg,
60:40). H NMR (CDCl3): δ = 7.35–7.21 (m, 5 H), 5.81 (m, 1 H),
0.27 mmol, 81% over 2 steps) as a white wax. IR: ν = 3351, 2960,
˜
5.16–5.06 (m, 2 H), 4.12 (qapp, J = 6.8 Hz, 1 H), 3.99 (dd, J = 7.8,
6.2 Hz, 1 H), 3.91 (dAB syst, J = 13.2 Hz, 1 H), 3.79 (dAB syst, J =
13.2 Hz, 1 H), 3.73 (tapp, J = 7.6 Hz, 1 H), 2.71 (qapp, J = 6.1 Hz,
1 H), 2.40–2.24 (m, 1 H), 2.14 (m, 1 H), 1.55 (br. s, 1 H), 1.39 (s,
3 H), 1.34 (s, 3 H) ppm. Only the following signals of the 13C NMR
spectroscopic data were assigned unambiguously. 13C NMR
(CDCl3): δ = 135.1 (d), 128.3 (d, 2 CH), 127.0 (d), 117.6 (t), 109.0
(s), 78.2 (d), 66.8 (t), 58.6 (d), 51.6 (t), 35.1 (t), 26.8 (q), 25.5
(q) ppm.
2932, 2871, 1699, 1498, 1454, 1390, 1365, 1246, 1169, 1102, 1065,
735, 697 cm–1. 1H NMR (CDCl3): δ = 7.36–7.24 (m, 5 H), 4.64 (m,
1 H), 4.58 (dAB syst, 2J = 11.7 Hz, 1 H), 4.45 (dAB syst, 2J = 11.7 Hz,
1 H), 3.71–3.41 (m, 2 H), 1.58–1.25 (m, 4 H), 1.43 (s, 9 H), 1.17
(d, 3J = 6.4 Hz, 3 H), 0.92 (tapp, 3J = 7.2 Hz, 3 H) ppm. 13C NMR
(CDCl3): δ = 155.9 (s), 138.8 (s), 128.4 (d, 2 C), 127.7 (d, 2 C),
127.5 (d), 78.9 (s), 77.0 (d), 70.8 (t), 53.9 (d), 31.6 (t), 28.4 (q, 3 C),
19.4 (t), 15.9 (q), 14.1 (q) ppm. MS (EI, 70 eV): m/z (%) = 172 (11)
[C3H7CH=NHBoc]+, 116 (59) [NHBoc]+, 92 (12), 91 (97) [C7H7]+,
72 (95), 65 (10), 57 (100) [tBu]+. HRMS (ESI): calcd. for
C18H29NO3Na [M + Na]+ 330.2040; found 330.2033. A solution of
(2S,3R)-N-Benzyl-2-(benzyloxy)hex-5-en-3-amine (11d):[99] The ge-
neral procedure for the one-pot oxidation/imine formation/allyl-
ation was applied to alcohol 1f (166 mg, 1 mmol). The analysis of
the 1H NMR spectroscopic data of the crude material indicated
tert-butyl[(2S*,3R*)-2-benzyloxyhexan-3-yl]carbamate
(77 mg,
0.25 mmol) in EtOH (10 mL) was hydrogenated in a flow manner
that 11d was a mixture of two diastereomers in a ratio of 11:1. using the H-Cube (Thales Nanotechnology Inc.) operating at 10–
Purification by flash chromatography on silica gel (PE/EtOAc, 15 bars of in situ generated H2 pressure at room temp. with a flow
from 90:10 to 80:20 + 0.1% Et3N) gave anti- and syn-11d (242 mg, rate of 1 mL/min. The catalyst bed (Cat-Cart) Pd/C (10%) used
0.82 mmol, 82%) as a yellow oil. Under these conditions, a sample was available from Thales. Upon concentration under reduced pres-
of pure anti-11d (147 mg, 0.5 mmol) was obtained. Data for anti sure, the residue (52 mg, 0.24 mmol) was dissolved in DMF (di-
diastereomer: Rf = 0.31 (PE/EtOAc, 80:20). [α]2D0 = +2.3 (c = 0.97,
methylformamide, 1 mL), and the resulting solution was added at
CHCl ). IR: ν = 3064, 3029, 2975, 2932, 1454, 1094, 1071, 1028, room temp. to a suspension of pentane-washed NaH (60% in oil,
˜
3
912 cm–1. H NMR (CDCl3): δ = 7.37–7.19 (m, 10 H), 5.78 (ddt,
14 mg, 0.36 mmol) in DMF (1 mL). After stirring at room temp.
for 3 h, the mixture was quenched with a saturated aqueous solu-
1
J = 17.2, 10.0, 7.1 Hz, 1 H), 5.08 (dqapp, J = 17.2, 1.5 Hz, 1 H),
5.04 (m, 1 H), 4.53 (dAB syst, J = 11.8 Hz, 1 H), 4.42 (dAB syst, J = tion of NH4Cl (20 mL), and the aqueous layer was extracted with
11.8 Hz, 1 H), 3.81 (dAB syst, J = 13.3 Hz, 1 H), 3.77 (dAB syst, J = Et2O (2ϫ20 mL). The combined organic layers were dried with
13.3 Hz, 1 H), 3.58 (qd, J = 6.3, 4.1 Hz, 1 H), 2.77 (m, 1 H), 2.35– MgSO4, filtered, and concentrated under reduced pressure. The
1
2.20 (m, 2 H), 1.66 (br. s, 1 H, NH), 1.23 (d, J = 6.3 Hz, 3 H) ppm.
