Rhodium-catalyzed multicomponent synthesis of chiral oxazolopiperidines

Article abstract of DOI:10.1016/j.tet.2010.03.064

A multicomponent reaction that employs an unsaturated carboxylic acid, a 1,2 or 1,3 amino alcohol and gaseous CO and H₂ has been discovered. Thus, hydrocarbonylation of the carboxylic acid double bond generates a linear aldehyde, that is, immediately transformed into an oxazolidine. Further microwave assisted intramolecular lactamization delivers oxazolopiperidines with the generation of six new bonds in a one-pot single step. Bicylic, tricyclic, tetracyclic, and spirocyclic oxazolopiperidines can be prepared in good yields and acceptable stereoselection. The reaction did not occur under conventional heating even at higher temperature and pressure and for longer time, showing that microwave heating is indispensable to the process.

Full text of DOI:10.1016/j.tet.2010.03.064

Tetrahedron 66 (2010) 3749–3753
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Rhodium-catalyzed multicomponent synthesis of chiral oxazolopiperidines
a
b
b
b
a,
*
´
Jessica Salvadori , Etienne Airiau , Nicolas Girard , Andre Mann , Maurizio Taddei
a
`
Dipartimento Farmaco Chimico Tecnologico, Universita degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy
b Laboratoire d’Innovation The´rapeutique, UMR 7200 CNRS-Universite´ de Strasbourg, Faculte´ de Pharmacie, 74 route du Rhin, 67401 Illkirch, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 January 2010
Received in revised form 10 March 2010
Accepted 16 March 2010
Available online 23 March 2010
A multicomponent reaction that employs an unsaturated carboxylic acid, a 1,2 or 1,3 amino alcohol and
gaseous CO and H2 has been discovered. Thus, hydrocarbonylation of the carboxylic acid double bond
generates a linear aldehyde, that is, immediately transformed into an oxazolidine. Further microwave
assisted intramolecular lactamization delivers oxazolopiperidines with the generation of six new bonds
in a one-pot single step. Bicylic, tricyclic, tetracyclic, and spirocyclic oxazolopiperidines can be prepared
in good yields and acceptable stereoselection. The reaction did not occur under conventional heating
even at higher temperature and pressure and for longer time, showing that microwave heating is
indispensable to the process.
Keywords:
Multicomponent reactions
Microwave heating
Diversity oriented synthesis
Hydrocarbonylation
Heterocycles
Ó 2010 Published by Elsevier Ltd.
1. Introduction
the two rings using a bis-electrophile and a bis-nucleophile.8
Amongst many types of nucleophiles investigated, the aldehyde is
The diversity oriented synthesis (DOS) approach, developed by
S. Schreiber at the beginning of the century,1 is nowadays a key area
for organic chemistry and chemical biology.2 The ultimate goal of
DOS is the understanding of biological problems through the
implementation of collections of structurally diverse molecules. For
this purpose, multicomponent reactions (MCR) play an important
role among the processes employed for diversity generation. In
MCR, a complex scaffold (often a cycle) is generated in one step
starting from more than two simple reagents.3 Originally based on
few reactions (Ugi, Passerini, Biginelli, Hantsh etc.), the MCR field, is
now experiencing a high level of innovation.4 Recently, many
new MCR based on transition metal catalysis have been also
discovered.5
Oxazolopiperidines are bicyclic heterocycles characterized by
the possibility of functionalization at C5 (electrophile), C6 (nucle-
ophile), and C8a (nucleophile) (Scheme 1). They can incorporate
a wide range of substituents for functional groups pairing behaving
as versatile synthetic intermediates and pluripotent scaffolds in
DOS.6 The oxazolopiperidine ring is also present in several natural
products and drug-like molecules,7 and can be considered as
often used for its high reactivity with amines. As 1,5-bis-aldehydes
(or adehydes carrying a terminal carboxylic functions) are relatively
unstable and have a high tendency to polymerize, we projected to
use an unsaturated carboxylic acid that, after Rh catalyzed hydro-
carbonylation to the homologous aldehyde, could react in situ with
amino alcohols as partners. In contrast with the results we recently
communicated,9 we did not want to activate the carboxylic acid in
order to avoid an additional step. Thus, we decided to apply
microwave dielectric heating to the reaction in order to force the
lactamization of the free carboxylic acid10 and to use exclusively
commercially available compounds for a truly MCR strategy.
Moreover, the use of microwave heating was preferred (respect to
the standard autoclave) in order to carry out the reaction inside
a small vial under low gas pressure,11 limiting the waste of H2/CO
and orienting toward a real atom-economic hydroformylation.12
Electrophiles
at C5
Nucleophiles at
Nucleophiles at
C8a
C6
a
privileged structure. The synthesis of oxazolopiperidine is
NH2
generally accomplished by first assembly of the six-membered ring
followed by closing of the second or by contemporary formation of
Rh(I)
OH
H2 CO
O
N
R1
O
O
OH
R2
1
2
3
R1
R2
Scheme 1. MCR approach for the synthesis of perhydro-oxazolopyridines.
* Corresponding author. e-mail address: taddei.m@unisi.it (M. Taddei).
0040-4020/$ – see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tet.2010.03.064

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J. Salvadori et al. / Tetrahedron 66 (2010) 3749–3753
2. Results and discussion
any stereoselectivity giving a cis/trans mixture. The ultimate
lactamization promoted by microwaves gave the product with the
same diastereomer composition.
