A Novel Entry to 3,4,5-Trisubstituted 2-Pyrrolidones from Isoxazoline-N-oxides

Article abstract of DOI:10.1055/s-0037-1610213

A novel strategy for the synthesis of stereochemically defined 3,4,5-trisubstituted 2-pyrrolidones was developed. The suggested approach involves reductive domino-type recyclization of 3-aminomethyl-substituted isoxazolines as a key stage. The latter are prepared via α-C-H functionalization of readily available isoxazoline-N-oxides.

Full text of DOI:10.1055/s-0037-1610213

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
©
Georg Thieme Verlag Stuttgart · New York
2018, 29, A–D
letter
A
en
Synlett
P. A. Zhmurov et al.
Letter
A Novel Entry to 3,4,5-Trisubstituted 2-Pyrrolidones from
Isoxazoline-N-oxides
Petr A. Zhmurova,1
O
N
PgHN
N3
H
H
Pavel Yu. Ushakova,b
Roman A. Novikova
Alexey Yu. Sukhorukov*a
Sema L. Ioffea
N
N
O
[H]
azidation
O
O
0
0
0
0
0-
0
0
3
4-
4
1
3
9-
4
5
3
R
OH
R
2
CO Et
R
CO2Et
[4+1]
6
4–94%, d.r. up to 5 : 1
NO2
a
S
N. D. Zelinsky Institute of Organic Chemistry, Leninsky Prospect 47,
Moscow, 119991, Russian Federation
R = Me, Ar, 3-(1-methyl)indolyl-
Pg = Boc, Ac
sukhorukov@ioc.ac.ru
Department of Chemistry, M. V. Lomonosov Moscow State University,
Leninskie Gory, 1, Str. 3, Moscow, 119991, Russian Federation
R
CO2Et
b
Received: 11.05.2018
Accepted after revision: 20.06.2018
Published online: 31.07.2018
isoxazoline-N-oxides 3.11 The latter are readily available
from nitrostyrenes 4 via a [4+1]-annulation with sulfur
ylides 5.12
DOI: 10.1055/s-0037-1610213; Art ID: st-2018-v0301-l
Abstract A novel strategy for the synthesis of stereochemically de-
fined 3,4,5-trisubstituted 2-pyrrolidones was developed. The suggested
approach involves reductive domino-type recyclization of 3-amino-
methyl-substituted isoxazolines as a key stage. The latter are prepared
via α-C–H functionalization of readily available isoxazoline-N-oxides.
F
O
O
O
H
H
Key words 2-pyrrolidones, isoxazolines, reduction, C–H functionaliza-
N
NH
tion, azides
N
NH
F3C
CF3
O
O
2
-Pyrrolidones are among privileged scaffolds for the
Merck's potent
hNK1 inhibitor
GSK's potent
PDE4 inhibitor
design of pharmaceutically relevant molecules, especially
those active against various central nervous system dis-
R
2
R
orders. Well-known examples include neuroprotor pirace-
R1
R
H
HO
O
2
c,d
2e,f
AlkO
O
tam,
antiepileptic agent levetiracetam, PDE4 inhibitor
N3
3
4
N
rolipram, respiratory stimulant doxapram, etc. Moreover,
substituted 2-pyrrolidones serve as precursors of GABA an-
alogues (such as pregabalin, baclofen, phenibut, etc.) and
corresponding pyrrolidines, including many natural alka-
N
NHPg
N
NH
O
H
O
1
2
5
6
7
R1 = H, OH
8
loids and bioactive molecules. Despite of a significant
AlkO
O
R
R
progress in the stereoselective synthesis of 2-pyrrolidones,
the access to their stereochemically defined 3,4,5-trisubsti-
tuted derivatives still remains a complicated issue.
AlkO
S
N
NO2
O
O
O
In our studies toward stereoselective total synthesis of
5
4
3
9
GSK’s potent PDE4 inhibitors and Merck’s human NK an-
Pg - protecting group
1
10
tagonist shown in Scheme 1 as well as their analogues, we
suggested hitherto unknown 5-aminomethyl-3-hydroxy-
substituted 2-pyrrolidones 1 as plausible intermediates in
the construction of fused pyrrolidine-imidazolidinone unit.
