Synthesis of bicyclic tetrahydropyridine enamides and enecarbamates by hetero-Cope rearrangement of nitroso cycloadducts

Article abstract of DOI:10.1007/s10593-018-2289-8

[Figure not available: see fulltext.] The hetero-Cope rearrangement reactions of inverse carbamate and amide nitroso Diels–Alder cycloadducts with 1,2-dihydropyridines to give novel tetrahydropyridine enamides and enecarbamates have been studied in detail

Full text of DOI:10.1007/s10593-018-2289-8

DOI 10.1007/s10593-018-2289-8
Chemistry of Heterocyclic Compounds 2018, 54(4), 458–468
Synthesis of bicyclic tetrahydropyridine enamides
and enecarbamates by hetero-Cope rearrangement
of nitroso cycloadducts
Francesco Berti1, Andrea Menichetti1, Valeria Di Bussolo1,2,
Lucilla Favero1, Mauro Pineschi1*
1 Dipartimento di Farmacia, Sede di Chimica Bioorganica e Biofarmacia, Università di Pisa,
33 Via Bonanno, Pisa 56126, Italy; e-mail: pineschi@farm.unipi.it
2 Dipartimento di Chimica e Chimica Industriale, Università di Pisa,
3 Via G. Moruzzi, Pisa 56124, Italy
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2018, 54(4), 458–468
Submitted December 18, 2017
Accepted after revision February 20, 2018
R1
From
amide nitroso
cycloadducts
(R1 = Bn, Ph)
Moderate to
good yields
O
N
N
O
R3
R3
O
COR2
[3,3] Rearrangement
1. R3M, R2COCl
2. "R1C(O)N=O"
N
O
O
R2
From
N
N
OH NH2
O
O
N
NH
O
carbamate nitroso
cycloadducts
R1OC
or
(R1 = Ot-Bu, OBn)
N
R3
COR2
R3
COR2
Poor yields
The hetero-Cope rearrangement reactions of inverse carbamate and amide nitroso Diels–Alder cycloadducts with 1,2-dihydropyridines to
give novel tetrahydropyridine enamides and enecarbamates have been studied in detail identifying optimal reaction conditions. The
possibility to obtain tetrahydropyridine enamides and carbamates containing a free OH at the C-4position is restricted to only particular
substitution patterns when dealing with carbamate nitroso cycloadducts. On the other hand, starting from easily available amide nitroso
cycloadducts and catalytic amounts of cuprous salts, it is now possible to obtain several substituted 4a,7,8a-tetrahydropyrido[4,3-e]-
[1,4,2]dioxazines in moderate to good yields.
Keywords: enamides, enecarbamates, tetrahydropyridines, nitroso Diels–Alder reaction, sigmatropic rearrangement.
Amine-activated olefins, such as enamides and ene-
carbamates, play an important role as intermediates in a
variety of organic transformations, and significant efforts
have been devoted to their efficient syntheses.1 Generally,
the preparation of six-membered endocyclic enamides/
enecarbamates can be achieved in a few steps starting from
δ-valerolactam2 or by electrochemical methoxylation of the
corresponding N-protected piperidine followed by elimina-
tion of methanol.3 However, these methods give a direct
access only to unsubstituted 1,2,3,4-tetrahydropyridines,
while the preparation of multifunctionalized derivatives
starting from simple precursors is scarcely reported,
notwithstanding its great synthetic potential.4
piperidines,5 but they have rarely been used for the
preparation of substituted 1,2,3,4-tetrahydropyridines. In a
seminal paper, Knaus reported the synthesis of acylnitroso
cycloadducts 1 using in situ generated nitroso dienophiles
(R1C(O)N=O) and 2-substituted 1,2-dihydropyridines
(Scheme 1).6a From this study it is known that the attack by
the dienophile occurs at the less hindered face of the
1,2-dihydropyridine, opposite the C-2-substituent, to give
the endo product.6a Moreover, Knaus and Streith
independently reported the hetero-Cope rearrangement of
1,2-dihydropyridines to afford stereospecifically the
corresponding 4a,7,8,8a-tetrahydropyrido[4,3-e][1,4,2]di-
oxazines 2 (Scheme 1).6 The reaction conditions reported
as leading to the rearrangement process were poorly
As a matter of fact, 1,2-dihydropyridine derivatives are
of great value as intermediates en route to functionalized
6b
defined (large amount of silicic acid in CH2Cl2 or very
0009-3122/18/54(4)-0458©2018 Springer Science+Business Media, LLC
458

Chemistry of Heterocyclic Compounds 2018, 54(4), 458–468
Scheme 1. State of the art of hetero-Cope rearrangements of acylnitroso-1,2-dihydropyridine cycloadducts
R1
R3
R3
N
OH
O
O
O
N
O
HO
HO
OH
R3
1. R3M, R2COCl
1 N
4
refs. 6a,b
ref. 6b
R2
2O
R2
O
N
2. "R1C(O)N=O"
3
[3.3] hetero-Cope
N
N
N
Nitroso DielsAlder R1
N
R3
R1OC
3 (R1 = OPh, OBn)
COR2
Azasugars
O
COR2
2 (R1 = Ph)
1
R3M = organometallic reagent
long reaction time (up to 15 days) were required).6a
Importantly, only benzoylnitroso cycloadducts 1 with very
few substitution patterns were considered, whereas
"carbamate" nitroso cycloadducts 3 proved to be unreactive
(Scheme 1). This behavior was ascribed to the decreased
electron-withdrawing effect of the carbonyl group attached
to N-3 atom, which is not sufficiently electron-withdrawing
to induce the C(4)–N(3) bond shift necessary for the
rearrangement reaction.6a Furthermore, only one synthetic
elaboration of compounds 2 has been reported, in which
dihydroxylation of the double bond followed by reductive
destruction of the dioxazine ring with Raney nickel were
the key steps to obtain racemic aminoarabinose and amino-
altrose derivatives (Scheme 1).6b
In that case, the corresponding bicyclic 1,4,2-dioxazine A
could be only hypothesized as a transient intermediate and
could not be isolated as generally found with benzoyl-
nitroso cycloadducts.6
An observation also was made regarding the critical role
of the reaction temperature, as treatment of compound 3a
in MeCN–H2O at temperatures higher than 85°C gave the
starting 1,2-dihydropyridine through a retro-Diels–Alder
reaction.