We began the exploration and optimisation process by using
a modified version of our unsaturated amide hydroformylation13
applied to a mixture of 3-butenoic acid (1a), (R)-phenylglycinol
(2a) in the presence of Rh(I) catalyst and a chelating ligand. The
initial reaction conditions in the presence of HRh(CO)(PPh3)3 with
different ligands, such as xantphos or biphephos gave the expected
product exclusively in the presence of TsOH (entries 1–3 in Table 1).
Therefore, TsOH was used as an additive to investigate the best pair
of catalyst/ligand (entries 4–8 in Table 1). Xantphos at 110 ꢀC gave
high conversion but low yields due to the formation of several
by-products. Using Rh(CO)2acac/biphephos the reaction was
cleaner and we also found that the yield of 3a increased working at
lower temperature (75 ꢀC) for longer time (60 min). At the same
time, the nature of the acid was investigated. Increasing the acid
strength did not give any improvement (entries 9–10 in Table 1),
whereas the less acid and more soluble PPTS (pyridinium p-tolue-
nesulfonate), (entry 11) gave better results. Increasing the reaction
time to 90 min, the yield of 3a increased further. The use of toluene
as the solvent did not modify the yield of 3a (entry 8 in Table 1)
whereas with CH2Cl2 or EtOH, 3a was not formed at all. It is worth
noticing that, if the reaction was carried under conventional heat-
ing (autoclave) compound 3a was not formed even at higher
temperature and pressure (entry 13), showing that microwave
heating was essential for the process. A possible explanation for
this effect is the more efficient heating provided in a microwave vial
respect to the stainless steel autoclave (heated outside with an oil
bath). With this apparatus, the starting materials start to degradate
before reacting.
However, the above mixture can be equilibrated with TFA in
CH2Cl2 toward the thermodynamically more stable trans-3a.14
Indeed a 85:15 mixture of trans/cis diastereomers was obtained
and pure trans-3a could be isolated by column chromatography in
65% yield (Scheme 2).
HOOC
H2/CO,
MW, Rh(I)
HN
2a, acid
CHO
O
O
OH
O
OH
1
TFA, CH2Cl2
O
N
O
N
O
O
MW
3a
trans-3a
Scheme 2. Process for the formation of trans-3a.
This result prompted us to extend the procedure to other
commercially available 1,2-amino-alcohols (2b–i) (Table 2) giving
the expected lactams 3b–j in moderate to good yields. Starting from
chiral amino alcohols 2b–d, the corresponding oxazolopiperidines
3b–d were always obtained as
a mixture of diastereomers.
However, TFA mediated equilibration was operative on compounds
3b,c allowing isolation of the trans isomers by column chroma-
tography (entries 1 and 2 in Table 2). Compound 3d, not stable
under the equilibration conditions, was isolated only as a mixture
of diastereomers. With more hindered amino alcohols 2e–g, the
cyclisation occurred with higher stereoselectivity (entries 3–5, 7 in
Table 2) and trans-3e–g were isolated without the resort of equil-
ibration. Compound 3f, obtained with high diastereoselectivity, is
the demethylated analog of Meyers’ (2R,3R,(8aS)-3-(hydrox-
ymethyl)-8a-methyl-2-phenyl-hexahydro-5H-[1,3]oxazolo[3,2a]-
pyridin-5-one)15 employed as a key intermediate in several natural
product syntheses.16 Our procedure is compatible with the pres-
ence of different functional groups potentially useful to increase
diversity, such as in the case of compounds 3d, 3f, and 3h and
tricyclic, tetracyclic, and spirocyclic compounds were prepared in
acceptable yields. Few variations are possible on the side of the
unsaturated carboxylic acid as very few compounds with this
structural connection are commercially available. Using acid 1b and
amino alcohol 2g, the corresponding tetracyclic oxazolopyridine
was formed and the trans-isomer 3j was isolated in acceptable
yields after column chromatography (entry 8 in Table 2). Using 1,3
amino alcohols 4a–c, the 6,6-bicyclic lactams 5a–c were obtained
in fairly good yields under comparable reaction conditions. How-
ever, a lower stereoselectivity was observed, as 5a–c were always
isolated as a mixture of the cis and trans isomers Table 3.
Table 1
Optimisation of the MCR between 3-butenoic acid, (R)-phenylglycinol, H2, and COa
H2/CO, MW,
Rh(I) cat, acid
NH2
OH
O
N
O
O
OH2
1a
2a
3a
Entry Catalyst/ligand
Acid
Time, temperature 3ab [%]
1
2
3
4
5
6
7
8
HRh(CO)(PPh3)3/xantphos
60 min, 70 ꢀ
60 min, 70 ꢀ
30 min, 70 ꢀ
30 min, 110 ꢀ
30 min, 70 ꢀ
30 min, 110 ꢀ
C
C
C
C
C
0
0
HRh(CO)(PPh3)3/biphephos
Rh(CO)2acac/xantphos
Rh(CO)2acac/xantphos
Rh(CO)2acac/biphephos
Rh(CO)2acac/biphephos
Rh(CO)2acac/biphephos
Rh(CO)2acac/biphephos
Rh(CO)2acac/biphephos
Rh(CO)2acac/biphephos
Rh(CO)2acac/biphephos
Rh(CO)2acac/biphephos
Rh(CO)2acac/biphephos
TsOH
TsOH
TsOH
TsOH
TsOH
TsOH
AcOH
TFA
15
35
45
25
56
60c
50
60
58
78
0d
C
60 min, 75 ꢀ
60 min, 75 ꢀ
60 min, 75 ꢀ
60 min, 75 ꢀ
C
C
C
C
C
C
9
10
11
12
13
BF3. Et2O 60 min, 75 ꢀ
PPTS
PPTS
90 min, 75 ꢀ
12 h, 75 ꢀ
C
a
3-Butenoic acid (1.0 equiv), (R)-phenylglycinol (1.1 equiv), H2/CO (1:1) at 6.89
105 Pa, Rh catalyst (0.01 equiv), ligand (0.04 equiv), acid (0.1 equiv), THF, microwave
dielectric heating at 150 W.
b
Yields of 3a isolated by column chromatography.