13C NMR (CDCl3): δ = 140.7 (s), 138.8 (s), 135.9 (d), 128.2, 128.1,
127.4, 127.3, 126.7 (d, 10 CH), 116.9 (t), 76.1 (d), 70.6 (t), 59.4 (d),
51.7 (t), 35.1 (t), 15.0 (q) ppm. MS (EI, 70 eV): m/z (%) = 254 (3)
[M – allyl]+, 160 (48) [BnNH=CH–(C3H5)]+, 92 (8), 91 (100)
[C7H7]+, 65 (9). HRMS (ESI): calcd. for C20H26NO [M + H]+
296.2009; found 296.2007. The enantiomeric excess was determined
by the formation of a salt with (S)-(+)-O-acetylmandelic acid.
(2S,3R)-N-benzyl-2-(benzyloxy)hex-5-en-3-amine (11d, 20.5 mg,
0.08 mmol) and (S)-(+)-O-acetylmandelic acid (15.6 mg,
0.08 mmol) were dissolved in CDCl3. The analysis of the 1H NMR
spectroscopic data of this salt in comparison to the data obtained
for the salt prepared from the racemic product showed the presence
of one diastereomer (de Ͼ 96%). Data for syn diastereomer: Only
the following signals were assigned unambiguously. 1H NMR
analysis of the H NMR spectroscopic data of the crude material
indicated that 11dЈ was a mixture of two diastereomers in a ratio
of 11:1. Purification by flash chromatography on silica gel (PE/
EtOAc, 60:40) gave 11dЈ (32 mg, 0.22 mmol, 89% over 2 steps) as
a colorless oil; R = 0.38 (PE/EtOAc, 50:50). IR: ν = 3262, 2959,
˜
f
2935, 2874, 1737, 1384, 1248, 1219, 1062, 1043, 959, 773, 756,
671 cm–1. HRMS (ESI): calcd. for C7H13NO2Na [M + Na]+
166.0839, found 166.0833. Data for major cis diastereomer: 1H
3
3
NMR (CDCl3): δ = 6.81 (br. s, 1 H), 4.77 (dq, J = 7.8 Hz, J =
6.6 Hz, 1 H), 3.79 (m, 1 H), 1.53–1.25 (m, 4 H), 1.34 (d, 3J =
6.6 Hz, 3 H), 0.96 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (CDCl3):
3
δ = 160.2 (s), 76.4 (d), 55.7 (d), 32.1 (t), 19.5 (t), 14.9 (q), 14.0
(q) ppm. MS (EI, 70 eV): m/z (%) = 143 (3) [M]+·, 100 (82) [M –
(C3H7)]+, 56 (100). Data for minor trans diastereomer: Only the
following signals were assigned unambiguously. 1H NMR (CDCl3):
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20171
/KAP1
Date: 04-04-12 16:36:12
Pages: 12
One-Pot Synthesis of Amines from Alcohols
δ = 4.29 (quintapp
,
3J = 6.2 Hz, 1 H), 3.40 (br. q, 3J = 6.2 Hz, 1
6 H), 5.88–5.72 (m, 2 H), 5.14–4.99 (m, 4 H), 4.07–4.03 (m, 3 H),
3.27 (ddt, J = 14.0, 5.9, 1.6 Hz, 1 H), 3.16 (ddt, J = 14.0, 6.2,
1.5 Hz, 1 H), 2.84 (m, 1 H), 2.38–2.33 (m, 2 H), 1.26 (br. s, 1
H) ppm. 13C NMR (CDCl3): δ = 142.6 (s), 142.5 (s), 137.0 (d),
134.7 (d), 128.3 (d, 2 CH), 128.1 (d, 3 CH), 128.0 (d), 126.3 (d, 2
CH), 126.2 (d, 2 CH), 118.2 (t), 115.9 (t), 109.6 (s), 78.3 (d), 67.7
(t), 58.3 (d), 50.3 (t), 35.2 (t) ppm. MS (EI, 70 eV): m/z (%) = 294
(3) [M – allyl]+, 112 (14), 110 (100) [C7H12N]+, 105 (24) [PhCO]+,
77 (23) [Ph]+, 68 (11). HRMS (ESI): calcd. for C22H26NO2 [M +
H]+ 336.1958; found 336.1952. Data for syn diastereomer: Rf = 0.18
(PE/EtOAc, 90:10). 1H NMR (CDCl3): δ = 7.55–7.44 (m, 4 H),
7.35–7.22 (m, 6 H), 5.91–5.72 (m, 2 H), 5.18–4.98 (m, 4 H), 4.16
(qapp, J = 6.8 Hz, 1 H), 4.01 (tapp, J = 7.3 Hz, 1 H), 3.91 (tapp, J =
7.3 Hz, 1 H), 3.31–3.21 (m, 2 H), 2.78 (qapp, J = 6.2 Hz, 1 H), 2.27
(m, 1 H), 2.11 (m, 1 H), 1.45 (br. s, 1 H) ppm. 13C NMR (CDCl3):
δ = 142.4 (s), 142.3 (s), 137.1 (d), 134.9 (d), 128.2 (d, 2 CH), 128.0
(d, 4 CH), 126.3 (d, 2 CH), 126.2 (d, 2 CH), 117.7 (t), 115.9 (t),
109.7 (s), 78.9 (d), 67.3 (t), 58.5 (d), 50.1 (t), 35.2 (t) ppm.