In continuation of our studies, we report in this paper a
full account about the generality of the [3,3]-sigmatropic
rearrangement starting from different kinds of nitroso Diels–
Alder cycloadducts with 1,2-dihydropyridines derived from
both amide and carbamate nitroso dienophiles.
Considering the remarkable importance that 4-hydroxy-
tetrahydropyridine derivatives have in various fields,4c it
was interesting to verify the generality of the thermal
rearrangement reported in Scheme 2 using differently
substituted carbamate nitroso cycloadducts 3b–g (Scheme 3).
In general, the synthesis of 2-substituted 1,2-dihydro-
pyridines 5a–e with different protecting groups on the
nitrogen atom used as starting material was accomplished
by nucleophilic addition of organometallic reagents or
NaBH4 to the corresponding N-protected acylpyridinium
salts using standard procedures (Scheme 3).5 The sub-
sequent nitroso Diels–Alder reactions afforded nearly equi-
molar mixtures of inverse and direct cycloadducts.6a,8 The
assignment of the regiochemistry was carried out by NMR
analysis as previously reported by Knaus et al.6a Inverse
cycloadducts 3b–g, object of this study, can be obtained in
a pure state by chromatographic purification on silica gel.
Compounds 3b–g were heated to 75°C in aqueous
MeCN in order to bring about the rearrangement process.
The influence of water is well-documented for Claisen
rearrangement and has been ascribed to the susceptibility to
hydrogen bond acceleration when the transition state is not
We recently had found reaction conditions (6% water in
MeCN at 75°C) that extended the [3.3]-sigmatropic
rearrangement to a carbamate-protected nitroso adduct,
such as N-Boc derivative 3a, enabling the preparation of
functionalized eneacetamide 4a in 55% yield (Scheme 2).7
Scheme 2. Thermal rearrangement
of carbamate-protected adduct 3a7
CO2Me
OH NHBoc
O
O
ref. 7
N
O
N
Boc
CO2Me
Me
MeCN, H2O
75°C, 8 h
55%
N
COMe
4a
3a
Ot-Bu
O
N
O
CO2Me
N
COMe
A
Scheme 3. Synthesis of carbamate nitroso cycloadducts with 2-substituted 1,2-dihydropyridines 3b–g
459

Chemistry of Heterocyclic Compounds 2018, 54(4), 458–468
Table 1. Results of the rearrangement of differently substituted
reaction conditions. To our delight, we found that Yb(OTf)3, a
water-tolerant Lewis acid, was able to catalyze at 10 mol %
load the rearrangement process of compound 3d to deliver
compound 7 at room temperature in 24 h with an increase
in yield and conversion (entry 7).
carbamate nitroso cycloadducts 3b–g*
Entry Substrate Conversion**, %
Product
Yield***, %
1
2
>95
60
Complex mixture
3b
3c
32
The lack of generality found for the previously
described reaction conditions led us to search for alterna-
tive methods to catalyze the [3,3]-sigmatropic rearrange-
ment. The hetero-Cope rearrangement of phenacetylnitroso
cycloadduct 1a was selected as a model reaction for the
optimization of reaction conditions for inverse
cycloadducts of the amide series. The preparation of this
compound was performed on a multigram scale by a
Fowler type reduction of pyridine moiety13 followed by
nitroso Diels–Alder reaction with in situ generated
phenacetyl nitroso derivative to give selectively the inverse
nitroso cycloadduct 1a with 24% isolated yield over two
steps (Scheme 4).
3
85
40
3d
First of all, the use of simple thermal reaction conditions
reported to be effective for the rearrangement of related
benzoyl-protected cycloadducts (48 h, 55–60°C)6a gave
incomplete conversion and a low yield even after a
prolonged reaction time (Table 2, entry 1). The thermal
rearrangement carried out in the presence of water using
MeCN–H2O, 30:1 (entry 2), gave an increased conversion,
but a lower yield, as several by-products were detected by
1H NMR. Complete conversion, but complex mixture of
products were obtained using the same solvent mixture at
room temperature in the presence of Lewis acid additives
(entries 3–5). Interestingly, bicyclic dioxazine 2a could be
obtained also using common Lewis acid in dichloro-
methane (DCM) in the absence of water at room
temperature (entries 6, 8, 10).
On the other hand, the use of a Brønsted acid and
Cu(II) salts in dichloromethane proved to be ineffective
(entries 7, 11–12). Copper sulfate, totally ineffective
at room temperature (entry 13), delivered the desired
product when the reaction was carried out at 75°C
(entry 15). It was noticed that Cu(I) salts were able to
catalyze the reaction in a variety of solvents (entries 16–18).
