Synthesis of cyclic allyl vinyl ethers using Pt(II)-catalyzed isomerization of oxo-alkynes

Article abstract of DOI:10.1016/j.tet.2009.01.065

Several alkynyl epoxides and one alkynyl allyl alcohol were isomerized to cyclic allyl vinyl ethers (3,4-dihydro-2H-1,4-oxazines) using PtCl₂ as the catalyst. Three of these allyl vinyl ethers were converted to 2-hydroxymorpholine derivatives b

Full text of DOI:10.1016/j.tet.2009.01.065

Tetrahedron 65 (2009) 2643–2648
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of cyclic allyl vinyl ethers using Pt(II)-catalyzed isomerization
of oxo-alkynes
*
Zezhou Wang, Xi Lin, Rudy L. Luck, Garrett Gibbons, Shiyue Fang
Department of Chemistry, Michigan Technological University, 1400 Townsend Drive, Houghton, MI 49931, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Several alkynyl epoxides and one alkynyl allyl alcohol were isomerized to cyclic allyl vinyl ethers
(3,4-dihydro-2H-1,4-oxazines) using PtCl2 as the catalyst. Three of these allyl vinyl ethers were converted
to 2-hydroxymorpholine derivatives by hydrolysis and two were converted to piperidine derivatives by
thermal Claisen rearrangement.
Received 2 December 2008
Received in revised form 29 December 2008
Accepted 5 January 2009
Available online 20 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Platinum
Alkynes
Enols
Cyclization
Sigmatropic rearrangement
Allyl vinyl ether
1. Introduction
pair of the oxygen and open the epoxide to form a more stable
cationic intermediate, which eliminates a proton to form the allyl
Allyl vinyl ethers are stable compounds, but under thermal
conditions, they undergo [3,3] sigmatropic shifts (Claisen rear-
rangements) to form carbon–carbon bonds in the absence of any
catalysts and reagents. Due to these features, in organic synthesis
they are valuable intermediates for the construction of highly
functionalized molecules.1 Allyl vinyl ethers are usually synthesized
via oxygen alkylation of enolates by an allyl electrophile such as
allyl tosylates. Because enolate alkylations are performed under
strongly basic conditions, they sometimes limit the application of
Claisen rearrangements.
vinyl ether 1 (Scheme 1). Alternatively, an allyl alcohol can be used
as the nucleophile, which attacks the vinyl cation and forms the
same type of products (1). The resulting allyl vinyl ethers were
expected to undergo [3,3] shift to form eight-membered cyclic
products. In this paper, we wish to report our results on the in-
vestigation of PtCl2-catalyzed isomerization of alkynyl epoxides
and an alkynyl allyl alcohol, and the [3,3] sigmatropic shift of the
resulting cyclic allyl vinyl ethers.
In recent years, some late transition metal salts such as Au(I),
Pd(II), and Pt(II) halides have been found capable of acting as soft
Lewis acids to activate alkynes toward nucleophilic attack.2 The
nucleophiles can be alkenes, azides, amines, alcohols, carbonyls,
furans, arenes, and stabilized carbonanions. When the nucleophile
is an alcohol, the product is a vinyl ether.3 Because such reactions
are usually performed under acidic conditions, we envisioned that
they could be used to form allyl vinyl ethers under conditions
complementary to the widely used basic conditions. Specifically,
when the nucleophile is an epoxide, the vinyl carbocation formed
by the alkyne and a soft Lewis acid would coordinate with the lone
M
M+
H
M+
H
H
-H+
Z
Z
Z
O
Or
OH
O
+M+
H
R
R
R
O
+H+
-M+
[3,3]
Z
O
Z
R
1
R
Z = NTs, O, C(CO2Et)2, C(SO2Ph)2
* Corresponding author. Tel.: þ1 906 487 2023; fax: þ1 906 487 2061.
E-mail address: shifang@mtu.edu (S. Fang).
Scheme 1. Proposed methods for allyl vinyl ether formation and their [3,3] sigma-
tropic shift.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.065

2644
Z. Wang et al. / Tetrahedron 65 (2009) 2643–2648
Table 1
Optimization of reaction conditions for Pt(II)-catalyzed isomerization of alkynyl
epoxidesa
Cat. (5 mol%), solvent
TsN
O
TsN
Reflux
O
2a
3a
Entry
Catalyst
Solvent
Time
Yieldb
1
2
3
4
5
6
Ph3PAuClc
PtCl2
PtCl2
PtCl2
PtCl4
PtCl2
ClCH2CH2Cl
ClCH2CH2Cl
PhMe
PhH
PhMe
24 h
24 h
24 h
12 h
24 h
24 h
50%
40%
62%
60%
62%
30%
1,4-Dioxane
a
Reactions were performed under nitrogen using distilled solvents.
Isolated yields.
AgSbF6 (5 mol %) was added.
b
c
Figure 1. X-ray determined single crystal structure of 4a.
2. Results and discussion
2.1. Isomerization of alkynyl epoxides
activity;5 however, we found little effect of the diene on this
isomerization reaction.
