Pd(ii)-Catalyzed aerobic 1,2-difunctionalization of conjugated dienes: Efficient synthesis of morpholines and 2-morpholones

Article abstract of DOI:10.1039/c8ob01291a

A novel and efficient methodology concerning the Pd(ii)-catalyzed intermolecular difunctionalization of conjugated dienes is reported to synthesize a series of functionalized morpholines and 2-morpholones. Widely distributed and easily obtained β-amino alcohols and α-amino acids, as starting nitrogen and oxygen sources, are successfully applied in the difunctionalization of conjugated dienes respectively. The majority of the desired products were obtained in moderate to excellent yields. Oxygen was successfully employed as a terminal oxidant. Further transformation of the generated products allowed for the expansion of structural diversity.

Full text of DOI:10.1039/c8ob01291a

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Pd(II)-catalyzed aerobic 1,2-difunctionalization of conjugated
dienes: efficient synthesis of morpholines and 2-morpholones
Ke Wen, a Zhengxing Wu, a Buyun Chen, a Jianzhong Chen a and Wanbin Zhang*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A novel and efficient methodology concerning the Pd(II)-catalyzed intermolecular difunctionalization of conjugated dienes
is reported, to synthesize a series of functionalized morpholines and 2-morpholones. Widely distributed and easily
obtained β-amino alcohols and α-amino acids, as starting nitrogen and oxygen sources, are successfully applied in
difunctionalization of conjugated dienes respectively. The majority of the desired products were obtained in moderate to
excellent yields. Oxygen was successfully employed as a terminal oxidant. Further transformation of the generated
www.rsc.org/
products
allowed
for
the
expansion
of
structural
diversity.
H
N
H
N
Introduction
H
N
1,4-Oxazine is one of the most important heterocyclic motifs
found in numerous natural products and important synthetic
intermediates.1 For example, morpholine and 2-morpholone,
are especially useful due to their presence in natural products
O
Ph
OMe
OMe
OMe
Chelonin A
OH
O
O
O
HN
EtO
Cl
Reboxetine
(antidepressant)
Dopamine inhibition
(antiinflammatory activity)
and drugs (Fig. 1).2 To date,
a number of intra- and
O
intermolecular synthetic strategies have been developed for
the preparation of 1,4-oxazines due to their broad
applicability. The most prominent intramolecular strategies
mainly include direct amination or oxygenation of alkenes or
alkynes catalyzed or mediated by different metals.3 For
representative intermolecular approaches, in 2008, a copper-
O
N
O
O
O
O
O
N
N
O
N
H
N
O
N
H
HN
O
F
Cl
Didepsipeptide
(Antimicrobial)
Tachykinin receptor
antagonist
Signal transduction
inhibition
catalyzed
strategy
exploring
aminooxygenation
of
Fig.
1
Representative bioactive structures containing
haloacetylenes was reported by Urabe and co-workers
(Scheme 1a).4 Aggarwal and co-workers have reported
procedures using β-amino alcohols and different sulfonium
salts to synthesize morpholine derivatives via an onium ion
electrophile (Scheme 1b).5 Other important intermolecular
examples are also related to two- or multicomponent
reactions initiated by in-situ generated nucleophiles or
electrophiles.6 Although excellent yields and selectivities have
been achieved using the aforementioned methodologies,
further developments in this field are still hindered by the
need for specially designed substrates or exotic reagents, poor
efficiency with regards to atom economy and the complexity
of the synthetic operations. Furthermore, to the best of our
knowledge, there is no report concerning intermolecular
catalytical synthesis of 2-morpholones.
morpholine and 2-morpholone.
Reported work:
Urabe's work
C6H13
OH
C6H13
OH
C6H13
HO
C6H13
O
Cu cat.
