Enantioselective synthesis of 3,4-dihydro-1,2-oxazepin-5(2 H)-ones and 2,3-dihydropyridin-4(1 H)-ones from β-substituted β- hydroxyaminoaldehydes

Article abstract of DOI:10.1021/jo402445r

The synthesis of 3,4-dihydro-1,2-oxazepin-5(2H)-ones and 2,3-dihydropyridin-4(1H)-ones from β-substituted β- hydroxyaminoaldehydes is reported. The β-hydroxyaminoaldehydes were prepared by enantioselective organocatalytic 1,4-addition of N-tert-butyl (tert-butyldimethylsilyl)oxycarbamate to α,β-unsaturated aldehydes (MacMillan protocol). Alkyne addition to the aldehydes followed by alcohol oxidation furnished N-Boc O-TBS-protected β-aminoynones. Removal of the TBS protecting group initiated a 7-endo-dig cyclization to yield previously unknown 3,4-dihydro-1,2-oxazepin-5(2H)-ones. Reductive cleavage of the N-O bond of the oxazepinones and Boc-deprotection provided 2-substituted 2,3-dihydropyridin- 4(1H)-ones via 6-endo-trig cyclization. 2,3-Dihydropyridin-4(1H)-ones are versatile intermediates that have been used for the synthesis of many alkaloids. The new protocol allows the synthesis of 3-dihydropyridin-4(1H)-ones carrying an array of substituents at C2 that cannot be prepared from commercial β-amino acids or by one-carbon homologation of proteinogenic amino acids. The use of readily available β-hydroxylaminoaldehydes expands the utility of our previously reported method to prepare 2,3-dihydropyridin-4(1H)-ones from β-amino acids as the source of diversity and chirality. A broad substrate scope is possible because β-aminoaldehydes can be prepared from α,β-unsaturated aldehydes by an enantioselective organocatalytic process.

Full text of DOI:10.1021/jo402445r

Article
pubs.acs.org/joc
Enantioselective Synthesis of 3,4-Dihydro-1,2-oxazepin-5(2H)‑ones
and 2,3-Dihydropyridin-4(1H)‑ones from β‑Substituted
β‑Hydroxyaminoaldehydes
Adwait R. Ranade and Gunda I. Georg*
University of Kansas, 1251 Wescoe Hall Drive, 4070 Malott Hall, Lawrence, Kansas 66045-7482, United States
Department of Medicinal Chemistry and Institute for Therapeutics Discovery & Development, University of Minnesota, 717
Delaware Street South East, Minneapolis, Minnesota 55414, United States
S
* Supporting Information
ABSTRACT: The synthesis of 3,4-dihydro-1,2-oxazepin-
5(2H)-ones and 2,3-dihydropyridin-4(1H)-ones from β-sub-
stituted β-hydroxyaminoaldehydes is reported. The β-hydrox-
yaminoaldehydes were prepared by enantioselective organo-
catalytic 1,4-addition of N-tert-butyl (tert-butyldimethylsilyl)-
oxycarbamate to α,β-unsaturated aldehydes (MacMillan
protocol). Alkyne addition to the aldehydes followed by alcohol
oxidation furnished N-Boc O-TBS-protected β-aminoynones.
Removal of the TBS protecting group initiated a 7-endo-dig
cyclization to yield previously unknown 3,4-dihydro-1,2-
oxazepin-5(2H)-ones. Reductive cleavage of the N−O bond
of the oxazepinones and Boc-deprotection provided 2-
substituted 2,3-dihydropyridin-4(1H)-ones via 6-endo-trig cycli-
zation. 2,3-Dihydropyridin-4(1H)-ones are versatile intermedi-
ates that have been used for the synthesis of many alkaloids. The new protocol allows the synthesis of 3-dihydropyridin-4(1H)-
ones carrying an array of substituents at C2 that cannot be prepared from commercial β-amino acids or by one-carbon
homologation of proteinogenic amino acids. The use of readily available β-hydroxylaminoaldehydes expands the utility of our
previously reported method to prepare 2,3-dihydropyridin-4(1H)-ones from β-amino acids as the source of diversity and
chirality. A broad substrate scope is possible because β-aminoaldehydes can be prepared from α,β-unsaturated aldehydes by an
enantioselective organocatalytic process.
(vinylogous amides). They are therefore less sensitive to
hydrolysis and oxidation reactions. The 2,3-dihydropyridin-
4(1H)-ones feature multiple reactive groups that can be
subjected to various synthetic transformations that modify the
basic scaffold,13,14 such as N-functionalization,15,16 C3-
functionalization,17 1,2-addition at C4, addition of electrophiles
at C5,18 1,4-addition at C6, and [2 + 2] cycloaddition19 with
the C5−C6 double bond (Figure 1).
INTRODUCTION
■
The objective of our work was to devise an enantioselective
synthesis of 2,6-disubstituted 2,3-dihydropyridin-4(1H)-ones
(Figure 1) that would expand the scope of existing methods.
Several effective methods exist to prepare 2,3-dihydropyridin-
4(1H)-ones enantioselectively (Figure 2).20 These methods
include Comins’ synthesis of 2,3-dihydropyridin-4(1H)-ones,
employing the addition of Grignard reagents to chiral N-
acylpyridinium salts (Figure 2, eq 1).1,13,21 This approach relies
on a sterically demanding C3 tri-isopropylsilyl (TIPS) group to
control regioselectivity and a carbamate linked chiral auxiliary
to achieve excellent diastereoselectivities. Both auxiliary groups
can be removed without racemization of the chiral center.
Charrette’s modification of Comins’ methodology employs (S)-
Figure 1. Reactivity profile of 2,3-dihydropyridin-4(1H)-ones.
2,3-Dihydropyridin-4(1H)-ones are versatile structures that
have utility for the synthesis of piperidine-containing natural
products, such as indolizidine and quinolizidine alkaloids,1,2 and
piperidine-containing bioactive molecules.3−8 They can also be
converted to substituted pyridines by oxidation.9−11 Compared
to the structurally closely related enamines, 2,3-dihydropyridin-
4(1H)-ones are relatively more stable12 as a result of the
conjugation of the enamine moiety to a carbonyl functionality
Received: November 3, 2013
© XXXX American Chemical Society
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Figure 2. Methods for the synthesis of chiral nonracemic 2,3-dihydropyridin-4(1H)-ones.
N-(1-methoxy-3-methylbutan-2-yl)benzamide to generate non-
racemic N-acylpyridinium salts (Figure 2, eq 2)22 that furnish
N-protected enaminones with excellent diastereo- and
regioselectivity. This system does not require a sterically
demanding group at C3 because the regioselectivity of the
reaction is achieved by a chelation-controlled addition of the
Grignard reagent to the pyridinium salt.