In particular, the higher yield of compound 2a in a shorter
reaction time was obtained with catalytic amounts of CuCl
in dichloroethane (DCE) at 75°C, which were identified as
the optimal reaction conditions for the rearrangement of
compound 1a (entry 14).
4
5
>90
<10
<10
>95
Complex mixture
3e
3f
Not determined
Not determined
6
7*4
3g
3d
65
7
* Unless stated otherwise, all reactions were carried out with a 0.15 M
solution of cycloadduct in MeCN–H2O, 15:1, at 75°C for 15 h.
** Conversion of the starting compound 3b–g determined by 1H NMR
examination of the crude mixture.
*** Isolated yield after chromatographic purification on silica gel.
*4 Reaction carried out with Yb(OTf)3 (10 mol %) at room temperature for
24 h.
exactly concerted.9 The results of the screening showed
that the substituent at position 6 and also the nature of the
protecting groups in compounds 3b–g exerted strong
influence on the outcome of the reaction (Table 1).
For example, changing from the carbomethoxymethyl
group (compound 3a, Scheme 2) to an alkyl chain (com-
pound 3b), a complex reaction mixture was obtained
(Table 1, entry 1). It was curious to find that bicyclic
1,4,2-dioxazin-3-one derivative 6 and the corresponding
monocyclic decarbonylated derivative 7, compounds
devoid of Boc protection, were obtained with low yields
starting from the corresponding Boc-nitroso cycloadducts
3c,d (entries 2 and 3). The rearrangement of carbamate
derivatives 3e,f, unsubstituted at the C-2 position, was not
effective, giving a very low conversion or a complex
mixture, respectively (entries 4–6). We also examined
alternative reaction conditions to verify if the
[3,3] rearrangement could be achieved using milder
To verify the scope of our procedure, the optimized
reaction conditions using a catalytic amount of CuCl were
applied to the rearrangement of several differently
substituted inverse nitroso cycloadducts 1b–k of the amide
Scheme 4. Synthesis and rearrangement of phenacetyl cycloadduct 1a to the corresponding bicyclic 1,2,4-dioxazine 2a
460

Chemistry of Heterocyclic Compounds 2018, 54(4), 458–468
Table 2. Screening of hetero-Cope rearrangement conditions with phenacetylnitroso cycloadduct 1a*
Yield
Entry
Solvent
Catalyst**
Conditions
Conversion***, %
of compound 2a***, %
1
2
DMSO
MeCN–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
DCM
none
none
60°C, 80 h
75°C, 48 h
rt, 19 h
59
65
47
42
3
Yb(OTf)3
In(OTf)3
CeCl3
>95
>95
>95
44
Complex mixture
4
rt, 2 h
Complex mixture
5
75°C, 18 h
rt, 20 days
rt, 3 h
Complex mixture
6
CeCl3
21
7
DCM
TsOH
>95
>95
>95
<5
Complex mixture
8
DCM
CuCl (1.0 equiv)
CuCl
rt, 6 days
75°C, 18 h
rt, 6 days
rt, 15 h
55
9
MeCN–H2O, 15:1
DCM
64
10
11
12
13
14
15
16
17
18
CuBr–Me2S
CuCl2
Not determined
DCM
>95
>95
<5
Complex mixture
DCM
Cu(OTf)2
CuSO4
rt, 1 h
Complex mixture
DCM
rt, 2 days
75°C, 10 h
75°C, 3 days
75°C, 3 days
75°C, 2 h
75°C, 3 days
Not determined
DCE
CuCl
>95
56
78
47
70
40
64
DCE
CuSO4
DCE
CuBr–Me2S
CuCl
>95
>95
>95
DCE–H2O, 15:1
MeCN–H2O
CuCl (1.0 equiv)
* All reactions were carried out with compound 1a (0.1 mmol) in 0.66 ml of the indicated solvent (unless stated otherwise, MeCN–H2O, 30:1).
** Unless stated otherwise, 20 mol % of each salt was used.
1
*** Conversion of compound 1a and yield of compound 2a determined by H NMR examination of the crude mixture using 2-methylnaphthalene as
internal standard.
series (Scheme 5). The corresponding bicyclic dioxazines
2a–k were obtained with variable isolated yields.
group on the adjacent nitrogen in the starting 1,2-dihydro-
pyridines 5a–j.
From the obtained data in the amide series, it is evident
that different protecting groups and different substituents
on the starting nitroso cycloadduct influence at some extent
the rearrangement process. Even if a complete rationali-
zation of the obtained results is not possible, it seems clear
from the corresponding reaction times and isolated yields
of compounds 2a–k, 6, and 7 that the presence of a
substituent at the C-6 position, such as Ph in compounds
of type 1, or CH2COOMe in compound 3a, influences
positively the rearrangement. The promotion of the
rearrangement can be reasonably explained by steric and
electronic effects of the R3 substituent and the protecting
The reaction of catalytic amounts of CuCl (20 mol %)
with carbamate-derived nitroso-Diels–Alder cycloadducts
proved to be very different. For example, when Boc-
protected cycloadduct 3g was subjected to a variety of
reaction conditions in the presence of catalytic amounts of
CuCl or other Lewis acid, only complex mixtures or very
low conversions were obtained. The data obtained in this
study showed that the rearrangement of carbamate
cycloadducts occurs only in the presence of water and with
particular substitution patterns (compounds 3a,c,d, Table 1).