Cu
(a)
(b)
N
O
TsHN
N
O
N
S
Br
Ts
Ts
Tol
Aggarwal's work
R2 OH
H
O
R2
R1
O
N
R2
R1
SR2
R2
R1
O
SR2
X
SR2
R1 NHPG
N
PG
N
PG
PG
This work:
O
OH
R'
Pd(OAc)2 (10 mol %)
R'
O
Cu(II), 2, DMSO
N
NHTs
or
R
R
Ts
R
(c)
O
OH
O
O
Pd(OAc)2 (10 mol %)
O
2, DMSO
R''
NHTs
R''
N
Ts
Metal-catalyzed intermolecular difunctionalization of
conjugated dienes provides a powerful tool for the formation
moderate to excellent yields
easily obtained starting materials
atom economic reactions
Scheme 1 Representative intermolecular 1,4-oxazine synthesis.
of heterocompounds.7 As part of continued research on the
Pd-catalyzed functionalization of alkenes, we recently reported
a solvent controlled regiodivergent 1,2-difunctionalization of
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Table 2 Optimization of reaction conditions for 2-morpholone
synthesisa
conjugated dienes for the synthesis of functionalized 1,4-
benzoxazines using o-amino phenols, with excellent yields and
selectivities.7l Based on these results, we envisioned that many
other useful structures could be obtained via this methodology
by using appropriate nucleophiles. Herein, we report the
preparation of morpholines and 2-morpholones using β-amino
alcohols or α-amino acids as nitrogen and oxygen sources
(Scheme 1c). The accessibility of the substrates renders our
reported strategy to be practical and effective.9 In addition,
the residual alkene moiety offers the possibility of further
structural derivatization.
Results and discussion
Reaction conditions were firstly examined for the synthesis of
morpholine via the reaction of tosyl protected 2-aminoethanol
1a with isoprene 2a. Preliminary study showed that compound
3aa, which has its alkenyl group adjacent to the nitrogen,
could be obtained in 15% yield using DMSO as the solvent,
Pd(OAc)2 as the catalyst and O2 (1 atm) as the oxidant (Table 1,
entry 1). Increasing the O2 pressure to 10 atm only lead to a
slight rise in yield (entry 2). MnO2, benzoquinone and 2,5-
dimethyl-p-benzoquinone were further screened as oxidants
when the reaction was performed under N2 but the results
were unsatisfactory (entries 3-5). A combination of 2,5-
dimethyl-p-benzoquinone and O2 did not provide a better
result (entry 6). To our delight, when Cu(OAc)2 was used as the
oxidant, the desired product was obtained in 78% yield (entry
7). Intriguingly, the desired product could be prepared in 87%
yield when O2 was employed as the terminal oxidant and a
a The reaction was carried out with 4a (0.2 mmol, 1 equiv), 2a
(2.0 mmol, 10 equiv.) and oxidant in DMSO (1 mL) in the
presence of Pd(OAc)2 (10 mol %) at 70 oC for 24 h unless
otherwise noted. b Isolated yields. c The BQ1 was 2,5-dimethyl-
p-BQ.
catalytic amount of Cu(OAc)2 was used (entry 8). Reducing the
loading of Cu(OAc)2 (entry 9), isoprene 2a (entry 10) and
Pd(OAc)2 (entry 11), led to a corresponding reduction in yield.
In continuation of the optimization of the reaction
conditions, we studied the reaction conditions for 2-
morpholone synthesis with tosyl protected glycine 4a. Initial
Table 1 Optimization of reaction conditions for morpholine
synthesisa
trials revealed that neither
a stoichiometric amount of
Cu(OAc)2 nor a combination of Cu(OAc)2 and O2 were suitable
for the reaction (Table 2, entries 1-2). Changing the oxidant to
benzoquinone resulted in 5aa being obtained in 27% yield
(entry 3). Interestingly, the alkenyl group of 5aa was adjacent
to the oxygen, differing from the synthesis of the morpholine
compounds. However, use of 2,5-dimethyl-p-benzoquinone
only gave a trace amount of product (entry 4). A slight
reduction of yield was observed when the loading of
benzoquinone was raised to 2 equivalent (entry 5). The
combination of benzoquinone and O2 (1 atm) did not improve
the result (entry 6). Several other oxidants were further
screened, including PhI(OAc)2 (entry 7), MnO2 (entry 8) and O2
(entry 9). To our delight, when O2 (1 atm) was the sole oxidant,
the desired product could be obtained in 14% yield (entry 9).