In this communication, we report a general synthetic route
to 2-pyrrolidones of type 1 via reduction of 3-azidomethyl-
substituted isoxazolines 2 prepared by the recently devel-
oped transition-metal-mediated α-C-H functionalization of
Scheme 1 Suggested approach to 5-aminomethyl-3-hydroxy-
substituted 2-pyrrolidones 1 via azides 2
To test the suggested synthetic strategy, a series of model
isoxazolines 2a–g was prepared following the original route
shown in Scheme 2. Initial conjugated nitroalkenes 4a–g
were converted into the corresponding isoxazoline-N-
oxides 3 by a [4+1] annulation with sulfur ylide 5 derived
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

B
Synlett
P. A. Zhmurov et al.
Letter
NaN3
NaI (cat)
Br acetone-H O
TMSBr
Et3N, CH2Cl2
–20 °C
R
R
R
R
R
ZnBr2
THF, 24 h
EtO
O
EtO
O
EtO
O
CH2Cl2
0–98%
EtO
O
4
2
N3
5
N
N
NO2
5
O
N
N
O
O
O
O
OTMS
4a–g
3a–g
6a–g
not isolated
7a–g
not purified
2a–g
2
R
a Me (65% from 3a)
b Ph (74% from 3b)
c 4-MeO-C6H4– (73% from 4c)
d 3-CypO-4-MeO-C6H3– (64% from 3d)
e 2-Cl-C6H4– (46% from 4e)
EtO
Br
Zn
N
O
Br
O
S
O
TMS
f 4-F-C6H4– (40% from 3f)
g 3-(N-methyl)indolyl (78% from 3g)
5
Scheme 2 One-pot synthesis of azides 2 from isoxazoline-N-oxides 3
from carbethoxymethyldimethylsulfonium bromide. Inde-
pendently on the nature of R substituents, products 3 had
exclusively 4,5-trans-disposition of substituents.
On the next stage, N-oxides 3 were subjected to silyla-
tion to generate N-silyloxyenamines 6, which were without
substituted isoxazolines Boc-8a–g in high isolated yields
(Scheme 3).1
5,16
Catalytic transformation of isoxazolines Boc-8 into pyr-
rolidones Boc-1 proved to be challenging (Scheme 4). Com-
plex mixtures of products were obtained when hydrogena-
tion of model isoxazoline Boc-8b was carried out over
Raney nickel (Ra-Ni), Lindlar, Pd-C, and Rh(PPh ) Cl cata-
isolation (one-pot) treated with ZnBr to give correspond-
2
ing bromides 7 via a Zn(II)-promoted S ′ substitution of the
N
3 3
OTMS group. Bromides 7 were then transformed into azides
lysts with only negligible amounts of target pyrrolidone
Boc-1b (see Table S1 in the Supporting information). Inter-
estingly, the unexpected ketone 9b and Boc-protected
diamine 10b were isolated from reactions with Ra-Ni, Pd-C,
and Rh(PPh ) Cl catalysts. These products most likely arise
from the retroaldol-type reaction of the imine intermediate
A formed upon the reductive cleavage of the N–O bond in
isoxazoline Boc-8b (Scheme 4). A related process was ob-
served in reaction of isoxazolines with Mo(CO)6,17 yet under
catalytic hydrogenation conditions no examples were docu-
mented to the best of our knowledge.
2
by treatment with sodium azide in the presence of NaI. It
should be noted that this highly efficient three-stage se-
quence delivered isoxazolines 2 in 40–78% yields without
column chromatography of intermediate bromides 7.13
Moreover, products 2c and 2e were prepared directly from
the corresponding nitroalkenes 4c,e (without isolation of
nitronates 3c,e) in 73% and 46% yields using two aqueous
workups and only one column chromatography. These re-
sults demonstrate high efficacy of processes involved in the
strategy shown in Scheme 2.