In all cases examined and in contrast with amide nitroso
cycloadducts, the corresponding bicyclic 1,4,2-dioxazine
Scheme 5. Scope of rearrangement reaction in the amide series in the optimized reaction conditions
and yields of compounds 2a–k (in parentheses)
461

Chemistry of Heterocyclic Compounds 2018, 54(4), 458–468
Scheme 6. Diverse reactivity of the C-3 carbon in the amide 2
and carbamate A/A' derivatives
Table 3. Results of population analysis for main conformers D, E
of structures 2e and A'
Atomic charge
on the C-3 atom
Entry Structure
πC=N energy, au π*C=N energy, au
1
2
3
4
2e (D)
2e (E)
A' (D)
A' (E)
+0.530
–0.34408
–0.34728
–0.36896
–0.37200
+0.01350
+0.00876
+0.03042
+0.03626
+0.529
+0.822
+0.792
stable one, with the 3-phenyl group in axial position, and
conformer E with the same group in equatorial position),
the C=N carbon shows a NBO atomic charge more strongly
positive in the case of intermediate A' (+0.822 and +0.792,
calculated for conformers D and E, respectively) than in
the case of compound 2e (+0.530 and +0.529, respectively)
(Fig. 1). A more polarized C=N bond in intermediate A' is
also confirmed by a larger energy difference between the
orbitals πC=N and π*C=N (+0.3994 and +0.4083 au,
calculated for conformers D and E, respectively) with
respect to the corresponding value found in the case of
derivative 2e (+0.3576 and +0.3560 au, respectively).
To summarize this part, the attack of water at the C-3
carbon of plausible intermediates A, A' gives a tetrahedral
intermediate that can evolve along two pathways a and b to
afford the corresponding hydrolyzed products 4a and 6 or 7
(Scheme 6).
In summary, we have studied in detail the hetero-Cope
rearrangement of differently substituted inverse acylnitroso
Diels–Alder cycloadducts. We have found that several
stable tetrahydropyridine enamides and enecarbamates
containing a bicyclic 1,4,2-dioxazine scaffold can been
obtained using a simple copper-catalyzed procedure
starting from amide nitroso cycloadducts. On the other
hand, when dealing with carbamate nitroso cycloadducts,
the corresponding bicyclic 1,4,2-dioxazine cannot be
isolated, and the obtaining of tetrahydropyridine enamide
and carbamate derivatives containing a free OH at the C-4
position is restricted to only particular substitution patterns
has never been isolated and only products 4a, 6, 7 derived
from a hydrolysis process have been isolated with low to
moderate yields. The formation of compounds 6 and 7 can
also be explained by isobutene elimination directly from
the Boc-containing bicyclic oxazine intermediate A'.
For a more comprehensive rationalization, we also
considered the different nature of the carbon at the C-3
position of the 1,2,4-dioxazine skeleton, dealing with a
O,O-dialkylhydroxamate when starting from amide nitroso
derivatives (compounds 2), or an alkoxyimidocarbonate in
compounds of type A/A' derived from carbamate nitroso
cycloadducts (Scheme 6). The possibility of the latter to
give hydrolysis products is reasonably related to the
increased electrophilicity of the C-3 carbon. Quantum-
chemical computations carried out with compound 2e and
intermediate A' showed that the C=N carbon in structure
A' is more electrophilic, and as a consequence, more
reactive toward the attack by water than the corresponding
C=N carbon of derivative 2e, as confirmed by the results of
NBO population analysis shown in Table 3.10 Regardless of
the chosen bicyclic conformation (conformer D, the most
Figure 1. Conformer D (left) and E (right) of compound 2e.
462

Chemistry of Heterocyclic Compounds 2018, 54(4), 458–468
and reaction conditions. Further studies will be devoted to
according to the general method II from phenyl pyridine-
1(2H)-carboxylate (5e) (201 mg, 1.0 mmol), N-hydroxy-
2-phenylacetamide (166 mg, 1.1 mmol), and Et4NIO4
(353 mg, 1.1 mmol) in CH2Cl2 (8.3 ml); reaction time 3 h.
Purification by flash chromatography (hexanes–AcOEt,
6:4, Rf 0.26). Yield 151 mg (43%), amorphous solid, mp
the biological evaluation of the obtained compounds.
Experimental
1H and 13C NMR spectra were recorded on a Bruker
Avance II spectrometer (250 and 62.5 MHz, respectively)
with the solvent resonance as the internal standard (CDCl3:
1
105–107°C. H NMR spectrum (CDCl3), δ, ppm (J, Hz):
1
7.26 ppm for H nuclei and 77.0 ppm for 13C nuclei;
7.58–7.00 (10H, m, H Ph); 6.99–6.65 (2H, m, 7,8-CH);
6.53–6.34 (1H, m, 4-CH); 4.98–4.76 (1H, m, 1-CH); 4.02–
3.52 (3H, m, 6-СH2, COCH2Ph); 3.30* (1H, d, J = 11.4)
and 3.20 (1H, d, J = 11.4, 6-СH2, rotamer ratio 45:55).
13C NMR spectrum (CDCl3), δ, ppm: 174.4; 172.4 and
172.0*; 152.0; 150.6; 133.6; 132.2; 131.5; 129.4; 129.3;
128.7; 128.4; 126.9; 125.7; 121.6 and 121.5*; 70.9 and
70.6*; 58.0 and 57.5*; 46.8* and 46.4; 40.9* and 40.1.
Found, m/z: 373.1167 [M+Na]+. C20H18N2NaO4. Calcu-
lated, m/z: 373.1159.