To probe the feasibility of this approach for allyl vinyl ether
formation, we prepared the alkynyl epoxide 2a by oxidation of the
corresponding enyne (see Supplementary data for details).4
Compound 2a was subjected to various isomerization conditions.
When AuCl, Ph3PAuCl (with AgSbF6), and PtCl2 were used as
catalyst, at rt in solvents such as benzene, toluene, and CH2Cl2, the
starting material remained unchanged even after a long reaction
time. We then performed the reactions at a higher temperature.
As shown in Table 1, when Ph3PAuCl/AgSbF6 was used as the
catalyst, in 1,2-dichloroethane at reflux, 2a was consumed in 24 h.
However, TLC indicated that a complex mixture was formed. With
careful purification by repeated flash column chromatography,
one pure compound was obtained in 50% yield (entry 1). Its
structure was proposed to be 3a through 1D and 2D NMR analysis.
Attempts to characterize other compounds in the mixture were
unsuccessful. We then used PtCl2 as the catalyst; in the same
solvent, after 24 h at reflux, 3a was obtained in 40% yield (entry
2). Although the yield was lower, the reaction was much cleaner
than when Ph3PAuCl/AgSbF6 was used. In order to reduce the
reaction time and to increase the yield, we changed the solvent to
toluene, which has a higher boiling point than DCE. Under similar
conditions, the reaction was complete in 24 h and 3a was
obtained in 62% yield (entry 3). Changing the solvent to benzene
and changing the catalyst to PtCl4 gave similar results (entries 4
and 5). When the more coordinating 1,4-dioxane was used as the
solvent, the yield was lowered significantly (30%, entry 6). Other
coordinating solvents such as THF and CH3CN gave yields of 3a
lower than 10%. The non-coordinating solvent CH2Cl2 also gave
unsatisfactory results; no conversion was observed in 24 h prob-
ably due to its low boiling point (not shown in Table 1). We also
tested the reaction in the presence of additives such as Et3N,
(F3CC]O)2O, and F3CSO3H; when PtCl2 was used as the catalyst
and benzene as the solvent, at reflux temperature, complex
mixtures were formed. It was reported that 1,5-hexadiene could
break apart the polymer formed by PtCl2 and increase its catalytic
The structure of allyl vinyl ether 3a differed from the expected 1.
In order to confirm the structure by X-ray analysis, we obtained
crystals as colorless thick long needles by slow evaporating of ac-
etone from its solution in a mixture of acetone and hexane. Un-
fortunately, the crystal melted under X-ray diffraction conditions.
Compound 3a was then converted to the cyclic hemiacetal 4a by
hydrolysis (Scheme 2). The structure of 4a was proposed by NMR
studies and confirmed by single crystal X-ray diffraction analysis
(Fig. 1).
Although the isomerization gave an unexpected product, the
reaction was interesting and a different allyl vinyl ether was
formed, which could still undergo a [3,3] shift.6 In addition, the new
compound contains a 1,4-morpholin core, which is found in many
bioactive compounds.7 Furthermore, the products from hydrolysis
and [3,3] shift of 3a are highly functionalized and may also find
biomedical applications.8 Based on these considerations, we de-
cided to investigate the scope of the reaction.
Among the reaction conditions studied (Table 1) and consider-
ing the ease of product purification and yield, the one shown in
entry 3 was chosen for substrate scope study. When the methyl
group of the tolyl moiety of the substrate was changed to a methoxy
group (2b), a similar yield of the allyl vinyl ether (3b) was obtained
(Table 2, entry 1). With phenyl (2c) and nitro groups (2d), the yields
were lowered to 47% (3c) and 36% (3d) (entries 2 and 3), re-
spectively. We next studied the effect of substitutions on the al-
kyne. Substrate 2e with a methyl group on the alkyne was therefore
subjected to isomerization. The reaction gave a more complex
mixture but product 3e could be obtained in 39% yield (entry 4).
When 2f, which has a phenyl group on the alkyne, was used,
product 3f was obtained in 22% yield (entry 5). However, with an
electron withdrawing ester group on the alkyne, 2g was isomerized
to 3g in a significantly higher yield (53%, entry 6). This result was
consistent with the observation made by Furstner and co-workers;
in their studies, they also found that electron deficient alkynes were
easier to be activated by soft Lewis acids toward nucleophilic
attack.9
OH
Two reaction pathways are possible for the formation of allyl
vinyl ethers 3 from alkynyl epoxides 2. Mechanism A is similar to
that shown in Scheme 1; it does not involve the assistance of the
sulfonamide group (Scheme 3). The epoxide attacks the vinyl cation
generated from the alkyne and Pt(II) to form a more stable tertiary
cation, which loses a proton to form intermediates 5. Protonation of
THF/20% HCl 1:2
TsN
O
TsN
3a
O
rt, 24 h
92%
4a
Scheme 2. Hydrolysis of 3a.