3
3
Alternatively, azidoisoxazolines 2b–d could be prepared
by the addition of in situ generated zinc azide to enamines
Fortunately, hydrogenation over Pt-C catalyst delivered
the desired product Boc-1b in 52% yield (together with 35%
6
b–d avoiding the synthesis of corresponding bromides
of 10b). Switching to Adam’s catalyst (PtO ) resulted in the
2
11a
7b–d as we described previously. However, overall yields
increase of yield of Boc-1b up to 87%. The product was ob-
tained as a chromatographically separable mixture of two
isomers in 5.1:1 ratio. The major isomer had all-cis disposi-
tion of substituents as determined by 2D NOESY NMR.
Using this procedure, other Boc-protected isoxazolines
Boc-8 were transformed into the corresponding pyrroli-
dones Boc-1 in good yields.18 However, hydrogenation of
chloro-substituted derivative Boc-8e involved cleavage of
C–Cl bond and resulted in a complex mixture of products.
In most cases, all-cis-isomers of products Boc-1 were
predominant. The only exception was 4-methyl-substituted
pyrrolidone Boc-1a, which was obtained as an equimolar
mixture of stereoisomers. These experimental results clear-
ly demonstrate that the stereochemical outcome of the
platinum-catalyzed hydrogenation of isoxazolines is gov-
erned mostly by the substituent at C-4 rather the substitu-
ent at C-5.
of products 2b–d were significantly lower (by ca. 10–30%,
see Supporting information) and the procedure required
isolation of labile intermediate enamines 6b–d.
Having developed an improved procedure for the syn-
thesis of 3-azidomethyl-substituted isoxazolines 2, we fo-
cused on the reduction of these products to target pyrroli-
dones 1. Initially, Staudinger reduction of the azido group
followed by in situ protection of emerging amino group was
performed, which delivered Boc-protected 3-aminomethyl-
14
R
R
PPh3, THF,
EtO
O
H O, then Boc O
EtO
O
2
2
NHBoc
4
N3
5
N
N
O
O
2a–g
Boc-8a–g
Yields: Boc-8a (91%), Boc-8b (97%), Boc-8c (64%), Boc-8d (94%)
Boc-8e (80%), Boc-8f (88%), Boc-8g (75%)
The cis-stereochemistry of products Boc-1 formed in
catalytic hydrogenation of isoxazolines 2 suggest that this
route cannot be utilized to obtain target PDE4 inhibitor and
Scheme 3 Staudinger reduction of the azido group in isoxazolines 2a–g
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

C
Synlett
P. A. Zhmurov et al.
Letter
O
R
O
O
O
R
70 bar H2
EtO
PtO2 (25 mol%)
NHBoc
EtO
O
NHBoc
NH2
O
CH3OH
0 °C
O
OH
PPh3, THF, H2O
then Ac2O
N
O
7
EtO
O
EtO
O
N
4
4
N3
H
Boc-8a–g
5
5
73%
N
N
O
–EtOH
O
H2, cat
R
CH3OH
2
d
Ac-8d
R
1. H2, PtO2 (30 mol%)
HO
O
CH OH
3
4
1
3
2
EtO
O
5
2. separation
of isomers
NHBoc
N
NHBoc
Boc-1a–c,f,g
ratio 4,5-cis/trans:
NH
H
OH
O
A
O
O
O
retro-
aldol
O
1
5
3
.1 : 1.0 (Boc-1a, 45%)
.1 : 1.0 (Boc-1b, 87%)
.5 : 1.0 (Boc-1c, 79%)
4.9 : 1.0 (Boc-1f, 77%)
.9 : 1.0 (Boc-1g, 80%)
CO2Et
HO
R
NHBoc
N
2
O
O
H
NH
N
HN
O
H
H2O
H2, cat
Rolipram
Ac-1d, 50%
R
NHBoc
R
NHBoc
Scheme 5 Synthesis of rolipram analogue Ac-1d
O
NH2
9b, R = Ph, 50%
10b, R = Ph, 40% (cat = Pd-C, 5 mol% Pd)
(
cat = Ra-Ni)
51% (cat = Rh(PPh3)3Cl, 5 mol%)
Funding Information
Scheme 4 Reduction of isoxazolines Boc-8
This work was supported by Russian Foundation for Basic Research
(grants #16-33-01063 and #17-33-80172_mol_ev).
