Gold(I)-catalysed [3+3] cycloaddition of propargyl acetals and nitrones

Article abstract of DOI:10.1016/j.tet.2016.04.058

In our series of investigations to expand the understanding of the gold(I) catalysis chemistry of propargyl acetals, a gold(I) catalysed [3+3] cycloaddition reaction of propargyl acetals with nitrones has been studied. A series of 5-methoxy-3,6-dihydro-2H

Full text of DOI:10.1016/j.tet.2016.04.058

Tetrahedron 72 (2016) 3270e3276
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Gold(I)-catalysed [3þ3] cycloaddition of propargyl acetals and
nitrones
*
Sigvart Evjen, Anne Fiksdahl
Department of Chemistry, Norwegian University of Science and Technology, Høgskoleringen 5, NO-7491 Trondheim, Norway
a r t i c l e i n f o
a b s t r a c t
Article history:
In our series of investigations to expand the understanding of the gold(I) catalysis chemistry of
propargyl acetals, a gold(I) catalysed [3þ3] cycloaddition reaction of propargyl acetals with nitrones
has been studied. A series of 5-methoxy-3,6-dihydro-2H-1,2-oxazine products with two stereogenic
centres were obtained in a cis-stereoselective manner. The formal [3þ3] cycloaddition reaction is
supposed to go through O-nucleophilic attack of the nitrone on the C1 position of the gold complex
generated from propargyl acetal followed by a final ring closure. An alternative C3 oxidation by ni-
trone affords aldehyde products and represents a competing pathway. The chemoselectivity of the
cycloaddition reaction is discussed in order to demonstrate the potential and limitations of the
reaction.
Received 20 January 2016
Received in revised form 6 April 2016
Accepted 21 April 2016
Available online 25 April 2016
Keywords:
Propargyl acetal
Gold(I) catalysis
[3þ3] Cycloaddition
Nitrone
Ó 2016 Elsevier Ltd. All rights reserved.
3,6,Dihydro-2H-1,2-oxazine
1. Introduction
and irreversibly lead to different stable products. The activating
effect provided by the C2-vinylalkoxy group in the MeO-vinyl-gold
Gold-catalysed reactions of propargyl esters are widely reported
in the literature.1a The gold catalysed activation process of prop-
argyl esters has shown to be a versatile strategy towards the gen-
eration of vinyl/enol gold carbene complexes.1beq The propargyl
esteregold approach represents an important supplement to the
conventional vinyl-metal carbenoids, generated in situ by metal-
catalysed diazo decomposition, for the preparation of effective
vinyl-carbene 1,3-dipolar reactants. The propargyl ester method
has been applied in gold catalysed cyclopropanation reactions2,9
(Scheme 1a) as well as in [2þ2],3a,b [3þ2],4aed [4þ2],5 [4þ3]6aed
and [3þ3]7 cycloaddition reactions.
carbenoid (20/200) facilitates subsequent reactions and explains the
high reactivity and ability of propargyl acetals to undergo cyclo-
additions. By trapping the intermediates with different CeC, CeN
multiple bond reactants, a great variety of complex cyclic products
were readily prepared by novel [2þ3], [2þ5] and combined tandem
cycloaddition reactions (Scheme 1bee).9e13
To expand the knowledge of the highly reactive propargyl ace-
tals, we wanted to investigate the potential of less common sub-
strates, such as the nitrone 1,3-dipoles, to undergo chemoselective
gold catalysed cycloaddition reactions.
1,3-Dipolar compounds are versatile and powerful synthetic
tools to form five-membered rings by [2þ3] cycloadditions with
dipolarophiles. However, reports on corresponding [3þ3] cyclo-
addition for the preparation of six-membered heterocyclic com-
pounds have been limited. Nevertheless, during the recent few
years, in particular, transition metal catalysed [3þ3] cycloadditions
have been developed. Such processes may typically involve active
vinyl-metallocarbene intermediates or donor-acceptor cyclo-
propenes, generated by Rh-catalysis from vinyldiazoacetates. Thus,
[3þ3] cycloadditions of nitrones with TBSO-vinyl-rhodium-
carbenes, generated from enoldiazoacetates, have been
reported.14aee These cycloadditions are facilitated by the stabilizing
effect provided by the TBSO vinylic group.
However, studies on gold(I)-catalysed reactions of the corre-
sponding propargyl acetals are scarce, with the exception of recent
work published by groups of Toste and Zhang.8 The Fiksdahl group
has carried out a number of studies on chemoselective gold(I)
catalysed cycloaddition reactions of propargyl acetals (1, Scheme
1bee).9e13 These substrates undergo gold-catalysed triple-bond
activation and alkoxy migrations-fragmentation processes to afford
the particularly reactive enol ether carbenoid/allylic gold(I) in-
termediates (20/200). It has been demonstrated that gold(I) activated
propargyl substrates exist in rapid equilibrium with these gold
species, allowing different novel cyclization pathways to take place
A number of additional 1,3-dipolar compounds have been ap-
plied and azomethine imines,14a,15aed azomethine ylides,16aee and
azides17 have also been utilised as [3þ3] cycloaddition reactants for
* Corresponding author. E-mail address: anne.fiksdahl@chem.ntnu.no (A.