Phenyl (1S*,4R*)-3-benzoyl-2-oxa-3,5-diazabicyclo-
[2.2.2]oct-7-ene-5-carboxylate (1b) was obtained according
to the general method II from phenyl pyridine-1(2H)-
carboxylate (5e) (201 mg, 1.0 mmol), N-hydroxybenzamide
(151 mg, 1.1 mmol), and Et4NIO4 (353 mg, 1.1 mmol) in
CH2Cl2 (8.3 ml); reaction time 2 h. Purification by flash
chromatography (hexanes–AcOEt, 8:2, Rf 0.46). Yield
195 mg (58%), white solid, mp 43–46°C. 1H NMR
spectrum (CD3CN), δ, ppm (J, Hz): 7.80–7.67 (2H, m,
H Ph); 7.60–7.36 (5H, m, H Ph); 7.32–7.10 (3H, m, H Ph);
6.91–6.60 (3H, m, 4,7,8-CH); 5.20–4.99 (1H, m, 1-CH);
4.11 (1H, dd, J = 11.2, J = 3.3), 3.87* (1H, dd, J = 11.3,
J = 3.4), 3.41 (1H, d, J = 11.4), and 3.24* (1H, d, J = 11.7,
6-СH2, rotamer ratio 55:45). 13C NMR spectrum (CD3CN,
65°C), δ, ppm: 170.9; 152.5; 134.8; 132.7; 131.9; 131.7;
131.4; 130.5; 129.8; 129.4; 126.81; 122.8; 72.2; 61.5* and
60.9; 48.0. Found, m/z: 359.1005 [M+Na]+. C19H16N2NaO4.
Calculated, m/z: 359.1002.
Benzyl (1S*,4R*)-3-(2-phenylacetyl)-2-oxa-3,5-diaza-
bicyclo[2.2.2]oct-7-ene-5-carboxylate (1c) was obtained
according to the general method II from benzyl pyridine-
1(2H)-carboxylate (5d) (215 mg, 1.0 mmol), N-hydroxy-
2-phenylacetamide (166 mg, 1.1 mmol), and Et4NIO4
(353 mg, 1.1 mmol) in CH2Cl2 (8.3 ml); reaction time 3 h.
Purification by flash chromatography (hexanes–AcOEt,
6:4, Rf 0.18). Yield 157 mg (43%), yellowish oil. 1H NMR
spectrum (CDCl3), δ, ppm (J, Hz): major rotamer: 7.40–
7.11 (10H, m, H Ph); 6.90–6.61 (2H, m 7,8-CH); 6.50–6.32
(1H, m, 4-CH); 5.21 (2H, AB system, J = 14.8, COOCH2Ph);
4.97–4.78 (1H, m, 1-CH); 3.81–3.50 (3H, m, 6-СH2,
COCH2Ph); 3.22–3.10 (1H, m, 6-СH2). 13C NMR spectrum
(CDCl3), δ, ppm: major rotamer: 175.4; 153.7; 135.9;
133.7; 132.6; 131.8; 129.5; 129.4; 128.9; 128.6; 128.1;
126.9; 71.0; 67.7; 57.6; 46.3; 40.1. Found, m/z: 387.1319
[M+Na]+. C21H20N2NaO4. Calculated, m/z: 387.1315.
Methyl (1S*,4R*,6R*)-6-phenyl-3-(2-phenylacetyl)-
2-oxa-3,5-diazabicyclo[2.2.2]oct-7-ene-5-carboxylate (1e)
was obtained according to the general method II from
methyl 2-phenylpyridine-1(2H)-carboxylate (5g) (215 mg,
1
CD3CN: 1.94 ppm for H nuclei and 1.32 ppm for 13C
nuclei). High-resolution ESI mass spectra were acquired in
positive ion mode on a Waters Q-TOF Premier spectro-
meter equipped with a nanoelectrospray ion source. Melting
points were determined on a Kofler apparatus and are
uncorrected. Analytical TLC were performed on silica gel
sheets with detection by exposure to ultraviolet light
(254 nm) and/or by immersion in an acidic staining
solution of p-anisaldehyde in EtOH. Silica gel 60 was used
for flash chromatography. Automated column chromato-
graphy was performed using prepacked silica gel cartridges
(27–53 μm) on a Biotage Isolera 1.5.2 equipment.
All reagents were purchased from commercially
available sources and without further purification. CuCl
(99.999% Strem Chemicals). Dichloroethane (99% Aldrich).
Anhydrous CH2Cl2 on molecular sieves and MeOH (HPLC
grade) were used as the reaction solvents. Solvents for
extraction and chromatography were distilled before use.
Compounds 1d11 and 1g6a were prepared in accordance
with the indicated literature procedures. 1,2-Dihydro-
pyridines 5a,b8b c,12 d,e13 f,14 g,15 h,6a i,16 j17 were obtained by
published procedures. Hydroxamic acids were obtained from
the corresponding acyl chlorides using known procedures.6a
Synthesis of inverse nitroso Diels–Alder cycloadducts
using hydroxamic acid derivatives 1a,c,e,f,h–k and 3b–g
(General procedure). Method I. A round-bottomed flask
was charged with the 1,2-dihydropyridine and an appro-
priate hydroxamic acid (1.1 equiv) in MeOH–H2O, 3:1
(0.17 M with respect to the 1,2-dihydropyridine), at 0°C.
NaIO4 (1.1 equiv) was slowly added, and the resulting
heterogeneous mixture was allowed to react until no 1,2-di-
hydropyridine was detected by TLC analysis. The reaction
mixture was concentrated and diluted with CH2Cl2 and
H2O to give a biphasic solution. The aqueous layer was
twice extracted with CH2Cl2, and the combined organic
phases were dried over MgSO4, filtered, and concentrated.