)(
hNK antagonist shown in Scheme 1, yet, it can be exploited
in the synthesis of their bioactive epimers.
1
Acknowledgment
9a
Motivated by the possibility of using our strategy to
access new PDE4 inhibitors structurally related to rolip-
ram, we have synthesized the acetyl-protected derivative
Authors thank Mr. Kevin Kurtz from BPS Bioscience for conducting
standard in vitro PDE4 inhibition assay on a contract basis.
3
Ac-1d from azido-substituted isoxazoline 2d via catalytic
hydrogenation of acetamide Ac-8d as shown in Scheme 5.
Similar to 4-aryl-substituted pyrrolidones Boc-1, product
Ac-1d was formed as a 3.1:1 mixture of stereoisomers with
all-cis isomer being predominant. The major isomer was
separated by column chromatography.
Supporting Information
Supporting Information contains experimental procedures, charac-
terization data, copies of NMR spectra, and details of in vitro PDE4
inhibition assay. Supporting information for this article is available
online at https://doi.org/10.1055/s-0037-1610213.
S
u
p
p
o
nrtIo
i
g
f
rm oaitn
S
u
p
p
ortioIgnfmr oaitn
Product Ac-1d contains the structural core of PDE4
inhibitor rolipram with two additional hydrogen bond
donor groups. However, in vitro testing of Ac-1d for PDE4
inhibition activity revealed that the compound is much less
potent compared to rolipram (10% inhibition of enzyme at
References and Notes
(1) Present address: A.N. Nesmeyanov Institute of Organoelement
Compounds, Vavilov Str. 28, 119991, Moscow, Russia.
(2) (a) Despinoy, X. L.; McNab, H. Tetrahedron 2000, 56, 6359.
1
0 μM concentration, see Table S2 in the Supporting Infor-
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In conclusion, we have developed a straightforward
(
b) Jouyban, A.; Fakhree, M. A. A.; Shayanfar, A. J. Pharm. Pharm.
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994, 19, 180. (d) Malykh, A. G.; Sadaie, M. R. Drugs 2010, 70,
1
access to all-cis 3,4,5-trisubstituted 2-pyrrolidones starting
from readily available nitroalkenes. It involves α-azidation
of isoxazoline-N-oxides and reductive-domino-type recy-
clization of 3-azidomethyl-substituted isoxazolines as key
stages. The suggested strategy has potential for application
in the synthesis of bioactive molecules and pharmaceuti-
cals relevant to central nervous system and immune disor-
ders. Target products can be accessed in an enantiomerical-
ly pure form, since approaches to the asymmetric synthesis
287. (e) Marson, A. G.; Hutton, J. L.; Leach, J. P.; Castillo, S.;
Schmidt, D.; White, S.; Chaisewikul, R.; Privitera, M.; Chadwick,
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Muccioli, G. G.; Robiette, R. Org. Biomol. Chem. 2016, 14, 10134.
(
h) Nay, B.; Riache, N.; Evanno, L. Nat. Prod. Rep. 2009, 26, 1044.
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(3) Zhu, J.; Mix, E.; Winblad, B. CNS Drug Rev. 2001, 7, 387.
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9, 26.
(
(
1
2b–d
of isoxazoline-N-oxides of type 3 are known.
