Stereoselective multicomponent assembly of enantiopure oxazolopiperidines and -azepines

Article abstract of DOI:10.1021/jo202455c

A multicomponent reaction (MCR) based on a cyclohydrocarbonylation (CHC) driven by hydroformylation was set up toward the efficient diastereoselective preparation of oxazolopiperidines (4a-e) and -azepines (7a-d). The bicyclic oxazolidines were obtained from chiral N-alkenylamino alcohols via transient cyclic iminium intermediates that underwent an intramolecular cyclization from the appendant oxygen. On the basis of a series of different experimental conditions, the diastereocontrol observed during the formation of the oxazolidines is best explained by the stereoelectronic effect induced by an A^1,3-strain in a common cyclic iminium intermediate (A). This new sequence is suitable for diversity oriented syntheses, allowing the preparation of enantiopure (S)- and (R)-coniceine in five steps from commercially available material.

Full text of DOI:10.1021/jo202455c

Article
pubs.acs.org/joc
Stereoselective Multicomponent Assembly of Enantiopure
Oxazolopiperidines and -azepines
Nicolas Zill,† Angele Schoenfelder,† Nicolas Girard,† Maurizio Taddei,‡ and Andre Mann†,*
̀
́
†Faculte
́
de Pharmacie, UMR 7200, CNRS-Universite
F-67401, Illkirch, France
‡Dipartimento Farmaco Chimico Tecnologico, Universita
́
de Strasbourg, Laboratoire d’Innovation Ther
́
apeutique 74, route du Rhin,
̀
degli Studi di Siena, Via A. Moro 2, 53100, Siena, Italy
S
* Supporting Information
ABSTRACT: A multicomponent reaction (MCR) based on a
cyclohydrocarbonylation (CHC) driven by hydroformylation
was set up toward the efficient diastereoselective preparation
of oxazolopiperidines (4a−e) and -azepines (7a−d). The
bicyclic oxazolidines were obtained from chiral N-alkenylami-
no alcohols via transient cyclic iminium intermediates that
underwent an intramolecular cyclization from the appendant oxygen. On the basis of a series of different experimental conditions,
the diastereocontrol observed during the formation of the oxazolidines is best explained by the stereoelectronic effect induced by
an A1,3-strain in a common cyclic iminium intermediate (A). This new sequence is suitable for diversity oriented syntheses,
allowing the preparation of enantiopure (S)- and (R)-coniceine in five steps from commercially available material.
into DOS libraries or as key intermediates in the syntheses of
piperidine alkaloids.14
INTRODUCTION
■
In the last decades, intense efforts have been dedicated to the
design of methods for the construction of functionalized
piperidines.1−3 From all that pertinent chemistry, three
templates emerged: (i) the chiral bicyclic lactam 1, originally
introduced by Meyers,4 further investigated by Amat and
Bosch;5 (ii) the acyl aminal 2 developed by Ojima via a
cyclohydrocarbonylation (CHC),6 recently implemented in our
group;7 and (iii) the cyano-oxazolidine 3a or the benzotriazole
variant 3b designed, respectively, by Husson and Katritzky
(Figure 1).8,9 Indeed, the versatility of the oxazolidine
Indeed, for the rapid construction of complex structures,
domino reactions are of great value, but in many cases efforts
are needed to reach the key substrates. Conversely, if reaction
partners can be taken from the feedstock, the MCR becames an
attractive tool for reaching complexity and for the elaboration
of sustainable organic syntheses.15 On the basis of our earlier
results, a project was initiated toward the assembly of chiral
bicyclic oxazolidines of type 4a via a multicomponent approach
based on the hydroformylation of terminal bromoalkenes
(Scheme 1). Bicyclo-oxazolidine 4a is a stable equivalent of 2-
piperideine with the capability of reacting at C2 as an iminium
ion or at C3 as an enamine and constitutes a valuable precursor
toward substituted piperidines.16,17 However, the reported
preparations of 4a from 3a or 3b have limitations owing the use
of a large excess of Ni/Raney for the decyanation step or the
removal of benzotriazole at C6.9,17 In this paper, we describe a
new sequence toward oxazolopyridines (4a−e) or oxazoloaze-
pines (7a−d) via a CHC−MCR reaction. As an application,
short syntheses of (+)- and (−)-coniceine are reported.
Figure 1. Templates 1, 2, 3a,b, and 4a for the construction of
piperidine alkaloids.
RESULTS AND DISCUSSION
chemistry has been demonstrated by several syntheses of
■
natural products and biologically relevant compounds.10−12
Recently, our group described an efficient route toward
As a preliminary study, we examined the viability of the
sequence via the intramolecular CHC process18,19 and
investigated the terminal hydroformylation of alkene 6
(Scheme 1a), prepared in 52% yields by microwave-assisted
reaction of (R)-phenylglycinol 5a with 4-bromobutene (1 equiv
of triethylamine and TBAI).20 Next, compound 6 was
submitted to hydroformylation in THF for 4 h at 65 °C with
Meyers oxazolidinones 1 through a domino process involving
the CHC of the amide constructed from 3-butenoic acid and
(R)-phenylglycinol.13 The aldehyde function introduced on the
terminal carbon via linear hydroformylation, and the presence
of two resident nucleophiles (N and O) produced a transient
acyliminium ending into the bicyclic oxazolidinone 1 or
analogues that can be implemented as single components
Received: December 7, 2011
Published: January 24, 2012
© 2012 American Chemical Society
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a
Scheme 1. Three Pathways (a−c) Designed toward Oxazolidine 4a
a
Reagents and conditions: (i) Rh(CO)2acac (1% mol), biphephos (2% mol), H2/CO (1/1) 4 bar THF, 4 h, 65°C; (ii) NEt3 (1 equiv), THF, rt, 1
day.
the conditions used in our recent work on the synthesis of
oxazolidines. After 6 h, both oxazolidines were present, the
imine (Im) is still visible, and the signals corresponding to
bicyclo-oxazolidine 4a appeared; after 18 h, the signals of
compound 4a were clearly identified as the major compound in
the crude mixture, suggesting that the alkylation of the imine
(Im) is the rate-determining step.