Z. Wang et al. / Tetrahedron 65 (2009) 2643–2648
2645
Table 2
OH
O
Substrate scope study of Pt(II)-catalyzed isomerization of alkynyl epoxidesa
O
S
O
3c
O
S
O
4c
THF/20% HCl 1:2
Ph
N
O
Ph
N
Entry
Substrate
Product
Yieldb
53%
rt, 24 h
90%
O
O
S N
O
3b
MeO
S N
MeO
O
1
CO2Et
HO
O
CO2H
O
2b
THF/20% HCl 1:2
TsN
3g
O
TsN
O
rt, 24 h
82%
O
S
O
2c
O
S N
O
4g
Ph
N
Ph
O
2
3
47%
36%
O
Scheme 4. Hydrolysis of 3c and 3g.
3c
O
S
O
O
S N
O
3d
O2N
N
O2N
O
O
2.2. Hydrolysis of allyl vinyl ether products
2d
Because some bioactive compounds contain the 2-hydroxy-
morpholine core of the hydrolysis products of 3,8 we were in-
terested to demonstrate that other cycloisomerization products
besides 3a could also be hydrolyzed. Compounds 3c and 3g were
chosen as examples. Under the same conditions for hydrolysis of 3a,
these two compounds were converted to 4c and 4g in 90% and 82%
isolated yields, respectively (Scheme 4).
O
S N
O
O
S
O
3e
N
O
4
5
39%
22%
O
2e
Ph
O
S
O
Ph
O
S N
O
N
O
O
2.3. Claisen rearrangement of allyl vinyl ether products
2f
3f
In order to demonstrate the capability of the allyl vinyl ethers to
undergo [3,3] shifts, 3a and 3d in toluene were stirred at 216 ꢀC in
sealed tubes for 60 h; products 8a and 8d were formed in 92% and
89% yields, respectively (Scheme 5). The harsh conditions required
for the reaction are a result of the highly constrained transition
state.6 The structures of the products were proposed by NMR
studies and that of 8d was confirmed by a single crystal X-ray dif-
fraction analysis (Fig. 2). Interestingly, the crystal of 8d was enan-
tiopure as evidenced by the fact that it crystallized in the space
group 19, P212121.
CO2Et
O
S N
O
CO2Et
O
S
O
N
O
6
53%
O
2g
3g
a
Reaction conditions: substrate, PtCl2 5 mol %, toluene, reflux, 24 h.
Isolated yields.
b
the platinated carbon atom followed by isomerization of the exo-
cyclic double bond into an endocyclic one under acidic conditions
gave the allyl vinyl ether products 3. However, because substrates
2f and 2g consistently form products 3f and 3g, which would re-
quire isomerization of a conjugated double bond to an isolated one,
we believe that this is less likely. Mechanism B involves the assis-
tance of the sulfonamide group. Pt(II) coordinates with the alknye
and the sulfonamide, and isomerizes the alkyne to allene 7. The
epoxide attacks the Pt(II)-activated allene followed by elimination
of a proton to give 6, which converts to 3. Because substrates
without the sulfonamide function such as those containing an
oxygen and a carbon linker between the alkyne and epoxide could
not be isomerized under similar conditions, mechanism B is more
likely than mechanism A.
2.4. Isomerization of an alkynyl allyl alcohol
Because the yields of the isomerization of alkynyl epoxides were
not ideal in some cases, we were interested to know if an alkynyl
allyl alcohol could be isomerized to the same type of products with
higher efficiency. For this purpose, compound 9 was subjected to
various conditions (Table 3). When distilled solvents were used, the
yields were generally low (entries 1–4). The only exception was
CH2Cl2, in which case 56% yield of 10 was obtained, but the reaction
took 72 h to complete (entry 4). However, when un-distilled
1,2-dichloroethane was used, the yield was higher (compare entry 5
with 3). With water saturated 1,2-dichloroethane as the solvent, the
Mechanism A
H+
Pt
Pt(II)
H
H
O
S
H
H+
-Pt(II)
Ar
N
ArSO2N
O
ArSO2N
O
O
O
H
5
ArSO2N
O
H+
Pt
Pt(II)
Pt(II)
O
H
3
H
O
S
O
H
H
O
-Pt(II)
Ar
N
ArSO2N
O
O
Ar
S
N
O
7
6
Mechanism B
Scheme 3. Potential mechanisms for the formation of allyl vinyl ether from alkynyl epoxide.

2646
Z. Wang et al. / Tetrahedron 65 (2009) 2643–2648
Table 3
O
Optimization of reaction conditions for Pt (II)-catalyzed isomerization of alkynyl
epoxides
Toluene
TsN
3a
O
O
216 °C, 60 h
92%
TsN
O2N
PtCl2 (5 mol%)
Solvent, reflux
8a
O
TsN
O
TsN
OH
O
O
S
O
10
Toluene
9
O2N
S
O
N
N
216 °C, 60 h
89%
Entry
Solvent
Time
Yielda
8d
3d
1
2
3
4
5
6
PhMe (distilled)
THF (distilled)
ClCH2CH2Cl (distilled)
CH2Cl2 (distilled)
ClCH2CH2Cl (un-distilled)
ClCH2CH2Cl (H2O saturated)
12 h
12 h
12 h
72 h
12 h
12 h
32%
30%
18%
56%
39%
71%
Scheme 5. [3,3] Sigmatropic shift of 3a and 3d.
yield was improved to 71%, which represented the highest yield for
preparing allyl vinyl ether using Pt(II)-catalyzed isomerization of
oxo-alkynes (entry 6). Thus, it was reasonable to test if wet solvents
could also improve the yields of isomerization of alkynyl epoxides.