The product could be prepared in 66% yield with excellent
chemoselectivity when the O2 pressure was increased to 5 atm
(entry 10). 10 atm of O2 provided a similar result for the
reaction (entry 11).
a The reaction was carried out with 1a (0.2 mmol, 1 equiv.), 2a
(2.0 mmol, 10 equiv.) and oxidant in DMSO (1 mL) in the
presence of Pd(OAc)2 (10 mol %) at 80 oC for 24 h unless
otherwise noted. b Isolated yields. c The BQ1 was 2,5-dimethyl-
p-BQ. d 2a (1 mmol, 5 equiv) was used. e Pd(OAc)2 (5 mol %)
was used.
With the optimized conditions (Table 1, entry 8; Table 2,
entry 10) in hand, we continued to test the substrate scope
(Table 3 and 4).10 Firstly, the morpholine scope was screened
(Table 3). In terms of the isoprene substrates, 1,2-
disubstituted β-amino alcohols
(3ba-3da) showed good
reactivities and good diastereoselectivities (>10:1) with the
alkenyl group adjacent to the nitrogen. 1,1-Dimethyl and 2,2-
2 | J. Name., 2012, 00, 1-3
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Table 3 Scope of morpholinesa,b,c
a The reaction was carried out with
(2.0 mmol, 10 equiv.), in the presence of Pd(OAc)2 (10 mol %),
4 (0.2 mmol, 1 equiv.), 2
o
in DMSO (1 mL), at 70 C for 24 h under oxygen (5 atm) in an
b
autoclave.
The ratios of diastereoselectivity
were
determined by H NMR analysis. c Isolated yields and ratios of
the two diastereoisomers were shown. 5 equiv. of diene was
1
a The reaction was carried out with
mmol, 10 equiv.), in the presence of Pd(OAc)2 (10 mol %),
1 (0.2 mmol, 1 equiv.), 2 (2
d
used. e2 equiv. of diene was used.
o
Cu(OAc)2 (20 mol %) in DMSO (1 mL), at 80 C for 24 h under
b
oxygen in a sealed tube. The ratios of diastereoselectivity
(>10:1) whilst maintaining moderate reactivity
(5da).
c
were determined by 1H NMR analysis. Isolated yields and
Moderate yields and good diastereoselectivities were further
obtained for a substrate bearing a phenyl group, irrespective
of the presence of electron-donating or electron-withdrawing
ratios of the two diastereoisomers were shown. d5 equiv. of
diene was used. e3 equiv. of diene was used.
groups on the phenyl ring (5ea-5ga). To our delight, the
dimethyl substituted substrates also gave good results (3ea
and 3fa). For mono-substituted substrates, the yields
remained good but the diastereoselectivities turned out to be
low for substrates bearing a methyl group or phenyl group
desired product could be obtained in 80% yield for a product
bearing a benzyl group (5ha). Substrates bearing electron-
donating group also showed good reactivity (5ia). Substrates
bearing electron-withdrawing group gave the corresponding
products in moderate yield (5ja). Use of 1,3-butadiene gave its
related product in 58% yield (5ab). For 2,3-dimethyl-1,3-
butadiene, the reaction proceeded smoothly with its
corresponding 2-morpholone being obtained in excellent yield
(
3ga-3ja). Use of 1,3-butadiene offered its corresponding
product in moderate yield (3ab). 2,3-Dimethyl-1,3-butadiene
generated 3ac, which contains a tertiary carbon center, in
moderate yield. A diene bearing a long carbon chain with an
epoxide functional group provided its corresponding product
in 80% yield (3ad). Intriguingly, 1-aryl-1,3-butadiene substrates
(
5ac).
(E)-penta-1,3-diene
underwent
internal
difunctionalization to give 5ad in 83% yield. Interestingly,
spiro-rings 5ae and 5af could be generated in moderate yields
with 2 equivalents of the appropriate dienes. The 1,4-
disubstituted 1,3-dienes were not compatible with the
reaction either.
showed good to excellent results (3ae-3ag). Notably, for the 1-
aryl-1,3-butadienes, the reactions could be accomplished with
3 equivalents of dienes, compared with the large dosage of
isoprene (10 equiv.). The difference between the solubility of
low-boiling and high-boiling dienes may serve as the reason.
We also tested 1,4-disubstituted 1,3-dienes such as 2,4-
hexadiene and 1,3-cyclohexadiene. However, the reactions
could not proceed possibly because the steric hindrance of the
substituted groups on the diene prevented the reaction from
proceeding.
Pd(OAc)2 (0.1 equiv.)
Cu(OAc)2 (0.2 equiv.)