Fiksdahl).
http://dx.doi.org/10.1016/j.tet.2016.04.058
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.

S. Evjen, A. Fiksdahl / Tetrahedron 72 (2016) 3270e3276
3271
Scheme 1. Cycloaddition reactions of propargyl substrates.9e13
the construction of a range of six-membered heterocyclic struc-
tures. New strategies for Cu catalysed [3þ3] cycloadditions of
azomethine imines and azomethine ylides have recently been
developed,15c,d,16c while other reactions are likewise promoted by
TiCl4,17 Yb18 or DABCO15c catalysis.
give rise to polysubstituted and highly functionalised 3,6-dihydro-
2H-1,2-oxazine products through
cycloaddition process (Scheme 1f).
a
formal uncommon [3þ3]
2. Results and discussion
In general, many different cycloaddition reactions are initiated
by gold activation of alkynes.19 In a very few cases, [3þ3] cycload-
ditions are involved. Furo-[1,2]oxazines have been prepared from
alkynyl-alkenones and nitrones by gold-catalysed step-wise double
cyclization, including [3þ3] 1,3-dipolar cycloaddition.20a The re-
actions were also successfully carried out in diastereo- and enantio-
selective manners.20b The formation of diazabicycles (pyrazolo[1,2-
a]pyridazines) from propargyl esters and azomethine imines
demonstrated a gold(III) catalysed [3þ3] cycloaddition reaction
including an vinyl-gold-carbenoid.7 Recently, a gold(I) catalysed
[3þ3] cycloaddition reaction of one 4-carboxylate propargyl acetal
and N-phenyl-N-benzylidene-nitrones have briefly been reported
to afford a 3,6-dihydro-2H-1,2-oxazine.8c 1,2-Oxazines derivatives
are reported as good mglur1 antagonists21 and show antibacterial
activity. Dihydro-1,2-oxazines are often prepared utilizing [4þ2]
cycloaddition strategies. Both the combination of nitroso hetero-
dienophiles with diene22,23 and nitrosoalkene heterodiene with
alkene are successful hetero-DielseAlder approaches24 as well as
some organocatalytic transformations.25 Reductive ring opening of
1,2-oxazines have been used in the synthesis of amino sugar
mimetics.26
2.1. Studies on reaction conditions
Introductory studies on the gold(I) catalysed [3þ3] cyclo-
addition reactions between propargyl acetal 1a and nitrone 4a
in dichloromethane gave full conversion in 30 min at room
temperature in the presence of 5 mol % of gold(I) catalyst I, [Au
{P(t-Bu)2(o-biphenyl)CH3CN}]-SbF6 (Table 1, entry 1), with the
[3þ3] cycloaddition product, 3,6-dihydro-2H-1,2-oxazine 5a,
being formed. However, under the initial condition, 3 equiv of
nitrone 4a were used and only minor amounts (8%) of product
5a was isolated. Two other products, aldehyde 6a and ketone
7a, were also identified, the ratio of products 5a:6a:7a was
10:10:80, as shown by 1H NMR analysis of the un-purified re-
action mixture.
The formation of aldehyde 6a is supposed to take place by
nitrone oxidation of the propargyl terminal carbon (Scheme 2 be-
low), while the major ketone product 7a is formally formed by
direct hydration of the propargyl acetal 1a alkyne moiety.
Performing the reaction under drying conditions, in the
presence of molecular sieves (entry 1, footnote c), did not change
the outcome of the reaction. Aqueous reaction conditions (10%
H2O in DCM, entry 2) significantly reduced the reactivity (8%
We herein report a study of gold(I) catalysed cycloaddition of
different terminal propargyl acetals and a number of nitrones to

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S. Evjen, A. Fiksdahl / Tetrahedron 72 (2016) 3270e3276
Table 1
Optimization studies of gold(I)-catalysed [3þ3] cycloaddition reactionsa
Entry
Gold-catalyst
Reactants
Time (h)
Conversion (%)
Products; distribution in crude mixture [%]b
5a
6a
7a
1
2
3
4
5
6
7
8
I
I
I
I
I
I
1aþ4a (3 equiv)c
1aþ4a (3 equiv)e
1af
0.5
24
24
0.5
0.25
24
24
24
24
24
99
8
0
99
99
6
28
0
24
<5
37
<5
<5
7
10 (8d)
14
d
46 (32d)
45
50
11
d
10 (10d)
13
d
42 (35d)
44
41
13
d
80(40d)
73
d
12 (8d)
11
9
4
d
1aþ4ac
1aþ4ag
1aþ4ae
I
1aþ4ah
di
1aþ4a
9
Ph3PAu(I)Cl
Ph3PAu(III)Cl3
PicAu(III)Cl2
I
Ph3PAu(I)Cl
Ph3PAu(III)Cl3
PicAu(III)Cl2
1aþ4a
15
d
9
<5
22
<5; prod. 8
<5; prod. 8
7; prod. 8
25; prod. 8
d
10
11
12
13
14
15
d
24
24
24
24
15
d
d
3þ4a
d
d
d
d
d
24
25
d
d
a
The general reactions were performed with 2a/3a (1 equiv) and 4a (1 equiv) in DCM (approx. c¼150 mM) together with 5 mol % catalyst (I: [Au{P(t-Bu)2(o-biphenyl)
CH3CN}]SbF6). The reactions were stirred at room temp before being quenched with NEt3.