2
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

D
Synlett
P. A. Zhmurov et al.
Letter
(
6) Costantino, G.; Macchiarulo, A.; Entrena Guadix, A.; Pellicciari,
water (0.195 mL, 10.8 mmol) was added. After 16 h di(tert-
butyl)dicarbonate (1.30 g, 6.0 mmol) was added, and the
mixture was stirred for additional 24 h. Then, volatiles were
removed in vacuum, and the residue was subjected to column
chromatography on silica gel (eluent hexane/EtOAc = 7:1 → 5:1
→ 3:1) to give 860 mg (97%) of Boc-protected amine Boc-8b.
Ethyl rel-(4S,5S)-3-{[(tert-Butoxycarbonyl)-amino]methyl}-
4-phenyl-4,5-dihydroisoxazole-5-carboxylate (Boc-8b)
R. J. Med. Chem. 2001, 44, 1827.
(7) Lapin, I. CNS Drug Rev. 2001, 7, 471.
(8) Sukhorukov, A. Y.; Sukhanova, A. A.; Zlotin, S. G. Tetrahedron
2016, 41, 6191.
(
9) (a) Brackeen, M. F.; Stafford, J. A.; Cowan, D. J.; Brown, P. J.;
Domanico, P. L.; Feldman, P. L.; Rose, D.; Strickland, A. B.; Veal, J.
M.; Verghese, M. J. Med. Chem. 1995, 38, 4848. (b) Zhmurov, P.
A.; Sukhorukov, A. Y.; Chupakhin, V. I.; Khomutova, Y. V.; Ioffe,
S. L.; Tartakovsky, V. A. Org. Biomol. Chem. 2013, 11, 8082.
1
Oil. R = 0.66 (hexane/EtOAc, 1:1). H NMR (300 MHz, CDCl ): δ =
f
3
7.40–7.27 (m, 3 H, m,p- C H ), 7.25–7.15 (d, J = 7.5 Hz, 2 H, o-
6
5
(
10) Morriello, G. J.; DeVita, R. J.; Mills, S. G.; Young, J. R.; Lin, P.;
Doss, G.; Chicchi, G. G.; DeMartino, J.; Kurtz, M. M.; Tsao, K.-L.
C.; Carlson, E.; Townson, K.; Wheeldon, A.; Boyce, S.; Collinson,
N.; Rupniak, N.; Moore, S. Bioorg. Med. Chem. 2008, 16, 2156.
11) (a) Zhmurov, P. A.; Khoroshutina, Y. A.; Novikov, R. A.;
Golovanov, I. S.; Sukhorukov, A. Y.; Ioffe, S. L. Chem. Eur. J. 2017,
C H ), 4.95 (br m, 1 H, NH), 4.89 (d, J = 5.2 Hz, 1 H, 5-H), 4.58 (d,
6 5
J = 5.2 Hz, 1 H, 4-H), 4.25 (q, J = 7.2 Hz, 2 H, OCH CH ), 3.98–3.86
2
3
(br m, 2 H, CH NH), 1.38 (s, 9 H, C(CH ) ), 1.30 (t, J = 7.1 Hz, 3 H,
2
3 3
13
OCH CH ). C NMR (75 MHz, JMOD, CDCl ): δ = 169.46 (OC=O),
2
3
3
(
158.11 and 155.29 (3-C and HNC=O), 136.57 (i-C H ), 129.40,
6
5
128.38 and 127.46 (o-C H , m-C H , and p-C H ), 85.73 (5-C),
6
5
6
5
6
5
23, 4570. (b) Sukhorukov, A. Y.; Kapatsyna, M. A.; Yi, T. L. T.;
79.78 (O-C(CH ) ), 61.95 (OCH CH ), 58.76 (4-C), 36.70
3 3 2 3
Park, H. R.; Naumovich, Y. A.; Zhmurov, P. A.; Khomutova, Y. A.;
Ioffe, S. L.; Tartakovsky, V. A. Eur. J. Org. Chem. 2014, 8148.
(CH NH), 28.21 (C(CH ) ), 14.06 (OCH CH ). HRMS: m/z calcd for
2 3 3 2 3
+
[C18H25N O ] : 349.1758; found: 349.1754.