OH
O
O2 (1 atm)
DMSO, 80 oC, 24 h
NHTs
N
Ts
1a
2a
3aa
4.0 mmol
0.86 g
70% yield
Pd(OAc)2 (0.1 equiv.)
O2 (5 atm)
O
OH
O
O
DMSO, 70 oC, 24 h
NHTs
Next, the 2-morpholone substrate scope was surveyed
using the optimized conditions (Table 4). For α-methyl and α-
ethyl amino acids, moderate yields and diastereoselectivities
were observed (5ba and 5ca). Interestingly, when iso-butyl
group was present, exellent diastereoselectivity was achieved
N
Ts
4a
2a
5aa
4.0 mmol
0.92 g
44% yield
Scheme 2 Scale-up synthesis.
Table 4 Scope of 2-morpholonesa,b,c
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To further test the scalability of our methodologies, we
Journal Name
down), a similar five-membered ring 15 was firstly formed by
4a and Pd(OAc)2. Tosyl group was also important for the
reaction as other protecting groups could not proceed the
reaction either (see the ESI†). Ligand exchange facilitated the
formation of complex 16. For complex 16, N-Pd bond inserts
performed the reactions on 4 mmol scale (Scheme 2). It turned
out that the chemoselectivities remained excellent but the
yields reduced at different levels.
A variety of transformations could be conducted on the
into alkene to give complex 17 12k,l
After the conversion from
.
complex 17 to 18 and the following reductive elimination,12m,n
product 5ab was formed.
Ph
O
Ph
O
m-CPBA (1.5 equiv)
DCM, 20 oC, 12 h
(a)
O
N
N
Ts
Ts
Me
6
3ia
87% overall yield
(dr 4:1)
O
O
Na/naphthalene (5.0 equiv)
(b)
(c)
Ph
N
H
Ph
N
THF, 0 o
1 h
C
Ts
7
3ja
77% yield
O
4-Propylhept-1-ene (3.0 equiv)
Grubbs II (5 mol %)
O
Toluene, 80 oC, 24 h
N
N
Ts
Ts
8
3ab
63% yield
Br
Br
O
O
O
O
Br2 (1.5 equiv)
(d)
Ph
N
CHCl3, 20 o
12 h
C
Ph
N
Ts
Ts
9
5ea
95% overall yield
(dr 4:1)
Me
Me
HO
O
O
O
DIBAL-H (2.5 equiv)
(e)
THF, -40 o
2 h
C
N
N
Ts
Ts
5ac
10
93% overall yield
(dr 2.5:1)
Scheme 3 Transformations of morpholine and 2-morpholone
derivatives.
morpholine and 2-morpholone compounds (Scheme 3).
Epoxidation of compound 3ia generated
diastereoselectivity (Scheme 3a). Deprotection of compound
3ja with Na/naphthalene gave morpholine in 77% yield
6 in 87% yield and 4:1
7
(Scheme 3b). Olefin metathesis between generated 3ab and 4-
propylhept-1-ene catalyzed by Grubbs II catalyst provided
compound 8, which contains a long carbon side chain, in 63%
yield (Scheme 3c). Dibromination of 5ea using Br2 could give
Scheme 4 Proposed reaction mechanism.
compound
9 in 95% yield and 4:1 diastereoselectivity (Scheme
Conclusions
3d). Interestingly, A ring-containing hemiacetal compound 10
could be produced by controlled reduction of 5ac in 93% yield
and 2.5:1 diastereoselectivity (Scheme 3e).11
The reaction mechanism was proposed according to the
preliminary mechanism study (see the ESI†).12 In the catalytic
In summary, we have developed a methodology concerning
the
difunctionalization of conjugated dienes, for the preparation of
series of valuable functionalized morpholines and 2-
Pd(II)-catalyzed
aerobic
intermolecular
1,2-
a
cycle of morpholine synthesis (Scheme 4, up),
a five-
morpholones. The direct oxidative difunctionalization of
conjugated dienes was achieved using oxygen as a terminal
oxidant. For most of the products, good yields and selectivities
were obtained. The efficient difunctionalization was achieved
utilizing a combination of 1,3-conjugated dienes and readily
available β-amino alcohols or α-amino acids.