b
Based on 1H NMR.
c
Identical results were also obtained when mol. sieve was added to the reaction mixture.
Isolated yields.
10% H2O/DCM was used as solvent.
d
e
f
No nitrone 4a was added.
g
The reaction was carried out in DCE at 50 ꢀC.
h
The reaction was carried out in acetonitrile.
No catalyst was added.
i
Scheme 2. Reaction mechanism for gold(I) catalysed [3þ3] cycloaddition8c of propargyl acetals 1a and nitrone 4a and competing reaction pathways.
conversion in 24 h), but the relative amount of the products (5a,
6a, and 7a) was practically not affected, indicating that the for-
mation of all three products, including the dominating hydration
of acetal 1a was nitrone-generated. Hence, no reaction took place
in the absence of nitrone 4a (entry 3). Applying only 1 equiv of
nitrone 4a, readily gave full conversion and successfully reduced
the amount of ketone 7a (12%, entry 4). The oxazine 5a and al-
dehyde 6a products were obtained in >40%, also at higher

S. Evjen, A. Fiksdahl / Tetrahedron 72 (2016) 3270e3276
3273
temperature (DCE, 50 ꢀC, 15 min, entry 5), while only partly
conversion (28%) of reactants was observed in acetonitrile, even
after 24 h (entry 7). Aqueous reaction conditions (10% H2O in
DCM) likewise reduced the reactivity (6% conversion in 24 h,
entry 6, see also entry 2), and no reaction took place in the ab-
sence of the gold catalyst (entry 8).
Table 2
Gold(I)-catalysed [3þ3] cycloaddition of propargyl acetals 1aec and nitrones 4aeia
A further solvent screening was not performed, as our previous
studies showed DCM as the best solvent in related reactions.10e12
The gold (I) catalyst I was applied according to optimum condi-
tions formerly developed for gold catalysed propargyl acetal
cycloadditions.10e12 Other catalytic systems were briefly tested to
observe possible new effects of other catalysts, however, both the
triphenylphosphane-based gold(I) and gold(III) catalysts, as well as
PicAu(III)Cl2 slowed down the reaction (5e37% conversion in 24 h,
entries 9e11). None of the reaction conditions or gold catalysts
enabled [3þ3] cycloaddition of the alternative propargyl acetate 3
with nitrone 4a, and only low conversion into aldehyde 8 was ob-
served (5e25% in 24 h, entries 12e15). The significantly lower re-
activity of propargyl esters is in accordance with our previous
observations.9e13
Entry Substrates Reaction time (full conv.) Prod. (% isolated yield)
5
6
7
1
2
3
4
5
6
7
8
1aþ4a
1aþ4b
1aþ4c
1bþ4a
1cþ4a
1aþ4d
1aþ4e
1aþ4f
1aþ4g
1aþ4h
1aþ4i
2 h
30 min
24 h
5a (32)
5b (<1)
5c (36)
5d (20)b
5e(<1)
5f (11)c
5g (<1)
(35) (8)
6a (47) 7a (15)
6a (36) 7a (6)
6b (21) 7b (20)b
6c (<1) 7c (19)c
6a (41) de
30 min
24 h (25% conv.)
30 min
10 min
25 min
15 min
30 min
2 h
6a (49) de
2.2. Reaction mechanism
5h (54/63d) 6a (17) de
9
10
11
5i (6)
5j (23)
d
6a (54) de
6a (29) de
6a(<1)f
The gold activated propargyl acetal 1a may undergo a 1,2-
alkoxy shift to generate the key gold(I) species alkoxyvinyl gold
carbenoid species 20 and the stabilized allyl cation 200 (Schemes 1
and 2). All our previous gold(I) catalysed regioselective cyclo-
additions9e13 of propargyl acetals, and also corresponding gold(III)
catalysed [3þ3] cycloaddition of propargyl esters with azome-
thine imines,7 take place with initial nucleophilic attack at the C3-
position (Scheme 2). In contrast, according to a proposed mech-
anism8c for the reaction of propargyl acetal 1a and nitrone 4a, the
gold catalyst activates the vinyl carbene for nucleophilic attack of
the nitrone at the C1-position to form a C1-nitrone adduct. The
final ring closure in the [3þ3] cycloaddition is facilitated by ac-
tivation provided by the methoxy group. A final de-auration al-
lows regeneration of the catalyst and affords the 1,2-oxazine
product 5a.