Toluene was used as the solvent.
Reaction carried out under conventional heating inside to a stainless steel
c
d
3. Conclusions
autoclave.
In conclusion, a new microwave assisted MCR has been dis-
covered employing a latent bi-electrophile and a bi-nucleophile.
A sequence of linear hydrocarbonylation, intermolecular forma-
tion of an oxazolidine followed by nucleophilic attack occurred
under microwave heating with the creation of six new bonds in
a single step. It has to be emphasized that as the starting compounds
Compound 3a was obtained as a 1:1 mixture of diastereomers,
suggesting a pathway of first regioselective hydrocarbonylation of
the terminal double bond, probably followed by the acid catalyzed
formation of the intermediate oxazolidine assisted by the Rh
coordination to the amino alcohol. This process does not provide

J. Salvadori et al. / Tetrahedron 66 (2010) 3749–3753
3751
Table 2
Table 3
Reaction with 1,2-amino alcohols
Reaction with 1,3 amino alcohols
R
H2/CO, Rh(CO)2acac/
biphephos, THF, MW
(150 W), 75°C, 90 min
H2/CO, Rh(CO)2acac/
biphephos, THF, MW
(150 W), 75°C, 90 min
R
NH2 OH
R
NH2
R
O
N
O
OH
R1
O
N
O
R1
O
OH
O
OH
1a-b
R2
R1
5a-c
R2
2b-i
R1
3b-j
R2
R2
1a
4a-c
Entry
1
Acid
Amino alcohol
Product
Yielda [%]
65
Entry
1
Acid
Amino alcohol
Product
Yield [%]
NH2 OH
NH2
1a
O
N
O
O
N
1a
R¼H
56a
65a
OH
R
O
4a
5a
R = PhCH2 2b
R = Me2CH 2c
R
R = PhCH2 3b.
R = Me2CH 3c
NH2 OH
O
N
O
2
1a
66
62
4b
NH2
5b
1a
R¼H
2
3
46b
O
N
OH
O
MeOOC
2d
MeOOC
3d
NH2 OH
O
N
O
NH2
3
1a
1a
R¼H
OH
62c
O
N
O
4c
5c
Ph
2e
Ph
3e
a
Isolated yield as a mixture of diastereomers approximatively 1:1.
NH2
represents a combination of DOS and MCR involving gaseous
reagents (CO and H2) that are scarcely exemplified, but have great
potentialities.
1a
R¼H
4
5
70d
OH
HO
O
N
O
2f
Ph
HO
Ph
3f
4. Experimental
NH2
4.1. General procedure for the Rh catalyzed multicomponent
synthesis of oxazolopiperidine, (3R,8aS)-3-Phenyltetrahydro-
2H-oxazolo[3,2-a]pyridin-5(3H)-one trans-3a
O
N
O
1a
R¼H
63c
OH
OH
3g
2g
A solution of dicarbonylacetylacetonato rhodium(I) (2.5 mg,
0.01 mmol) and biphephos (6.3 mg, 0.02 mmol) in anhydrous
degassed THF (2 mL), was introduced into a microwave vial
containing a THF solution (2 mL) of the acid 1a (183 mg, 1.0 mmol),
(R)-2-amino-2-phenylethanol 2a (137 mg, 1.0 mmol) and PPTS
(25 mg, 0.2 mmol) under inert atmosphere. The solution was sub-
mitted to pressurized syngas (H2/CO 1:1) (Discover microwave
synthesizer equipped with the gas addition kit)17 at 6.89 105 Pa and
heated at 75 ꢀC by microwave irradiation at 150 W (value pre-
viously settled on the microwave oven) for 90 min. The flask was
cooled and the internal gas released. Aqueous saturated Na2CO3
solution was added and the aqueous layer was extracted three
times with EtOAc. The organic layer was dried over Na2SO4. After
filtration and concentration in vacuo the crude mixture was
dissolved in dry CH2Cl2 (1 mL) and TFA (193 mg, 1.7 mmol) was
added at 0 ꢀC. The mixture was stirred at rt for 24 h, then aqueous
saturated Na2CO3 solution was added and the mixture was
extracted three times with EtOAc. The organic layer was dried over
Na2SO4 and the crude was purified by flash chromatography (98:2
EtOAc–MeOH) to give trans-3a as a pale yellow solid (103 mg, 65%).
Mp 87–89 ꢀC (lit.14 88–90 ꢀC); IR (neat) 2930, 2871, 1650, 1443,
NH2
1a
R¼H
O
N
N
6
7
HO
50b
O
O
2h
HO
3h
NH2
OH
2i
1a
R¼H
O
O
65
3i
NH2
N
O
1b
R¼Me
8
56c
OH
2g
3j
a
Isolated yield of the trans isomer after TFA mediated equilibration (24 h at rt).
Isolated yield before equilibration.
Obtained as a 4:1 mixture of trans/cis diastereomers. Yields of the trans isomer
b
c
isolated by column chromatography.
Obtained as a 8:1 mixture of trans/cis diastereomers. Yields of the trans isomer
isolated by column chromatography.