that furnished enantioselectivities with 56−97% ee with
nonbranched alkylzinc reagents (Figure 2, eq 3).23
Other approaches utilize the asymmetric hetero-Diels−Alder
reaction of imines with a Danishefsky’s diene either by using
chiral auxiliaries such as 2,3,4,6-tetra-O-pivaloyl-β-D-galactopyr-
anosylamine (Figure 2, eq 4) attached to the imine24−28 or by
employing a chiral catalyst (Figure 2, eq 5).29−32 Recently, the
Rovis group published a facile highly enantioselective synthesis
of the bicyclic indolizidinone core via Rh(I)·CKphos-catalyzed
A catalytic enantioselective addition of organozinc reagents
to N-acylpyridinium salts was reported by the Feringa group
B
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cycloaddition of alkynes and 1,1-disubstituted alkenyl iso-
cyanates (Figure 2, eq 6).33
Gouault et al. developed a gold-catalyzed enantioselective
synthesis of 2,6-disubstituted pyridones from the amino-
ynones, which were synthesized from the chiral pool of
amino acids (Figure 2, eq 7).34
plished the synthesis of indolizidine and quinolizidine alkaloids
boehmeriasin A,38 tylocrebrine,40 antofine,39,40 and ipalbidine.39
An advantage of this process is that many β-amino acids are
commercially available or can be prepared from α-amino acids
by Arndt−Eistert43 or cyanohydrin homologation.44 However,
this method relies largely on the availability of the 20
proteinogenic amino acids and therefore limits the scope to
the side chains to those present in the naturally occurring
amino acids. In the case of the Arndt−Eistert homologation,
the handling of explosive diazomethane reagent is re-
quired.45−47
Many other techniques have been developed to synthesize
enantiopure β-amino acids. Detailed reviews on advances in the
synthesis of β-amino acids and their derivatives have been
published by Sibi48 and by Juaristi and Soloshonok.49,50
MacMillan and co-workers recently developed a different
strategy for generating β-amino aldehydes by enantioselective
organocatalytic conjugate addition of N-siloxycarbamate
nucleophiles to α,β-unsaturated aldehydes.51 This methodology
is operationally simple and uses an inexpensive and
commercially available imidazolidinone catalyst that is available
in both enantiomeric forms. A variety of functional groups are
tolerated in this process, and the resulting β-amino aldehydes
are synthesized with high enantiomeric purity. Given the
synthetic utility of this well-developed strategy, we decided to
employ it to generate β-hydroxylamino aldehydes as precursors
for synthesizing novel chiral nonracemic 2,3-dihydropyridin-
4(1H)-ones.
RESULTS AND DISCUSSION
■
Although many methods for the synthesis of chiral nonracemic
2,3-dihydropyridin-4(1H)-ones have proven to be effective,
there are drawbacks depending on the exact method, such as
multistep preparation of the starting material, limited scope for
the introduction of substituents at C2, requirement to remove
auxiliary groups, difficult-to-remove auxiliary groups, or the
enantiomer of the chiral auxiliary or chiral catalyst may not be
readily available. A limitation common to most procedures with
the exception of the Rovis method is that they require multiple
subsequent steps if bicyclic enaminones are the target
compounds. In contrast to the above-mentioned approaches,
our group developed a chiral pool method employing readily
available chiral nonracemic β-amino acids as the starting
materials (Scheme 1), thereby incorporating asymmetry as well
as diversity into the target compounds.
Scheme 1. Synthesis of Amino Acid-Derived
Enaminones14,35
Our planned route to synthesize 2,6-disubstituted 2,3-
dihydropyridin-4(1H)-ones 1, is summarized in Scheme 2.
Scheme 2. Retrosynthetic Route to 2,3-Dihydropyridin-
4(1H)-ones 1
This approach not only provides an enantioselective route to
2-substitited 2,3-dihydropyridin-4(1H)-ones but also is a
concise and direct route to form bicyclic 2,3-dihydropyridin-
4(1H)-ones when cyclic amino acids such as homoproline,
homopipecolic acid, and cis-2-(methylamino)cyclohexane-
carboxylic acid are employed as the starting β-amino acids
(Scheme 1).14,35−42
As shown in Scheme 1, Weinreb amides of β-amino acids are
reacted with readily available alkynyl Grignard reagents to form
amino ynones. After Boc deprotection with formic acid and
addition of NaI (or using HCl), the ynone is converted to a
ketovinyl halide, which is not isolated. The addition of base to
the reaction mixture deprotonates the amine, which undergoes
a 6-endo-trig ring closure to form 2,3-dihydropyridin-4(1H)-
ones. Using bicyclic 2,3-dihydropyridin-4(1H)-ones we accom-
The targeted 2,3-dihydropyridin-4(1H)-ones 1, could be
obtained by reductive cleavage of the N−O bond of N-hydroxy
2,3-dihydropyridin-4(1H)-ones 2, which would be derived from
the ynones 3, after removal of the Boc- and TBS-protecting
groups. The ynone could be prepared by oxidation of propargyl
alcohol 4, obtained by addition of alkynyl nucleophiles to β-
hydroxylamino aldehydes 5. The β-hydroxylamino aldehydes 5
can be prepared using MacMillan’s procedure.51
The preparation of the β-hydroxylamino aldehydes 5 started
with the synthesis of N-Boc-O-TBS-protected hydroxylamine 6
and α,β-unsaturated aldehydes 7 (Scheme 3). We prepared
compound 6 from commercially available N-Boc-hydroxyl-
amine by silylation of the hydroxyl group. Because only 2-
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After subjecting the diastereomeric propargyl alcohols 4 to
MnO2 oxidation in refluxing 1,2-dichloroethane for 24 h,
ynones 3 were obtained and directly used in the next step
(Table 2). In an attempt to simultaneously remove both amine
Scheme 3. Synthesis of β-Hydroxylamino Aldehydes 5
Table 2. Two-Step Synthesis of 3,4-Dihydro-1,2-oxazepin-
5(2H)-ones 8 from Propargyl Alcohols 4
a
entry (compound)
R1
R2
yield (%)
1 (8a)
2 (8b)
3 (8c)
4 (8d)
5 (8e)
6 (8f)
7 (8g)
8 (8h)
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
Ph
77
91
23
64
73
52
43
48
4-MeO(C6H4)
4-CF3(C6H4)
thiophen-3-yl
Me
hexenal (7a) was commercially available, we prepared α,β-
unsaturated aldehydes 7b and 7c from the corresponding
aldehydes and commercially available (triphenylphosphor-
anylidene)acetaldehyde by a Horner−Wadsworth−Emmons
reaction.52 The β-hydroxylamino aldehydes 5 were synthesized
using the MacMillan protocol (Scheme 3).51 The spectral data
and the optical rotation of aldehyde 5a matched those reported
by MacMillan. To confirm the optical purity of aldehyde 5b, we
converted 5b to (3R,5S)-tert-butyl 3-((1,3-dioxoisoindolin-2-
yl)methyl)-5-hydroxyisoxazolidine-2-carboxylate. The optical
rotation of this compound also matched MacMillan’s report.51
Aldehyde 5c was reduced to the corresponding alcohol and
then converted to a Mosher ester.53 On the basis of the 19F
NMR spectrum of its Mosher ester, the enantiomeric ratio was
determined to be 90.5:9.5.
tert-Bu
PhthN−CH2
BnO−CH2
4-MeO(C6H4)
4-MeO(C6H4)
a
Yield over two steps.
protecting groups, we treated ynone 3a with 4 N HCl in
dioxane followed by basification using excess K2CO3 and
methanol. No product was formed, and starting material 3a
decomposed completely. Therefore, we decided to use an
orthogonal strategy to deprotect the TBS group first. When a
TBAF solution (1 M in THF) was slowly added to ynone 3a at
room temperature, TLC analysis of the reaction mixture
showed complete disappearance of the starting material and the
appearance of a single new product spot within a few minutes.
NMR analysis of the product revealed that an unusual 7-endo-
dig addition product (i.e., the novel seven-membered
oxazepinone 8a) had formed. Subjecting all ynones 3 to the
same reaction conditions furnished oxazepin-5-ones 8a−8h
(Table 2).
For the synthesis of propargyl alcohols 4 (Table 1), alkynyl
nucleophiles were generated by adding n-BuLi to a THF
Table 1. Synthesis of Propargyl Alcohols 4
The proposed mechanism of cyclization is shown in Scheme
4. After the removal of the silyl group, the oxygen anion attacks
the triple bond in Michael fashion, yielding oxazepin-5-ones 8
as a 7-endo-dig-cyclization product.
entry (compound)
R1
R2
yield (%)
1 (4a)
2 (4b)
3 (4c)
4 (4d)
5 (4e)
6 (4f)
7 (4g)
8 (4h)
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
Ph
64
33
83
26
55
70
21
46
4-MeO(C6H4)
4-CF3(C6H4)
thiophen-3-yl
Me
Scheme 4. Proposed Mechanism of Cyclization
tert-Bu
PhthN−CH2
BnO−CH2
4-MeO(C6H4)
4-MeO(C6H4)
solution of the alkynes at −78 °C. When R2 was methyl, we
used commercially available propynyl magnesium bromide. The
aldehydes 5 were added to the alkynyl nucleophiles at −78 °C
to provide propargyl alcohols 4 (Table 1) as a 1:1 mixture of
diastereomers.