The formation of the aldehyde product 6a represents a com-
peting reaction pathway via an alternative nitrone attack at the C3
position. The resulting C3-nitrone adduct forms the aldehyde 6a by
oxidation through NeO bond cleavage and ring closure does not
take place. The benzaldimine leaving group may hydrolyse into
benzaldehyde during work-up. A similar C3 oxidation reaction has
been developed27 for the Au(I) catalysed nitrone oxidation of non-
terminal propargylic esters with the 8-methylquinoline N-oxide,
a
The general reactions were performed with 1 (1 equiv) and 4 (1 equiv) in DCM
(approx. c¼250 mM) together with 5 mol % catalyst I ([Au{P(t-Bu)2(o-biphenyl)
CH3CN}]SbF6). The reactions were stirred at rt before being quenched with NEt3.
b
Approximate yields based on 1H NMR analysis of product mixture.
c
Unstable product.
d
Total yield of 5g formed in the reaction, as shown by 1H NMR of the crude
product mixture.
e
Minor amounts observed by 1H NMR were not isolated.
Only trace amount was identified, due to challenging chromatographic separa-
f
tion of complex product mixture.
rich nitrone 4b (p-OMe) mainly afforded the C3 oxidation alde-
hyde 6a product (47%, entry 2). An activating ERG para-substituent
(OMe) on the propargyl acetal 1b afforded a product mixture (5d,
6b, 7b; 1:1:1; entry 4), while an EWG para-substituent (NO2) did
not allow full conversion on the propargyl acetal 1c at all (24 h,
entry 5).
The reactivity of the N-aryl-nitrones 4deh (entries 6e10) was
also influenced by the electronic character of the N-aryl groups, as
the p-chlorophenylnitrones 4f and 4h readily produces the oxazine
products 5h and 5i (entries 8, 10). The N-p-chlorophenylnitrone 4f
was most effective and selective, affording more than 60% total
yield in 25 min and 54% after complex chromatographic purifica-
tion of target oxazine product 5h (entry 8). The ERG aryl-N-phe-
nylnitrones 4d, 4e and 4g were highly reactive, but afforded mainly
aldehyde 6a (40e50%, entries 6, 7, 9). The cyclic nitrone 4i and
acetal 1a gave a full conversion, but the target oxazine product
could not be observed in the obtained complex product mixture
(entry 11).
Previously, one deactivated non-terminal 3-carboxylate-
propargyl acetal was briefly reported to undergo chemoselective
[3þ3] cycloaddition to give related 1,2-oxazine products.8c
However, a prerequisite for the reaction, in the presence of
Ph3PAuOTf and additional molecular sieve, was that both nitrone
substituents had to be aromatic, as the 12 h reaction only was
successful for aryl-N-phenylnitrones 4d and 4g. No reaction took
place with N-Me-nitrone 4b. In contrast, our present results
show that terminal propargyl acetals 1 undergo [3þ3] cycload-
dition with both N-Me-nitrones and diaryl nitrones in the
presence of the active gold catalyst ([Au{P(t-Bu)2(o-biphenyl)
CH3CN}]SbF6).
giving rise to
a-carboxy-a,b-unsaturated ketones. This C3 prop-
argylic esteroxidation regioselectivity is ascribed to inductive po-
larization by the electron-withdrawing ester moiety.
2.3. Reactivity
The novel [3þ3] cycloaddition reaction was further studied by
modifying the substrates. The results from the reactions after full
conversion of propargyl acetals 1aec and nitrones 4aei in the
presence of Au[P(t-Bu)2(o-biphenyl)CH3CN]SbF6 in DCM are pre-
sented in Table 2. Modifying the electronic properties of the
propargyl acetals and nitrone reactants proved to affect the re-
activity and the outcome of the reactions.
The reactivity of the N-Me-nitrones 4b,c (entries 2e3) and the
propargyl acetals 1b,c (entries 4e5) increased/decreased with the
respective electron releasing and electron withdrawing group
(ERG/EWG) character of the para-substituent (OMe/NO2) on the
phenyl moiety. The electron-deficient nitrone 4c (p-NO2, entry 3)
slowed down the reaction (24 h), but the same product distribution
was obtained as above (entry 1). However, the activated electron-

3274
S. Evjen, A. Fiksdahl / Tetrahedron 72 (2016) 3270e3276
In all successful reactions, complete cis-diastereoselectivity was
stirred for the given duration and the solvent was removed in
vacuo. Products 5, 6 and 7 were isolated by flash chromatography
using an appropriate eluent system.
obtained. The configuration of cis-1,2-oxazine 5a was determined
based on NOESY NMR experiment, indication proximity of methine
protons H3 and H6. The result is in accordance with previously
proposed stereochemistry.8c No other diastereomers were
observed.