1307, 996, 698 cmꢁ1
; d 7.36–7.32
1H NMR (CDCl3, 400 MHz)
d
(m, 2H), 7.28–7.24 (m, 3H), 5.27 (t, J¼7.8 Hz, 1H), 5.02 (dd, J¼9.0,
4.6 Hz, 1H), 4.48 (dd, J¼8.9, 8.0 Hz, 1H), 3.76 (dd, J¼9.0, 7.8 Hz, 1H),
2.52 (ddt, J¼18.0, 5.7, 1.7 Hz, 1H), 2.39–2.29 (m, 1H), 2.34 (ddd,
J¼18.0, 11.4, 6.4 Hz, 1H), 2.0–1.93 (m, 1H), 1.77 (tddd, J¼13.8, 11.4,
5.9, 2.8 Hz, 1H), 1.54 (dddd, J¼13.6, 12.7, 9.1, 3.3 Hz, 1H); 13C NMR
(vinylacetic acid and the amino alcohols) are commercially avail-
able, the preparation of oxazolopiperidines is now very competitive
in respect to the previous reported methods. Finally this process
(CDCl3, 50 MHz)
d 168.9 (C), 139.6 (C), 128.8 (CH), 127.5 (CH), 126.1

3752
J. Salvadori et al. / Tetrahedron 66 (2010) 3749–3753
20
(CH), 88.7 (CH), 72.4 (CH2), 58.1 (CH), 31.3 (CH2), 28.4 (CH2),17.1
30.9 (CH2), 29.3 (CH2), 16.7 (CH2), 14.1 (CH3); [
a
]
þ77.3 (c 1.0,
D
20
22
(CH2); [
a
]
ꢁ87.5 (c 0.6, CH2Cl2) {lit.14
[
a]
ꢁ88.0 (c 0.6, CH2Cl2)};
CHCl3). HRMS-ESI (m/z): [MþH]þ calcd 232.1332; found 232.1330.
D
D
LRMS-ESI (m/z): 218 (MþH)þ, 240 (MþNa). HRMS-ESI (m/z):
[MþH]þ calcd 218.1176; found 218.1169.
4.1.5. (2R,3R,8aS)-3-(Hydroxymethyl)2-phenylhexahydro-ox-
azolo[3,2-a]pyridin-5-one 3f. Compound 3f was prepared following
the general procedure starting from (1R,2R)-2-amino-1-phenyl-
propane-1,3-diol 2f (70 mg, 0.77 mmol), 1a (66 mg, 0.77 mmol),
and PPTS (20 mg, 0.08 mmol) in THF. The residue was purified by
flash chromatography (95:5 CH2Cl2–MeOH) to give 3f as a colorless
4.1.1. (3S,8aS)-3-Benzylhexahydro-5H-[1,3]oxazolo[3,2-a]pyridin-5-
one trans-3b. Compound 3b was prepared following the general
procedure starting from (R)-2-amino-3-phenyl-1-propanol 2b
(100 mg, 0.66 mmol), 1a (68 mg, 0.79 mmol), and PPTS (8.3 mg,
0,03 mmol) in THF. The residue was purified by flash chromato-
graphy on silica gel (98:2 EtOAc–MeOH) to give 3b as a white solid
(85 mg, 56%). Mp 65–66 ꢀC. IR (neat) 1637, 1450, 1412, 999,
oil (133 mg, 70%); 1H NMR (CDCl3, 200 MHz)
d 7.34–7.20 (m, 5H),
4.94 (dd, J¼10.0, 3.2 Hz, 1H), 4.63 (br s, 1H), 4.60–4.58 (d, J¼8.0 Hz,
1H), 4.01 (td, J¼12.0, 8 Hz, 1H), 3.82–3.79 (m, 1H), 3.69–3.64
(m, 1H), 2.25–2.17 (m, 2H), 1.81–1.52 (m, 4H). ES-MS (m/z): 270.1
[MþNa]þ. HRMS-ESI (m/z): [MþH]þ calcd 247,2897; found
247,2894.
702 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
d 7.32–7.28 (m, 2H), 7.25–7.20
(m, 3H), 4.54–4.47 (m, 2H), 4.03 (dd, J¼9.0, 7.6 Hz, 1H), 3.62
(dd, J¼9.0, 7.6 Hz,1H), 3.28 (dd, J¼13.4, 3.7 Hz,1H), 2.80 (dd, J¼13.4,
9.2 Hz, 1H), 2.50 (ddt, J¼18.1, 6.0, 1.8 Hz, 1H), 2.31 (ddd, J¼18.1, 11.8,
6.7 Hz, 1H), 2.25–2.19 (m, 1H), 1.94–1.87 (m, 1H), 1.64 (tddd, J¼13.8,
11.6, 6.0, 2.8 Hz, 1H), 1.40 (dddd, J¼13.8, 12.6, 9.2, 3.3 Hz, 1H); 13C
4.1.6. (4aS,5aS,10bR)-2,3,4,4a,6,10b-Hexahydro-1H,5aH-in-
deno[10,20:4,5][1,3]oxazolo[3,2-a]pyridin-1-one 3g. Compound 3g
was prepared following the general procedure starting from (1R,2S)-
1-amino-2,3-dihydro-1H-inden-2-ol 2g (123 mg, 0.85 mmol), 1a
(156 mg, 0.85 mmol), and TsOH (16 mg, 0.08 mmol) in THF. The
residue was purified by flash chromatography (98:2 CH2Cl2–MeOH)
to give 3h as a white solid (148 mg, 76%). IR (neat) 3010, 2950, 1655,
NMR (CDCl3, 50 MHz)
d 168.7 (C), 136.9 (C), 129.6 (CH), 128.6 (CH),
126.7 (CH), 87.3 (CH), 69.3 (CH2), 55.1 (CH), 37.8 (CH2), 31.4 (CH2),
20
28.2 (CH2), 17.2 (CH2); [
a]
ꢁ30.7 (c 1.0, CHCl3). HRMS-ESI (m/z):
D
[MþH]þ calcd 232.1332; found 220.1330.