D
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We assigned the identity of the 7-endo-dig products on the
basis of the H NMR chemical shifts of the vinylic protons
Table 3. Synthesis of 2,3-Dihydropyridin-4(1H)-ones 1
1
(Figure 3). For compounds 8, we observed a chemical shift for
entry (compound)
R1
R2
yield (%)
1 (1a)
2 (1b)
3 (1c)
4 (1d)
5 (1e)
6 (1f)
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
Ph
60
4-CF3(C6H4)
thiophen-3-yl
Me
78
Figure 3. Chemical shifts of vinylic protons (5.3−5.9 ppm) for
compounds 8 in comparison with 3a,4-dihydrooxepinone 9 (5.2
ppm),54 4-oxo-3,4-dihydro-2H-pyran 10 (5.3 ppm),58 and (Z)-2-
benzylidene-4-methyldihydro-2H-pyran-3(4H)-one 11 (6.7 ppm).59
88
100
100
75
tert-Bu
BnO−CH2
4-MeO(C6H4)
the vinyl proton at 5.3 ppm for aliphatic R2 groups and at 5.8−
5.9 ppm for aromatic R2 groups, which is in accordance with
shifts reported in the literature for similar compounds like 6,7-
dihydrooxepin-4(5H)-ones (5.3−5.8 ppm),54,55 5-substituted
furanones (5.3 ppm),56 and 2-substituted dihydropyranones
(5.3 ppm).56−58 This also ruled out the possibility that 6-exo-
trig products had formed, in which case the 1H NMR chemical
shifts for the vinyl protons would be expected at 6.7 ppm.59
A literature search indicated that this particular seven-
membered scaffold has not been reported before, although 1,2-
oxazepines are a known class of compounds.60 Various methods
have been reported for the synthesis of the 1,2-oxazepine core.
These include pyrolysis of cyclic N-oxides,60−62 double
Michael-type addition of hydroxylamine to heptadienone,63
intramolecular N-alkylation of a hydroxylamine derivative,64
intramolecular O-alkylation,65 ring-closing metathesis of
alkenes tethered by hydroxylamine,66 Pd-catalyzed [4 + 3]
cycloaddition of γ-methylidene-δ-valerolactones with nitro-
nes,67 ring enlargement of bicyclic dibromo-1,2-oxazines,68
gold(I)-catalyzed 1,3-dipolar cycloaddition of alkynyl cyclo-
propyl oximes with nitrones,69 and cyclocondensation of
chalcone-based 1,5-diketones and hydroxylamine.70 In all of
these reports, the structures of the final 1,2-oxazepine
derivatives obtained are different from 1,2-oxazepinones 8.
For example, some of the above-mentioned examples of
oxazepines are fused with heterocycles or a benzene ring, do
not possess unsaturation in the ring, and, many of those
compounds, are devoid of a ketone moiety in their structures.
Scaffold 8 contains an α,β-unsaturated ketone within the ring
system that is bonded to oxygen at the β-position, thus
featuring also an enol ether moiety.
materials. The advantage of this method is that a wide variety
aminoaldehydes 5 with different substituents can be prepared
from α,β-unsaturated aldehydes employing MacMillan’s
enantioselective organocatalytic method. The α,β-unsaturated
aldehydes are readily accessible by reacting aldehydes with
(triphenyphosphoranylidene)acetaldehyde. Another result from
this research is the identification of 3,4-dihydro-1,2-oxazepin-
5(2H)-ones 8 that represent a novel structural type. The one-
flask reductive cleavage of the N−O bonds of these
intermediates followed by Boc-deprotection furnished the
targeted 2,3-dihydropyridin-4-(1H)-ones 1. The 2,3-dihydro-
pyridin-4-(1H)-ones 1, and oxazepinones 8, constitute unique
six- and seven-membered scaffolds that can be used for the
synthesis of diverse compound libraries. Additional chemical
transformations can be carried out (Figure 1) to diversify these
scaffolds further.
EXPERIMENTAL SECTION
All commercially available reagents and solvents were used without
further purification. Flash column chromatography was carried out on
silica gel. TLC was conducted on silica gel 250 μm, F254 plates. H
■
1
NMR spectra were recorded at 400 MHz on a NMR instrument.
Chemical shifts are reported in ppm with TMS as an internal standard
(TMS, 0.0 ppm). Data are reported as follows: chemical shift,
multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; br, broad; and
m, multiplet), integration, and coupling constants (Hz). 13C NMR
spectra were recorded at 100 MHz with complete proton decoupling.
Chemical shifts are reported in ppm with the solvent as internal
standard (CDCl3, 77.2 ppm). High-resolution mass spectrometry was
carried out using ESI-TOF. IR spectra were recorded on a FT-IR
spectrometer and are reported in terms of frequency of absorption
(cm−1). Optical rotations were measured on a polarimeter at a
concentration (c) of grams per 100 mL.
General Procedure for the Synthesis of α,β-Unsaturated
Aldehydes 7. (E)-Hex-2-enal (7a). This compound is commercially
available.
General Procedure for the Synthesis of α,β-Unsaturated
Aldehydes 7b and 7c.52 A toluene solution (0.13 M) of
(triphenylphosphoranylidene)acetaldehyde (1.0 equiv) and appropri-
ate starting aldehyde (1.0 equiv) was heated under reflux for 4 to 5 h
under an argon atmosphere. After the solvent was evaporated in vacuo,
the residue was purified by silica gel chromatography.
Following MacMillan’s precedence that the N−O bond can
be cleaved easily with SmI2, we subjected oxazepinones 8 to
reduction with SmI2 followed by treatment with TFA to
remove the Boc group and isolated the 2,3-dihydropyridin-
4(1H)-ones 1 (Table 3) as the reaction products.
CONCLUSIONS
■
We have extended the scope of our previously reported method
for the synthesis of 3,4-dihydro-1,2-oxazepin-5(2H)-ones 1 by
utilizing aminoaldehydes 5 instead of β-amino acids as starting
E
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(E)-4-(1,3-Dioxoisoindolin-2-yl)but-2-enal (7b).52 Purification of
the crude reaction product by silica gel column chromatography (30%
EtOAc/hexanes) provided the title compound as clear oil in 81% yield
2H), 4.59−4.65 (m, 1H), 7.32−7.35 (m, 5H), 9.75 (t, 1H, J = 2.1 Hz).
13C NMR (100 MHz, CDCl3) δ −4.4, 18.1, 26.0, 28.1, 43.8, 57.8, 69.5,
73.1, 82.0, 127.6, 128.5, 131.8, 137.9, 158.6, 199.9. HRMS m/z [M +
Na] calcd for C22H37NNaO5Si, 446.2339; found, 446.2343. [α]D25
+1.80 (c 0.500, CHCl3). The enantiomeric ratio was determined by
converting the title compound into the corresponding alcohol. For
synthesizing the alcohol, the title compound was dissolved in MeOH
(2.5 M) and cooled to 0 °C. To this was added NaBH4 (4.0 equiv).
After stirring for 1 h, the reaction mixture was quenched with 1.0 M
NaHSO4(aq) and then the extracted with diethyl ether (3 × 10 mL).
The combined organic layer was dried over Na2SO4 and concentrated
in vacuo. The crude alcohol was then converted into the Mosher ester
by reaction with (S)-(+)-α-methoxy-α-(trifluoromethyl)phenylacetyl
chloride (MTPA-Cl). The ratio of the two resulting diastereomeric
compounds was determined to be 90.5:9.5 by 19F NMR. 19F NMR
(400 MHz, CDCl3) δ −71.54 (major peak), −72.12 (minor peak).
General Procedure for the Synthesis of Propargyl Alcohols
4a−d and 4f−h. The alkyne (1.5 equiv) was dissolved in dry THF
(2.0 M) and cooled to −78 °C. A solution of n-butyllithium (2.5 M in
hexanes, 1.3 equiv) was then added dropwise. The mixture was stirred
for 30 min at −78 °C, and then the β-hydroxylamino aldehyde (5a−c,
1.0 equiv) was added slowly. The mixture was stirred for 4 to 5 h.