2
5
(12) (a) Kumaran, G.; Kulkarni, G. H. Synthesis 1995, 1545. (b) An, J.;
Lu, L.-Q.; Yang, Q.-Q.; Wang, T.; Xiao, W.-J. Org. Lett. 2013, 15,
(16) Unfortunately, direct catalytic hydrogenation of model isoxazo-
line 2f (conditions: 70 bar H , 70 °C, CH OH, PtO catalyst, 25
2
3
2
542. (c) Zhu, C.-Y.; Deng, X.-M.; Sun, X.-L.; Zheng, J.-C.; Tang, Y.
mol%) in the presence of Boc O led to a complex mixture of
2
Chem. Commun. 2008, 738. Review: (d) Tabolin, A. A.;
Sukhorukov, A. Y.; Ioffe, S. L.; Dilman, A. D. Synthesis 2017, 49,
indecipherable products, in which target pyrrolidone Boc-1f
was not detected.
3
255.
(17) (a) Nitta, M.; Kobayashi, T. Chem. Lett. 1983, 12, 51. (b) Tranmer,
G. K.; Tam, W. Org. Lett. 2002, 4, 4101.
(
13) Typical Procedure
To a stirred solution of isoxazoline-N-oxide 3b (573 mg, 2.3
mmol) in CH Cl (10 mL) cooled to –20 °C was added Et N (0.96
(18) Typical Procedure
Platinum dioxide (30 mg) was placed in a vial equipped with a
magnetic stirrer bar and charged with a solution of isoxazoline
2
2
3
mL, 6.9 mmol) followed by (CH ) SiBr (0.6 mL, 4.6 mmol) under
3
3
argon atmosphere. The reaction mixture was stirred for 20 min
at –20 °C and then kept in a freezer (ca. –18 °C) for 72 h with
occasional shaking. The resulting mixture was warmed up to rt,
Boc-8b (180 mg, 0.517 mmol) in CH OH (5 mL). The vial was
3
placed in a steel autoclave which was then flushed and filled
with H2 to a pressure of 70 bar and the mixture was stirred at
70°C for 9 h. Then, the autoclave was cooled to rt and slowly
depressurized. The solution was filtered through Celite and con-
centrated in vacuum. The residue was subjected to column
chromatography on silica gel (eluent CH Cl /CH OH = 20:1 →
and a solution of ZnBr (517 mg, 2.3 mmol) in THF (20 mL) was
2
added. The mixture was stirred until dissolution of precipitate
and then kept overnight at rt. The resulting solution was poured
into methyl tert-butyl ether (100 mL) and 0.25 M NaHSO solu-
4
2
2
3
tion (50 mL). The aqueous layer was back-extracted with
methyl tert-butyl ether (50 mL). Combined organic layers were
washed with water (50 mL) and brine (50 mL), dried (Na SO ),
and evaporated in vacuum to give crude bromide 7b. The latter
was dissolved in acetone (25 mL), then NaN3 (598 mg, 9.2
mmol), NaI (35 mg, 0.23 mmol), and water (3 mL) were added.
The reaction mixture was intensively stirred for 3 h at rt and
then poured into methyl tert-butyl ether (100 mL) and water
10:1) to give 137 mg (87%) of pyrrolidone Boc-1b as white solid
(d.r. 5.1:1). Two fractions were collected, first one contained
pure all-cis isomer, second fraction contained ca. 3:1 mixture of
all-cis and 4,5-trans isomers.
2
4
[tert-Butyl
(4-hydroxy-3-phenyl-5-oxopyrrolidin-2-yl)
methyl]carbamate (Boc-1b)
Mp 211–212 °С. R = 0.12 (CH Cl /2-PrOH, 20:1). 1H NMR (400
f
2
2
MHz, DMSO-d , COSY, NOESY, HSQC, all-cis-Boc-1b): δ = 7.72 (s,
6
(50 mL). The aqueous layer was back-extracted with methyl
1 H, NH), 7.31–7.12 (m, 5 H, o,m,p-C H ), 6.59 (br t, 1 H, NHBoc),
6
5
tert-butyl ether (50 mL). Combined organic layers were washed
5.80–5.00 (br, 1 H, OH), 4.41 (d, J = 7.0 Hz, 1 H, 3-H), 3.80–3.72
(m, 1 H, 5-H), 3.66 (dd, J = 7.0, 5.9 Hz, 1 H, 4-H), 2.85–2.71 and
with water (50 mL) and brine (50 mL), dried (Na SO ), and evap-
2
4
13
orated in vacuum. The residue was subjected to column chro-
2.45–2.32 (2 m, 1 H and 1 H, CH N), 1.35 (s, 9 H, C(CH ) ).