membered Pd(II) complex 11, which contained both O-Pd bond
and N-Pd bond was firstly formed by 1a and Pd(OAc)2.12a-f
Notably, tosyl group was very important for the reaction as
other protecting groups, such as acetamide, Boc group and Cbz
group, could not facilitate the morpholine synthesis (see the
ESI†). We speculated that the strong electron-withdrawing
tosyl group made the N-H bond more acidic, which could
facilitate the formation of bidentate Pd(II)-complex 11 to
continue the subsequent catalytic cycle. Afterwards, ligand
Experimental section
exchange by the diene generated complex 12
underwent insertion of the alkene to O-Pd bond and produced
complex 13 12g,h
Complex 13 was then converted to a more
stable π-allyl Pd(II)-intermediate 14 Product 3ab was
generated from 14 by the formation of C-N bond via reductive
elimination.12i,j The Pd(0) was re-oxidized to Pd(II) to finish the
catalytic cycle. In terms of 2-morpholone synthesis (Scheme 4,
, which
All reactions were performed in oven-dried flask, sealed tube
or autoclave under air, and the workup was operated in air,
unless otherwise noted. The commercially available reagents
were used without further purification. All the solvents used
were purified according to standard procedures. The
purification of products with column chromatography was
.
.
4 | J. Name., 2012, 00, 1-3
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carried out using silica gel (100-200 mesh). The NMR spectra 131.6, 130.3, 127.8, 115.4, 81.0, 46.6, 45.9, 21.6, 18.3. HRMS
were recorded on Bruker Advance III HD 400 (400 MHz, 1H; (ESI) calcd for C14H17NO4S [M+H]+296.0957, found 296.0958.
1
100 MHz, 13C) or Varian MERCURY plus-400 (400 MHz, H; 100
Procedure for the synthesis of transformation product 6
MHz, 13C) spectrometer and dealed with the software
Under air, 3ia (71.5 mg, 0.2 mmol, 1 equiv.) and m-CPBA
MestReNova. HRMS was performed on a Waters Micromass Q-
(70%-75%, 51.7 mg, 0.3 mmol, 1.5 equiv.) was added to 5 mL
TOF Premier Mass Spectrometer. Melting points were
o
dry DCM and the mixture was stirred at 20 C for 12 h. After
measured with SGW X-4 micro melting point apparatus. X-Ray
the completion of reaction, the mixture was washed with
crystallography data were collected using an Xcalibur Atlas
saturated NaHCO3 solution (5 mL, 2 times) and H2O (5 mL,
Gemini ultra diffractometer.
once). The organic layer was collected and dried over Na2SO4.
The dienes were commercially available or prepared
The solvent was then evaporated and purification by
according to the literatures.13
chromatography (PE:EA = 3:1) gave pure product
6 as white
General procedure for the synthesis of functionalized gummy oil (dr = 4:1, 65.0 mg, 87% overall yield; 46.8 mg
morpholines 3
To a sealed tube (15 mL) were added substrate
isolated for major isomer, 10.5 mg isolated for minor isomer).
1
(0.2 For major isomer: H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.2
1
mmol, 1 equiv.), Pd(OAc)2 (4.4 mg, 0.1 equiv.), Cu(OAc)2 (7.3 Hz, 2H), 7.39 – 7.29 (m, 5H), 7.20 (d, J = 6.8 Hz, 2H), 4.08 – 3.93
mg, 0.2 equiv.) and DMSO (1 mL) at room temperature. The (m, 3H), 3.83 (d, J = 14.6 Hz, 1H), 3.41 (dd, J = 12.4, 3.8 Hz, 1H),
resulting mixture was kept stirring for 15 min. Afterwards, the 3.29 (d, J = 4.8 Hz, 1H), 3.20 (dd, J = 14.6, 11.4 Hz, 1H), 2.69 (d,
system was degassed and recharged with O2 for three times. J = 4.8 Hz, 1H), 2.46 (s, 3H), 1.42 (s, 3H). 13C NMR (100 MHz,
Finally, the conjugated diene
2 was added and the tube was CDCl3) δ 144.0, 138.4, 138.1, 130.1, 128.6, 128.4, 127.1, 125.7,
sealed and heated to 80 oC. After stirring for 24 h, the mixture 76.0, 63.7, 55.6, 53.9, 52.7, 48.2, 21.6, 20.3. For minor isomer:
was cooled to room temperature and firstly filtered through a 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.4 Hz, 2H), 7.40 – 7.27
thin silica gel pad (100-200 mesh) using EtOAc to remove (m, 7H), 4.30 (d, J = 12.4 Hz, 1H), 4.22 (dd, J = 11.2, 3.2 Hz, 1H),
DMSO and metal species. The solvent was then removed by 3.84 (dd, J = 13.8, 3.2 Hz, 1H), 3.67 (dd, J = 12.4, 4.4 Hz, 1H),
rotary evaporation. The residue was purified by preparative 3.47 (d, J = 4.2 Hz, 1H), 3.23 (dd, J = 13.8, 11.2 Hz, 1H), 2.97 (d,
TLC on silica gel (PE:EA = 5:1) to give the product
3
.