polysubstitued piperidines:21 Rh(CO)2acac as the precatalyst
and biphephos as the ligand in a pressurized autoclave with
syngas (H2/CO: 1/1, 4 bar). From the reaction mixture,
bicyclo-oxazolidine 4a16 was isolated as a mixture of epimers at
C8a (cis/trans: 9/1, only distinguishable in NMR, inseparable
by chromatography)22 in 75% yield. Aldehyde 7, resulting from
the linear hydroformylation of alkene 6, can be considered as
the trigger of the domino reaction toward oxazolidine 4a. In the
crude reaction mixture, a minor side product was identified as
the N-butyl derivative of phenylglycinol 6′23 (in 10% yield),
resulting from the hydrogenation of the terminal double bound
of homoallylamine 6. Encouraged by these preliminary results,
we attempted the MCR−CHC sequence (Scheme 1b). A
mixture of 4-bromobutene, (R)-phenylglycinol, basic additives,
the catalyst, and syngas was submitted to the above hydro-
formylative conditions in an autoclave. As expected, the bicyclic
adduct 4a was isolated in 63% yield. Interestingly, the same
epimeric ratio at C8a (cis/trans: 9/1) was obtained as in the
intramolecular version, but no traces of the overreduction
adduct 6′ were found in the crude reaction mixture, suggesting
that hydroformylation of 4-bromobutene precedes the N-
alkylation. In order to get a deeper insight into the reaction
pathway, a control experiment was designed (Scheme 1c). On
the basis of the assumption (see above) that the terminal
hydroformylation of 4-bromobutene (to give 5-bromopenta-
nal)24 is faster than the N-alkylation of 5a with bromobutene,
5-bromopentanal (prepared by oxidation of the corresponding
alcohol)24 was reacted with the amino alcohol 5a and TEA in
THF-d8 at rt, and the reaction was monitored by 1H NMR over
the time. At first, the signal of the aldehyde disappeared rapidly,
and signals corresponding to the oxazolidines and the
corresponding imine were identified. After 1 h, a 1:1 mixture
of the two oxazolidines (Oxcis/Oxtrans) was observed. In the
meantime, the signals corresponding to the imine diminished
perceptively: the imine is consumed at the expense of the
These observations suggested that the imine (Im) and two
oxazolidines (Oxcis or Oxtrans) are equilibrating under
thermodynamic control. Surprisingly none of the oxazolidines
Oxcis or Oxtrans seems to undergo an intramolecular N-
alkylation as shown by the absence of NMR signals of the final
adduct 4a in the early stage of the reaction. It seems that Oxcis
or Oxtrans are not the direct precursors of the two epimeric
oxazolidines present in 4a. Therefore, the question about the
origin of the distribution of the epimers in 4a is still open.
Epimerization at C8a could be evoked once the bicyclic
oxazolidines (4a) were formed, but under the presently basic or
neutral conditions it is unlikely that ring-opening/closing could
occur.25,26 Such an equilibration has been observed by Husson
solely during the epimerization of a crude mixture of 3a after a
treatment with Lewis acids.27,28 But the fact that in the
intramolecular route (a) and both intramolecular CHC routes
(b and c) the same ratio of epimers at C8a is observed is
intriguing. Therefore, in order to rationalize the above results,
the iminium (A) is suspected to be the common intermediate
in all three pathways a−c. To validate this proposal, our
arguments are as follows: (i) For the intramolecular reaction
(route a), the hydroformylation delivers the transient terminal
aldehyde in 7 and the aminal is formed and evolves toward the
cyclic iminium (A), which as a strong electrophile is trapped by
the resident primary alcohol. The presence of an A1,3-strain29 in
iminium (A) may be responsible for the formation of the major
cis epimer at C8a, the thermodynamic compound (Scheme 2).
(ii) For the MCR−CHC (route b) or intermolecular (route c)
pathways, intermediate A can be reached from the imine adduct
which is in equilibrium with the two oxazolidines; indeed, the
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Scheme 2. A1,3-Strain in the Iminium Transition States TS1
and TS2
oxazolidine 4e were obtained in good yields but with variable
diastereoselectivities (Scheme 3). The observed diasteroselec-
tivity can be correlated with the size of the substituents. In the
bicyclic series [4.3.0] for compounds 4a, 4d, and 4e with bulky
R1 and/or R2 groups (Ph, Me and Ph, and indanyl) a high cis/
trans ratio is observed, whereas with substituents such as R1 =
benz or isPr in 4b and 4c the cis/trans ratio was lower. This
observation is counterintuitive as the size of the substituents are
roughly similar and suggests to consider also the presence of an
A1,2-strain in the corresponding iminiums (see Scheme 1,
formula A). The probable existence of both A1,2- and A1,3-strain
complicates the analysis of the data. A definitive explanation is
awaiting further work. In the azepine [5.3.0] series, the
corresponding oxazolidines 7a−d were obtained in acceptable
yields (except for 7d), but with an appreciable erosion of the
cis/trans ratio.31 Probably, accounting for a greater flexibilty in
the 7-membered ring, the A1,3-strain is operating to a lesser
extend.
imine nitrogen realizes a substitution on the bromide producing
the electrophilic iminium (A) which fate has been analyzed
before.
From all these results, the existence of a transient iminium of
type A as the common intermediate in the CHC and MCR−
CHC sequences has gained some support.
Therefore, it appears that, for stereoelectronic reasons,
antiparallel attack and an A1,3-strain may constitute the driving
forces for the conversion of transient (A) to oxazolidine 4a.
The imine hydrogen (Ha) is eclipsing the tertiary hydrogen
(Hb) of the chiral auxiliary rather than the phenyl ring; thus, cis-
4, the major isomer is obtained by Re face attack on the imine
(TS 1), whereas for the minor trans 4a, a Si face attack is
operating (TS 2). It is worth mentioning that the cyclization of
(A) to oxazolidine 4 should be a disfavored process as a 5-endo-
trig ring closure, according to Balwin’s rules. But it has been
reported that the Baldwin’s rules are less tightened for
quaternary iminium salts bearing a full charge on the
nitrogen.30
In order to get an additional support for the above
mechanistic explanations, we decided to replace (R)-phenyl-
glycinol (5a) by its homologue (S)-3-amino-3-phenylpropan-
ol.32 In this case, if the MCR−CHC is operating with
bromobutene and/or -pentene, a 6-endo-trig cyclization should
take place toward the oxazine, a pathway favored by Baldwin’s
rules. Indeed, when the MCR−CHC sequence was performed
using the standard conditions, the expected cis-oxazines 8 and 9
were obtained as single diastereomers in 73% and 85% yields,
respectively (Scheme 4). The presence of the Bohlman bands
Scheme 4. CHC-MCR Syntheses of Oxazines 8 and 9
First to explore the scope of the MCR−CHC, and second to
get some support to the transient existence of the intermediate
iminium (A), the construction of various sizes of decorated
oxazolidines was performed from several amino-alcohols 5a−e
from the chiral pool and 4-bromobutene or 5-bromopentene as
partners in the MCR−CHC reaction. Indeed, the size of the
substituent (R1 and R2) present on the stereocenter should
have an impact on the A1,3-strain and consequently modify the
cis/trans ratio of the final oxazolidines. Selecting the standard
reaction conditions and the CHC−MCR route (b), the
expected bicycles [4.3.0] 4a−d, [5.3.0] 7a−d and the tricyclic
in IR and extensive NMR studies revealed a trans-decalin
structure for both oxazines. Despite a greater entropic penalty
(one methylene difference) in respect to the formation of 4a or
Scheme 3. Multicomponent Reactions toward Oxazolidines 4a−e and 7a−d Driven by Hydroformylation
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a
Scheme 5. Synthesis of the Two Epimeric Coniceines
a
Conditions and reagents: (i) vinylMgBr, THF, 0 °C to rt; (ii) BzCl, TEA, DMAP, THF, rt and separation by column chromatography; (iii)
Rh(CO)2acac (1% mol), biphephos (2% mol), H2/CO (1/1) 4 bar THF, 4 h, 65°C; (iv) Pd(OH)2 30% w/w, MeOH, rt, then HCl in Et2O (2 N).
7a, the A1,3-strain in this case seems to operate cleanly as only
the cis diastereomer is isolated. The above results concur to
reactions were carried out in oven-dried or flamed vessels and
performed under argon. Solvents were dried and purified by
conventional methods prior use. Et2O and THF were freshly distilled
validate the proposal: that the stereochemical outcome during
from sodium/benzophenone and dichloromethane was distilled from
the formation of the oxazolidines is driven by an efficient A1,3-
CaH2. Toluene was distilled from sodium. Caution: the handling of
strain.
H2/CO needs special safety equipment. Flash column chromatography
was performed with silica gel 60, 0.040−0.063 mm (230−400 mesh).