H) ppm. 13C NMR (CDCl3): δ = 159.9 (s), 79.2 (d), 59.7 (d), 37.1
(t), 20.3 (q), 18.9 (t), 14.0 (q) ppm.
Benzyl (4S)-[-1-(Benzylamino)but-3-en-1-yl]-2,2-dimethyloxazolid-
ine-3-carboxylate (11e): The general procedure for the one-pot oxi-
dation/imine formation/allylation was applied to alcohol 1g
(197 mg, 0.74 mmol). Because of the carbamate functionality in
11e, the diastereomeric ratio could not be determined by the analy-
sis of the NMR spectroscopic data of the crude material. Purifica-
tion by flash chromatography on silica gel (PE/EtOAc, 90:10) gave
pure 11e (175 mg, 0.44 mmol, 60%) as a yellow oil. Rf = 0.59 (PE/
EtOAc, 70:30); [α]2D0 = +26.7 (c = 1.03, CHCl ). IR: ν = 2980, 2937,
˜
3
1698, 1403, 1347, 1256, 1089, 1069 cm–1. 1H NMR ([D6]DMSO,
395 K): δ = 7.40–7.16 (m, 10 H), 5.79 (ddt, J = 17.1, 10.1, 7.1 Hz,
1 H), 5.15–4.94 (m, 2 H), 5.11 (dAB syst, J = 12.3 Hz, 1 H), 5.06
(dAB syst, J = 12.3 Hz, 1 H), 4.08 (dd, J = 8.6, 2.6 Hz, 1 H), 3.98
(m, 1 H), 3.91 (dd, J = 8.6, 6.6 Hz, 1 H), 3.78 (dAB syst, J = 13.4 Hz,
1 H), 3.68 (dAB syst, J = 13.4 Hz, 1 H), 3.08 (m, 1 H), 2.80 (br. s, 1
H), 2.22 (m, 1 H), 2.10 (m, 1 H), 1.56 (s, 3 H), 1.45 (s, 3 H) ppm.
Benzyl (1S*)-N-Allyl-1-{(4S*)-2,2-diphenyl-1,3-dioxolan-4-yl}but-3-
13C NMR ([D6]DMSO, 395 K): δ = 151.9 (s), 140.6 (s), 136.0 (s) enylcarbamate (15): Benzyl chloroformate (70 μL, 0.49 mmol,
135.4 (d), 127.6 (d, 2 CH), 127.3 (d, 2 CH), 127.1 (d, 4 CH), 125.8
(d, 2 CH), 115.5 (t), 93.3 (s), 65.6 (t), 63.4 (t), 59.6 (d), 57.0 (d),
51.1 (t), 35.8 (t), 25.6 (q), 23.2 (q) ppm. MS (EI, 70 eV): m/z (%) =
1.5 equiv.) was added to a solution of the pure anti-14 (110 mg,
0.33 mmol, 1 equiv.) and DIPEA (0.16 mL, 0.99 mmol, 3 equiv.) in
CH2Cl2 (7 mL) at 0 °C. The mixture was warmed to room temp.
353 (1) [M – allyl]+, 160 (70) [BnNH=CH–(C3H5)]+, 92 (8), 91 (100) After stirring for 16 h, water (10 mL) was added, and the aqueous
[C7H7]+, 65 (6). HRMS (ESI): calcd. for C24H31N2O3 [M + H]+
395.2329; found 395.2328.
layer was extracted with CH2Cl2 (3ϫ20 mL). The combined or-
ganic layers were dried with MgSO4, filtered, and concentrated un-
der reduced pressure. Purification by flash chromatography on sil-
ica gel (PE/EtOAc, from 98:2 to 90:10) gave compound 15 (139 mg,
0.3 mmol, 90%) as a colorless oil; Rf = 0.37 (PE/EtOAc, 90:10).