However, it has already been shown that with water such reactions
gave different products4 and therefore this was not pursued.
a
Isolated yields.
CDCl3 at
d
77.00 ppm for 13C; residue CD2HC(O)CD3 at
24.80 ppm for 13C).
d
2.05 ppm
for 1H and CD3C(O)CD3 at
d
3. Conclusions
4.2. 6-Methyl-2-(1-methylethenyl)-4-[(4-methylphenyl)-
sulfonyl]-3,4-dihydro-2H-1,4-oxazine (3a)
We have developed a method for the preparation of cyclic allyl
vinyl ethers under acidic conditions. These conditions are com-
plementary to the normally used strongly basic conditions. The
resulting allyl vinyl ether products could be hydrolyzed to cyclic
hemiacetals and could undergo a [3,3] sigmatropic shift to give
piperidines. Studies on extending the scope of the reaction to
substrates with linkers between the alkyne and the oxo function
other than sulfonamide and preparing higher order allyl vinyl
ethers to form medium-sized cycles are underway.
To a round-bottomed flask charged with 2a (1.0 g, 3.41 mmol)
and PtCl2 (45 mg, 0.17 mmol) was added toluene (25 ml) via sy-
ringe. The reaction mixture was heated to reflux for 24 h. Solvents
were removed under reduced pressure. The residue was parti-
tioned between water and CH2Cl2. The organic phase was dried
over anhydrous Na2SO4, filtered, and solvents were removed under
reduced pressure. Purification by flash column chromatography
(hexanes/ether 4:1, SiO2) gave 3a as a white solid (615 mg, 62%):
Rf¼0.18 (hexanes/ether 4:1, SiO2); mp 62–63 ꢀC; 1H NMR (CDCl3)
4. Experimental section
4.1. General
d
7.63 (d, J¼8.2 Hz, 2H), 7.30 (d, J¼8.1 Hz, 2H), 5.82 (s, 1H), 4.90
(s, 1H), 4.85 (s, 1H), 3.79 (d, J¼13.6 Hz, 1H), 3.32 (d, J¼9.5 Hz, 1H),
2.80 (dd, J¼13.6, 9.2 Hz, 1H), 2.40 (s, 3H), 1.74 (s, 3H), 1.61 (s, 3H);
13C NMR (CDCl3)
d 143.9, 140.6, 140.5, 133.7, 129.7, 127.5, 113.3, 99.5,
All reactions were performed in oven-dried glassware under
a nitrogen atmosphere using standard Schlenk techniques. Re-
agents and solvents available from commercial sources were used
as received unless otherwise noted. Toluene, benzene, and THF
were distilled from Na/benzophenone ketyl. 1,2-Dichloroethane,
1,4-dioxane, CH2Cl2, and pyridine were distilled over CaH2. Thin
layer chromatography (TLC) was performed using Sigma–Aldrich
74.5, 46.4, 21.5, 18.4, 17.7; HRMS (FAB) m/z calcd for C15H19NO3S
[M]þ 293.1086, found 293.1087. The compound was crystallized as
colorless needles by slow evaporation of acetone from its solution
in a mixture of acetone and hexane. X-ray diffraction studies at rt
failed due to the low melting point of the crystal. As shown in Table
1, other conditions were also used to convert 2a to 3a. The pro-
cedures were the same as described above. The only differences
were using different catalysts, solvents, and reaction times.
TLC plates, silica gel 60F-254 over glass support, 0.25
Flash column chromatography was performed using Selecto Sci-
entific silica gel, particle size 32–63
m. 1H and 13C NMR spectra
were measured on a Varian UNITY INOVA spectrometer at 400 MHz
and 100 MHz, respectively; chemical shifts ( ) were reported in
reference to solvent peaks (residue CHCl3 at
7.24 ppm for 1H and
mm thickness.
m
4.3. 6-Methyl-2-(1-methylethenyl)-4-[(4-methoxylphenyl)-
sulfonyl]-3,4-dihydro-2H-1,4-oxazine (3b)
d
d
Following the procedure for the synthesis of 3a, 2b (1.5 g,
4.85 mmol) and PtCl2 (64.6 mg, 0.24 mmol) gave 3b as a colorless
oil (796.4 mg, 53%): Rf¼0.27 (hexanes/ether 3:1, SiO2); 1H NMR
(CDCl3)
d
7.68 (d, J¼9.0 Hz, 2H), 6.97 (d, J¼9.0 Hz, 2H), 5.81 (s, 1H),
4.88 (d, J¼15.8 Hz, 2H), 3.84 (s, 3H), 3.76 (d, J¼13.4 Hz, 1H), 3.35 (d,
J¼9.3 Hz, 1H), 2.80 (dd, J¼13.7, 9.4 Hz, 1H), 1.75 (s, 3H), 1.62 (s, 3H);
13C NMR (CDCl3)
d 163.2, 140.7, 140.6, 129.7, 129.6, 128.3, 114.3,
113.3, 99.6, 74.5, 55.6, 46.5, 18.4, 17.7; HRMS (FAB) m/z calcd for
C15H19NO4S [M]þ 309.1035, found 309.1033.