J = 4.8 Hz, 1H), 2.57 (d, J = 4.8 Hz, 1H), 2.45 (s, 3H), 1.39 (s, 3H).
Colorless 13C NMR (100 MHz, CDCl3) δ 143.9, 138.5, 137.4, 129.9, 128.6,
3-(prop-1-en-2-yl)-4-tosylmorpholine (3aa)
.
1
gummy oil, 48.9 mg, 87% yield. H NMR (400 MHz, CDCl3) δ 128.4, 127.0, 125.9, 67.3, 57.5, 55.5, 55.2, 48.1, 29.3, 21.6,
7.72 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 5.09 – 5.00 (m, 20.6. HRMS (ESI) calcd for C20H23NO4S [M+H]+ 374.1426, found
2H), 4.13 – 4.07 (m, 1H), 3.98 (dd, J = 12.0, 2.4 Hz, 1H), 3.69 – 374.1440.
3.63 (m, 1H), 3.50 – 3.35 (m, 4H), 2.44 (s, 3H), 1.75 (s, 3H). 13C
Procedure for the synthesis of transformation product 7
NMR (100 MHz, CDCl3) δ 143.5, 140.9, 137.2, 129.8, 127.3,
Under N2 atmosphere, naphthalene (1.0 g, 7.8 mmol) and
115.2, 67.8, 65.9, 57.7, 42.2, 21.6, 20.8. HRMS (ESI) calcd for
Na (170.0 mg, 7.4 mmol) were dissolved in 15 mL dry THF and
C14H19NO3S [M+H]+ 282.1164, found 282.1174.
the resulting mixture wad vigrously stirred for 3 h at room
General procedure for the synthesis of functionalized 2- temperature. Under N2 atmosphere, 3ja (71.5 mg, 0.2 mmol, 1
morpholones 5
To a glass tube (15 mL) were added substrate
equiv) was dissolved in 2 mL dry THF and the resulting solution
(0.2 was cooled to 0 oC. To the solution was added the above
4
mmol, 1 equiv.), Pd(OAc)2 (4.4 mg, 0.1 equiv.) and DMSO (1 Na/naphthalene mixture (1.9 mL, 5.0 equiv) at 0 oC and the
mL) at room temperature. The resulting mixture was kept mixture was further stirred for
stirring for 15 min with the tube in an autoclave. Afterwards, maintaining. After the completion of reaction, the mixure was
the conjugated diene was added and the tube was quenched with saturated NH4Cl solution (2 mL) and extraced
1 h with temperature
2
immediately capped with a plastic cap with a tiny hole on it with EA (5 mL, 3 times). The organic layer was collected and
(for the ingression of O2). The autoclave was sealed, charged dried over Na2SO4. The solvent was then evaporated and
with O2 (5 atm) and heated to 70 oC. After stirring for 24 h, the purification by chromatography (PE:EA = 8:1) gave pure
1
as white gummy oil (31.1 mg, 77% yield). H NMR
mixture was cooled to room temperature and firstly filtered product
7
through a thin silica gel pad (100-200 mesh) using EtOAc to (400 MHz, CDCl3) δ 7.52 – 7.28 (m, 5H), 5.18 – 5.13 (m, 1H),
remove DMSO and metal species. The solvent was then 4.92 – 4.88 (s, 1H), 4.03 (dd, J = 10.2, 3.0 Hz, 1H), 3.85 (ddd, J =
removed by rotary evaporation. The residue was purified by 32.6, 10.8, 2.8 Hz, 2H), 3.59 – 3.47 (m, 1H), 3.30 (td, J = 10.6,
preparative TLC on silica gel (PE:EA = 5:1) to give the product
5.