4.3. 5-Methoxy-2-methyl-3,6-diphenyl-3,6-dihydro-2H-1,2-
oxazine (5a), 2-methoxy-3-phenylacrylaldehyde (6a) and 1-
((2-methoxypropan-2-yl)oxy)-1-phenylpropan-2-one (7a)
3. Conclusions
Compounds 5a, 6a and 7a were prepared according to the
General procedure using propargyl acetal 1a (54 mg, 0.26 mmol)
and nitrone 4a (36 mg, 0.26 mmol). Flash chromatography
(n-pentane/EtOAc 100:1) and re-purification by a second flash
column (n-pentane/EtOAc 20:1) afforded 5a, 6a and 7a as col-
ourless liquids.
We have studied a gold(I) catalysed [3þ3] cycloaddition reaction
for the stereoselective formation of cis-1,2-oxazine derivatives. 3,6-
Dihydro-2H-1,2-oxazine products 5 were readily prepared in
moderate yields (23e54% isolated) from highly reactive phenyl-
propargyl acetals 1 and nitrones 4 in the presence of a gold(I)
catalyst. The reaction is supposed to follow an uncommon [3þ3]
cycloaddition pathway via a controlled nitrone O-attack at the gold
carbene C1 position.
The outcome of the reaction is strongly dependant of the cata-
lyst activity and the electronic nature of the reactants, as the [3þ3]
cycloaddition method is quite sensitive to catalyst and (de)acti-
vating groups in both substrates. We have demonstrated that the
main challenge to successfully produce 3,6-dihydro-2H-1,2-
oxazines 5 by the gold-nitrone cycloaddition method is the ap-
propriate choice of suitable propargyl substrates and gold catalysts
to precisely tune the reactivity towards regioselective O-nitrone
attack at the gold-carbene-C1 position and subsequent ring clo-
sure.8c The most activated and electron-rich substrates tended to
follow the competing reaction pathway by gold catalysed nitrone
attack at the C3 position and subsequent oxidation27 to mainly af-
ford the aldehyde product 6.
5a: (25 mg, 32%) Rf¼0.35 (n-pentane/EtOAc); 1H NMR (400 MHz,
CDCl3) d (ppm) 7.55e7.57 (m, 2H, Ar), 7.27e7.39 (m, 8H, Ar), 5.18 (s,
1H, CHeO), 4.88 (s, 1H, CH]C), 4.25 (s, 1H, CHeN), 3.56 (s, 3H,
OeCH3), 2.37 (s, 3H, NeCH3); 13C NMR (400 MHz, CDCl3)
d
(ppm)
154.2, 139.9, 139.6, 128.6, 128.8, 128.5, 128.1, 127.9, 98.1, 78.6, 69.1,
54.8, 43.0; IR (thin film, cmꢁ1) 2961, 1670, 1213, 714, 695; HRMS
(ASAP) calcd for C18H20NO2 [MþH]þ 282.1494, obsd 282.1496.
6a: (34 mg, 35%) Rf¼0.60 (n-pentane/EtOAc 10:1); 1H NMR
(400 MHz, CDCl3)
d (ppm) 9.37 (s, 1H, CH]O), 7.80e7.82 (m, 2H,
Ar), 7.40e7.41 (m, 3H, Ar), 6.55 (s, 1H, CH]C), 3.97 (s, 3H, OeCH3);
13C NMR (400 MHz, CDCl3)
d (ppm) 189.5, 154.1, 135.0, 133.3, 130.2,
130.0, 128.7, 58.8; IR (thin film, cmꢁ1) 2940, 1683, 1455, 1359, 1150,
1032, 692; HRMS (ASAP) calcd for C10H11O2 [MþH]þ 163.0759, obsd
163.0758. 1H and 13C NMR shifts of 6a were consistent with those in
the literature.29
7a: (5 mg, 8%) Rf¼0.19 (n-pentane/EtOAc 10:1); 1H NMR
The results contribute to a better understanding of the chem-
istry of propargyl acetals in the presence of gold(I), which have
been shown to undergo a diversity of cycloaddition reactions with
different reactants.9e13
(400 MHz, CDCl3)
d (ppm) 7.44e7.46 (m, 2H, Ar), 7.35e7.37 (m, 2H,
Ar), 7.31e7.33 (m, 1H, Ar), 5.14 (s, 1H, CHeO), 3.09 (s, 3H, OeCH3),
2.10 (s, 3H, COeCH3), 1.40 (s, 3H, CeCH3), 1.32 (s, 3H, CeCH3); 13C
NMR (400 MHz, CDCl3)
d (ppm) 207.6, 137.7, 128.6, 128.0, 126.7,
101.7, 79.0, 42.9, 25.1, 24.8.