(7aS)-7-Allyl-6-benzyl-3,3-dimethyltetrahydroimidazo[1,5-c]oxazol-
5(3H)-one (11eЈ): EtMgBr (3 m in Et2O, 55 μL, 0.165 mmol,
1.65 equiv.) was added at 0 °C to a solution of 11e (39 mg,
0.1 mmol, 1 equiv.) in CH2Cl2 (2 mL), and the reaction mixture
was heated to reflux. After 18 h, the reaction medium was diluted
with CH2Cl2 (10 mL), and the resulting mixture was washed with
a saturated aqueous solution of NH4Cl (5 mL). The combined or-
ganic layers were dried with MgSO4, filtered, and concentrated un-
der reduced pressure. Purification by chromatography on silica gel
(PE/EtOAc, 85:15) gave compound 11eЈ (20 mg, 0.07 mmol, 70%)
IR: ν = 3065, 3032, 2957, 1697, 1450, 1407, 1249, 1227, 1207, 1083,
˜
1
1028, 992, 952, 915 cm–1. H NMR (CDCl3, rotamers): δ = 7.53–
7.42 (m, 4 H), 7.37–7.22 (m, 11 H), 5.86–5.53 (m, 2 H), 5.18–4.91
(m, 6 H), 4.40–4.20 (m, 1 H), 4.20–3.63 (m, 5 H), 2.67–2.33 (m, 2
H) ppm. 13C NMR (CDCl3, rotamers): δ = 156.5, 156.2 (s), 142.3
(s, 2 C), 136.8, 136.4 (s), 135.1, 135.0, 134.6 (d, 2 CH), 128.6, 128.5,
128.3, 128.2, 128.0, 127.8, 126.3, 126.2, 126.1 (d, 15 CH), 117.7,
117.5, 117.0 (t, 2 C), 110.5 (s), 78.1 (d), 68.3, 68.2 (t), 67.5, 67.3
(t), 59.1 (d), 47.7 (t), 33.1 (t) ppm. MS (EI, 70 eV): m/z (%) = 428
(2) [M – allyl]+, 244 (7) [C7H11NCbz]+, 200 (11), 105 (13) [PhCO]
+, 91 (100) [C7H7]+, 77 (9) [Ph]+. HRMS (ESI): calcd. for
C30H31NO4Na [M + Na]+ 492.2145; found 492.2140.
as a colorless oil. [α]2D0 = +36.9 (c = 1.01, CHCl ). IR: ν = 2981,
˜
3
2930, 1700, 1405, 1370, 1316, 1235, 1208, 1040, 918, 804, 767, 735,
699 cm–1. 1H NMR (CDCl3): δ = 7.38–7.22 (m, 5 H), 5.63 (m, 1
H), 5.12–5.06 (m, 2 H), 4.77 (dAB syst,
2J = 15.4 Hz, 1 H), 4.06
2
3
(dAB syst, J = 15.3 Hz, 1 H), 4.03 (td, J = 8.9, 6.1 Hz, 1 H), 3.90
(dd, 2J = 8.1 Hz, 3J = 6.2 Hz, 1 H), 3.65 (dd, 3J = 9.2 Hz, 2J = Benzyl (2S*)-2-{(4S*)-2,2-Diphenyl-1,3-dioxolan-4-yl}-1,2,3,6-tetra-
8.5 Hz, 1 H), 3.60 (m, 1 H), 2.55 (m, 1 H), 2.06 (m, 1 H), 1.76 (s,
3 H), 1.43 (s, 3 H) ppm. 13C NMR (CDCl3): δ = 160.6 (s), 136.8
(s), 132.8 (d), 128.8 (d, 2 C), 128.2 (d, 2 C), 127.7 (d), 118.8 (t),
95.4 (s), 63.9 (t), 58.8 (d), 52.4 (d), 45.8 (t), 33.8 (t), 29.2 (q), 23.9
(q) ppm. MS (EI, 70 eV): m/z (%) = 271 (1) [M – Me]+, 245 (20)
hydropyridine-1-carboxylate (16):[101] Grubbs second-generation
catalyst (G-II, 14 mg, 0.016 mmol, 0.1 equiv.) was added to a solu-
tion of 15 (74 mg, 0.16 mmol, 1 equiv.) in CH2Cl2 (4 mL). After
stirring at room temp. for 4.5 h, the reaction mixture was concen-
trated under reduced pressure. Purification by flash chromatog-
[M – allyl]+, 215 (18), 92 (8), 91 (100) [C7H7]+, 65 (12). HRMS raphy on silica gel (PE/EtOAc, 90:10) gave compound 16 (63 mg,
(ESI): calcd. for C17H22N2O2Na [M + Na]+ 309.1573; found
309.1573.
0.14 mmol, 91%) as a brownish oil; Rf = 0.25 (PE/EtOAc, 90:10).
1H NMR (CDCl3, rotamers): δ = 7.53–7.40 (m, 4 H), 7.38–7.20
(m, 11 H), 5.78 (m, 1 H), 5.62 (m, 1 H), 5.22–5.05 (m, 2 H), 4.55–
4.21 (m, 3 H), 4.04–3.84 (m, 2 H), 3.52, 3.42 (2 br. d, J = 18.6 Hz,
1 H), 2.60–2.23 (m, 2 H) ppm. 13C NMR (CDCl3, rotamers): δ =
155.7, 155.2 (s), 142.5, 142.4 (s, 2 C), 136.6, 136.4 (s), 128.6, 128.2,
128.1, 128.0, 126.3, 126.2 (d, 15 CH), 123.4, 122.9, 122.8 (d, 2 CH),
110.2 (s), 75.2, 74.8 (d), 67.9, 67.5 (t), 67.4 (t), 51.0, 50.4 (d), 41.1,
40.9 (t), 25.6, 25.2 (t) ppm.