4.1.2. (3S,8aR)-3-Isopropylhexahydro-5H-[1,3]oxazolo[3,2-a]pyridin-
5-one trans-3c. Compound 3c was prepared following the general
procedure starting from (S)-(þ)-2-amino-3-methyl-1-butanol 2c
(100 mg, 0.97 mmol), 1a (83 mg, 0.97 mmol), and PPTS (21 mg,
0.9 mmol) in THF. The residue was purified by flash chromatogra-
phy (97:3 EtOAc–MeOH) to give 3c as a yellow oil (115 mg, 65%). IR
1450,1390 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
d
7.57 (d, J¼8,1H), 7.27–
7.16 (m, 3H), 5.89 (d, J¼6.4,1H), 5.05–5.01 (m,1H), 4.68–4.65 (m,1H),
3.34–3.28 (m, 1H), 3.13–3.09 (m, 1H), 2.43–2.42 (m, 1H), 2.36–2.32
(m, 1H), 2.21–2.18 (m, 1H), 1.87–1.84 (m, 1H), 1.60–1.47 (m, 2H); 13C
NMR (CDCl3, 100 MHz)
d 167.7 (C), 141.5 (C), 139.6 (C), 128.7 (CH),
127.5 (CH), 126.6 (CH), 124.7 (CH), 84.8 (CH), 79.1 (CH), 62.4 (CH),
20
(neat) 2957, 2873, 1648, 1464 cmꢁ1
;
1H NMR (CDCl3, 300 MHz)
38.7 (CH2), 31.2 (CH2), 28.2 (CH2), 17.2 (CH2); [
a
]
þ43.2 (c 1.0,
D
d
4.73 (dd, J¼8.6, 4.7 Hz, 1H), 4.18 (td, J¼7.5, 6.4 Hz, 1H), 4.03 (dd,
CHCl3). ES-MS (m/z): 252.1 [MþNa]þ. HRMS-ESI (m/z): [MþH]þ
J¼8.3, 8.0 Hz, 1H), 3.66 (dd, J¼8.6, 6.9 Hz, 1H), 2.49 (br ddt, J¼17.9,
5.8, 1.9 Hz, 1H), 2.34–2.10 (m, 3H), 1.95–1.85 (m, 1H), 1.66 (tddd,
J¼13.7, 11.0, 6.1, 2.6 Hz, 1H), 1.42 (tdd, J¼13.0, 8.6, 3.3 Hz, 1H), 0.92
(d, J¼6.5 Hz, 3H), 0.89 (d, J¼6.5 Hz, 3H); 13C NMR (CDCl3, 50 MHz)
calcd 230.1176; found 230.1169.
4.1.7. 3-(Hydroxymethyl)-hexahydrooxazol[3-2a]pyridin-5-one
3h. Compound 3h was prepared following the general procedure
starting from serinol 2h (70 mg, 0.77 mmol), 1a (66 mg,
0.77 mmol), and PPTS (20 mg, 0.08 mmol) in THF. The residue was
purified by flash chromatography (95:5 CH2Cl2–MeOH) to give 3h
d
169.3 (C), 87.7 (CH), 66.6 (CH2), 59.2 (CH), 31.7 (CH2), 30.1 (CH),
20
20
28.5 (CH2), 19.1 (CH2), 17.0 (CH3); [
a
]
þ3.2 (c 1.0, CHCl3) {lit.18
[a]
D
D
þ13 (c 1.1, EtOH)}. HRMS-ESI (m/z): [MþH]þ calcd 184.1332; found
184.1328.
as a colorless oil (65 mg 50%); 1H NMR (CDCl3, 200 MHz)
d 4.75–
4.68 (m, 1H), 4.27–4.21 (m, 1H), 3.66–3.57 (m, 2H),3.42–3.37
4.1.3. (3R,8aR)-methy-l5-oxohexahydro-2H-oxazolo[[3,2-a]pyridine-
(m, 2H), 2.51–2.40 (m, 2H), 1.70–1.63 (m, 2H),1.49–1.41 (m, 2H); 13C
3-carboxylate 3d. Compound 3d was prepared following the gen-
NMR (CDCl3, 100 MHz) d 168.9, 89.5, 67.9, 56.8, 32.8, 33.2, 20.9.
eral procedure starting from
L-Serine methylester (131 mg,
ES-MS (m/z): 194.3 [MþNa]þ. HRMS-ESI (m/z): [MþH]þ calcd
0.85 mmol), 1a (73 mg, 0.85 mmol), and PPTS (20 mg, 0.08 mmol)
in THF. The residue was purified by flash chromatography (95:5
CH2Cl2–MeOH) to give 3d as a colorless oil (78 mg 46%). IR (neat)
171.0895; found 171.0899.
4.1.8. Tetrahydrospiro[cyclopentane-1,30-oxazolo[3,2-a]pyridin]-
50(20H)-one 3i. Compound 3i was prepared following the general
procedure starting from (1-aminocyclopentyl)methanol 2i (88 mg,
0.77 mmol), 1a (66 mg, 0.77 mmol), and PPTS (20 mg, 0.08 mmol)
in THF. The residue was purified by flash chromatography (98:2
CH2Cl2–MeOH) to give 3i as a white solid (97 mg, 65%); 1H NMR
2953,1720,1645,1450 cmꢁ1; 1H NMR (CDCl3, 200 MHz)
d 4.75–4.68
(m, 1H), 4.39 (t, J¼6.3, 1H), 4.09 (q, J¼6.8, 1H), 3.77–3.61 (m, 4H),
2.25–2.17 (m, 2H), 1.81–1.52 (m, 4H); 13C NMR (CDCl3, 50 MHz)
d
170.1 (C), 167.5 (C), 87.1 (CH), 66.9 (CH), 53.2 (CH3), 52.6 (CH2),
20
33.2 (CH2), 32.7 (CH2), 19.6 (CH2); [
a
]
D
þ19.8 (c 1.0, CHCl3). ES-MS
(m/z): 200.09 [Mþ1]þ. HRMS-ESI (m/z): [MþH]þ calcd 200.0917;
(CDCl3, 400 MHz)
d
4.69 (dd, J¼10.0, 3.2 Hz, 1H), 3.89 (d, J¼8 Hz,
found 200.0935.