The significance of oxazolidine 4a is demonstrated in a short
synthesis of the two epimeric (+)- and (−)-coniceines (Scheme
5). Indeed, when 4a was treated with vinylmagnesium bromide
in THF at 0 °C, the vinylpiperidines 10/10′ were isolated as an
unseparable mixture of diastereomers (1/7 ratio) in 94%
yield.33 The stereochemistry observed for the major isomer 10
is best explained with an axial attack of the vinyl-Grignard to an
iminium intermediate as illustrated in several reports.26,34,35 An
improvement of the diastereoselectivity is still imperative, and
efforts on this line are underway in our laboratory. Anyway for a
convenient chromatographical separation, benzoylation of the
primary alcohol was necessary. Each purified diastereomer (11
or 11′) was submitted to a terminal hydroformylation under the
standard conditions, returning the epimeric aldehydes 12 and
12′. A final domino hydrogenolysis, encompassing N-
deprotection and cyclizing reductive amination gave the natural
indolizidine (+)-coniceine and (−)-coniceine in four steps from
oxazolidine 4a. The present synthesis to coniceine compares
favorably with recent reported routes in term of number of
steps and yields.36 It is noteworthy that the present synthesis of
coniceine is using two times CO and H2 as the main reagents in
the syntheses of 4a, 10, and 10′ to achieve two linear
hydrofomylations and finally a deprotective hydrogenolysis for
reaching coniceine.
Aluminum-backed plates precoated with silica gel 60 (UV254) were
used for thin-layer chromatography and were visualized by staining
with KMnO4. 1H, 13C spectra were recorded on different
spectrometers (400 MHz/100 MHz), (300 MHz/75 MHz), or (200
MHz/50 MHz). Conditions are specified for each spectrum
(temperature 25 °C unless specified). Splitting patterns are designated
as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; sex,
sextuplet; br, broad. Chemical shifts (δ) are given in ppm relative to
the resonance of their respective residual solvent peak, CHCl3 (7.27
1
ppm, H; 77.16 ppm, the middle peak, 13C). The connectivity and
relative stereochemistry were deduced from COSY90, HSQC, and
HMBC experiments. Infrared spectra were taken with an FT-IR
apparatus. High- and low-resolution mass spectroscopy analyses were
conducted on the ESI mode. Melting points were determined in open
capillary tubes and are uncorrected. Specific rotations were measured
using a 10 cm cell with a Na 589 nm filter: values are given in 10−1
deg·cm3·g−1.
(R)-2-(But-3-enylamino)-2-phenylethanol (6).20 A sealed tube
containing a solution of (R)-phenylglycinol (5a) (500 mg, 3.65 mmol)
in 15 mL of anhydrous THF, 1 equiv of 4-bromobut-1-ene (371 μL,
3.65 mmol), 1 equiv of triethylamine (507 μL, 3.65 mmol), and 1
equiv of tetrabutylammonium iodide (1.45 g, 3.65 mmol) was stirred
at 130 °C for 10 min in a microwave. The solution was quenched with
water, extracted by EtOAc, dried on Na2SO4, filtered, and
concentrated. The crude residue was purified by flash chromatography
(CH2Cl2/MeOH 9/1) to yield the desired product as pale yellow solid
(360 mg, 52%): TLC (CH2Cl2/MeOH 9/1) Rf 0,33; mp 46−48 °C;
[α]20D −57.4 (c 1.5 in CHCl3); IR (neat) νmax/cm−1 3289, 2920, 2838,
CONCLUSION
■
1
In conclusion, CHC−MRC driven by hydroformylation of
mixtures of chiral amino alcohols and bromo-alkenes generates
bicylic oxazolidines in good yields. In these sequences, not only
the performance of the hydroformylation has to be considered
but even better oxazolidine 4a and analogues are now easily
available in one step on a large scale. Based on a series of
experiments comparing intra- or intermolecular routes, the
observed diastereoselectivity seems to be correlated with an
A1,3-strain existing in a transient cyclic iminium. The herein
reported access to 4a should facilitate the assembly of natural
products, specially for diversity-oriented syntheses of piper-
idines or azepines.
1640, 1492, 1453; H NMR (400 MHz, CDCl3) δ (ppm) 7.39−7.26
(m, 5H), 5.76 (ddt, J = 17.2 Hz, 10.2 Hz, 6.8 Hz, 1H, H2), 5.11−5.01
(m, 2H, H1), 3.82 (dd, J = 8.6 Hz, 4.7 Hz, 1H, H6), 3.73 (dd, J = 10.8
Hz, 4.4 Hz, 1H, H5), 3.59 (dd, J = 10.6 Hz, 8.7 Hz, 1H, H6), 2.74 (br s,
2H, NH, OH), 2.71−2.54 (m, 2H, H4), 2.33−2.22 (m, 2H, H3); 13C
NMR (100 MHz, CDCl3) δ (ppm) 140.4 (C), 136.3 (CH) 128.9
(CH), 127.9 (CH), 127.4 (CH), 116.8 (CH2), 66.6 (CH2), 64.7
(CH), 46.4 (CH2), 34.3 (CH2); LRMS-ESI m/z 192.1 [M + H]+.
(3R,8aR)-3-Phenylhexahydro-2H-oxazolo[3,2-a]pyridine (cis-
4a) and (3R,8aS)-3-Phenylhexahydro-2H-oxazolo[3,2-a]-
pyridine (trans-4a). In a reactor under argon containing a solution
of 100 mg of 6 (0.52 mmol) in 10 mL of anhydrous THF were added
Rh(CO)2acac (1.4 mg, 1 mol %) and biphephos (8.2 mg, 2 mol %).
The solution was stirred for 4 h at 65 °C under a syngas pressure of 4
bar (H2/CO 1/1). The solution was then concentrated and purified by
flash chromatography (pentane/EtOAc 9/1) to yield the desired
product as brown solid (80 mg, 75%). Mixture of two diastereomers
(91/9 cis/trans): TLC (pentane/EtOAc 9/1); Rf 0.20; mp 39−41 °C;
EXPERIMENTAL SECTION
General Experimental Methods. All reagents were used as
purchased from commercial suppliers without further purification. The
■
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1
IR (neat) νmax/cm−1 2941, 1453, 1120; H NMR (400 MHz, CDCl3)
(+)-norephedrine (5d) and 4-bromobut-1-ene without TBAI. Color-
less oil (43%). Mixture of two diastereomers (91/9 cis/trans): TLC
(pentane/EtOAc 9/1) Rf 0.45; IR (neat) νmax/cm−1 2941, 2855, 1493,
1455; 1H NMR (400 MHz, CDCl3) δ (ppm) for cis isomer 7.38−7.21
(m, 5H), 4.97 (d J = 7.9 Hz, 1H, H3), 3.61 (dd, J = 9.6 Hz, 2.5 Hz, 1H,
H4), 3.07−3.01 (m, 1H, H8), 2.78 (qd, J = 7.1 Hz, 6.2 Hz, 1H, H2),
2.13−1.52 (m, 7H, H5, H6, H7, H8), 0.65 (d, J = 6.5 Hz, 3H, H1), for
trans isomer (diagnostic peaks only) 5.39 (d, J = 6.9 Hz, 1H), 4.79
(dd, J = 3.5 Hz, 3.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm)
for cis isomer 140.4 (C), 128.1 (CH), 127.9 (CH), 127.7 (CH), 94.9
(CH), 82.1 (CH), 61.7 (CH), 48.3 (CH2), 30.5 (CH2), 25.1 (CH2),
22.9 (CH2), 13.9 (CH3); HRMS-ESI calcd for C14H20NO 218.1539,
found 218.1545.