(1S*)-N-Allyl-1-{(4S*)-2,2-diphenyl-1,3-dioxolan-4-yl}but-3-
enamine (14): The general procedure for the one-pot oxidation/
imine formation/allylation was applied to alcohol 12[92] (256 mg,
1 mmol). The analysis of the 1H NMR spectroscopic data of the
crude material indicated that 14 was a mixture of two dia-
stereomers in a ratio of 3.4:1. Purification by flash chromatography
on silica gel (PE/EtOAc, from 95:5 to 90:10) gave anti- and syn-14
(182 mg, 0.54 mmol, 54%) as a colorless oil. Under these condi-
tions, a sample of the pure anti-14 (114 mg, 0.34 mmol) was ob-
tained. Data for anti diastereomer: Rf = 0.30 (PE/EtOAc, 90:10).
(S*,S*)-Dexoxadrol:[86] Pd/C (10%, 4 mg) was added to a solution
of 16 (59 mg, 0.13 mmol, 1 equiv.) in EtOH (3 mL). After stirring
at room temp. for 24 h under 1 atm of H2, the reaction mixture
IR: ν = 3063, 2890, 1450, 1264, 1206, 1087, 1070, 1028, 992, 952, was filtered through Celite, and the filtrate was concentrated under
˜
914 cm–1. 1H NMR (CDCl3): δ = 7.55–7.44 (m, 4 H), 7.35–7.22 (m,
reduced pressure. The crude residue was dissolved in CH2Cl2
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

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Date: 04-04-12 16:36:12
Pages: 12
C. Guérin, V. Bellosta, G. Guillamot, J. Cossy
FULL PAPER
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
S. Bähn, S. Imm, L. Neubert, M. Zhang, H. Neumann, M.
Beller, ChemCatChem 2011, 3, 1853–1864.
A. Corma, S. Iborra, A. Velty, Chem. Rev. 2007, 107, 2411–
2502.
W. He, L. Wang, C. Sun, K. Wu, S. He, J. Chen, P. Wu, Z. Yu,
Chem. Eur. J. 2011, 17, 13308–13317.
A. Martínez-Asencio, D. J. Ramο´n, M. Yus, Tetrahedron 2011,
67, 3140–3149.
Y. Zhang, X. Qi, X. Cui, F. Shi, Y. Deng, Tetrahedron Lett.
2011, 52, 1334–1338.
X. Cui, Y. Zhang, F. Shi, Y. Deng, Chem. Eur. J. 2011, 17,
1021–1028.
R. Cano, D. J. Ramón, M. Yus, J. Org. Chem. 2011, 76, 5547–
5557.
A. J. A. Watson, A. C. Maxwell, J. M. J. Williams, J. Org.
Chem. 2011, 76, 2328–2331.
W. Zhang, X. Dong, W. Zhao, Org. Lett. 2011, 13, 5386–5389.
H. Ohta, Y. Yuyama, Y. Uozumi, Y. M. A. Yamada, Org. Lett.
2011, 13, 3892–3895.
T. Suzuki, Chem. Rev. 2011, 111, 1825–1845.
Y. Du, S. Oishi, S. Saito, Chem. Eur. J. 2011, 17, 12262–12267.
M. H. S. A. Hamid, C. L. Allen, G. W. Lamb, A. C. Maxwell,
H. C. Maytum, A. J. A. Watson, J. M. J. Williams, J. Am.
Chem. Soc. 2009, 131, 1766–1774.
(20 mL), and the resulting solution was washed with aqueous
NaOH (2 m solution, 10 mL). The organic layer was dried with
MgSO4, filtered, and concentrated under reduced pressure. Purifi-
cation by flash chromatography on silica gel (CH2Cl2/MeOH, from
98:2 to 90:10) gave dexoxadrol (19 mg, 0.06 mmol, 46%) as a color-
less oil. The physical and spectroscopic data matched with those
described in the literature.[86] Rf = 0.36 (CH2Cl2/MeOH, 90:10). 1H
NMR (CDCl3): δ = 7.57–7.44 (m, 4 H), 7.37–7.22 (m, 6 H), 4.14
(tdapp, J = 6.9, 1.4 Hz, 1 H), 4.04 (m, 1 H), 3.94 (tdapp, J = 7.2,
1.4 Hz, 1 H), 3.06 (br. d, J = 11.6 Hz, 1 H), 2.83 (br. d, 2J =
11.4 Hz, 1 H), 2.59 (br. t, J = 11.5 Hz, 1 H), 2.08 (br. s, 1 H), 1.81
(br. d, J = 12.6 Hz, 1 H), 1.70 (br. d, J = 13.0 Hz, 1 H), 1.58 (br.