1H), 3.56 (d, J¼8 Hz, 1H), 2.51–2.21 (m, 6H), 1.52–1.38 (m, 8H); 13C
NMR (CDCl3, 100 MHz)
d 168.76, 87.4, 76.4, 57.9, 34.5, 31.0, 23.4,
4.1.4. (2S,3R,8aS)-3-Methyl-2-phenylhexahydro-5H-[1,3]ox-
azolo[3,2-a]pyridin-5-one trans-3e. Compound 3e was prepared
19.6. ES-MS (m/z): 218.2 [MþNa]þ. HRMS-ESI (m/z): [MþH]þ calcd
195.1259; found 195.1263.
following the general procedure starting from
D
-(þ)-norephedrine
Compound 3j. Compound 3j was prepared following the general
procedure starting from (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-
ol 2g (123 mg, 0.85 mmol), 1b (176 mg, 0.85 mmol), and TsOH
(16 mg, 0.08 mmol) in THF. The residue was purified by flash chro-
matography (98:2 CH2Cl2–MeOH) to give 3j as a white solid
(128 mg, 56%). IR (neat) 3010, 2950,1655,1450,1390 cmꢁ1; 1H NMR
2e (100 mg, 0.66 mmol), 1a (56 mg, 0.66 mmol), and PPTS (15 mg,
0.6 mmol) in THF. The residue was purified by flash chromatogra-
phy (98:2 EtOAc–MeOH) to give 3e as a colorless oil (94 mg, 62%). IR
(neat) 2958, 1628, 1448, 1329 cmꢁ1 1H NMR (CDCl3, 300 MHz)
;
d
7.38–7.26 (m, 5H), 5.28 (dd, J¼9.3, 4.2 Hz, 1H), 5.14 (d, J¼6.1 Hz,
1H), 4.87 (dq, J¼6.6, 6.6 Hz, 1H), 2.53–2.44 (m, 1H), 2.41–2.29
(CDCl3, 400 MHz)
1H), 5.05–5.01 (m, 1H), 4.68–4.65 (m, 1H), 3.34–3.28 (m, 1H), 3.13–
3.09 (m, 1H), 2.21–2.18 (m, 1H), 1.87–1.84 (m, 1H), 1.56 (s, 6H), 1.60–
d
7.57 (d, J¼8,1H), 7.27–7.16 (m, 3H), 5.89 (d, J¼6.4,
(m, 2H),1.99–1.90 (m,1H),1.78–1.63 (m,1H),1.61–1.48 (m,1H), 0.81
(d, J¼6.6 Hz, 3H); 13C NMR (CDCl3, 50 MHz)
d 167.6 (C), 137.4 (C),
128.4 (CH), 127.8 (CH), 126.1 (CH), 86.0 (CH), 80.0 (CH), 53.4 (CH),
1.47 (m, 2H); 13C NMR (CDCl3, 100 MHz)
d 167.7 (C), 141.5 (C), 139.6

J. Salvadori et al. / Tetrahedron 66 (2010) 3749–3753
3753
Org. Biomol. Chem. 2008, 6, 1149–1158; (d) Peuchmaur, M.; Wong, Y.-S. Comb.
Chem. High Throughput Screening 2008, 11, 587–601.
(C), 128.7 (CH), 127.5 (CH), 126.6 (CH), 124.7 (CH), 84.8 (CH), 79.1
(CH), 62.4 (CH), 38.7 (CH2), 36.6 (C), 28.2 (CH2),17.2 (CH2),12.1 (CH3)
3. (a) Sunderhaus, J. D.; Martin, S. F. Chem.dEur. J. 2009, 15, 1300–1308; (b)
Gonzalez-Lopez, M.; Shaw, J. T. Chem. Rev. 2009, 109, 164–189; (c) Groenendaal,
B.; Ruijter, E.; Orru, R. V. A. Chem. Commun. 2008, 5474–5489; (d) Shestopalov,
A. M.; Shestopalov, A. A.; Rodinovskaya, L. A. Synthesis 2008, 1–25; (e) Akrito-
poulou-Zanze, I.; Djuric, S. W. Heterocycles 2007, 73, 125–146; (f) Banfi, L.;
Guanti, G.; Riva, R.; Basso, A. Curr. Opin. Drug Discovery Dev. 2007, 10, 704–714;
20
[
a]
þ73.2 (c 1.0, CHCl3). ES-MS (m/z): 280.1 [MþNa]þ. HRMS-ESI
D
(m/z): [MþH]þ calcd 257.3276; found 257.3256.