When the reaction was complete, as indicated by TLC, the mixture
was quenched by adding an aqueous saturated solution of ammonium
chloride. The aqueous layer was separated and extracted three times
with ethyl ether. The organic layers were combined, washed with water
and then with brine, dried over anhydrous magnesium sulfate, filtered,
and concentrated in vacuo.
1
(1.8 g). IR (thin film) 1772, 1703, 1679, 1466, 733 cm−1. H NMR
(400 MHz, CDCl3) δ 4.57 (dd, 2H, J1 = 1.7 and J2 = 5 Hz), 6.12−6.18
(ddt, 1H, J1 = 1.7, J2 = 7.6 and J3 = 15.8 Hz), 6.83 (dt, 1H, J1 = 5 and J2
= 15.8 Hz), 7.77 (dd, 2H, J1 = 3 and J2 = 5.5 Hz), 7.90 (dd, 2H, J1 = 3
and J2 = 5.5 Hz), 9.57 (d, 1H, J = 8 Hz) ppm. 13C NMR (100 MHz,
CDCl3) δ 38.4, 123.7, 131.8, 133.1, 134.4, 149.0, 167.5, 192.5 ppm.
HRMS m/z [M + Na] calcd for C12H9NNaO3, 238.0480; found,
238.0484.
(E)-4-(Benzyloxy)but-2-enal (7c). Purification of the crude reaction
product by silica gel column chromatography (20% EtOAc/hexanes)
provided the title compound as clear oil in 85% yield (2.0 g). The
spectral data of the title compound was in agreement with that found
in the literature.71
Synthesis of tert-Butyl (tert-Butyldimethylsilyl)oxycarba-
mate (6). To a round-bottomed flask was added N-Boc hydroxyl-
amine (1.0 equiv) in CH2Cl2 (0.2 M) and triethylamine (1.1 equiv),
and the flask was cooled to 0 °C. To this solution was added TBSCl
(1.0 equiv) as liquid, and the reaction mixture was allowed to warm to
room temperature and stirred for an additional 12 h. Upon completion
of the reaction, the reaction mixture was poured into a separatory
funnel and washed with water and brine. The organic layer was
separated, dried over MgSO4, and concentrated in vacuo. The resulting
residue was purified by silica gel chromatography (10% ether/hexanes)
to provide the title compound as a low-melting solid in 95% yield
(0.88 g). The spectral data of compound 6 matched with that
described in the literature.51
General Procedure for the Synthesis β-Hydroxylaminoalde-
hydes (5).51 A round-bottomed flask equipped with a magnetic stirrer
bar was charged with the pTSA salt of (2R,5R)-5-benzyl-2-tert-butyl-3-
methylimidazolidin-4-one (0.2 equiv) and the appropriate α,β-
unsaturated aldehyde (7) (3.0 equiv) in CHCl3 (1.0 M for 7) and
was then cooled to −20 °C. tert-Butyl (tert-butyldimethylsilyloxy)-
carbamate 6 (1.0 equiv) was added in one portion as a solid, and the
reaction was maintained at −20 °C for 24−36 h. After completion of
the reaction, the reaction mixture was filtered through a silica gel plug,
eluted with diethyl ether, and concentrated in vacuo. The residue was
purified by silica gel chromatography. The spectral data for new
compounds 5b and 5c is given below.
(R)-tert-Butyl (tert-Butyldimethylsilyl)oxy(1-(1,3-dioxoisoindolin-
2-yl)-4-oxobutan-2-yl)carbamate (5b). Purification by silica gel
column chromatography (30% EtOAc/hexanes) provided the title
compound as clear oil in 39% yield (168 mg, er 93.5:6.5). IR (thin
film) 3442, 2945, 2909, 2849, 1719, 1395, 1364, 1252, 1169 cm−1. 1H
NMR (400 MHz, CDCl3) δ 0.12 (s, 3H), 0.16 (s, 3H), 0.86 (s, 9H),
1.45 (s, 9H), 2.70 (dd, 1H, J1 = 1.5, J2 = 6.1, and J3 = 17.2 Hz), 2.98
(ddd, 1H, J1 = 1.8, J2 = 7.8, and J3 = 17.2 Hz), 3.80 (dd, 1H, J1 = 6.4
and J2 = 13.8 Hz), 4.09 (dd, 1H, J1 = 9.7 and J2 = 16.6 Hz), 4.60 (p,
1H, J = 6.7 Hz), 7.69 (dd, 2H, J1 = 3 and J2 = 5.5 Hz), 7.82 (dd, 2H, J1
= 3 and J2 = 5.5 Hz), 9.73 (t, 1H, J = 1.6 Hz). 13C NMR (100 MHz,
CDCl3) δ −4.8, 17.9, 25.8, 28.1, 39.0, 44.7, 56.8, 82.3, 123.3, 132.1,
134.0, 157.7, 167.9, 199.2. HRMS m/z [M + Na] calcd for
C23H34N2NaO6Si, 485.2084; found, 485.2089. [α]2D5 −27.0 (c 0.500,
CHCl3). The enantiomeric ratio was determined by further derivatiz-
ing the title compound to form (3R,5S)-tert-butyl 3-((1,3-dioxoisoin-
dolin-2-yl)methyl)-5-hydroxyisoxazolidine-2-carboxylate following a
literature procedure.51 The spectral data and the specific optical
rotation ([α]2D5 −60.0 (c 0.600, CHCl3)) of this compound matched
the literature value.51
(R)-tert-Butyl 1-(Benzyloxy)-4-oxobutan-2-yl((tert-butyldimethyl-
silyl)oxy)carbamate (5c). Purification by silica gel column chromatog-
raphy (20% Et2O/hexanes) provided the title compound as clear oil in
68% yield (583 mg). IR (thin film) 3430, 2945, 2930, 2858, 1728,
1479, 1455, 1388, 1368, 1310, 1251, 1168, 1109, 841, 786, 698 cm−1.
1H NMR (400 MHz, CDCl3) δ 0.14 (d, 6H, J = 1.7 Hz), 0.94 (s, 9H),
1.46 (s, 9H), 2.59 (ddd, 1H, J1 = 2.1, J2 = 7.3, and J3 = 16.5 Hz), 2.76
(ddd, 1H, J1 = 2.1, J2 = 7.3, and J3 = 16.5 Hz), 3.50 (dd, 1H, J1 = 7.2
and J2 = 9.4 Hz), 3.73 (dd, 1H, J1 = 6.7 Hz and J2 = 9.4 Hz), 4.52 (s,
tert-Butyl (tert-Butyldimethylsilyl)oxy((4S)-6-hydroxy-8-phenyl-
oct-7-yn-4-yl)carbamate (4a). Purification by silica gel column
chromatography (20% Et2O/hexanes) provided the title compound
as pale yellow oil in 64% yield (631 mg). IR (thin film) 3350, 3028,
1
2925, 1708, 1600, 1384, 1364, 1158, 758, 698 cm−1. H NMR (400
MHz, CDCl3) δ 0.19−0.20 (m, 6H), 0.92−0.96 (m, 12H), 1.46−1.49
(m, 12H), 1.75−1.87 (m, 2H), 2.19−2.34 (m, 1H), 3.96−4.10 (br m,
1H), 4.66−4.73 (m, 1H), 7.28−7.30 (m, 3H), 7.40−7.44 (m, 2H). 13C
NMR (100 MHz, CDCl3) δ −4.5, 13.9, 18.2, 19.9, 26.0, 28.3, 35.6,
40.6, 60.2, 61.5, 81.5, 84.5, 89.8, 122.8, 128.2, 131.7, 158.3. HRMS m/
z [M + Na] calcd for C25H41NNaO4Si, 470.2703; found, 470.2692.