d, J = 12.4 Hz, 1 H), 1.47–1.23 (m, 2 H), 1.08 (qdapp, J = 12.1,
3.8 Hz, 1 H) ppm. 13C NMR (CDCl3): δ = 142.3 (s), 142.1 (s), 128.3
(d, 2 CH), 128.2 (d, 3 CH), 128.1 (d), 126.4 (d, 2 CH), 126.3 (d, 2
CH), 109.6 (s), 79.7 (d), 66.1 (t), 58.1 (d), 46.8 (t), 28.6 (t), 26.5 (t),
24.6 (t) ppm. MS (EI, 70 eV): m/z (%) = 125 (1) [M – Ph2CHO]+,
105 (9), 84 (100) [C5H10N]+, 77 (9) [Ph]+, 56 (8).
[30]
[31]
[32]
[33]
[34]
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra of the new prepared
compounds.
[35]
[36]
[37]
[38]
M. J. Climent, A. Corma, S. Iborra, Chem. Rev. 2011, 111,
1072–1133.
Acknowledgments
D. B. Ramachary, S. Jain, Org. Biomol. Chem. 2011, 9, 1277–
1300.
A. Bruggink, R. Schoevaart, T. Kieboom, Org. Process Res.
Dev. 2003, 7, 622–640.
C. Vaxelaire, P. Winter, M. Christmann, Angew. Chem. Int. Ed.
2011, 50, 3605–3607.
The authors gratefully acknowledge financial support and a grant
to C. G. by PCAS.
[39]
[40]
L. Blackburn, R. J. K. Taylor, Org. Lett. 2001, 3, 1637–1639.
For a recent report on the use of a catalytic amount of MnO2,
in the presence of a base and air, to promote the N-alkylation
of amines and sulfonamides by employing activated alcohols
as alkylating agents, see: X. Yu, C. Liu, L. Jiang, Q. Xu, Org.
Lett. 2011, 13, 6184–6187.
C. Guérin, V. Bellosta, G. Guillamot, J. Cossy, Org. Lett. 2011,
13, 3534–3537.
A. De Mico, R. Margarita, L. Parlanti, A. Vescovi, G. Piancat-
elli, J. Org. Chem. 1997, 62, 6974–6977.
[1] M. B. Smith, J. March, March’s Advanced Organic Chemistry,
Wiley-Interscience, New York, 2001.
[2] S. Das, S. Zhou, D. Addis, S. Enthaler, K. Junge, M. Beller,
Top. Catal. 2010, 53, 979–984.
[3] R. Reguillo, M. Grellier, N. Vautravers, L. Vendier, S. Sabo-
Etienne, J. Am. Chem. Soc. 2010, 132, 7854–7855.
[4] A. Johansson, Contemp. Org. Synth. 1995, 2, 393–407.
[5] S. Kobayashi, H. Ishitani, Chem. Rev. 1999, 99, 1069–1094.
[6] M. Breuer, K. Ditrich, T. Habicher, B. Hauer, M. Keßeler, R.
Stürmer, T. Zelinski, Angew. Chem. 2004, 116, 806; Angew.
Chem. Int. Ed. 2004, 43, 788–824.
[7] V. I. Tararov, A. Börner, Synlett 2005, 203–211.
[8] G. K. Friestad, A. K. Mathies, Tetrahedron 2007, 63, 2541–
2569.
[41]
[42]
[43]
[44]
[45]
[46]
K. Geoghegan, S. Kelleher, P. Evans, J. Org. Chem. 2011, 76,
2187–2194.
G. B. Shinde, N. C. Niphade, S. P. Deshmukh, R. B. Toche,
V. T. Mathad, Org. Process Res. Dev. 2011, 15, 455–461.
G. Bijukumar, B. Maloyesh, B. S. Bhaskar, A. Rajendra, Synth.
Commun. 2008, 38, 1512–1517.
O. R. Thiel, C. Bernard, W. Tormos, A. Brewin, S. Hirotani,
K. Murakami, K. Saito, R. D. Larsen, M. J. Martinelli, P. J.
Reider, Tetrahedron Lett. 2008, 49, 13–15.
X. Wang, Y. Chen, R. Crockett, J. Briones, T. Yan, C. Orihuela,
B. Zhi, J. Ng, Tetrahedron Lett. 2004, 45, 8355–8358.
A. F. Abdel-Magid, K. G. Carson, B. D. Harris, C. A. Maryan-
off, R. D. Shah, J. Org. Chem. 1996, 61, 3849–3862.
To avoid the addition of MeOH, and thus be able to use Na-
BH(OAc)3 as a reducing agent, some experiments have been
achieved using ammonium trifluoroacetate which is more solu-
ble in CH2Cl2 than ammonium formate. However, the desired
primary amine was obtained with yields less than 19%.