4.2 Hz, 2H), 1.83 – 1.77 (m, 4H).13C NMR (100 MHz, CDCl3) δ
6-(prop-1-en-2-yl)-4-tosylmorpholin-2-one (5aa). White 144.2, 140.6, 128.5, 127.8, 127.3, 111.8, 73.4, 71.3, 61.4, 60.5,
1
gummy oil, 39.1 mg, 66% yield. H NMR (400 MHz, CDCl3) δ 20.1. HRMS (ESI) calcd for C13H17NO [M+H]+ 204.1388, found
7.68 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 5.12 – 5.10 (m, 204.1377.
1H), 5.10 – 5.07 (m, 1H), 4.92 (dd, J = 9.0, 3.0 Hz, 1H), 4.15 (dd,
Procedure for the synthesis of transformation product 8
J = 17.6, 1.2 Hz, 1H), 3.73 (ddd, J = 12.8, 3.2, 1.2 Hz, 1H), 3.60
Under N2 atmosphere, 3ab (53.5 mg, 0.2 mmol, 1 equiv)
(d, J = 17.6 Hz, 1H), 2.84 (dd, J = 12.8, 9.0 Hz, 1H), 2.46 (s, 3H),
and Grubbs II Catalyst (8.4 mg, 0.01 mmol, 0.05 equiv) were
1.78 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 164.4, 145.0, 138.9,
added to 3 mL of dry toluene and the resulting mixute was
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stirred for 15 min at room temperature. Afterwards, the evaporated and purification by preparative TLC (PE:EA = 5:1)
mixure was heated to 80 oC followed by the dropwise addition afforded the product 10 as white solid (dr = 2.5:1, 57.9 mg, 93%
of 4-propylhept-1-ene (84.8 mg, 0.6 mmol, 3 equiv). The overall yield). Mp = 171~172 °C. For major isomer: 1H NMR
resulting mixture was stirred at 80 oC for 24 h. After the (400 MHz, CDCl3) δ 7.62 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 7.8 Hz,
completion of the reaction, the solvent was evaporated and 2H), 5.21 – 5.16 (m, 1H), 5.11 – 5.07 (m, 1H), 4.99 (br, 1H), 3.91
purification by flash column chromatography (PE:EA = 5:1) (d, J = 12.0 Hz, 1H), 3.70 (d, J = 10.4 Hz, 1H), 2.87 (d, J = 5.6 Hz,
provided the product
8 as white gummy oil (47.6 mg, 63% 1H), 2.45 (s, 3H), 2.11 (d, J = 11.6 Hz, 1H), 2.06 – 1.95 (m, 1H),
yield). 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.4 Hz, 2H), 7.27 1.79 (s, 3H), 1.25 (s, 3H). 13C NMR (100 MHz, CDCl3) δ144.1,
(d, J = 8.0 Hz, 2H), 5.65 – 5.54 (m, 1H), 5.46 (dd, J = 15.6, 7.6 Hz, 143.8, 132.0, 129.9, 127.8, 114.4, 88.9, 76.1, 51.0, 50.3, 26.4,
1H), 4.18 – 4.06 (m, 1H), 3.81 (dt, J = 11.4, 3.0 Hz, 1H), 3.69 (qd, 21.6, 18.7. For minor isomer: 1H NMR (400 MHz, CDCl3) δ 7.62
J = 11.4, 3.0 Hz, 2H), 3.63 – 3.54 (m, 1H), 3.36 (dt, J = 12.4, 2.6 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 7.8 Hz, 2H), 5.18 (br, 1H), 5.14 –
Hz, 1H), 3.30 – 3.17 (m, 1H), 2.42 (s, 3H), 1.95 – 1.87 (m, 1H), 5.11 (m, 1H), 4.93 – 4.89 (m, 1H), 3.39 (d, J = 12.4 Hz, 1H), 3.15
1.81 (dt, J = 14.2, 7.2 Hz, 1H), 1.38 – 1.27 (m, 3H), 1.23 – 1.08 – 3.07 (m, 2H), 2.83 (d, J = 11.6 Hz, 1H), 2.45 (s, 3H), 2.06 –
(m, 6H), 0.86 (td, J = 7.2, 2.8 Hz, 6H). 13C NMR (100 MHz, CDCl3) 1.95 (m, 1H), 1.82 (s, 3H), 1.39 (s, 3H). 13C NMR (100 MHz,
δ 143.3, 136.2, 133.8, 129.5, 127.7, 125.3, 71.5, 66.6, 56.1, CDCl3) δ 147.6, 144.2, 132.2, 129.9, 127.7, 111.3, 89.4, 76.1,
42.2, 36.9, 36.4, 35.9, 35.7, 21.5, 19.8, 19.7, 14.5, 14.5. HRMS 52.1, 51.0, 22.3, 18.8. HRMS (ESI) calcd for C15H21NO4S [M+H]+
(ESI) calcd for C21H33NO3S [M+H]+380.2295, found 380.2298.