4. Experimental
4.1. General
4.4. 5-Methoxy-2-methyl-3-(4-nitrophenyl)-6-phenyl-3,6-
dihydro-2H-1,2-oxazine (5c)
All reactions were performed under nitrogen atmosphere.
Commercial grade reagents were used as received. Dry solvents
were collected from a solvent purification system. All reactions
were monitored by GLC and thin-layer chromatography (TLC)
using silica gel 60 F254 (0.25 mm thickness). Flash chromatog-
raphy was carried out using silica gel 60 (0.040e0.063 mm). 1H
and 13C NMR spectra were recorded using a 400 or 600 MHz
Compound 5c was prepared according to the General procedure
using propargyl acetal 1a (118 mg, 0.58 mmol) and nitrone 4c
(110 mg, 0.61 mmol). Flash chromatography (n-pentane/EtOAc 5:1)
afforded 5c as a yellow oil (68 mg, 36%) Rf¼0.13 (n-pentane/EtOAc
10:1); 1H NMR (400 MHz, CDCl3)
d (ppm) 8.18e8.20 (m, 2H, Ar),
7.51e7.56 (m, 4H, Ar), 7.36e7.43 (m, 3H, Ar), 5.22 (s, 1H, CHeO),
4.81 (s, 1H, CH]C), 4.38 (s, 1H, CHeN), 3.58 (s, 3H, OeCH3), 2.38 (s,
spectrometer. Chemical shifts are reported in ppm (d) downfield
3H, NeCH3); 13C NMR (400 MHz, CDCl3)
d (ppm) 155.1, 148.6, 147.6,
from tetramethylsilane (TMS) as internal standard. Coupling
constants (J) are reported in Hertz (Hz). The attributions of the
chemical shifts were determined by means of COSY, HMQC, HMBC
and NOESY experiments. Melting points (mp) were determined
using a Stuart apparatus and are uncorrected. Accurate mass
determination was performed on a ‘Synapt G2-S’ Q-TOF in-
strument from Waters. Samples were ionized with the use of
ASAP probe, no chromatography separation was used before the
mass analysis. IR spectra were obtained using a Smart Endurance
reflection cell.
138.9, 129.5, 128.5, 128.2, 124.3, 123.8, 96.6, 78.6, 58.2, 55.9, 43.1; IR
(thin film, cmꢁ1) 2966, 1662, 1517, 1345, 1210, 1070, 838, 727, 696;
HRMS (ASAP) calcd for
327.1346.
C
18H19N2O4 [MþH]þ 327.1345, obsd
4.5. 5-Methoxy-6-(4-methoxyphenyl)-2-methyl-3-phenyl-3,6-
dihydro-2H-1,2-oxazine (5d)
Compound 5d was prepared according to the General procedure
using propargyl acetal 1b (102 mg, 0.44 mmol) and nitrone 4a
(59 mg, 0.44 mmol). Attempted purification by flash chromatog-
raphy (n-pentane/EtOAc 10:1) afforded 5d in an oily yellow mixture
with 6b and 7b. Products 5d and 7b were characterized in this
mixture.
Propargyl acetals 1aec8b and nitrones 4aei28 were generated as
previously described. 1H and 13C NMR shifts were consistent with
those in the literature.
4.2. General procedure for gold-catalysed reactions
5d: (32 mg, 23%) Rf¼0.13 (n-pentane/EtOAc 10:1); 1H NMR
The relevant propargyl acetal 1aec (1 equiv) and nitrone
(1 equiv) were dissolved in dichloromethane (c¼250 mM) and Au
[P(t-Bu)2(o-biphenyl)]SbF6 (5 mol %) was added. The reaction was
(400 MHz, CDCl3) d (ppm) 7.50e7.52 (m, 2H, Ar), 7.36e7.40 (m, 5H,
Ar), 6.95e6.97 (m, 2H, Ar) or 6.89e6.91 (m, 2H, Ar), 5.16 (s, 1H,
CHeO), 4.90 (s, 1H, CH]C), 4.28 (s, 1H, CHeN), 3.85 (s, 3H, OeCH3),

S. Evjen, A. Fiksdahl / Tetrahedron 72 (2016) 3270e3276
3275
3.58 (s, 3H, OeCH3), 2.38 (s, 3H, NeCH3); HRMS (ASAP) calcd for
7.12e7.13 (m, 2H, Ar), 6.93e6.94 (m, 2H, Ar), 6.86e6.87 (m, 1H, Ar),
6.76e6.77 (m, 2H, Ar), 5.46 (s, 1H, CHeO), 5.22 (d,1H, J¼6.4, CHeN),
5.12 (d, 1H, J¼4.3, CH]C), 3.75 (s, 3H, OeCH3), 3.58 (s, 3H, OeCH3);
C
19H22NO3 [MþH]þ 312.1600, obsd 312.1600.