4.4. 6-Methyl-2-(1-methylethenyl)-4-[(4-phenylphenyl)-
sulfonyl]-3,4-dihydro-2H-1,4-oxazine (3c)
Following the procedure for the synthesis of 3a, compound 3c
was prepared using 2c (1.5 g, 4.23 mmol) and PtCl2 (56.2 mg,
0.21 mmol). Purification by flash column chromatography (hex-
anes/ether 3:1, SiO2) gave 3c as a light yellow oil (698.4 mg, 47%):
Figure 2. X-ray determined single crystal structure of 8d.

Z. Wang et al. / Tetrahedron 65 (2009) 2643–2648
2647
Rf¼0.28 (hexanes/ether 3:1, SiO2); 1H NMR (CDCl3)
d
7.84 (d,
1.58 (s, 3H), 1.18 (t, J¼7.3 Hz, 3H); 13C NMR (CDCl3)
d
169.4, 144.1,
J¼9.1 Hz, 2H), 7.73 (d, J¼8.4 Hz, 2H), 7.59 (d, J¼7.5 Hz, 2H), 7.46 (t,
J¼7.2 Hz, 2H), 7.41 (t, J¼7.2 Hz, 1H), 5.90 (br s, 1H), 4.91 (br s, 1H),
4.88 (br s, 1H), 3.86 (d, J¼13.7 Hz, 1H), 3.43 (d, J¼9.5 Hz, 1H), 2.88
(dd, J¼13.8, 9.5 Hz, 1H), 1.79 (s, 3H), 1.64 (s, 3H); 13C NMR (CDCl3)
140.1, 137.3, 133.6, 129.8, 127.6, 113.5, 103.0, 74.8, 60.8, 46.4, 38.0,
21.5, 18.3, 14.1; HRMS (FAB) m/z calcd for C18H23NO5S [M]þ
365.1297, found 365.1300.
d
145.8, 140.7, 140.4, 138.9, 135.1, 129.0, 128.5, 127.9, 127.6, 127.2,
4.9. 2-Hydroxyl-2-methyl-6-(1-methylethenyl)-4-[(4-
methylphenyl)sulfonyl]-morpholine (4a)
113.4, 99.4, 74.5, 46.4, 18.3, 17.7; HRMS (FAB) m/z calcd for
C20H21NO3S [M]þ 355.1242, found 355.1244.
A solution of 3a (246 mg, 0.84 mmol) in THF (5.0 ml) and 20%
HCl (10.0 ml) was stirred vigorously. After 24 h, TLC indicated that
the reaction was complete. The reaction mixture was extracted by
CH2Cl2 for three times, the organic layers were combined, and dried
over anhydrous Na2SO4. After filtration, solvents were evaporated
under reduced pressure. Purification by flash column chromatog-
raphy (hexanes/acetone 4:1, SiO2) gave 4a as a white solid (242 mg,
92%): Rf¼0.34 (hexanes/ether 1:1, SiO2); mp 112–113 ꢀC; 1H NMR
4.5. 6-Methyl-2-(1-methylethenyl)-4-[(4-nitrophenyl)-
sulfonyl]-3,4-dihydro-2H-1,4-oxazine (3d)
Following the procedure for the synthesis of 3a, compound 3d
was prepared using 2d (2.4 g, 7.45 mmol) and PtCl2 (99.2 mg,
0.37 mmol). Purification byflash column chromatography (hexanes/
ether 4:1, SiO2) gave 3d as a light yellow oil (864.0 mg, 36%): Rf¼0.17
(hexanes/ether 4:1, SiO2); 1H NMR (CDCl3)
d
8.36 (d, J¼8.8 Hz, 2H),
(CDCl3)
d
7.61 (d, J¼8.6 Hz, 2H), 7.32 (d, J¼8.6 Hz, 2H), 4.97 (s, 1H),
7.93 (d, J¼8.9 Hz, 2H), 5.83 (s,1H), 4.92 (br s,1H), 4.86 (br s,1H), 3.82
(d, J¼13.5 Hz,1H), 3.49 (d, J¼8.8 Hz,1H), 2.88 (dd, J¼13.4, 9.3 Hz,1H),
4.88 (s, 1H), 4.43 (d, J¼10.4 Hz, 1H), 3.69 (d, J¼11.5 Hz, 1H), 3.58 (dd,
J¼11.5, 1.8 Hz, 1H), 2.41 (s, 3H), 2.23 (d, J¼11.3 Hz, 1H), 2.05 (t,
1.75 (s, 3H), 1.63 (s, 3H); 13C NMR (CDCl3)
d 150.2, 142.5, 141.5, 139.9,
J¼11.3 Hz, 1H), 1.68 (s, 3H), 1.38 (s, 3H); 13C NMR (CDCl3)
d 144.2,
128.5, 124.4, 113.8, 98.6, 74.9, 46.3, 18.3, 17.7; HRMS (FAB) m/z calcd
141.6, 132.2, 129.9, 127.8, 112.9, 93.3, 71.1, 53.4, 48.9, 26.0, 21.5, 19.0;
HRMS (FAB) m/z calcd for C15H22NO4S [MþH]þ 312.1270, found
312.1271. To confirm the structure of 4a, crystals were obtained as
colorless needles by slow evaporation of hexanes into the solution
of 4a in a mixture of hexanes and acetone at rt. The structure of 4a
was then unambiguously determined by X-ray diffraction analysis
(Fig. 1). The crystallographic data (excluding structure factors;
CCDC no. 714713) have been deposited to the Cambridge Crystal-
lographic Data Center. Copies of these data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK; fax: þ44 1223 336033 or via e-mail: deposit@ccdc.cam.uk or
via www.ccdc.cam.ac.uk/conts/retrieving.html.