4.1.9. Hexahydropyrido[2,1b][1,3]oxazin-6(2H)-one 5a. Compound
5a was prepared following the general procedure as described
above from 3-amino-1-propanol 4a (63 mg, 0.85 mmol), 1a (73 mL,
´
(g) Domling, A. Chem. Rev. 2006, 106, 17–89; (h) Tejedor, D.; Gonzalez-Cruz, D.;
Santos-Expo´sito, A.; Marrero-Tellado, J. J.; De Armas, P.; Garcı´a-Tellado, F. Chem.
dEur. J. 2005, 11, 3503–3510; (i) Marcaccini, S.; Torroba, T. In Multicomponent
Reactions; Zhu, J., Bienayme´, H., Eds.; Wiley-VCH: Weinheim, 2005; pp 33–75;
(j) Zhu, J. Eur. J. Org. Chem. 2003, 7, 1133–1144.
0.85 mmol), and PPTS (20 mg, 0.08 mmol) in THF. The residue was
purified by flash chromatography (98:2 CH2Cl2–MeOH) to give 5a
as a colorless oil (99 mg, 65%); 1H NMR (CDCl3, 400 MHz)
d 4.73–
4. Ganem, B. Acc. Chem. Res. 2009, 42, 463–472.
5. Some selected recent examples: (a) Lu, W.; Song, W.; Hong, D.; Lu, P.; Wang, Y.
Adv. Synth. Catal. 2009, 351, 1768–1772; (b) Horiguchi, H.; Hirano, K.; Satoh, T.;
Miura, M. Adv. Synth. Catal. 2009, 351, 1431–1436; (c) Sharghi, H.; Khalifeh, R.;
Doroodmand, M. M. Adv. Synth. Catal. 2009, 351, 207–218; (d) DeBenedetto, M.
V.; Green, M. E.; Wan, S.; Park, J.-H.; Floreancig, P. E. Org. Lett. 2009, 11, 835–
838; (e) Gonza´les-Go´mez, J. C.; Foubelo, F.; Yus, M. Tetrahedron Lett. 2008, 49,
2343–2347.
4.65 (m, 2H), 4.06–4.02 (m, 1H), 3.72–3.66 (m, 1H), 2.71–2.64
(m, 1H), 2.35–2.29 (m, 2H), 1.98–1.73 (m, 4H), 1.63–1.60 (m, 1H),
1.47–1.44 (m, 1H); 13C NMR (CDCl3, 400 MHz) 169.4 (C), 86.2 (CH),
67.8 (CH2), 40.9 (CH2), 32.7 (CH2), 29.2 (CH2), 25.5 (CH2), 17.3 (CH2).
ES-MS (m/z): 178.1 [MþNa]þ. HRMS-ESI (m/z): [MþH]þ calcd
155.0946; found 155.0942.
6. (a) Bouet, A.; Oudeyer, S.; Dupas, G.; Marsais, F.; Levacher, V. Tetrahedron:
Asymmetry 2008, 19, 2396–2401; (b) Escolano, C.; Amat, M.; Bosch, J. Chem.
´
´
dEur. J. 2006, 12, 8198–8207; (c) Amat, M.; Bassas, O.; Llor, N.; Canto, M.; Perez,
M.; Molins, E.; Bosch, J. Chem.dEur. J. 2006, 12, 7872–7881; (d) Groaning, M. D.;
Meyers, A. I. Tetrahedron 2000, 56, 9843–9873; (e) Amat, M.; Llor, N.; Bosch, J.
Tetrahedron Lett. 1994, 35, 2223–2226; (f) Royer, J.; Husson, H.-P. Heterocycles
1993, 36, 1493–1496; (g) Romo, D.; Meyers, A. I. Tetrahedron 1991, 47, 9503–
9569; (h) Meyers, A. I.; Lefker, B. A.; Sowin, T. J.; Westrum, L. J. J. Org. Chem.
1989, 54, 4243–4246.
4.1.10. 4-Phenylhexahydro-2H,6H-pyrido[2,1-b][1,3]oxazin-6-one
5b. Compound 5b was prepared following the general procedure as
described above from 3-amino-3-phenylpropan-1-ol 4a (128 mg,
0.85 mmol), 1a (73 mL, 0.85 mmol), and PPTS (20 mg, 0.08 mmol) in
THF. The residue was purified by flash chromatography (98:2
CH2Cl2–MeOH) to give 5b as a colorless oil (129 mg, 66%); 1H NMR
7. (a) Someno, T.; Kunimoto, S.; Nakamura, H.; Naganawa, H.; Ikeda, D. J. Antibiot.
2005, 58, 56–60; (b) Vilar, R. M.; Gil-Longo, J.; Daranas, A. H.; Souto, M. L.;
(CDCl3, 400 MHz)
d 7.44 (m, 2H), 7.30 (m, 1H), 7.17 (m, 2H), 4.83
´
´
Fernandez, J. J.; Peixinho, S.; Barral, M. A.; Santafe, G.; Rodrigueza, J.; Jimenez, C.
Bioorg. Med. Chem. 2003, 11, 2301–2306; (c) Gang, S.; Ohta, S.; Chiba, H.; Jhodo,
O.; Nomura, H.; Nagamatsu, Y.; Yoshimoto, A. J. Antibiot. 2001, 54, 304–308; (d)
Asai, Y.; Nonaka, N.; Suzuki, S.-I.; Nishio, M.; Takahashi, K.; Shima, H.; Ohmori,
K.; Onuki, T.; Komatsubara, K. J. Antibiot. 1999, 52, 607–613; (e) Mericli, A. H.;
Mericli, F.; Seyhan, V.; Ulubelen, A.; Desai, H. K.; Joshi, B. S.; Teng, Q.; Pelletier,
W. Heterocycles 1997, 54, 1955–1961; (f) Martin, E.; Sevilla, M. A.; Moran, A.;
Martin, M. L.; Roman, L. S. J. Auton. Pharm. 2001, 3, 413–419; (g) Martin, E.;
Moran, A.; Martin, M. L.; Roman, L. S.; Puebla, P.; Medarde, M.; Caballero, E.; San
Feliciano, A. Bioorg. Med. Chem. Lett. 2000, 10, 319–323.