δ (ppm) for cis isomer: 7.43−7.23 (m, 5H), 4.17 (dd, J = 7.7 Hz, 7.7
Hz, 1H, H2), 3.70 (dd, J = 9.7 Hz, 2.9 Hz, 1H, H3), 3.65 (dd, J = 8.2
Hz, 8.2 Hz, 1H, H2), 3.54 (dd, J = 8.2 Hz, 8.2 Hz, 1H, H1), 2.90−2.81
(m, 1H, H7), 2.08−1.96 (m, 2H, H4, H7), 1.93−1.81 (m, 1H, H5),
1.68−1.46 (m, 3H, H4, H6), 1.43−1.25 (m, 1H, H5), for trans isomer
(diagnostic peaks only) 4.47−4.38 (m, 2H), 4.29−4.24 (m, 1H), 3.97
(dd, J = 7.9 Hz, 4.4 Hz, 1H), 2.75−2.63 (m, 2H); 13C NMR (100
MHz, CDCl3) δ (ppm) for cis isomer: 139.3 (C), 128.7 (CH), 128.1
(CH), 127.9 (CH), 94.9 (CH), 73.2 (CH2), 67.4 (CH), 48.1 (CH2),
30.7 (CH2), 25.1 (CH2), 22.8 (CH2); LRMS-ESI m/z 204.1 [M +
H]+.
General Procedure for the One-Pot Synthesis. In a reactor
under argon containing a solution of the amino alcohol (5a−e) (100
mg) in 10 mL of anhydrous THF are added 2 equiv of alkyl bromide, 1
equiv of triethylamine, 1 equiv of tetrabutylammonium iodide, 1 mol
% of Rh(CO)2acac, and 2 mol % of biphephos. The solution is stirred
for 4 h at 65 °C under a syngas pressure of 4 bar (H2/CO 1/1). The
solution is then concentrated and purified by flash chromatography to
yield the desired product (4a−e or 7a−d).
(4aS,5aS,10bR)-2,3,4,4a,6,10b-Hexahydro-1H,5aH-indeno-
[1′,2′:4,5][1,3]oxazolo[3,2-a]pyridine (cis-4e). Reaction between
(1R,2S)-(+)-cis-1-amino-2-indanol (5e) and 4-bromobut-1-ene with-
out TBAI. Colorless oil (113 mg, 78%). Mixture of two diastereomers
(90/10 cis/trans): TLC (pentane/EtOAc 9/1) Rf 0.49; IR (neat) νmax
/
cm−1 2940, 2860, 1491, 1454; H NMR (400 MHz, CDCl3) δ (ppm)
7.42−7.00 (m, 4 H), 4.93 (t, J = 8 Hz, 1H), 4.61 (d, J = 6 Hz, 1H),
4.06 (s, 1H), 3.11 (2H), 2.96 (m, 1H), 2.63 (m, 1H), 1.80−1.40 (m,
6H); 13C NMR (100 MHz, CDCl3) δ (ppm) 135.8, (C), 134.3 (C),
126.9 (CH), 126.4 (CH), 126.0 (CH), 124.3 (CH), 91.3 (CH), 82.1
(CH), 72.3 (CH), 42.6 (CH2), 33.2 (CH2), 30.6 (CH2), 25.6 (CH2),
22.4 (CH2); HRMS-ESI calcd for C14H18NO 216.1383, found
216.1384.
1
(3R,8aR)-3-Phenylhexahydro-2H-oxazolo[3,2-a]pyridine (cis-
4a) and (3R,8aS)-3-Phenylhexahydro-2H-oxazolo[3,2-a]-
pyridine (trans 4a). Reaction between (R)-phenylglycinol (5a) and
4-bromobut-1-ene without TBAI. Brown solid (63%). Mixture of two
diastereomers (91/9 cis/trans).
(3R,8aR)-3-Benzylhexahydro-2H-oxazolo[3,2-a]pyridine (cis-
4b) and (3R,8aS)-3-Benzylhexahydro-2H-oxazolo[3,2-a]-
pyridine (trans-4b). Reaction between (R)-phenylalaninol (5b)
and 4-bromobut-1-ene without TBAI. Colorless oil (51%). Mixture of
two diastereomers (77/23 cis/trans): TLC (pentane/EtOAc 9/1) Rf
(3R,9aR)-3-Phenyloctahydrooxazolo[3,2-a]azepine (cis-7a)
and (3R,9aS)-3-Phenyloctahydrooxazolo[3,2-a]azepine (trans-
7a).31 Reaction between (R)-phenylglycinol (5a) and 5-bromopent-1-
ene. Colorless oil (48%). Mixture of two diastereomers (71/29 cis/
trans): TLC (pentane/Et2O 9/1) Rf 0.44; IR (neat) νmax/cm−1 2926,
0.16; IR (neat) νmax/cm−1 2936, 2854, 1496, 1453; H NMR (400
1
1
MHz, CDCl3) δ (ppm) 7.35−7.15 (m, 10H), 4.52 (t, J = 3.4 Hz, 1H,
H4′), 3.99 (dd, J = 8.0 Hz, 6.8 Hz, 1H, H3′), 3.81 (dd, J = 7.7 Hz, 7.7
Hz, 1H, H3), 3.65 (dd, J = 8.2 Hz, 8.2 Hz, 1H, H3), 3.56 (dd, J = 9.4
Hz, 2.6 Hz, 1H, H4), 3.43 (dd, J = 7.8 Hz, 3.7 Hz, 1H, H3′), 3.35
(dddd, J = 9.0 Hz, 6.9 Hz, 6.0 Hz, 4.1 Hz, 1H, H2′), 3.18−3.13 (m, 1H,
H8), 3.10 (dd, J = 13.5 Hz, 4.3 Hz, 1H, H1), 3.03 (dd, J = 14.2 Hz, 6.3
Hz, 1H, H1′), 2.85 (dddd, J = 9.3 Hz, 8.4 Hz, 7.6 Hz, 4.7 Hz, 1H, H2),
2.78−2.72 (m, 1H, H8′), 2.65 (dd, J = 13.5 Hz, 9.2 Hz, 1H, H1), 2.60−
2.50 (m, 2H, H1′, H8′), 2.11 (td, J = 10.9 Hz, 3.3 Hz, 1H, H8), 2.03−
1.93 (m, 1H, H5, H5′), 1.93−1.80 (m, 1H, H6, H5′), 1.71−1.23 (m, 4H,
H5, H6, H7, H6′, H7′); 13C NMR (100 MHz, CDCl3) δ (ppm) for cis
isomer: 138.7 (C), 128.9 (CH), 128.7 (CH), 126.5 (CH), 94.8 (CH),
70.7 (CH2), 63.9 (CH), 48.4 (CH2), 37.9 (CH2), 30.2 (CH2), 24.9
(CH2), 22.5 (CH2), for trans isomer: 139.1 (C), 129.3 (CH), 128.6
(CH), 126.4 (CH), 88.6 (CH), 67.8 (CH2), 66.4 (CH), 49.5 (CH2),
39.3 (CH2), 27.2 (CH2), 25.1 (CH2),19.2 (CH2); HRMS-ESI calcd
for C14H20NO 218.1539, found 218.1541.