7b: (23 mg, 21%) Rf¼0.13 (n-pentane/EtOAc 10:1); 1H NMR
(400 MHz, CDCl3)
d
(ppm) 7.36e7.40 (m, 2H, Ar), 6.95e6.97 (m, 2H,
13C NMR (600 MHz, CDCl3)
d (ppm) 158.8, 154.5, 148.2, 137.0, 131.9,
Ar) or 6.89e6.91 (m, 2H, Ar), 5.12 (s, 1H, CHeO), 3.82 (s, 3H,
OeCH3), 3.11 (s, 3H, OeCH3), 2.11 (s, 3H, CH3), 1.41 (s, 3H, CH3), 1.34
(s, 3H, CH3).
129.3, 129.0, 128.5, 128.3, 128.2, 122.3, 118.0, 113.4, 97.0, 79.7, 63.2,
55.1, 54.9; IR (thin film, cmꢁ1) 1601, 1512, 1454, 1251, 1161, 1024,
832, 744, 697. HRMS (ASAP) calcd for C24H24NO3 [MþH]þ 374.1756,
obsd 374.1754.
4.6. 2-Methoxy-3-(4-methoxyphenyl)acrylaldehyde (6b)
4.10. 3-(4-Chlorophenyl)-5-methoxy-2,6-diphenyl-3,6-
dihydro-2H-1,2-oxazine (5j)
Compound 6b was obtained by subsequent flash chromatogra-
phy (n-pentane/DCM 3:1) of the mixture of 5d, 6b and 7b above,
giving 6b as colourless oil (19 mg, 22%) Rf¼0.13 (n-pentane/EtOAc
Compound 5j was prepared according to the General procedure
using propargyl acetal 1a (98 mg, 0.48 mmol) and nitrone 4h
(115 mg, 0.50 mmol). Flash chromatography (n-pentane/EtOAc
100:1) gave 5j as a colourless wax (42 mg, 23%) Rf¼0.56 (n-pentane/
10:1); 1H NMR (400 MHz, CDCl3)
d (ppm) 9.31 (s, 1H, CH]O),
7.78e7.80 (m, 2H, Ar), 6.93e6.94 (m, 2H, Ar), 6.52 (s, 1H, CH]C),
3.94 (s, 3H, OeCH3), 3.87 (s, 3H, OeCH3); 13C NMR (400 MHz,
EtOAc 10:1); 1H NMR (600 MHz, CDCl3)
d (ppm) 7.49e7.50 (m, 2H,
CDCl3)
d (ppm) 181.3, 161.1, 152.9, 134.6, 132.2, 126.1, 114.2, 58.7,
55.4; IR (thin film, cmꢁ1) 1681, 1601, 1510, 1256, 1176, 1154, 1032. 1H
and 13C NMR shifts of 6b were consistent with those in the
literature.28
Ar), 7.40e7.41 (m, 2H, Ar), 7.39e7.40 (m, 1H, Ar), 7.31e7.32 (m, 2H,
Ar), 7.19e7.20 (m, 2H, Ar), 7.13e7.15 (m, 2H, Ar), 6.92e6.93 (m, 2H,
Ar), 6.88e6.90 (m, 1H, Ar), 5.46 (s, 1H, CHeO), 5.25 (d, 1H, J¼4.0,
CHeN), 5.10 (d, 1H, J¼4.5, CH]C), 3.58 (s, 3H, OeCH3). 13C NMR
4.7. 5-Methoxy-2,3,6-triphenyl-3,6-dihydro-2H-1,2-oxazine
(5f)
(600 MHz, CDCl3)
d (ppm) 155.1, 148.0, 138.6, 136.8, 133.2, 130.0,
129.0, 128.7, 128.5, 128.4, 128.3, 122.6, 117.9, 96.3, 79.7, 62.9, 55.1; IR
(thin film, cmꢁ1) 1686, 1598, 1492, 1454, 1210, 1148, 1091, 1025,
1013, 833, 760, 745, 698; HRMS (ASAP) calcd for C23H21NO2Cl
[MþH]þ 378.1261, obsd 378.1254.