The resulting residue was subjected to flash chromato-
graphy on silica gel.
Method II. An oven-dried Schlenk tube was loaded with
the 1,2-dihydropyridine, CH2Cl2 (to make 0.12 M solution),
and an appropriate hydroxamic acid (1.1 equiv) under
argon protection. The resulting mixture was cooled to –78°C,
and a 1.0 M solution of Et4NIO4 (1.1 equiv) in CH2Cl2 was
added over 5–15 min. The dry ice/acetone bath was
removed allowing the reaction mixture to reach room
temperature. Upon disappearance of the 1,2-dihydro-
pyridine (TLC), the solvent was removed to afford a
residue that was first triturated with acetone or AcOEt and
then purified by silica gel flash chromatography.
Phenyl (1S*,4R*)-3-(2-phenylacetyl)-2-oxa-3,5-diaza-
bicyclo[2.2.2]oct-7-ene-5-carboxylate (1a) was obtained
* Here and below in Experimental, one asterisk (*) denotes a signal of
minor rotamer.
463

Chemistry of Heterocyclic Compounds 2018, 54(4), 458–468
1.0 mmol), N-hydroxy-2-phenylacetamide (166 mg,
1H NMR spectrum (CD3CN, 65°C), δ, ppm (J, Hz): 7.35–
7.16 (5H, m, H Ph); 6.78–6.68 (1H, m, 7(8)-CH); 6.58 (1H,
dd, J = 5.8, J = 1.8, 4-CH); 6.51–6.41 (1H, m, 8(7)-CH);
5.01–4.94 (1H, m, 1-CH); 3.87 (1H, dt, J = 9.6, J = 3.8,
6-CH); 3.70 (3H, s, OCH3); 3.67–3.50 (2H, m, COCH2Ph);
1.82–1.64 (1H, m) and 1.33–1.11 (1H, m, CH2CH3); 0.89
(3H, t, J = 7.5, CH2CH3). 13C NMR spectrum (CD3CN, 65°C),
δ, ppm: 168.0; 156.8; 135.9; 133.0; 130.8; 129.6; 129.5;
127.8; 74.7; 60.5; 60.4; 53.6; 41.0; 25.4; 10.6. Found, m/z:
339.1321 [M+Na]+. C17H20N2NaO4. Calculated, m/z:
339.1315.
1-((1S*,4R*,6R*)-5-Acetyl-6-hexyl-2-oxa-3,5-diazabi-
cyclo[2.2.2]oct-7-en-3-yl)-2-phenylethanone (1j) was
obtained according to the general method I from 1-(2-hexyl-
pyridin-1(2H)-yl)ethanone (5a) (207 mg, 1.0 mmol),
N-hydroxy-2-phenylacetamide (166 mg, 1.1 mmol), and
NaIO4 (235 mg, 1.1 mmol) in methanol–water (6.0 ml);
reaction time 8 h. Purification by flash chromatography
(hexanes–AcOEt, 6:4, Rf 0.14). Yield 107 mg (30%), oil.
1H NMR spectrum (CD3CN, 65°C), δ, ppm (J, Hz): 7.41–
7.16 (5H, m, H Ph); 6.85–6.68 (1H, m, 7(8)-CH); 6.59–
6.34 (2H, m, 4,8(7)-CH); 4.96 (1H, br. s, 1-CH); 4.04 (1H,
d, J = 8.3, 6-CH); 3.72–3.53 (2H, m, COCH2Ph); 2.11 (3H,
s, COCH3); 1.42–1.05 (10H, m, (CH2)5CH3); 0.91 (3H, t,
J = 6.6, (CH2)5CH3). 13C NMR spectrum (CD3CN, 65°C),
δ, ppm: 171.1; 155.7; 135.8; 132.4; 130.7; 129.6; 129.5;
127.9; 75.1; 61.4; 58.6; 41.5; 40.9; 32.6; 31.6; 30.1; 26.6;
23.4; 14.5. Found, m/z: 379.1999 [M+Na]+. C21H28N2NaO3.
Calculated, m/z: 379.1992.
1-[(1S*,4R*,6R*)-5-Benzoyl-6-(phenylethynyl)-2-oxa-
3,5-diazabicyclo[2.2.2]oct-7-en-3-yl]-2-phenylethanone (1k)
was obtained according to the general method I from
phenyl[2-(phenylethynyl)pyridin-1(2H)-yl]methanone (5j)
(285 mg, 1.0 mmol), N-hydroxy-2-phenylacetamide (166 mg,
1.1 mmol), and NaIO4 (235 mg, 1.1 mmol) in methanol–
water (6.0 ml); reaction time 3 h. Purification by flash
chromatography (hexanes–AcOEt, 7:3, Rf 0.19). Yield 243 mg
(56%), amorphous solid. 1H NMR spectrum (CDCl3),
δ, ppm (J, Hz): 7.59–7.16 (15H, m, H Ph); 6.87 (1H, s,
7(8)-CH); 6.64–6.49 (2H, m, 4,8(7)-CH); 5.28–5.03 (2H,
m, 1,6-CH); 3.70–3.53 (2H, m, COCH2Ph). 13C NMR
spectrum (CDCl3), δ, ppm: 173.0; 169.9; 133.3; 132.0;
131.1; 129.6; 129.5; 129.3; 128.9; 128.8; 128.6; 128.3;
127.7; 127.3; 127.1; 121.9; 83.3; 73.4; 60.5; 48.5; 40.4.
Found, m/z: 457.1529 [M+Na]+. C28H22N2O3Na. Calcu-
lated, m/z: 457.1523.