for C14H16N2O5S [M]þ 324.0780, found 324.0778.
4.6. 6-Ethyl-2-(1-methylethenyl)-4-[(4-methylphenyl)sulfonyl]-
3,4-dihydro-2H-1,4-oxazine (3e)
Following the procedure for the synthesis of 3a, compound 3e
was prepared using 2e (1.8 g, 5.90 mmol) and PtCl2 (78.0 mg,
0.30 mmol). Purification by flash column chromatography (hex-
anes/ether 4:1, SiO2) gave 3e as a light yellow oil (670.0 mg, 39%):
Rf¼0.23 (hexanes/ether 4:1, SiO2); 1H NMR (CDCl3)
d 7.59 (d,
J¼7.9 Hz, 2H), 7.26 (d, J¼7.9 Hz, 2H), 5.79 (s, 1H), 4.84 (s, 1H), 4.80 (s,
1H), 3.75 (d, J¼13.7 Hz, 1H), 3.25 (d, J¼9.3 Hz, 1H), 2.75 (dd, J¼13.6,
8.9 Hz, 1H), 2.35 (s, 3H), 2.00 (q, J¼7.5 Hz, 2H), 1.57 (s, 3H), 0.96 (t,
4.10. 2-Hydroxyl-2-methyl-6-(1-methylethenyl)-4-[(4-
phenylphenyl)sulfonyl]-morpholine (4c)
J¼7.5 Hz, 3H); 13C NMR (CDCl3)
d 145.6, 143.8, 140.5, 133.5, 129.6,
127.3, 113.0, 98.6, 74.2, 46.5, 25.1, 21.4, 18.3, 11.4; HRMS (FAB) m/z
calcd for C16H21NO3S [M]þ 307.1242, found 307.1244.
Following the procedure for the synthesis of 4a, 3c (202.0 mg,
0.57 mmol) was hydrolyzed in THF (5.0 ml) and 20% HCl (10.0 ml).
Product 4c was obtained as a white solid after purification by flash
column chromatography (hexanes/acetone 4:1, SiO2; 191.2 mg,
90%): Rf¼0.13 (hexanes/acetone 4:1, SiO2); mp 138–139 ꢀC; 1H NMR
4.7. 6-Benzyl-2-(1-methylethenyl)-4-[(4-methylphenyl)-
sulfonyl]-3,4-dihydro-2H-1,4-oxazine (3f)
(CDCl3)
d
7.81 (d, J¼8.8 Hz, 2H), 7.74 (d, J¼8.4 Hz, 2H), 7.59 (d,
Following the procedure for the synthesis of 3a, compound 3f
was prepared using 2f (956.0 mg, 2.60 mmol) and PtCl2 (34.5 mg,
0.13 mmol). Purification by flash column chromatography (hex-
anes/ether 4:1, SiO2) gave 3f as a light yellow oil (211.3 mg, 22%):
J¼7.2 Hz, 2H), 7.46 (t, J¼7.2 Hz, 2H), 7.40 (t, J¼6.8 Hz, 1H), 5.00 (s,
1H), 4.90 (s, 1H), 4.49 (d, J¼10.4 Hz, 1H), 3.78–3.66 (m, 3H), 2.33 (d,
J¼11.2 Hz, 1H), 2.15 (t, J¼11.2 Hz, 1H), 1.70 (s, 3H), 1.42 (s, 3H); 13C
Rf¼0.19 (hexanes/ether 4:1, SiO2); 1H NMR (CDCl3)
d
7.62 (d,
NMR (CDCl3)
d 146.1, 141.6, 138.9, 133.7, 129.0, 128.6, 128.2, 127.8,
127.2, 112.9, 93.3, 71.0, 53.3, 48.8, 26.1, 18.9; HRMS (FAB) m/z calcd
J¼8.6 Hz, 2H), 7.32–7.20 (m, 5H), 7.16 (d, J¼8.3 Hz, 2H), 5.90 (s, 1H),
4.87 (s, 1H), 4.80 (s, 1H), 3.82 (d, J¼13.3 Hz, 1H), 3.34 (s, 2H), 3.32 (d,
J¼9.3 Hz, 1H), 2.81 (dd, J¼13.1, 9.6 Hz, 1H), 2.42 (s, 3H), 1.58 (s, 3H);
for C20H24NO4S [MþH]þ 374.1426, found 374.1428.