Compound 5f was prepared according to the General procedure
using propargyl acetal 1a (207 mg, 1.01 mmol) and nitrone 4d
(203 mg, 1.03 mmol). Flash chromatography (n-pentane/EtOAc
100:1) followed by a second flash column (n-pentane/DCM/EtOAc
100:2:1) gave 5f as a colourless liquid (38 mg, 11%) Rf¼0.46 (n-
4.11. 1-((2-Methoxypropan-2-yl)oxy)-1-(4-nitrophenyl)
propan-2-one (7c)
pentane/EtOAc 10:1); 1H NMR (600 MHz, CDCl3)
d (ppm) 7.52e7.54
(m, 2H, Ar), 7.24e7.37 (m, 5H, Ar), 7.22e7.23 (m, 2H, Ar), 7.19e7.20
(m, 1H, Ar), 7.11e7.14 (m, 2H Ar), 6.93e6.94 (m, 2H, Ar), 6.85e6.87
(m, 1H, Ar), 5.46 (s, 1H, CHeO), 5.27 (d, 1H, J¼3.5 Hz, CHeN), 5.13 (d,
1H, J¼4.3 Hz, CH]C), 3.58 (s, 3H, OeCH3). 13C NMR (600 MHz,
Compound 7c was prepared according to the General procedure
using propargyl acetal 1c (130 mg, 0.52 mmol) and nitrone 4a
(71 mg, 0.53 mmol). Flash chromatography (n-pentane/EtOAc 5:1)
gave 7c as a yellow oil (26 mg, 19%) Rf¼0.16 (n-pentane/EtOAc
10:1); 1H NMR (400 MHz, CDCl3)
d (ppm) 8.21e8.23 (m, 2H, Ar),
CDCl3)
d (ppm) 154.5, 148.1, 140.0, 137.0, 129.0, 128.5, 128.4, 128.3,
128.2, 128.1, 127.3, 122.3, 118.0, 96.7, 79.5, 63.4, 54.9; IR (thin film,
cmꢁ1) 2925, 1599, 1492, 1453, 1225, 1174, 1054, 753, 696; HRMS
(ASAP) calcd for C23H22NO2 [MþH]þ 344.1651, obsd 344.1647.
7.65e7.67 (m, 2H, Ar), 5.23 (s, 1H, CHeO), 3.09 (s, 3H, OeCH3), 2.15
(s, 3H, COeCH3), 1.44 (s, 3H, CeCH3), 1.33 (s, 3H, CeCH3). 13C NMR
(400 MHz, CDCl3)
d (ppm) 206.8, 147.8, 145.0, 127.2, 123.8, 102.2,
78.3, 49.4, 25.1, 24.7.
4.8. 2-(4-Chlorophenyl)-5-methoxy-3,6-diphenyl-3,6-
dihydro-2H-1,2-oxazine (5h)
4.12. 3-Oxo-1-phenylprop-1-en-2-yl acetate (8)
Compound 5h was prepared according to the General procedure
using propargyl acetal 1a (116 mg, 0.57 mmol) and nitrone 4f
(133 mg, 0.58 mmol). Flash chromatography (n-pentane/EtOAc
100:1) gave 5h as a colourless wax (116 mg, 54%) Rf¼0.54 (n-pen-
Compound 8 was prepared according to the General procedure
using propargyl ester 3 (46 mg, 0.26 mmol) and nitrone 4a (38 mg,
28 mmol) with PicAuCl2 (5 mol %) as catalyst. Flash chromatogra-
phy (n-pentane/EtOAc 20:1) gave 8 as a colourless oil (12 mg, 25%).
1H and 13C NMR shifts of 8 were consistent with those in the
literature.30
tane/EtOAc 10:1); 1H NMR (600 MHz, CDCl3)
d (ppm) 7.51e7.52 (m,
2H, Ar), 7.41e7.43 (m, 2H, Ar), 7.38e7.40 (m, 1H, Ar), 7.35e7.37 (m,
2H, Ar), 7.24e7.26 (m, 2H, Ar), 7.21e7.22 (m, 1H, Ar), 7.06e7.07 (m,
2H, Ar), 6.83e6.85 (m, 2H, Ar), 5.45 (s, 1H, CHeO), 5.20 (d, 1H,
Supplementary data
J¼3.4 Hz, CHeN), 5.11 (d, 1H, J¼4.3, CH]C), 3.57 (s, 3H, OeCH3); 13
C
NMR (600 MHz, CDCl3)
d (ppm) 154.4, 146.7, 139.6, 136.8, 129.0 (2
Supplementary data (spectroscopic data; 1H and 13C NMR) as-
sociated with this article can be found in the online version, at
http://dx.doi.org/10.1016/j.tet.2016.04.058.
diff. C, as shown by HMBC), 128.6, 128.4, 128.3, 128,22, 128,17, 127.5,
119.3, 96.7, 79.8, 63.8, 54.9; IR (thin film, cmꢁ1) 1670, 1488, 1453,
1225, 1174, 1058, 828, 760, 731, 698; HRMS (ASAP) calcd for
C
23H21NO235Cl [MþH]þ 378.1261, obsd 378.1255.
References and notes
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(113 mg, 0.50 mmol). Flash chromatography gave 5i as a colourless
oil containing anisaldehyde (11 mg, 6%) Rf¼0.29 (n-pentane/EtOAc
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