Y. Yamamoto, N. Asao, Chem. Rev. 1993, 93, 2207–2293.
R. Bloch, Chem. Rev. 1998, 98, 1407–1438.
[9] T. C. Nugent, M. El-Shazly, Adv. Synth. Catal. 2010, 352, 753–
819.
[10] J.-H. Xie, S.-F. Zhu, Q.-L. Zhou, Chem. Rev. 2011, 111, 1713–
1760.
[11] R. Severin, S. Doye, Chem. Soc. Rev. 2007, 36, 1407–1420.
[12] T. E. Müller, K. C. Hultzsch, M. Yus, F. Foubelo, M. Tada,
Chem. Rev. 2008, 108, 3795–3892.
[13] K. D. Hesp, M. Stradiotto, ChemCatChem 2010, 2, 1192–1207.
[14] D. Crozet, M. Urrutigoity, P. Kalck, ChemCatChem 2011, 3,
1102–1118.
[47]
[48]
[49]
[15] J. S. Yadav, A. Antony, T. S. Rao, B. V. Subba Reddy, J. Or-
ganomet. Chem. 2011, 696, 16–36.
[16] F. Collet, C. Lescot, P. Dauban, Chem. Soc. Rev. 2011, 40,
1926–1936.
[17] T. A. Ramirez, B. Zhao, Y. Shi, Chem. Soc. Rev. 2012, 41, 931–
942.
[18] M. H. S. A. Hamid, P. A. Slatford, J. M. J. Williams, Adv.
Synth. Catal. 2007, 349, 1555–1575.
[50]
[51]
[52]
[53]
T. R. Ramadhar, R. A. Batey, Synthesis 2011, 1321–1346.
S. Kobayashi, S. Iwamoto, S. Nagayama, Synlett 1997, 1099–
1101.
S. J. Veenstra, P. Schmid, Tetrahedron Lett. 1997, 38, 997–1000.
J. S. Panek, N. F. Jain, J. Org. Chem. 1994, 59, 2674–2675.
T. Akiyama, J. Iwai, Y. Onuma, H. Kagoshima, Chem. Com-
mun. 1999, 2191–2192.
[19] T. D. Nixon, M. K. Whittlesey, J. M. J. Williams, Dalton Trans.
2009, 38, 753–762.
[54]
[55]
[56]
[20] G. E. Dobereiner, R. H. Crabtree, Chem. Rev. 2010, 110, 681–
703.
[21] G. Guillena, J. D. Ramón, M. Yus, Chem. Rev. 2010, 110,
1611–1641.
10
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20171
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Pages: 12
One-Pot Synthesis of Amines from Alcohols
[57] Y. Masuyama, J. Tosa, Y. Kurusu, Chem. Commun. 1999, 1075–
1076.
[58] L. Niimi, K.-I. Serita, S. Hiraoka, T. Yokozawa, Tetrahedron
Lett. 2000, 41, 7075–7078.
[81] Y. Yamamoto, T. Komatsu, K. Maruyama, J. Org. Chem. 1985,
50, 3115–3121.
[82] Y. Yamamoto, T. Komatsu, K. Maruyama, J. Chem. Soc.,
Chem. Commun. 1985, 814–816.
[59] B. Choucair, H. Léon, M.-A. Miré, C. Lebreton, P. Mosset,
Org. Lett. 2000, 2, 1851–1853.
[60] J. V. Schaus, N. Jain, J. S. Panek, Tetrahedron 2000, 56, 10263–
10274.
[83] W. R. Hardie, J. Hidalgo, I. F. Halverstadt, R. E. Allen, J. Med.
Chem. 1966, 9, 127–136.
[84] A. Thurkauf, P. C. Zenk, R. L. Balster, E. L. May, C. George,
F. I. Carroll, S. W. Mascarella, K. C. Rice, A. E. Jacobson,
M. V. Mattson, J. Med. Chem. 1988, 31, 2257–2263.
[85] M. Sax, B. Wunsch, Curr. Top. Med. Chem. 2006, 6, 723–732.
[86] P. Etayo, R. Badorrey, M. Díaz-de-Villegas, J. Gálvez, P.
López-Ram-de-Víu, Synlett 2010, 1775–1778.
[87] M. Pagliaro, R. Ciriminna, H. Kimura, M. Rossi, C.
Della Pina, Angew. Chem. 2007, 119, 4516; Angew. Chem. Int.
Ed. 2007, 46, 4434–4440.
[88] C.-H. Zhou, J. N. Beltramini, Y.-X. Fan, G. Q. Lu, Chem. Soc.
Rev. 2008, 37, 527–549.
[89] A. Behr, J. Eilting, K. Irawadi, J. Leschinski, F. Lindner, Green
Chem. 2008, 10, 13–30.
[90] T. J. Murray, C. J. Forsyth, Org. Lett. 2008, 10, 3429–3431.
[91] B. Duthion, T.-X. Métro, D. Gomez Pardo, J. Cossy, Tetrahe-
dron 2009, 65, 6696–6706.
[92] M. Sax, K. Ebert, D. Schepmann, B. Wibbeling, B. Wünsch,
Bioorg. Med. Chem. 2006, 14, 5955–5962.