2854, 1492, 1451; H NMR (400 MHz, CDCl3) δ (ppm) 7.48−7.21
(m, 10H), 4.96 (dd, J = 7.7 Hz, 3.8 Hz, 1H, H3′), 4.33−4.25 (m, 2H,
H3, H2′), 4.17−4.06 (m, 2H, H2, H1′), 3.76 (dd, J = 9.1 Hz, 6.9 Hz, 1H,
H1), 3.69 (dd, J = 9.0 Hz, 7.1 Hz, 1H, H2), 3.57 (dd, J = 8.5 Hz, 8.5
Hz, 1H, H2′), 2.93−2.79 (m, 2H, H8, H8′), 2.72 (dd, J = 13.1 Hz, 8.1
Hz, 1H, H8′), 2.32−2.22 (m, 1H, H8), 2.15−2.06 (m, 1H, H4), 1.92−
1.43 (m, 15H, H4, H5, H6, H7, H4′, H5′, H6′, H7′); 13C NMR (100 MHz,
CDCl3) δ (ppm) for cis isomer 139.8 (C), 128.7 (CH), 127.9 (CH),
127.4 (CH), 97.6 (CH), 73.7 (CH2), 70.1 (CH), 49.4 (CH2), 35.5
(CH2), 28.8 (CH2), 25.7 (CH2), 23.7 (CH2), for trans isomer: 141.2
(C), 128.6 (CH), 127.8 (CH), 127.5 (CH), 96.3 (CH), 73.6 (CH2),
68.7 (CH), 49.5 (CH2), 32.0 (CH2), 30.4 (CH2), 28.6 (CH2), 23.9
(CH2); HRMS-ESI calcd for C14H20NO 218.1545, found 218.1543.
(3R,9aR)-3-Benzyloctahydrooxazolo[3,2-a]azepine (cis-7b)
and (3R,9aS)-3-Benzyloctahydrooxazolo[3,2-a]azepine (trans-
7b). Reaction between (R)-phenylalaninol (5b) and 5-bromopent-1-
ene. Colorless oil (84%). Mixture of two diastereomers (59/41 cis/
trans): TLC (pentane/EtOAc 9/1) Rf 0.43; IR (neat) νmax/cm−1 2925,
(3S,8aS)-3-Isopropylhexahydro-2H-oxazolo[3,2-a]pyridine
(cis-4c) and (3S,8aR)-3-Isopropylhexahydro-2H-oxazolo[3,2-a]-
pyridine (trans-4c). Reaction between (S)-valinol (5c) and 4-
bromobut-1-ene without TBAI. Colorless oil (40%). Mixture of two
diastereomers (69/31 cis/trans): TLC (pentane/EtOAc 9/1) Rf 0.31;
1
2853, 1495, 1452; H NMR (400 MHz, CDCl3) δ (ppm) 7.33−7.16
(m, 10H), 4.73 (dd, J = 8.9 Hz, 3.9 Hz, 1H, H4′), 4.11 (dd, J = 9.0 Hz,
3.0 Hz, 1H, H4), 3.95 (dd, J = 8.2 Hz, 6.6 Hz, 1H, H3′), 3.79 (dd, J =
7.9 Hz, 6.9 Hz, 1H, H3), 3.70 (dd, J = 7.6 Hz, 7.6 Hz, 1H, H3), 3.43
(dd, J = 8.2 Hz, 7.1 Hz, 1H, H3′), 3.26 (dddd, J = 7.9 Hz, 6.7 Hz, 6.7
Hz, 6.7 Hz, 1H, H2′), 3.09−2.90 (m, 5H, H1, H2, H9, H1′, H9′), 2.70−
2.54 (m, 3H, H1, H1′, H9′), 2.34 (ddd, J = 12.3 Hz, 8.7 Hz, 4.7 Hz, 1H,
H9), 2.06 (dddd, J = 13.0 Hz, 5.3 Hz, 5.3 Hz, 3.0 Hz, 1H, H5), 2.02−
1.94 (m, 1H, H5′), 1.83−1.35 (m, 14H, H5,H6, H7, H8, H5′, H6′, H7′,
H8′); 13C NMR (100 MHz, CDCl3) δ (ppm) for cis isomer 139.1 (C),
129.2 (CH), 128.5 (CH), 126.4 (CH), 97.9 (CH), 70.9 (CH2), 66.6
(CH), 50.3 (CH2), 39.6 (CH2), 35.0 (CH2), 28.8 (CH2), 25.6 (CH2),
23.5 (CH2), for trans isomer 139.4 (C), 129.3 (CH), 128.5 (CH),
126.3 (CH), 95.1 (CH), 70.3 (CH2), 67.8 (CH), 51.0 (CH2), 40.0
(CH2), 31.4 (CH2), 30.3 (CH2), 29.6 (CH2), 23.2 (CH2); LRMS-ESI
m/z 232.1
IR (neat) νmax/cm−1 2938, 2871, 1456, 1406; H NMR (400 MHz,
1
CDCl3) δ (ppm) 4.25 (dd, J = 3.7 Hz, 2.2 Hz, 1H, H4′), 4.02 (dd, J =
7.8 Hz, 7.8 Hz, 1H, H3′), 3.76 (dd, J = 7.9 Hz, 1H, H3), 3.67 (dd, J =
7.9 Hz, 2.6 Hz, 1H, H4), 3.60 (dd, J = 8.1 Hz, 8.1 Hz, 1H, H3), 3.34
(dd, J = 8.3 Hz, 5.1 Hz, 1H, H3′), 2.89 (ddd, J = 10.9 Hz, 4.3 Hz, 4.3
Hz, 1H, H8), 2.69−2.61 (m, 1H, H8′), 2.56−2.38 (m, 3H, H2, H2′, H8′),
2.16−2.07 (m, 1H, H8), 2.03−1.23 (m, 14H, H1, H5, H6, H7, H1′, H5′,
H6′, H7′), 0.99 (d, J = 6.6 Hz, 3H, CH3′), 0.93 (d, J = 6.8 Hz, 3H, CH3),
0.86 (d, J = 6.8 Hz, 3H, CH3), 0.79 (d, J = 6.7 Hz, 3H, CH3′); 13C
NMR (100 MHz, CDCl3) δ (ppm) for cis isomer 94.4 (CH), 68.1
(CH), 66.5 (CH2), 47.3 (CH2), 29.8 (CH2), 27.7 (CH), 25.1 (CH2),
22.1 (CH2), 20.3 (CH3), 17.1 (CH3), for trans isomer 88.7 (CH), 73.7
(CH), 66.7 (CH2), 51.2 (CH2), 31.5 (CH), 26.6 (CH2), 25.3 (CH2),
20.9 (CH3), 19.0 (CH2), 18.9 (CH3); HRMS-ESI calcd for C10H20NO
170.1539, found 170.1539.