312.1270, found 312.1278.
Procedure for the synthesis of transformation product 9
Under air, 5ea (74.3 mg, 0.2 mmol, 1 equiv) was added to
2 mL CHCl3 and the resulting mixure was stirred at 0 oC. Br2
(0.02 mL, 0.3 mmol, 1.5 equiv) was dissolved in 2 mL CHCl3.
The resulting Br2 solution was added to the above mixuture
Conflicts of interest
There are no conflicts of interest to declare.
o
dropwise at 0 C with vigrous stirring. After the addition, the
o
system was heated up to 20 C and stirred for 12 h. After the
Acknowledgements
This work was partially supported by the National Natural
Science Foundation of China (No. 21472123 and
21620102003), the Science and Technology Commission of
Shanghai Municipality (No. 15JC1402200), and the Shanghai
Municipal Education Commission (No. 201701070002E00030).
completion of the reaction, saturated Na2SO3 solution (0.5 mL)
was added to the reaction and the resulting mixture was
extracted with DCM (5 mL, 2 times) and washed with H2O (5
mL, 2 times). The organic layer was collected and dried over
Na2SO4. The solvent was evaporated to give the product
9 as
white gummy oil (dr = 4:1, 100.9 mg, 95% overall yield; 76.3
mg isolated for major isomer, 16.8 mg isolated for minor
isomer), which was pure enough. For major isomer: 1H NMR
(400 MHz, CDCl3) δ 7.74 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 6.2 Hz,
2H), 7.46 – 7.35 (m, 5H), 5.74 (s, 1H), 4.32 (dd, J = 11.2, 3.6 Hz,
1H), 4.04 (dd, J = 11.8, 3.6 Hz, 1H), 3.72 (d, J = 11.2 Hz, 1H),
3.66 (d, J = 11.2 Hz, 1H), 3.50 (t, J = 11.4 Hz, 1H), 2.45 (s, 3H),
1.75 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.8, 144.9, 133.7,
133.2, 130.2, 129.5, 129.0, 127.5, 125.5, 76.3, 61.9, 60.1, 44.3,
38.9, 26.3, 21.7. For minor isomer: 1H NMR (400 MHz, CDCl3) δ
7.76 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 7.47 – 7.35 (m,
5H), 5.73 (s, 1H), 4.25 (dd, J = 11.2, 3.8 Hz, 1H), 4.07 (d, J = 10.2
Hz, 1H), 3.84 (dd, J = 11.8, 3.8 Hz, 1H), 3.63 (dd, J = 23.8, 10.8
Hz, 2H), 2.45 (s, 3H), 1.68 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
165.5, 145.0, 133.5, 133.1, 130.3, 129.5, 129.1, 127.6, 125.7,
74.6, 62.8, 60.3, 45.2, 38.8, 26.6, 21.7. HRMS (ESI) calcd for
C20H21Br2NO4S [M+H]+529.9636, found 529.9644.
Notes and references
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Procedure for the synthesis of transformation product 10
Under N2 atmosphere, 5ac (61.9 mg, 0.2 mmol, 1 equiv)
was added to 10 mL dry THF. The solution was then cooled to -
o
40 C. With vigrous stirring, DIBAL-H (1.0 mol/L in toluene, 0.5
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o
The resulting mixture was then stirred under at -40 C for 2 h.
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3
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6 | J. Name., 2012, 00, 1-3
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ARTICLE
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