[93] T. Rische, P. Eilbracht, Synthesis 1997, 1331–1337.
[94] B. Goument, L. Duhamel, R. Mauge, Bull. Soc. Chim. Fr. 1993,
130, 459–466.
[61] M. Billet, P. Klotz, A. Mann, Tetrahedron Lett. 2001, 42, 631–
634.
[62] T. Ollevier, T. Ba, Tetrahedron Lett. 2003, 44, 9003–9005.
[63] P. Phukan, J. Org. Chem. 2004, 69, 4005–4006.
[64] M. Sugiura, K. Hirano, S. Kobayashi, J. Am. Chem. Soc. 2004,
126, 7182–7183.
[65] S. Kobayashi, K. Hirano, M. Sugiura, Chem. Commun. 2005,
104–106.
[66] J.-R. Ella-Menye, W. Dobbs, M. Billet, P. Klotz, A. Mann, Tet-
rahedron Lett. 2005, 46, 1897–1900.
[67] D. J. Lipomi, J. S. Panek, Org. Lett. 2005, 7, 4701–4704.
[68] H. Rani Kalita, P. Phukan, Synth. Commun. 2005, 35, 475–481.
[69] J. D. Sieber, J. P. Morken, J. Am. Chem. Soc. 2006, 128, 74–75.
[70] G. Smitha, B. Miriyala, J. S. Williamson, Synlett 2005, 839–
841.
[71] M. Sugiura, K. Hirano, S. Kobayashi, Org. Synth. 2006, 83,
170–176.
[72] M. Sugiura, C. Mori, S. Kobayashi, J. Am. Chem. Soc. 2006,
128, 11038–11039.
[73] Q.-Y. Song, B.-L. Yang, S.-K. Tian, J. Org. Chem. 2007, 72,
[95] A. B. Holmes, A. L. Smith, S. F. Williams, L. R. Hughes, Z.
Lidert, C. Swithenbank, J. Org. Chem. 1991, 56, 1393–1405.
[96] H. Lebel, O. Leogane, Org. Lett. 2005, 7, 4107–4110.
[97] M. Goubert, L. Toupet, M.-E. Sinibaldi, I. Canet, Tetrahedron
2007, 63, 8255–8266.
[98] T. Vilaivan, C. Winotapan, T. Shinada, Y. Ohfune, Tetrahedron
Lett. 2001, 42, 9073–9076.
5407–5410.
[74] M. Rueping, A. P. Antonchick, Angew. Chem. 2008, 120,
10244; Angew. Chem. Int. Ed. 2008, 47, 10090–10093.
[75] K. K. Pasunooti, M. L. Leow, S. Vedachalam, B. K. Gorityala,
X.-W. Liu, Tetrahedron Lett. 2009, 50, 2979–2981.
[76] J. C. González-Gómez, M. Medjahdi, F. Foubelo, M. Yus, J.
Org. Chem. 2010, 75, 6308–6311.
[77] H. Ren, W. D. Wulff, J. Am. Chem. Soc. 2011, 133, 5656–5659.
[78] D. D. Dhavale, L. Gentilucci, M. G. Piazza, C. Trombini, Lie-
bigs Ann. Chem. 1992, 1289–1295.
[99] G. Cainelli, D. Giacomini, P. Galletti, A. Quintavalla, Eur. J.
Org. Chem. 2002, 3153–3161.
[100] G. Cardillo, M. Orena, S. Sandri, J. Org. Chem. 1986, 51,
713–717.
[79] Y. Yamamoto, S. Nishii, K. Maruyama, T. Komatsu, W. Ito, J.
Am. Chem. Soc. 1986, 108, 7778–7786.
[80] Y. Yamamoto, T. Komatsu, K. Maruyama, J. Am. Chem. Soc.
1984, 106, 5031–5033.
[101] A. Banerjee, D. Schepmann, J. Köhler, E.-U. Würthwein, B.
Wünsch, Bioorg. Med. Chem. 2010, 18, 7855–7867.
Received: February 13, 2012
Published Online: ᭿
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11

Job/Unit: O20171
/KAP1
Date: 04-04-12 16:36:12
Pages: 12
C. Guérin, V. Bellosta, G. Guillamot, J. Cossy
FULL PAPER
Amine Synthesis
A mild, nonepimerizing one-pot oxidation/
imine-iminium formation/nucleophilic ad-
dition sequence for the N-alkylation of
amines with alcohols is reported. Reducing
agents and allylboronic esters have been
successfully used as nucleophiles. This se-
quence of reactions was used to achieve the
short syntheses of the biologically active
compounds cinacalcet and dexoxadrol.
C. Guérin, V. Bellosta, G. Guillamot,
J. Cossy* ......................................... 1–12
Synthesis of Amines from Alcohols in a
Nonepimerizing One-Pot Sequence – Syn-
thesis of Bioactive Compounds: Cinacalcet
and Dexoxadrol
Keywords: Amines / Amination / Alcohols /
Alkylation / Allylation / Green chemistry
12
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