13C NMR (CDCl3)
d 144.0, 143.3, 140.4, 137.5, 133.6, 129.7, 128.6,
4.11. [2-Hydroxyl-6-(1-methylethenyl)-4-[(4-methylphenyl)-
sulfonyl]-morpholine-2-yl]acetic acid (4g)
128.3, 127.6, 126.5, 113.2, 101.2, 74.5, 46.6, 38.4, 21.5, 18.4; HRMS
(ESI) m/z calcd for C21H24NO3S [MþH]þ 370.1477, found 370.1473.
Following the procedure for the synthesis of 4a, 3g (326.5 mg,
0.89 mmol) was hydrolyzed in THF (5.0 ml) and 20% HCl (10.0 ml).
Product 4g was obtained as a white solid by precipitation by adding
hexanes into its solution in acetone dropwise (258.9 mg, 82%):
4.8. Ethyl [2-(1-methylethenyl)-4-[(4-methylphenyl)-
sulfonyl]-3,4-dihydro-2H-1,4-oxazine-6-yl]acetate (3g)
Following the procedure for the synthesis of 3a, compound 3g
was prepared using 2g (2.6 g, 7.0 mmol) and PtCl2 (93.5 mg,
0.35 mmol). Purification by flash column chromatography (hex-
anes/ether 4:1, SiO2) gave 3g as a light yellow oil (1.4 g, 53%):
Rf¼0.06 (EtOAc, SiO2); mp 137–138 ꢀC; 1H NMR (CD3C(O)CD3)
d 7.67
(d, J¼8.2 Hz, 2H), 7.44 (d, J¼8.2 Hz, 2H), 4.97 (s, 1H), 4.86 (s, 1H),
4.56 (d, J¼10.4 Hz, 1H), 3.82 (dd, J¼11.4, 1.8 Hz, 1H), 3.67 (d,
J¼11.4 Hz, 1H), 2.72 (d, J¼11.2 Hz, 1H), 2.66 (d, J¼11.2 Hz, 1H), 2.47
(d, J¼11.4 Hz, 1H), 2.43 (s, 3H), 2.11 (t, J¼10.9 Hz, 1H), 1.67 (s, 3H);
Rf¼0.18 (hexanes/ether 4:1, SiO2); 1H NMR (CDCl3)
d 7.64 (d,
J¼8.2 Hz, 2H), 7.30 (d, J¼8.2 Hz, 2H), 6.02 (s, 1H), 4.88 (s, 1H), 4.83
(s, 1H), 4.09 (q, J¼7.2 Hz, 2H), 3.77 (d, J¼13.5 Hz, 1H), 3.34 (d,
J¼9.1 Hz, 1H), 3.02 (s, 2H), 2.83 (dd, J¼13.5, 9.3 Hz, 1H), 2.39 (s, 3H),
13C NMR (CD3C(O)CD3)
d 171.8, 144.7, 143.3, 134.0, 130.8, 128.7,
112.6, 94.2, 71.8, 52.4, 49.6, 44.0, 21.4, 18.9; HRMS (FAB) m/z calcd
for C16H22NSO6 [MþH]þ 356.1168, found 356.1170.

2648
Z. Wang et al. / Tetrahedron 65 (2009) 2643–2648
4.12. 1-(1,2,3,6-Tetrahydro-4-methyl-1-(4-methylphenyl)-
sulfonyl-2-pyridinyl)-ethanone (8a)
The only differences were using different solvents and reaction
times.
A solution of 3a (160 mg, 0.6 mmol) in toluene under a nitrogen
atmosphere in a sealed tube was heated to 216 ꢀC in an oil bath for
60 h. After cooling to rt, the solvent was removed under reduced
pressure. Purification of the residue by flash column chromatogra-
phy (hexanes/ether 3:1, SiO2) gave 4a as a white solid (146 mg, 92%):
Rf¼0.29 (hexanes/ether 1:1, SiO2); mp 99–101 ꢀC; 1H NMR (CDCl3)
Acknowledgements
Financial supports from US NSF (CHE-0647129), MTU Chemistry
Department, Research Excellence Fund and Summer Un-
dergraduate Research Fellowship (G.G.); the assistance from Mr.
Jerry L. Lutz (NMR), Mr. Shane Crist (computation), and Mr. Dean W.