(dd, JA¼JB¼7 Hz, 1H), 4.38 (dd, JA¼JB¼8 Hz, 1H), 4.16 (m, 1H), 3.79
(m, 1H), 2–42–1.69 (m, 8H); 13C NMR (CDCl3, 400 MHz) 168.4 (C),
132.2 (C), 127.8 (CH), 126.4 (2CH),125.6 (2CH), 86.2 (CH), 68.1 (CH2),
58.4 (CH), 33.5 (CH2), 32.6 (CH2), 30.6 (CH2), 19.5 (CH2). ES-MS
(m/z): 254.1 [MþNa]þ. HRMS-ESI (m/z): [MþNa]þ calcd 254.2801;
found 254.2810.
8. Couty, F.; Evano, G. In Comprehensive Heterocyclic Chemistry III; Katritzky, A. R.,
Ramsden, C. A., Scriven, E. F. V., Taylor, R. J., Eds.; Elsevier Ltd.: Oxford, 2008;
Vol. 11, pp 409–499.
9. Airiau, E.; Girard, N.; Mann, A.; Salvadori, J.; Taddei, M. Org. Lett. 2009, 11,
5314–5317.
10. Orrling, K. M.; Wu, X.; Russo, F.; Larhed, M. J. Org. Chem. 2008, 73, 8627–8630.
11. (a) Petricci, E.; Mann, A.; Rota, A.; Schoenfelder, A.; Taddei, M. Org. Lett. 2006, 8,
3725–3727; (b) Petricci, E.; Mann, A.; Salvadori, J.; Taddei, M. Tetrahedron Lett.
2007, 48, 8501–8504; (c) Cardullo, F.; Donati, D.; Merlo, G.; Paio, A.; Petricci, E.;
Taddei, M. Synlett 2009, 47–50.
4.1.11. (4aRS,6aR,10aS)-decahydro-1H,6H-pyrido[1,2-a][3,1]benzox-
azin-1-one 5c. Compound 5c was prepared following the general
procedure as described above from 4c (109 mg, 0.85 mmol), 1a
(73 mL, 0.85 mmol), and PPTS (20 mg, 0.08 mmol) in THF. The res-
idue was purified by flash chromatography (98:2 CH2Cl2–MeOH) to
give 5b as a colorless oil (104 mg, 62%); 1H NMR (CDCl3, 400 MHz)
d
4.68 (m, 1H), 3.70 (m, 3H), 2.32–1.79 (m, 7H), 1.60–1.48 (m, 3H),
1.30–1.05 (m, 4H); 13C NMR (CDCl3, 400 MHz) 170.2 (C), 85.9 (CH),
68.5 (CH2), 57.5 (CH), 34.4 (CH2), 32.8 (CH2), 32.1 (CH2), 28.7 (CH2),
24.8 (CH2), 23.6 (CH2), 22.6 (CH2), 19.5 (CH2). ES-MS (m/z): 231.2
[MþNa]þ. HRMS-ESI (m/z): [MþNa]þ calcd 232.2764; found
232.2761.
12. In a 10 mL vial, the gas present under the reaction conditions is roughly 3 mmol
for 1 mmol of substrate.
13. Airiau, E.; Spangenberg, T.; Girard, N.; Schoenfelder, A.; Salvadori, J.; Taddei, M.;
Mann, A. Chem.dEur. J. 2008, 14, 10938–10948 For cyclohydrocarbonylation of
unsaturated amides see also: (a) Chiou, W.-H.; Mizutani, N.; Ojima, I. J. Org.
Chem. 2007, 72, 1871–1882; (b) Chiou, W.-H.; Schoenfelder, A.; Sun, L.; Mann,
A.; Ojima, I. J. Org. Chem. 2007, 72, 9418–9425.
14. Amat, M.; Bosch, J.; Hidalgo, J.; Cant, M.; Prez, M.; Llor, N.; Molins, E.;
Miravitlles, C.; Orozco, M.; Luque, J. J. Org. Chem. 2000, 65, 3074–3084.
15. Meyers, A. I.; Lefker, B. A. Tetrahedron 1987, 43, 5663–5676 The stereochemistry
of 3f was assigned by comparison with the reported spectroscopic properties.
16. (a) Liu, H.-J.; Sun, D. Heterocycles 2000, 52, 1251–1260; (b) Lemieux, R. M.;
Meyers, A. I. J. Am. Chem. Soc. 1998, 120, 5453–5457; (c) Schwarz, J. B.; Devine,
P. N.; Meyers, A. I. Tetrahedron 1997, 53, 8795–8806; (d) Resek, J. E.; Meyers, A. I.
Synlett 1995, 145–146; (e) Devine, P. N.; Meyers, A. I. J. Am. Chem. Soc. 1994, 116,
2633–2634.
Acknowledgements
`
´ ´ ´ `
This work was supported by the Ministere delegue a l’Enseigne-
´
`
ment Superieur et a la Recherche (EA) and by CEM Italia (Bergamo).
References and notes
17. For a more exaustive description of this commercially available device see:
http://www.cem.com/page163.html.
18. Micouin, L.; Quirion, J.-C.; Husson, H.-P. Synth. Commun. 1996, 26, 1605–1611.
1. Schreiber, S. L. Science 2000, 287, 1964–1967.
2. (a) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46–58; (b) Tan,
D. S. Nat. Chem. Biol. 2005, 1, 74–84; (c) Spandl, R. J.; Bender, A.; Spring, D. R.