tert-Butyl (tert-Butyldimethylsilyl)oxy((4S)-6-hydroxy-8-(4-
methoxyphenyl)oct-7-yn-4-yl)carbamate (4b). Purification by silica
gel column chromatography (20% Et2O/hexanes) provided the title
compound as pale yellow oil in 33% yield (240 mg). IR (thin film)
1
3348, 2925, 2858, 1708, 1598, 1384, 1364, 1177, 835 cm−1. H NMR
(400 MHz, CDCl3) δ 0.18−0.20 (m, 6H), 0.91−0.95 (m, 12H), 1.36−
1.43 (m, 3H), 1.45−1.48 (m, 9H), 1.72−1.89 (m, 2H), 2.17−2.32 (m,
1H), 3.79 (s, 3H), 3.97−4.09 (br m, 1H), 4.64−4.70 (m, 1H), 6.81 (d,
2H, J = 6.8 Hz), 7.35 (d, 2H, J = 6.8 Hz). 13C NMR (100 MHz,
CDCl3) δ −4.5, 13.9, 18.1, 19.9, 26.0, 28.3, 35.6, 40.7, 55.2, 60.2, 61.5,
81.8, 84.5, 88.8, 113.8, 115.0, 133.1, 158.3, 159.5. HRMS m/z [M +
Na] calcd for C26H43NNaO5Si, 500.2808; found, 500.2799.
tert-Butyl (tert-Butyldimethylsilyl)oxy((4S)-6-hydroxy-8-(4-
(trifluoromethyl)phenyl)oct-7-yn-4-yl)carbamate (4c). Purification
by silica gel column chromatography (20% Et2O/hexanes) provided
the title compound as pale yellow oil in 83% yield (617 mg). IR (thin
1
film) 3252, 2925, 2854, 1710, 1458, 1383, 1364, 1168, 875 cm−1. H
NMR (400 MHz, CDCl3) δ 0.18−0.20 (m, 6H), 0.91−0.96 (m, 12H),
1.46−1.49 (m, 12H), 1.81−1.91 (m, 2H), 2.19−2.35 (m, 1H), 3.92−
4.10 (br m, 1H), 4.67−4.72 (m, 1H), 7.52−7.56 (m, 4H). 13C NMR
(100 MHz, CDCl3) δ −4.5, 13.9, 18.2, 19.9, 26.0, 28.3, 31.6, 40.4, 60.1,
61.4, 81.7, 82.1, 92.4, 125.12, 125.20, 127.9, 131.9, 131.9, 158.3.
HRMS m/z [M + Na] calcd for C26H40F3NNaO4Si, 538.2576; found,
538.2566.
tert-Butyl (tert-Butyldimethylsilyl)oxy((4S)-6-hydroxy-8-(thio-
phen-3-yl)oct-7-yn-4-yl)carbamate (4d). Purification by silica gel
column chromatography (20% Et2O/hexanes) provided the title
compound as pale yellow oil in 26% yield (149 mg). IR (thin film)
1
3258, 2960, 2932, 1708, 1456, 1383, 1369, 1158, 849 cm−1. H NMR
(400 MHz, CDCl3) δ 0.19−0.20 (m, 6H), 0.91−0.93 (m, 3H), 0.96
(d, 9H, J = 2.8 Hz), 1.48 (d, 12H, J = 9.1 Hz), 1.79−1.87 (m, 2H),
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2.20−2.33 (m, 1H), 3.95−4.09 (br m, 1H), 4.68 (dq, 1H, J1 = 6.5 and
J2 = 11.8 Hz), 7.09 (m, 1H, J1 = 1.2, J2 = 2.4, and J3 = 5 Hz) 7.24 (dd,
1H, J1 = 3 and J2 = 5 Hz), 7.42 (ddd, 1H, J1 = 1.1, J2 = 3.0, and J3 = 4.2
Hz). 13C NMR (100 MHz, CDCl3) δ −4.5, 13.9, 18.1, 19.9, 26.0, 28.3,
35.6, 40.6, 60.2, 61.5, 79.6, 81.9, 89.8, 121.8, 125.1, 128.8, 129.9, 158.3.
HRMS m/z [M + Na] calcd for C23H39NNaO4SSi, 476.2267; found,
476.2260.
reaction, as indicated by TLC, the reaction mixture was filtered
through a pad of Celite. The solution was concentrated in vacuo to
give the title compound as a crude oil. The crude product was used in
the next step assuming quantitative yield because complete conversion
was observed.
General Procedure for the Synthesis of Oxazepin-5-ones
8a−h. The ynone (3a−h, 1.0 equiv) was dissolved in THF (0.028 M),
and tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 2.5
equiv) was added at room temperature. After stirring for 1 min, the
reaction was complete, as indicated by TLC. The reaction mixture was
quenched with silica gel and concentrated in vacuo. The yields shown
below refer to the two-step conversion of propargyl alcohols 4 to
oxazepin-5-ones 8.
(S)-tert-Butyl 5-Oxo-7-phenyl-3-propyl-4,5-dihydro-1,2-oxaze-
pine-2(3H)-carboxylate (8a). Purification by silica gel column
chromatography (25% Et2O/hexanes) provided the title compound
as yellow oil in 77% yield (173 mg). IR (thin film) 3402, 3069, 3026,
2925, 1710, 1664, 1619, 1493, 1452, 1384, 1367, 1158, 759, 699 cm−1.
1H NMR (400 MHz, CDCl3) δ 0.96 (t, 3H, J = 7.3 Hz), 1.40 (q, 2H, J
= 7.4 Hz), 1.49 (s, 9H), 1.65−1.74 (m, 1H), 1.79−1.88 (m, 1H),
2.85−2.93 (m, 2H), 4.59 (dq, 1H, J1 = 7.2 and J2 = 9.3 Hz), 5.89 (s,
1H), 7.41−7.49 (m, 3H), 7.92 (dt, 2H, J1 = 1.3 and J2 = 7 Hz). 13C
NMR (100 MHz, CDCl3) δ 13.8, 19.0, 28.3, 35.3, 47.3, 58.3, 83.1,
108.3, 127.6, 127.9, 131.7, 132.0, 153.2, 173.5, 197.9. HRMS m/z [M
+ Na] calcd for C19H25NNaO4, 354.1682; found, 354.1680. [α]D25
−2.40 (c 0.500, CHCl3).
tert-Butyl tert-Butyldimethylsilyloxy((4S)-6-hydroxynon-7-yn-4-
yl)carbamate (4e). To a solution of 5a (1.00 equiv) in dry THF
(0.05 M) at −78 °C under argon was slowly added 1-propynyl
magnesium bromide (0.500 M in tetrahydrofuran, 4.00 equiv). The
reaction mixture was stirred at −78 °C and monitored by TLC. After 4
to 5 h, when the reaction was complete as indicated by TLC, the
mixture was quenched by adding an aqueous saturated solution of
ammonium chloride. The mixture was diluted with ethyl ether and
washed with brine. The separated organic layer was dried over MgSO4,
filtered, and concentrated in vacuo. Purification of the resulting residue
by silica gel column chromatography (20% Et2O/hexanes) provided
the title compound as yellow oil in 55% yield (317 mg). IR (thin film)
3212, 2961, 2933, 1709, 1384, 1364, 1142 cm−1. 1H NMR (400 MHz,
CDCl3) δ 0.14−0.15 (m, 6H), 0.87−0.90 (m, 3H), 0.90−0.92 (d, 9H,
J = 8 Hz), 1.34−1.40 (m, 3H), 1.44 (s, 9H), 1.69−1.72 (m, 2H), 1.79
(s, 3H), 2.01−2.17 (m, 1H), 3.86−4.00 (br m, 1H), 4.34−4.42 (m,
1H). 13C NMR (100 MHz, CDCl3) δ −4.5, 3.6, 13.9, 18.1, 19.8, 26.1,
28.3, 35.6, 40.9, 59.8, 61.1, 80.0, 80.5, 81.8, 158.3. HRMS m/z [M +
Na] calcd for C20H39NNaO4Si, 408.2546; found, 408.2556.