(3S,9aS)-3-Isopropyloctahydrooxazolo[3,2-a]azepine (cis-7c)
and (3S,9aR)-3-Isopropyloctahydrooxazolo[3,2-a]azepine
(trans-7c). Reaction between (S)-valinol (5c) and 5-bromopent-1-
ene. Colorless oil (35%). Mixture of two diastereomers (50/50 cis/
trans): TLC (pentane/EtOAc 9/1) Rf 0.77; IR (neat) νmax/cm−1 2925,
2866, 1452, 1383; 1H NMR (400 MHz, CDCl3) δ (ppm) 4.47 (dd, J =
(2S,3R,8aR)-3-Methyl-2-phenylhexahydro-2H-oxazolo[3,2-
a]pyridine (cis-4d) and (2S,3R,8aS)-3-Methyl-2-phenylhexahy-
dro-2H-oxazolo[3,2-a]pyridine (trans-4d). Reaction between
2250
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The Journal of Organic Chemistry
Article
9.2 Hz, 4.4 Hz, 1H, H4′), 4.12 (dd, J = 9.0 Hz, 3.0 Hz, 1H, H4), 4.0
(dd, J = 8.3 Hz, 7.4 Hz, 1H, H3′), 3.79−3.68 (m, 2H, H3), 3.30 (dd, J =
7.8 Hz, 7.8 Hz, 1H, H3′), 3.10 (ddd, J = 13.6 Hz, 10.2 Hz, 1.0 Hz, 1H,
H9′), 2.94 (ddd, J = 12.2 Hz, 6.1 Hz, 6.1 Hz, 1H, H9), 2.66−2.54 (m,
2H, H2, H2′), 2.51−2.35 (m, 2H, H9, H9′), 2.05−1.94 (m, 2H, H5, H5′),
1.81−1.32 (m, 16H, H1, H5, H6, H7, H8, H1′, H5′, H6′, H7′, H8′), 0.99 (d,
J = 6.7 Hz, 3H, CH3′), 0.89 (d, J = 3.2 Hz, 3H, CH3), 0.87 (d, J = 3.2
Hz, 3H, CH3), 0.80 (d, J = 6.7 Hz, 3H, CH3′); 13C NMR (100 MHz,
CDCl3) δ (ppm) 97.9 (CH), 95.2 (CH), 73.8 (CH), 70.2 (CH), 68.7
(CH2), 67.4 (CH2), 52.9 (CH2), 50.8 (CH2), 34.9 (CH2), 32.6 (CH),
30.8 (CH2), 30.5 (CH2), 30.4 (CH), 29.2 (CH2), 25.7 (CH2), 24.1
(CH2), 22.9 (CH2), 20.5 (CH3), 19.5 (CH3), 18.7 (CH3), 17.4
(CH3); HRMS-ESI calcd for C11H22NO [M + H]+ 184.1696, found
184.1700.
benzoyl chloride, 1.4 mL of triethylamine (10.14 mmol), and 105 mg
(0.92 mmol) of 4-(dimethylamino)pyridine. The mixture was stirred
overnight at room temperature. The solution was then hydrolyzed by
water, extracted by CH2Cl2, dried on Na2SO4, filtered, and
concentrated. The crude residue was purified by flash chromatography
(pentane/Et2O 95/5) to yield the desired products 11 and 11′ into
two separable diastereomers.
(R)-2-Phenyl-2-((S)-2-vinylpiperidin-1-yl)ethyl benzoate (11).
Colorless oil (309 mg, 10%): TLC (pentane/Et2O 95/5) Rf 0.31;
[α]20D −66.8 (c 1.5 in CHCl3); IR (neat) νmax/cm−1 2931, 1716, 1602,
1449; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.87 (dd, J = 8.3 Hz, 1.5
Hz, 2H), 7.47−7.10 (m, 8H), 5.81 (ddd, J = 17.4 Hz, 10.2 Hz, 8.8 Hz,
1H, H8′), 5.15 (dd, J = 17.2 Hz, 1.8 Hz, 1H, H9′), 5.12 (dd, J = 10.2 Hz,
1.8 Hz, 1H, H9′), 4.78 (dd, J = 9.7 Hz, 6.6 Hz, 1H, H2′), 4.48−4.35 (m,
2H, H1′, H2′), 2.85 (ddd, J = 11.2 Hz, 3.6 Hz, 3.6 Hz, 1H, H3′), 2.74
(ddd, J = 9.4 Hz, 3.3 Hz, 3.3 Hz, 1H, H7′), 1.73 (ddd, J = 11.2 Hz, 11.2
Hz, 2.6 Hz, 1H, H3′) 1.55−0.93 (m, 6H, H4′, H5′, H6′); 13C NMR (100
MHz, CDCl3) δ (ppm) 166.6 (C), 142.7 (CH), 136.0 (C), 132.8
(CH), 130.7 (C), 129.7 (CH), 129.0 (CH), 128.4 (CH), 128.0 (CH),
127.4 (CH), 116.2 (CH2), 64.5 (CH2), 63.7 (CH), 61.5 (CH), 46.7
(CH2), 34.6 (CH2), 26.2 (CH2), 23.8 (CH2); HRMS-ESI calcd for
C22H26NO2 [M + H]+ 336.1964, found 336.1959.
(2S,3R,9aR)-3-Methyl-2-phenyloctahydrooxazolo[3,2-a]-
a z e p i n e (c i s - 7 d ) a n d ( 2 S , 3 R , 9 a S ) - 3 - M e t h y l - 2 -
phenyloctahydrooxazolo[3,2-a]azepine (trans-7d). Reaction
between (+)-norephedrine (5d) and 5-bromopent-1-ene. Colorless
oil (32%). Mixture of two diastereomers (77/23 cis/trans): TLC
(pentane/EtOAc 9/1) Rf 0.63; IR (neat) νmax/cm−1 2928, 2856, 1494,
1
1454.6; H NMR (400 MHz, CDCl3) δ (ppm) 7.33−7.08 (m, 10H),
5.11 (d, J = 5.9 Hz, 1H, H3′), 4.96 (dd, J = 9.1 Hz, 3.6 Hz, 1H, H4′),
4.89 (d, J = 7.9 Hz, 1H, H3), 4.04 (dd, J = 8.9 Hz, 2.5 Hz, 1H, H4),
3.38 (qd, J = 6.6 Hz, 6.6 Hz, 1H, H2′), 2.99−2.79 (m, 3H, H2, H9, H9′),
2.15−1.35 (m, 17H, H5, H6, H7, H8, H9, H5′, H6′, H7′, H8′), 0.62 (d, J =
6.9 Hz, 3H, H1′), 0.59 (d, J = 6.7 Hz, 3H, H1); 13C NMR (100 MHz,
CDCl3) δ (ppm) for cis isomer 140.6 (C), 128.0 (CH), 126.6 (CH),
97.7 (CH), 82.6 (CH), 63.9 (CH), 49.7 (CH2), 34.4 (CH2), 28.1
(CH2), 26.4 (CH2), 22.6 (CH2), 15.3 (CH3), for trans isomer 140.6
(C), 128.2 (CH), 127.6 (CH), 127.2 (CH), 94.9 (CH), 80.7 (CH),
64.6 (CH), 50.2 (CH2), 33.0 (CH2), 29.3 (CH2), 29.2 (CH2), 23.4
(CH2), 13.9 (CH3); HRMS-ESI calcd for C15H22NO 232.1696, found
232.1698.