C
2
3 3
matography on silica gel (eluent hexane/EtOAc = 7:1 → 5:1 →
NMR (101 MHz, CDCl , HSQC, all-cis-Boc-1b): δ = 176.36 (C=O),
3
3
:1) to give 470 mg (74% based on nitronate 3b) of azide 2b as a
155.32 (OC=O), 135.74 (i-C H ), 129.85, 127.56 and 126.52
6
5
1
colorless oil. H NMR spectrum of product 2b is in agreement
with literature data. (Alternatively, azide 2b can be prepared
from isoxazoline-N-oxide 3b following method described in
(o,m,p-C H ), 77.87 (C(CH ) ), 70.51 (3-C), 53.56 (5-C), 48.62 (4-
6 5 3 3
11a
C), 42.84 (CH N), 28.12 (C(CH ) ). Characteristic 2D NOESY cor-
2 3 3
1
relations: H-3/H-4, H-3/H-5, H-4/H-5, H-5/CH N, Ph/CH N.
H
2
2
11a
ref. in 40% yield).
NMR (400 MHz, DMSO-d , COSY, NOESY, HSQC, 4,5-trans-Boc-
6
(
14) For reduction of isoxazolines, see: (a) Jäger, V.; Grund, H.; Buß,
V.; Schwab, W.; Müller, I.; Schohe, R.; Franz, R.; Ehrler, R. Bull.
Soc. Chim. Belg. 1983, 92, 1039. (b) Kozikowski, A. P. Acc. Chem.
Res. 1984, 17, 410. (c) Zhu, C.-Y.; Sun, X.-L.; Deng, X.-M.; Zheng,
J.-C.; Tang, Y. Tetrahedron 2008, 64, 5583. (d) Nagireddy, R. J.;
Raheem, M.-A.; Haner, J.; Tam, W. Curr. Org. Synth. 2011, 8, 659.
15) Typical Procedure
1b): δ = 7.85 (s, 1 H, NH), 7.31–7.12 (m, 5 H, o,m,p-C H ), 6.86
6
5
(br t, 1 H, NHBoc), 5.80–5.00 (br, 1 H, OH), 4.14 (d, J = 7.2, 1 H, 3-
H), 3.71–3.67 (m, 1 H, 5-H), 3.28–3.23 (m, 1 H, 4-H), 3.18–3.06
and 2.99–2.89 (2 m, 1 H and 1 H, CH N), 1.35 (s, 9 H, C(CH ) ).
2
3 3
13
C NMR (101 MHz, CDCl , HSQC, 4,5-trans-Boc-1b): δ = 175.22
3
(C=O), 155.66 (OC=O), 138.09 (i-C H ), 129.07, 127.72 and
6
5
(
126.32 (o,m,p-C H ), 79.11 (C(CH ) ), 70.39 (3-C), 57.58 (5-C),
6
5
3 3
To a stirred solution of azide 2b (700 mg, 2.55 mmol) in THF (13
mL) was added PPh3 (836 mg, 3.19 mmol) in several portions
with intensive stirring. After 30 min (gas evaluation completed)
48.76 (4-C), 43.75 (CH N), 28.12 (C(CH ) ). Characteristic 2D
2
3
3
NOESY correlations: H-3/H-4, H-4/CH N. HRMS: m/z calcd for
2
+
[C16H23N O ] : 307.1652; found: 307.1647.
2
4
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D