tert-Butyl (tert-Butyldimethylsilyl)oxy((4S)-6-hydroxy-9,9-dime-
thyldec-7-yn-4-yl)carbamate (4f). Purification by silica gel column
chromatography (15% Et2O/hexanes) provided the title compound as
pale yellow oil in 70% yield (277 mg). IR (thin film) 3224, 2964, 2934,
2874, 1709, 1459, 1383, 1369, 1163 cm−1. 1H NMR (400 MHz,
CDCl3) δ 0.15 (s, 3H), 0.17 (s, 3H), 0.93−0.95 (m, 12H), 1.21 (s,
9H), 1.48−1.50 (m, 12H), 1.70−1.77 (m, 2H), 2.07−2.22 (m, 1H),
2.47−2.52 (m, 1H), 3.80−4.01 (br m, 1H), 4.42−4.46 (m, 1H). 13C
NMR (100 MHz, CDCl3) δ −4.5, 13.9, 18.1, 19.9, 26.1, 27.3, 28.3,
31.0, 35.6, 41.2, 59.8, 61.2, 79.8, 81.7, 93.3, 158.3. HRMS m/z [M +
Na] calcd for C23H45NNaO4Si, 450.3016; found, 450.3011.
(S)-tert-Butyl 7-(4-Methoxyphenyl)-5-oxo-3-propyl-4,5-dihydro-
1,2-oxazepine-2(3H)-carboxylate (8b). Purification by silica gel
column chromatography (20% Et2O/hexanes) provided the title
compound as yellow oil in 91% yield (112 mg). IR (thin film) 3400,
2961, 2933, 1709, 1659, 1604, 1510, 1458, 1384, 1369, 1332, 1256,
1
1177, 841 cm−1. H NMR (400 MHz, CDCl3) δ 0.96 (t, 3H, J = 7.3
Hz), 1.38−1.42 (m, 2H), 1.49 (s, 9H), 1.64−1.73 (m, 1H), 1.78−1.85
(m, 1H), 2.83−2.94 (m, 2H), 3.86 (s, 3H), 4.57 (dq, 1H, J1 = 7 and J2
= 9.9 Hz), 5.80 (s, 1H), 6.93 (d, 2H, J = 9 Hz), 7.87 (d, 2H, J = 9 Hz).
13C NMR (100 MHz, CDCl3) δ 13.8, 19.0, 28.3, 35.4, 47.1, 55.5, 58.4,
82.9, 106.8, 114.1, 124.3, 129.8, 153.2, 162.6, 174.0, 197.9. HRMS m/z
[M + Na] calcd for C20H27NNaO5, 384.1787; found, 384.1782. [α]D25
−6.20 (c 0.500, CHCl3).
tert-Butyl (tert-Butyldimethylsilyl)oxy((2R)-1-(1,3-dioxoisoindolin-
2-yl)-4-hydroxy-6-(4-methoxyphenyl)hex-5-yn-2-yl)carbamate (4g).
Purification by silica gel column chromatography (20% EtOAc/
hexanes) provided the title compound as pale yellow oil in 21% yield
(40 mg). IR (thin film) 3352, 2900, 1711, 1667, 1384, 1364, 1177, 825
(S)-tert-Butyl 5-Oxo-3-propyl-7-(4-(trifluoromethyl)phenyl)-4,5-
dihydro-1,2-oxazepine-2(3H)-carboxylate (8c). Purification by silica
gel column chromatography (20% Et2O/hexanes) provided the title
compound as yellow oil in 23% yield (19.5 mg). IR (thin film) 3400,
2925, 2854, 1737, 1683, 1650, 1459, 1384, 1364, 1324, 1246, 1169,
1
cm−1. H NMR (400 MHz, CDCl3) δ 0.15−0.19 (m, 6H), 0.87 (d,
9H, J = 6.1 Hz), 1.42 (s, 4H), 1.48 (s, 5H), 1.88−2.01 (m, 1H), 2.43
(ddd, 1H, J1 = 3.2, J2 = 7.8, and J3 = 14.2 Hz), 3.80 (s, 3H), 3.89−4.04
(m, 1H), 4.11−4.20 (m, 1H), 4.28−4.39 (br m, 1H), 4.72−4.79 (m,
1H), 6.80 (m, 2H, J1 = 2.6 and J2 = 9.0 Hz), 7.28−7.35 (m, 2H), 7.69
(dd, 2H, J1 = 3.0 and J2 = 5.5 Hz), 7.82 (ddd, 2H, J1 = 1.4, J2 = 3.0, and
J3 = 5.4 Hz). 13C NMR (100 MHz, CDCl3) δ −4.9, 17.9, 25.8, 28.1,
37.5, 40.5, 55.2, 60.4, 61.4, 82.4, 85.0, 87.9, 113.8, 123.3, 132.1, 133.1,
134.0, 157.6, 159.5, 168.0. HRMS m/z [M + Na] calcd for
C32H42N2NaO7Si, 617.2659; found, 617.2651.
1
875 cm−1. H NMR (400 MHz, CDCl3) δ 0.97 (t, 3H, J = 7.3 Hz),
1.37−1.40 (m, 2H), 1.50 (s, 9H), 1.63−1.75 (m, 1H), 1.79−1.88 (m,
1H), 2.92 (d, 2H, J = 8.5 Hz), 4.59 (dq, 1H, J1 = 7 and J2 = 9.6 Hz),
5.95 (s, 1H), 7.68 (d, 2H, J = 8.3 Hz), 8.05 (d, 2H, J = 8.2 Hz). 13C
NMR (100 MHz, CDCl3) δ 13.8, 18.9, 28.3, 35.3, 47.4, 58.5, 83.4,
109.9, 125.5, 125.6, 128.1, 133.0, 135.4, 153.1, 171.7, 197.7. HRMS m/
z [M + Na] calcd for C20H24F3NNaO4, 422.1555; found, 422.1553.
[α]2D5 +3.00 (c 0.500, CHCl3).
tert-Butyl ((2R)-1-(Benzyloxy)-4-hydroxy-6-(4-methoxyphenyl)-
hex-5-yn-2-yl)((tert-butyldimethylsilyl)oxy)carbamate (4h). Purifica-
tion by silica gel column chromatography (20% Et2O/hexanes)
provided the title compound as pale yellow oil in 46% yield (240 mg).
IR (thin film) 3350, 2967, 2900, 2833, 1713, 1384, 1364, 1178, 850
(S)-tert-Butyl 5-Oxo-3-propyl-7-(thiophen-3-yl)-4,5-dihydro-1,2-
oxazepine-2(3H)-carboxylate (8d). Purification by silica gel column
chromatography (20% Et2O/hexanes) provided the title compound as
yellow oil in 64% yield (45.4 mg). IR (thin film) 3401, 2961, 2931,
1
1709, 1662, 1618, 1457, 1383, 1369, 1254, 1158, 1088, 849 cm−1. H
1
cm−1. H NMR (400 MHz, CDCl3) δ 0.18−0.19 (m, 6H), 0.95 (s,
NMR (400 MHz, CDCl3) δ 0.97 (t, 3H, J = 7.3 Hz), 1.38−1.44 (m,
2H), 1.47 (s, 9H), 1.63−1.72 (m, 1H), 1.78−1.87 (m, 1H), 2.84−2.95
(m, 2H), 4.54 (dq, 1H, J1 = 7 and J2 = 9.6 Hz), 5.82 (s, 1H), 7.31−
7.33 (dd, 1H, J1 = 1.3 and J2 = 5.1 Hz), 7.36 (dd, 1H, J1 = 3 and J2 =
5.1 Hz), 8.08 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 13.8, 19.0, 28.3,
35.4, 47.3, 58.0, 82.9, 107.9, 125.8, 126.8, 128.9, 134.3, 153.1, 168.9,
197.9. HRMS m/z [M + Na] calcd for C17H23NNaO4S, 360.1246;
found, 360.1237. [α]2D5 −1.80 (c 0.500, CHCl3).