Seppala (electronics); and an NSF equipment grant (CHE-9512445)
are all gratefully acknowledged.
d
7.64 (d, J¼8.3 Hz, 2H), 7.24 (d, J¼8.1 Hz, 2H), 5.18 (br s,1H), 4.62 (d,
J¼7.0 Hz, 1H), 4.05 (br d, J¼16.9 Hz, 1H), 3.67 (br d, J¼18.0 Hz, 1H),
2.38 (s, 3H), 2.33 (d, J¼17.4 Hz,1H), 2.19 (s, 3H),1.98 (br d, J¼20.1 Hz,
1H), 1.55 (s, 3H); 13C NMR (CDCl3)
d 205.8, 143.4, 136.7, 131.0, 129.5,
127.0,116.2, 59.9, 42.3, 28.4, 26.6, 23.1, 21.4; HRMS (ESI) m/z calcd for
Supplementary data
C15H20NO3S [MþH]þ 294.1164, found 294.1169.
Synthesis and characterization of substrates, and 1H and 13C
NMR spectra of all new compounds. Supplementary data associated
with this article can be found in the online version, at doi:10.1016/
j.tet.2009.01.065.
4.13. 1-(1,2,3,6-Tetrahydro-4-methyl-1-(4-nitrophenyl)sulfonyl-
2-pyridinyl)-ethanone (8d)
References and notes
Following the procedure for the synthesis of 8a, 8d was pre-
pared from 3d (268.1 mg, 0.83 mmol). The crude product was pu-
rified by flash column chromatography (hexanes/ether 4:1, SiO2)
giving 8d (237.9 mg, 89%) as a light yellow solid: Rf¼0.16 (hexanes/
1. (a) Majumdar, K. C.; Alam, S.; Chattopadhyay, B. Tetrahedron 2008, 64, 597–643;
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ether 4:1, SiO2); mp 152–153 ꢀC; 1H NMR (CDCl3)
d 8.32 (d,
J¼9.0 Hz, 2H), 7.95 (d, J¼8.9 Hz, 2H), 5.27 (s, 1H), 4.72 (d, J¼6.9 Hz,
1H), 4.08 (d, J¼17.4 Hz, 1H), 3.71 (d, J¼17.1 Hz, 1H), 2.42 (d,
J¼17.4 Hz, 1H), 2.25 (d, J¼34.2 Hz, 1H), 2.15 (s, 3H), 1.63 (s, 3H); 13C
NMR (CDCl3)
d 204.4, 150.0, 145.3, 130.7, 128.3, 124.2, 116.5, 60.4,
42.5, 29.8, 26.6, 23.2; HRMS (ESI) m/z calcd for C14H16N2O5S [M]þ
324.0780, found: 324.0776. To confirm the structure of 8d, crystals
were obtained as light yellow thick needles by slow evaporation of
acetone from the solution of 8d in a mixture of hexanes and acetone
at rt. The structure of 8d was then unambiguously determined by
X-ray diffraction analysis (Fig. 2). The crystallographic data (ex-
cluding structure factors; CCDC no. 714714) have been deposited to
the Cambridge Crystallographic Data Center.
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4.14. 6-Methyl-2-(2-methyl-1-propen-1-yl)-4-[(4-methylphenyl)-
sulfonyl]-3,4-dihydro-2H-1,4-oxazine (10)
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Compound 9 (38 mg, 0.124 mmol), PtCl2 (1.6 mg, 0.006 mmol),
and CH2ClCH2Cl (saturated with water, 25 ml) were combined and
heated to reflux for 12 h. After cooling to rt, the reaction mixture
was partitioned between CH2Cl2 and water. The aqueous phase was
extracted with CH2Cl2. The organic phases were combined, dried
over anhydrous Na2SO4, filtered, and solvents were removed under
reduced pressure. Purification by flash column chromatography
(hexanes/ether 9:1, SiO2) gave 10 as a light yellow oil (27 mg, 71%):
Rf¼0.57 (hexanes/ether 1:1, SiO2); 1H NMR (CDCl3)
d 7.65 (d,
J¼8.4 Hz, 2H), 7.30 (d, J¼8.4 Hz, 2H), 5.82 (s, 1H), 4.96 (dt, J¼8.8,
1.2 Hz, 1H), 3.76 (dt, J¼9.2, 2.0 Hz, 1H), 3.61 (dt, J¼13.6, 1.6 Hz, 1H),
2.81 (dd, J¼13.6, 9.2 Hz, 1H), 2.41 (s, 3H), 1.73 (s, 3H), 1.68 (d,
8. (a) Azumi, M.; Ogawa, K.; Fujita, T.; Takeshita, M.; Yoshida, R.; Furumai, T.;
Igarashi, Y. Tetrahedron 2008, 64, 6420–6425; (b) Viswanadha, S.; Mcgilliard, M. L.;
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Martinez, A. Pharmazie 1995, 50, 768–769.
J¼1.2 Hz, 3H), 1.42 (d, J¼1.2 Hz, 3H); 13C NMR (CDCl3)
d 144.0, 140.6,
139.5, 134.2, 130.0, 127.8, 120.4, 99.6, 69.5, 46.9, 26.0, 21.7, 18.4, 18.1.
HRMS (ESI) m/z calcd for C16H22NO3S [MþH]þ 308.1320, found
308.1325. As shown in Table 3, other conditions were also used to
convert 9 to 10. The procedures were the same as described above.
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