(R)-2-Phenyl-2-((R)-2-vinylpiperidin-1-yl)ethyl Benzoate
(11′): colorless oil (2.320 g, 75%); TLC (pentane/Et2O 95/5) Rf
0.47; [α]20D +43.9 (c 1.5 in CHCl3); IR (neat) νmax/cm−1 2931, 1716,
1
1602, 1449; H NMR (400 MHz, CDCl3) δ (ppm) 8.01 (dd, J = 7.7
Hz, 1.5 Hz, 2H), 7.61−7.24 (m, 8H), 5.96 (ddd, J = 17.3 Hz, 10.2 Hz,
8.7 Hz, 1H, H8), 5.24 (dd, J = 17.3 Hz, 1.6 Hz, 1H, H9), 5.14 (dd, J =
10.3 Hz, 1.8 Hz, 1H, H9), 4.86 (dd, J = 11.5 Hz, 5.7 Hz, 1H, H2), 4.80
(dd, J = 11.2 Hz, 6.6 Hz, 1H, H2), 4.51 (dd, J = 6.5 Hz, 5.8 Hz, 1H,
H1), 3.43 (ddd, J = 9.0 Hz, 9.0 Hz, 2.8 Hz, 1H, H7), 2.81 (ddd, J =
11.5 Hz, 4.5 Hz, 3.5 Hz, 1H, H3), 2.42 (ddd, J = 11.4 Hz, 9.9 Hz, 3.0
Hz, 1H, H3), 1.81−1.29 (m, 6H, H4, H5, H6); 13C NMR (100 MHz,
CDCl3) δ (ppm) 166.7 (C), 141.5 (CH), 141.0 (C), 133.0 (CH),
130.4 (C), 129.8 (CH), 128.5 (CH), 128.3 (CH), 128.1 (CH), 126.9
(CH), 116.3 (CH2), 63.6 (CH), 62.8 (CH2), 60.6 (CH), 46.2 (CH2),
34.4 (CH2), 26.4 (CH2), 23.9 (CH2); HRMS-ESI calcd for
C22H26NO2 [M + H]+ 336.1964, found 336.1961
(R)-2-((S)-2-(3-Oxopropyl)piperidin-1-yl)-2-phenylethyl Ben-
zoate (12). In a reactor under argon containing a solution of 11 (137
mg, 0.41 mmol) in 10 mL of anhydrous THF were added
Rh(CO)2acac (1 mg, 1 mol %) and biphephos (6 mg, 2 mol %).
The solution was stirred during 4 h at 65 °C under a syngas pressure of
4 bar (H2/CO 1/1). The solution was then concentrated and purified
by flash chromatography (pentane/Et2O 7/3) to yield the desired
product as a colorless oil (94 mg, 63%): TLC (pentane/Et2O 7/3) Rf
0.33; [α]20D −47.5 (c 1.3 in CHCl3); IR (neat) νmax/cm−1 2931, 2855,
2719, 1715; 1H NMR (400 MHz, CDCl3) δ (ppm) 9.66 (t, J = 1.6 Hz,
1H, H10), 7.93−7.77 (m, 2H), 7.51−7.11 (m, 8H), 4.69 (dd, J = 11.1
Hz, 7.0 Hz, 1H, H2), 4.39 (dd, J = 11.3 Hz, 6.1 Hz, 1H, H2), 4.25 (dd,
J = 7.0 Hz, 6.1 Hz, 1H, H1), 2.86−2.70 (m, 1H, H3), 2.62−2.24 (m,
3H, H7, H9), 2.20−2.09 (m, 1H, H3), 1.99−1.83 (m, 2H, H8), 1.63−
1.12 (m, 6H, H4, H5, H6); 13C NMR (100 MHz, CDCl3) δ (ppm)
202.7 (CH), 166.5 (C), 138.3 (C), 133.1 (CH), 130.4 (C), 129.7
(CH), 128.7 (CH), 128.5 (CH), 128.4 (CH), 127.7 (CH), 66.1
(CH2), 61.5 (CH), 55.1 (CH), 45.2 (CH2), 40.3 (CH2), 28.9 (CH2),
24.7 (CH2), 22.2 (CH2), 22.0 (CH2); HRMS-ESI calcd for
C23H28NO3 [M + H]+ 366.2069, found 366.2064.
(4S,9aR)-4-Phenyloctahydropyrido[2,1-b][1,3]oxazine (cis-8).
Reaction between (S)-3-amino-3-phenylpropan-1-ol and 4-bromobut-
1-ene without TBAI. Colorless oil (73%): TLC (pentane/EtOAc 9/1)
Rf: 0.25; [α]20 +92.6 (c 1.5 in CHCl ); IR (neat) vmax/cm−1 3026.1,
̃
D
3
1
2940.5, 2844.9, 1491.6; H NMR (400 MHz, CDCl3) δ (ppm) 7.43−
7.24 (m, 5H), 4.10 (ddd, J = 11.6 Hz, 4.9 Hz, 1.6 Hz, 1H, H3), 3.70
(ddd, J = 12.6 Hz, 11.1 Hz, 2.4 Hz, 1H, H3), 3.59 (dd, J = 9.2 Hz, 2.9
Hz, 1H, H4), 3.17 (dd, J = 11.4 Hz, 3.2 Hz, 1H, H1), 2.72−2.67 (m,
1H, H8), 2.13−2.03 (m, 1H, H2), 1.92−1.86 (m, 1H, H5), 1.81−1.59
(m, 4H, H2, H5, H7, H8), 1.49−1.36 (m, 3H, H7, H6); 13C NMR (100
MHz, CDCl3) δ (ppm) 143.5 (C), 128.6 (CH), 127.7 (CH), 127.3
(CH), 93.9 (CH), 68.2 (CH), 67.5 (CH2), 50.3 (CH2), 35.6 (CH2),
32.2 (CH2), 25.5 (CH2), 23.7 (CH2); LRMS-ESI m/z 218.1 [M +
H]+.
(4S,10aR)-4-Phenyloctahydro-2H-[1,3]oxazino[3,2-a]azepine
(cis-9). Reaction between (S)-3-amino-3-phenylpropan-1-ol and 5-
bromobut-1-ene. Colorless oil (85%): TLC (pentane/EtOAc 9/1) Rf
1
0.31; IR (neat) νmax/cm−1 3024, 2962, 1494; H NMR (400 MHz,
CDCl3) δ (ppm) 7.50−7.19 (m, 5H), 4.33 (d, J = 6.1 Hz, 6.1 Hz, 1H,
H4), 4.21−4.13 (m, 1H, H3), 3.90−3.75 (m, 2H, H1, H3), 2.65 (ddd, J
= 14.1 Hz, 9.3 Hz, 1.9 Hz, 1H, H9), 2.20−1.22 (m, 11H, H2, H5, H6,
H7, H8, H9); 13C NMR (100 MHz, CDCl3) δ (ppm) 143.2 (C), 128.4
(CH), 127.7 (CH), 127.1 (CH), 94.0 (CH), 67.9 (CH2), 65.7 (CH),
43.4 (CH2), 36.0 (CH2), 30.1 (CH2), 30.0 (CH2), 29.6 (CH2), 22.1
(CH2); LRMS-ESI m/z 232.1 [M + H]+.
(R)-2-Phenyl-2-(2-vinylpiperidin-1-yl)ethanol (10/10′)..32 To
a solution of oxazolo-piperidine 4a (2 g, 9.84 mmol) in 60 mL of THF
at 0 °C was added slowly 40 mL of vinylmagnesium bromide (39.35
mmol, 1.0 M in THF). The solution was warmed to room temperature
and stirred overnight. The solution was quenched by NH4Cl, then
extracted by EtOAc, dried on Na2SO4, filtered, and concentrated. The
crude residue was purified by flash chromatography (pentane/EtOAC
6/4) to yield the desired product as a colorless oil (2.147 g, 94%):
TLC (pentane/EtOAc 6/4) Rf 0.43; IR (neat) νmax/cm−1 3396.4,
2930.8, 2853.4, 1642.0; LRMS-ESI m/z 232.1 [M + H]+.