(S)-tert-Butyl 7-Methyl-5-oxo-3-propyl-4,5-dihydro-1,2-oxaze-
pine-2(3H)-carboxylate (8e). Purification by silica gel column
chromatography (20% Et2O/hexanes) provided the title compound
as yellow oil in 73% yield (60.1 mg). IR (thin film) 3400, 2962, 2933,
1710, 1667, 1384, 1365, 1254, 1142 cm−1. 1H NMR (400 MHz,
9H), 1.44 (s, 5H), 1.46 (s, 4H), 1.90−2.08 (m, 1H), 2.19−2.29 (m,
1H), 3.61 (ddd, 1H, J1 = 6.9, J2 = 9.7, and J3 = 26.2 Hz), 3.76−3.82
(m, 4H), 4.21−4.35 (m, 1H), 4.55−4.57 (m, 2H), 4.70−4.79 (m, 1H),
6.81 (d, 2H, J = 8.8 Hz), 7.32−7.37 (m, 7H). 13C NMR (100 MHz,
CDCl3) δ −4.7, 18.0, 26.0, 28.2, 38.1, 55.2, 60.4, 61.2, 71.0, 73.0, 81.8,
84.9, 88.2, 113.8, 114.9, 125.9, 127.6, 128.4, 133.1, 137.9, 158.4, 159.6.
HRMS m/z [M + Na] calcd for C31H45NNaO6Si, 578.2914; found,
578.2909.
General Procedure for the Synthesis of Ynones 3a−h. The
propargyl alcohol (4a−h, 1.0 equiv) was dissolved in 1,2-dichloro-
ethane (0.035 M), and activated MnO2 (30 equiv) was added. The
reaction mixture was refluxed overnight. After completion of the
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CDCl3) δ 0.95 (t, 3H, J = 7.3 Hz), 1.36−1.40 (m, 2H), 1.48 (s, 9H),
1.55−1.61 (m, 1H), 1.74−1.81 (m, 1H), 2.10 (s, 3H), 2.82 (d, 2H, J =
3.81 (dq, 1H, J1 = 5.1, J2 = 5.8, and J3 = 11.6 Hz), 4.89 (br s, 1H), 5.40
(s, 1H), 7.42−7.53 (m, 5H). 13C NMR (100 MHz, CDCl3) δ 14.0,
18.8, 36.5, 41.5, 53.2, 98.8, 126.1, 129.1, 130.9, 135.9, 161.2, 193.3.
HRMS m/z [M + Na] calcd for C14H17NNaO, 238.1208; found,
238.1198. [α]2D5 −61.4 (c 0.500, CHCl3).
7.9 Hz), 4.38−4.46 (dq, 1H, J1 = 7 and J2 = 9.6 Hz), 5.31 (s, 1H). 13
C
NMR (100 MHz, CDCl3) δ 13.7, 19.1, 19.9, 28.2, 35.1, 47.4, 56.7,
82.6, 110.2, 152.6, 173.9, 197.6. HRMS m/z [M + Na] calcd for
C14H23NNaO4, 292.1525; found, 292.1512. [α]2D5 +5.80 (c 0.500,
CHCl3).
(S)-2-Propyl-6-(4-(trifluoromethyl)phenyl)-2,3-dihydropyridin-
4(1H)-one (1b). (78% yield, 9.80 mg). IR (thin film) 3401, 2900, 1625,
1
1533, 1384, 1325, 827 cm−1. H NMR (400 MHz, CDCl3) δ 1.01 (t,
(S)-tert-Butyl 7-tert-Butyl-5-oxo-3-propyl-4,5-dihydro-1,2-oxaze-
pine-2(3H)-carboxylate (8f). Purification by silica gel column
chromatography (10% Et2O/hexanes) provided the title compound
as yellow oil in 52% yield (52.4 mg). IR (thin film) 3402, 2964, 2934,
2874, 1739, 1710, 1628, 1459, 1383, 1369, 1318, 1255, 1163 cm−1. 1H
NMR (400 MHz, CDCl3) δ 0.95 (t, 3H, J = 7.3 Hz), 1.24 (s, 9H),
1.35−1.43 (m, 2H), 1.48 (s, 9H), 1.55−1.64 (m, 1H), 1.74−1.83 (m,
1H), 2.72 (dd, 1H, J1 = 7.8 and J2 = 14.9 Hz), 2.86 (dd, 1H, J1 = 7.8
and J2 = 14.9 Hz), 4.46 (dq, 1H, J1 = 7.3 and J2 = 9.6 Hz), 5.34 (s,
1H). 13C NMR (100 MHz, CDCl3) δ 13.7, 19.2, 28.26, 28.29, 34.4,
36.7, 47.1, 57.1, 82.7, 105.4, 153.3, 181.9, 199.0. HRMS m/z [M + Na]
calcd for C17H29NNaO4, 334.1995; found, 334.1988. [α]2D5 +14.2 (c
0.500, CHCl3).
3H, J = 7.3 Hz), 1.44−1.50 (m, 2H), 1.69−1.74 (m, 2H), 2.41 (dd,
1H, J1 = 13 Hz and J2 = 16.2 Hz), 2.53 (dd, 1H, J1 = 4.9 Hz and J2 =
16.2 Hz), 3.79−3.86 (m, 1H), 4.88 (br s, 1H), 5.38 (s, 1H), 7.64 (d,
2H, J = 8.2 Hz), 7.71 (d, 2H, J = 8.2 Hz). 13C NMR (100 MHz,
CDCl3) δ 13.9, 18.8, 36.5, 41.4, 53.4, 99.7, 126.0, 126.1, 126.6, 132.8,
139.42, 159.6, 193.2. HRMS m/z [M + Na] calcd for C15H16F3NNaO,
306.1082; found, 306.1078. [α]2D5 −21.4 (c 0.500, CHCl3).
(S)-2-Propyl-6-(thiophen-3-yl)-2,3-dihydropyridin-4(1H)-one (1c).
(88% yield, 19.6 mg). IR (thin film) 3271, 2925, 1605, 1573, 1526,
1384, 1261, 787 cm−1. 1H NMR (400 MHz, CDCl3) δ 0.99 (t, 3H, J =
7.3 Hz), 1.43−1.49 (m, 2H), 1.64−1.75 (m, 2H), 2.37 (dd, 1H, J1 =
12.8 Hz and J2 = 16.1 Hz), 2.49 (dd, 1H, J1 = 4.8 Hz and J2 = 16.1 Hz),
3.74−3.82 (m, 1H), 5.03 (br s, 1H), 5.42 (s, 1H), 7.25 (dd, 1H, J1 =
1.3 Hz and J2 = 5.1 Hz), 7.40 (dd, 1H, J1 = 2.9 Hz and J2 = 5.1 Hz),
7.60 (dd, 1H, J1 = 1.3 Hz and J2 = 2.9 Hz). 13C NMR (100 MHz,
CDCl3) δ 14.0, 18.8, 36.5, 41.6, 53.1, 98.3, 124.5, 125.3, 127.2, 137.2,
155.7, 193.4. HRMS m/z [M + Na] calcd for C12H15NNaOS,
244.0772; found, 244.0764. [α]2D5 −128.2 (c 0.5000, CHCl3).
(R)-tert-Butyl 3-((1,3-Dioxoisoindolin-2-yl)methyl)-7-(4-methoxy-
phenyl)-5-oxo-4,5-dihydro-1,2-oxazepine-2(3H)-carboxylate (8g).