1.1 mmol), and Et4NIO4 (353 mg, 1.1 mmol) in CH2Cl2
(8.3 ml); reaction time 2 h. Purification by flash chromato-
graphy (hexanes–AcOEt, 7:3, R 0.23). Yield 273 mg (75%),
semisolid. 1H NMR spectrum (CD3CN, 65°C), δ, ppm
(J, Hz): 7.37–7.12 (10H, m, H Ph); 6.89–6.78 (2H, m,
7,8-CH); 6.12 (1H, dd, J = 10.0, J = 5.3, NCHN); 5.15 (1H,
d, J = 3.6, NCHCH); 5.06–4.98 (1H, m, CHCHO); 3.75–
3.54 (5H, m, OCH3, COCH2Ph). 13C NMR spectrum
(CD3CN), δ, ppm: 174.4; 151.2; 137.7; 135.4; 133.2;
130.6; 130.2; 129.3; 128.9; 128.6; 127.7; 127.5; 76.3; 60.9;
59.9; 53.7; 40.7. Found, m/z: 387.1319 [M+Na]+.
C21H20N2NaO4. Calculated, m/z: 387.1321.
1-((1S*,4R*,6R*)-5-Acetyl-6-phenyl-2-oxa-3,5-diaza-
bicyclo[2.2.2]oct-7-en-3-yl)-2-phenylethanone (1f) was
obtained according to the general method II from 1-(2-phenyl-
pyridin-1(2H)-yl)ethanone (5h) (199 mg, 1.0 mmol),
N-hydroxy-2-phenylacetamide (166 mg, 1.1 mmol), and
Et4NIO4 (353 mg, 1.1 mmol) in CH2Cl2 (8.3 ml); reaction
time 3 h. Purification by flash chromatography (hexanes–
AcOEt, 7:3, Rf 0.23). Yield 160 mg (46%), yellow solid,
mp 132–137°C. 1H NMR spectrum (CD3CN), δ, ppm
(J, Hz): major rotamer: 7.42–7.17 (10H, m, H Ph); 7.15–
7.08 (1H, m) and 6.94–6.81 (1H, m, 7,8-CH); 6.24–6.02
(1H, m, 4-CH); 5.26–5.14 (1H, m, 6-CH); 5.10–4.99 (1H,
m, 1-CH); 3.79–3.64 (2H, m, COCH2Ph); 2.22 (3H, s,
COCH3). 13C NMR spectrum (CD3CN), δ, ppm: 174.1* and
173.5; 171.0* and 170.4; 137.6* and 137.4; 135.5; 133.4;
132.5; 130.6; 130.1; 129.7; 129.5; 129.3* and 129.3; 129.1;
128.3; 128.0; 127.7; 127.5; 76.5 and 76.4*; 61.7 and 60.3*;
61.1 and 56.6*; 40.7; 23.3 and 21.9*. Found, m/z:
371.1370. [M+Na]+. C21H20N2NaO3. Calculated, m/z:
371.1336.
Phenyl (1S*,4R*,6R*)-6-phenyl-3-(2-phenylacetyl)-2-
oxa-3,5-diazabicyclo[2.2.2]oct-7-ene-5-carboxylate (1h)
was obtained according to the general method I from
phenyl 2-phenylpyridine-1(2H)-carboxylate (5c) (277 mg,
1.0 mmol), N-hydroxy-2-phenylacetamide (166 mg,
1.1 mmol), and NaIO4 (235 mg, 1.1 mmol) in methanol–
water (6.0 ml); reaction time 7 h. Purification by flash
chromatography (hexanes–AcOEt, 8:2, Rf 0.07). Yield
1
307 mg (72%), amorphous solid, mp 51–54°C H NMR
spectrum (CD3CN, 65 °C), δ, ppm (J, Hz): 7.45–7.13 (13H,
m, H Ph); 7.08–6.82 (4H, m, H Ph, 7,8-CH); 6.22 (1H, dt,
J = 5.7, J = 1.5, 4-CH); 5.31 (1H, br. s, 6-CH); 5.15–5.03
(1H, m, 1-CH); 3.74 (2H, AB system, J = 15.2, COCH2Ph).
13C NMR spectrum (CD3CN, 65°C), δ, ppm: 170.9; 152.3;
140.3; 137.7; 135.8; 133.1; 130.8; 130.5; 129.8; 129.6;
129.0; 128.0; 127.9; 126.8; 122.6; 76.6; 61.8; 60.4; 41.1.
Found, m/z: 449.1479 [M+Na]+. C26H22N2NaO4. Calcu-
lated, m/z: 449.1472.
tert-Butyl (1S*,4R*,6R*)-5-acetyl-6-hexyl-2-oxa-3,5-
diazabicyclo[2.2.2]oct-7-ene-3-carboxylate (3b) was
obtained according to the general method II from
1-(2-hexylpyridin-1(2H)-yl)ethanone (5a) (107 mg, 0.6 mmol),
tert-butyl hydroxycarbamate (88 mg, 0.66 mmol), and
Et4NIO4 (212 mg, 0.66 mmol) in CH2Cl2 (5.0 ml); reaction
time 4 h. Purification by flash chromatography (hexanes–
AcOEt, 7:3, Rf 0.15). Yield 73 mg (36%), yellowish sticky
Methyl (1S*,4R*,6R*)-6-ethyl-3-(2-phenylacetyl)-2-oxa-
3,5-diazabicyclo[2.2.2]oct-7-ene-5-carboxylate (1i) was
obtained according to the general method II from methyl
2-ethylpyridine-1(2H)-carboxylate (5i) (167 mg, 1.0 mmol),
N-hydroxy-2-phenylacetamide (166 mg, 1.1 mmol), and
Et4NIO4 (353 mg, 1.1 mmol) in CH2Cl2 (8.3 ml); reaction
time 3 h. Purification by flash chromatography (hexanes–
AcOEt, 7:3, Rf 0.19). Yield 123 mg (39%), semisolid.