(R)-2-((R)-2-(3-Oxopropyl)piperidin-1-yl)-2-phenylethyl Ben-
zoate (12′). In a reactor under argon containing a solution of 11′
(335 mg, 1.00 mmol) in 10 mL of anhydrous THF were added
Rh(CO)2acac (2.6 mg, 1 mol %) and biphephos (16 mg, 2 mol %).
The solution was stirred during 4 h at 65 °C under a syngas pressure of
4 bar (H2/CO 1/1). The solution was then concentrated and purified
by flash chromatography (pentane/Et2O 7/3) to yield the desired
product as a colorless oil (304 mg, 83%): TLC (pentane/Et2O 7/3) Rf
0.33; [α]20D +24.5 (c 1.5 in CHCl3); IR (neat) νmax/cm−1 2931, 2855,
2719, 1715; 1H NMR (400 MHz, CDCl3) δ (ppm) 9.78 (t, J = 1.6 Hz,
1H, H10), 8.03−7.91 (m, 2H), 7.63−7.25 (m, 8H), 4.79 (dd, J = 11.4
Hz, 5.6 Hz, 1H, H2), (dd, J = 4.59 Hz, 6.3 Hz, 1H, H2), 4.37 (dd, J =
Procedure for 11/11′. To a solution of 10/10′ (2.133 g, 9.22
mmol) in 40 mL of CH2Cl2 were added 1.18 mL (10.14 mmol) of
2251
dx.doi.org/10.1021/jo202455c | J. Org. Chem. 2012, 77, 2246−2253

The Journal of Organic Chemistry
Article
6.0 Hz, 6.0 Hz, 1H, H1), 2.93−2.85 (m, 1H, H7), 2.80−2.71 (m, 1H,
H3), 2.66−2.57 (m, 1H, H3), 2.54−2.41 (m, 2H, H9), 2.19−2.06 (m,
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1H, H8), 1.94−1.82 (m, 1H, H8), 1.80−1.31 (m, 6H, H4, H5, H6); 13
C
NMR (100 MHz, CDCl3) δ (ppm) 202.6 (CH), 166.6 (C), 141.4 (C),
133.2 (CH), 130.3 (C), 129.8 (CH), 128.6 (CH), 128.5 (CH), 128.2
(CH), 127.5 (CH), 65.4 (CH2), 61.1, 55.4, 44.8 (CH2), 40.6 (CH2),
28.1 (CH2), 24.5 (CH2), 22.0 (CH2), 21.9 (CH2); HRMS-ESI calcd
for C23H28NO3 [M + H]+ 366.2069, found 366.2060.
(S)-(−)-Coniceine, HCl. To a solution of 12 (94 mg, 0.26 mmol)
in 5 mL of MeOH was added 30% in weight of Pd(OH)2 (28 mg).
The solution was stirred overnight. The solution was filtered. HCl in
Et2O was added to form the corresponding salt, which was then
concentrated and purified by flash chromatography (CH2Cl2/MeOH
9/1) to yield the desired product as a white solid (32 mg, 77%): TLC
(CH2Cl2/MeOH 9/1) Rf 0.38; mp 175−176 °C; [α]20D +1.4 (c 1.0 in
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1
EtOH); IR (neat) νmax/cm−1 3396, 2945, 1644, 1549; H NMR (400
MHz, CDCl3) δ (ppm) 12.34−11.33 (m, 1H, NH), 3.88−3.53 (m,
2H), 2.96−2.54 (m, 3H), 2.44−1.73 (m, 10H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 67.3 (CH), 52.6 (CH2), 52.2 (CH2), 28.5 (CH2),
27.6 (CH2), 22.9 (CH2), 22.8 (CH2), 19.7 (CH2); LRMS-ESI m/z
126.1 [M + H]+.
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(R)-(+)-Coniceine, HCl. To a solution of 12′ (232 mg, 0.63 mmol)
in 5 mL of MeOH was added 30% in weight of Pd(OH)2 (70 mg).
The solution was stirred overnight. The solution was filtered. HCl in
Et2O was added to form the corresponding salt, which was then
concentrated and purified by flash chromatography (CH2Cl2/MeOH
9/1) to yield the desired product as a white solid (83 mg, 81%): TLC
(CH2Cl2/MeOH 9/1) Rf 0.38; mp 175−176 °C; [α]20D −1.5 (c 1.0 in
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Association for Chemical and Molecular Sciences: EuCheMS Brussel,
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EtOH) [lit.36 [α]23 −1.5 (c 1.0 in EtOH)]; IR (neat) νmax/cm−1
D
3396.9, 2945.1, 1644.9, 1549.6; 1H NMR (400 MHz, CDCl3) δ (ppm)
12.34−11.33 (m, 1H, NH), 3.88−3.53 (m, 2H), 2.96−2.54 (m, 3H),
2.44−1.73 (m, 10H); 13C NMR (100 MHz, CDCl3) δ (ppm) 67.3
(CH), 52.6 (CH2), 52.2 (CH2), 28.5 (CH2), 27.6 (CH2), 22.9 (CH2),
22.8 (CH2), 19.7 (CH2); LRMS-ESI m/z 126.1 [M + H]+.
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ASSOCIATED CONTENT
■
(19) Rhodium-catalyzed hydroformylation of protected N-allyl
phenylglycinol as an N,O-aminal was reported when our work was
in progress: Vasylyev, M.; Alper, H. Angew Chem, Int. Ed. 2009, 48,
1287−1290.
S
* Supporting Information
Experimental characterization data; 1H and 13C for all
compounds 4a−e, 7a−d, 8, 9, 10/10′, 11/11′, 12/12′,
(+)-coniceine, and (−)-coniceine. This material is available
free of charge via the Internet at http://pubs.acs.org.
(20) Agami, C.; Couty, F.; Poursoulis, M.; Vaissermann, J.
Tetrahedron 1992, 48, 431−42.
(21) Arena, G.; Zill, N.; Salvadori, J.; Girard, N.; Mann, A.; Taddei,
M. Org. Lett. 2011, 13, 2294−2297.
(22) The suggestion of one reviewer to submit one of the epimer of
4a to the initial hydroformylative reaction conditions could not be
examined because HPLC conditions to obtain a pure epimer of 4a
could not be found.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: andre.mann@pharma.u-strasbg.fr.
Notes
(23) Chini, M.; Crotti, P.; Macchia, F. J. Org. Chem. 1991, 56, 5939−
5942.
The authors declare no competing financial interest.
(24) Brodfuehrer, P. R.; Chen, B.-C.; Sattelberg, T. R. Sr; Smith, P.
R.; Reddy, J. P.; Stark, D. R.; Quinlan, S. L.; Reid, J. G. J. Org. Chem.
1997, 62, 9192−9202.
ACKNOWLEDGMENTS
■
This work was supported by a grant from the Minister
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e
Del
́
eg
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ue
́
a
̀
l’Enseignement Super
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ieur et a
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la Recherche (N.Z.).
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MIUR (Rome) is acknowledged for a grant within the PRIN
2009, project no. 2009RMW3Z5-006.
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A.; Gnecco, D. Heterocycles 2007, 26, 2699−2708.
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Syntheses; Wiley: New York, 1998; Coll. Vol. 9, pp 176-179.
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DEDICATION
■
This paper is dedicated to Professor Henri-Philippe Husson for
his authoritative contribution to heterocyclic chemistry.
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