Purification by silica gel column chromatography (30% EtOAc/
hexanes) provided the title compound as yellow oil in 43% yield (13.7
mg). IR (thin film) 3400, 2900, 1718, 1667, 1603, 1450, 1384, 1364,
1
1256, 1177, 826 cm−1. H NMR (400 MHz, CDCl3) δ 1.31 (s, 9H),
2.88 (m, 1H, J1 = 5.8 and J2 = 12.9 Hz), 3.08 (m, 1H), 3.85−3.89 (m,
4H), 4.14 (dd, 1H, J1 = 7.6 and J2 = 14.1 Hz), 5.00 (dq, 1H, J1 = 6.6
and J2 =10.8 Hz), 5.83 (s, 1H), 6.93 (d, 2H, J = 8.9 Hz), 7.74 (dd, 2H,
J1 = 3 and J2 = 5.4 Hz), 7.87−7.90 (m, 4H). 13C NMR (100 MHz,
CDCl3) δ 28.0, 39.1, 44.8, 55.4, 56.9, 83.4, 106.7, 114.1, 123.5, 123.9,
129.9, 132.1, 134.1, 152.5, 162.8, 168.0, 175.1, 196.2. HRMS m/z [M
+ Na] calcd for C26H26N2NaO7, 501.1638; found, 501.1632. [α]D25
−80.6 (c 0.500, CHCl3).
(S)-6-Methyl-2-propyl-2,3-dihydropyridin-4(1H)-one (1d). (100%
yield, 11.0 mg). IR (thin film) 3271, 2967, 2926, 1617, 1592, 1533,
1
1384 cm−1. H NMR (400 MHz, CDCl3) δ 0.96 (t, 3H, J = 7.3 Hz),
1.37−1.43 (m, 2H), 1.55−1.61 (m, 2H), 1.96 (s, 3H), 2.25 (dd, 1H, J1
= 13.1 Hz and J2 = 16 Hz), 2.38 (dd, 1H, J1 = 4.9 Hz and J2 = 16.1
Hz), 3.59−3.67 (m, 1H), 4.57 (br s, 1H), 4.95 (s, 1H). 13C NMR (100
MHz, CDCl3) δ 13.9, 18.6, 21.3, 36.6, 41.2, 53.2, 99.5, 161.3, 192.8.
HRMS m/z [M + Na] calcd for C9H15NNaO, 176.1051; found,
176.1045. [α]2D5 −15.8 (c 0.500, CHCl3).
(R)-tert-Butyl 3-(Benzyloxymethyl)-7-(4-methoxyphenyl)-5-oxo-
4,5-dihydro-1,2-oxazepine-2(3H)-carboxylate (8h). Purification by
silica gel column chromatography (20% Et2O/hexanes) provided the
title compound as yellow oil in 48% yield (80.0 mg). IR (thin film)
3400, 2967, 2900, 2833, 1750, 1733, 1667, 1604, 1384, 1364, 1257,
(S)-6-tert-Butyl-2-propyl-2,3-dihydropyridin-4(1H)-one (1e).
(100% yield, 32.4 mg). IR (thin film) 3301, 2959, 2925, 1605, 1513,
1465, 1384, 1364 cm−1. 1H NMR (400 MHz, CDCl3) δ 0.97 (t, 3H, J
= 7.3 Hz), 1.19 (s, 9H), 1.39−1.43 (m, 2H), 1.56−1.66 (m, 2H), 2.24
(dd, 1H, J1 = 12.6 and J2 = 16.1 Hz), 2.40 (dd, 1H, J1 = 4.9 and J2 =
16.1 Hz), 3.55−3.63 (m, 1H), 4.76 (br s, 1H), 5.12 (s, 1H). 13C NMR
(100 MHz, CDCl3) δ 13.9, 18.8, 28.6, 35.3, 36.3, 41.1, 53.1, 96.0,
172.6, 193.5. HRMS m/z [M + Na] calcd for C12H21NNaO, 218.1521;
found, 218.1518. [α]2D5 −73.4 (c 0.500, CHCl3).
1
1178, 850 cm−1. H NMR (400 MHz, CDCl3) δ 1.45 (s, 9H), 2.86−
2.99 (m, 2H), 3.58−3.62 (dd, 1H, J1 = 8 and J2 = 12 Hz), 3.74−3.78
(dd, 1H, J1 = 8 and J2 = 10 Hz), 3.85 (s, 3H), 4.56 (m, 2H), 4.83 (dq,
1H, J1 = 6.6 and J2 =10.8 Hz), 5.82 (s, 1H), 6.93 (d, 2H, J = 8.9 Hz),
7.26 (m, 3H), 7.33 (m, 2H), 7.87 (d, 2H, J = 8.8 Hz). 13C NMR (100
MHz, CDCl3) δ 28.2, 44.2, 55.4, 57.8, 69.6, 73.1, 83.1, 106.9, 114.1,
124.2, 127.6, 127.7, 128.4, 129.9, 137.8, 153.3, 162.7, 173.9, 197.2.
HRMS m/z [M + Na] calcd for C25H29NNaO6, 462.1893; found,
462.1886. [α]2D5 −50.8 (c 0.500, CHCl3).
(R)-2-(Benzyloxymethyl)-6-(4-methoxyphenyl)-2,3-dihydropyri-
din-4(1H)-one (1f). (75% yield, 16.4 mg). IR (thin film) 3401, 2918,
1
1604, 1508, 1384, 1258, 833 cm−1. H NMR (400 MHz, CDCl3) δ
General Procedure for the Synthesis of 2,3-Dihydropyridin-
4(1H)-ones 1a−f. To an oven-dried 10 mL round-bottomed flask
charged with corresponding oxazepin-5-one 1 (1.00 equiv) in degassed
MeOH (1 mL) was added SmI2 (0.100 M in tetrahydrofuran, 3.00
equiv) under an argon atmosphere. The deep-blue solution was
allowed to stir at room temperature until the reaction turned pale
yellow (2 min) or was deemed complete by TLC. The solvent was
removed in vacuo, and the residue was then resuspended in
dichloromethane (20 mL). The organic layer was washed successively
with aqueous 1 M NaHSO4, H2O, and brine, dried over MgSO4, and
concentrated in vacuo to give crude compound. To a solution of this
crude compound in dichloromethane (1 mL) was added trifluoroacetic
acid (TFA). The reaction mixture was stirred until TLC showed that
the reaction was complete (∼24 h). The reaction mixture was then
diluted with DCM (20 mL) and washed with saturated NaHCO3
solution, and brine. The organic layer was dried (MgSO4), filtered, and
concentrated to afford the pure title compound.
2.30−2.42 (m, 2H), 3.62−3.67 (m, 2H), 3.85 (s, 3H), 3.99−4.07 (m,
1H), 4.59 (s, 2H), 5.37 (s, 1H), 5.47 (br s, 1H), 6.94 (d, 2H, J = 8.8
Hz), 7.32−7.37 (m, 5H), 7.46 (d, 2H, J = 8.8 Hz). 13C NMR (100
MHz, CDCl3) δ 37.7, 52.7, 55.5, 71.6, 73.4, 97.9, 114.4, 127.5 127.8,
128.1, 128.6, 137.4, 160.9, 161.8, 191.8. HRMS m/z [M + Na] calcd
for C20H21NNaO3, 346.1419; found, 346.1418. [α]2D5 −86.4 (c 0.500,
CHCl3).
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
(S)-6-Phenyl-2-propyl-2,3-dihydropyridin-4(1H)-one (1a). (60%
yield, 13.7 mg). IR (thin film) 3403, 2900, 2858, 1617, 1531, 1384,
1325, 759, 699 cm−1. 1H NMR (400 MHz, CDCl3) δ 1.00 (t, 3H, J =
7.3 Hz), 1.43−1.57 (m, 2H), 1.64−1.74 (m, 2H), 2.40 (dd, 1H, J1 =
12.9 Hz and J2 = 16.1 Hz), 2.51 (dd, 1H, J1 = 4.9 Hz and J2 = 16.1 Hz),
Corresponding Author
*E-mail: georg@umn.edu.
Notes
The authors declare no competing financial interest.
H
dx.doi.org/10.1021/jo402445r | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(34) Gouault, N.; Le Roch, M.; Cheignon, A.; Uriac, P.; David, M.
Org. Lett. 2011, 13, 4371−4373.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the NIH
(grant nos. P41 GM076302 and P41 GM081267) and the
University of Minnesota through the Vince and McKnight
Endowed Chairs (to G.I.G).
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