1
oil. H NMR spectrum (CDCl3), δ, ppm (J, Hz): 6.86–6.65
(1H, m) and 6.64–6.42 (1H, m, 7,8-CH); 6.01 (1H, d,
J = 5.4, 4-CH); 4.98–4.81 (1H, m, 1-CH); 4.19 (1H, dt,
J = 9.5, J = 3.8) and 3.95* (1H, m, 6-CH, rotamer ratio
75:25); 2.32–2.11 (4H, m, COCH3, CH2(CH2)4CH3); 1.95–
464

Chemistry of Heterocyclic Compounds 2018, 54(4), 458–468
1.79 (1H, m, CH2(CH2)4CH3); 1.58–1.44 (9H, m, C(CH3)3);
47.2; 28.2. Found, m/z: 369.1424 [M+Na]+. C18H22N2NaO5.
1.40–1.16 (8H, m, CH2(CH2)4CH3); 0.86 (3H, t, J = 6.0,
(CH2)5CH3). 13C NMR spectrum (CDCl3), δ, ppm: 170.3
and 170.2*; 156.3 and 156.2*; 131.0* and 129.9; 129.3 and
128.2*; 83.1 and 82.9*; 73.1 and 72.4*; 63.1 and 62.8*;
58.4 and 58.3*; 57.4; 32.7; 31.6; 30.5; 29.2; 28.1; 25.8 and
25.7*; 22.6 and 22.5*; 22.1; 14.1 and 14.0*. Found, m/z:
361.2102 [M+Na]+. C18H30N2O4Na. Calculated, m/z: 361.2098.
tert-Butyl (1S*,4R*,6R*)-5-benzoyl-6-phenyl-2-oxa-
3,5-diazabicyclo[2.2.2]oct-7-ene-3-carboxylate (3c) was
obtained according to the general method II from phenyl-
(2-phenylpyridin-1(2H)-yl)methanone (5b) (78 mg, 0.3 mmol),
tert-butyl hydroxycarbamate (44 mg, 0.33 mmol), and
Et4NIO4 (106 mg, 0.33 mmol) in CH2Cl2 (2.5 ml); reaction
time 2 h. Purification by flash chromatography (hexanes–
AcOEt, 7:3, Rf 0.22). Yield 51 mg (43%), yellow amorphous
Calculated, m/z: 369.1421.
Dibenzyl (1S*,4R*)-2-oxa-3,5-diazabicyclo[2.2.2]oct-
7-ene-3,5-dicarboxylate (3f) was obtained according to
the general method
I from benzyl pyridine-1(2H)-
carboxylate (5d) (229 mg, 2.0 mmol), benzyl hydroxy-
carbamate (367 mg, 2.2 mmol), and NaIO4 (235 mg,
2.2 mmol) in methanol–water (12.0 ml); reaction time 1 h.
Purification by flash chromatography (hexanes–AcOEt,
7:3, Rf 0.17). Yield 289 mg (38%), amorphous solid.
1H NMR spectrum (CD3CN), δ, ppm (J, Hz): 7.47–7.24
(10H, m, H Ph); 6.77–6.67 (1H, m) and 6.60 (1H, td,
J = 6.0, J = 2.9, 7,8-CH); 6.40 (1H, dd, J = 5.5, J = 1.7,
4-CH); 5.21–5.09 (4H, m, 2COOCH2Ph); 4.99–4.86 (1H,
m, 1-CH); 3.82–3.65 (1H, m) and 3.08 (1H, dd, J = 11.3,
J = 5.9, 6-СH2). 13C NMR spectrum (CD3CN), δ, ppm:
major rotamer: 159.1; 157.7; 137.6; 136.9; 131.3; 131.0;
129.5 (2 signals); 129.3; 129.1; 128.9 (2C); 128.8; 128.7;
71.0; 68.7; 68.1; 61.4; 47.1. Found, m/z: 403.1271 [M+Na]+.
C21H20N2NaO5. Calculated, m/z: 403.1264.
1
solid. H NMR spectrum (CDCl3), δ, ppm (J, Hz): 7.63–
6.98 (10H, m, H Ph); 6.88–6.71 (1H, m) and 6.41–6.25
(1H, m, 7,8-CH); 6.03 (1H d, J = 4.6, 4-CH); 5.56–5.42
(1H, m, 6-CH); 4.98 (1H, s, 1-CH); 1.46 (9H, s, C(CH3)3).
13C NMR spectrum (CDCl3), δ, ppm: 170.6; 157.0; 136.9;
134.6; 131.1; 129.7; 129.6; 128.8; 128.6; 128.0; 127.9;
126.5; 83.3; 80.2; 57.1* and 56.7; 28.2. Found, m/z:
415.1637 [M+Na]+. C23H24N2NaO4. Calculated, m/z:
415.1628.
3-tert-Butyl 5-phenyl (1S*,4R*)-2-oxa-3,5-diazabi-
cyclo[2.2.2]oct-7-ene-3,5-dicarboxylate (3g) was obtained
according to the general method II from phenyl pyridine-
1(2H)-carboxylate (5e) (1.44 mmol, 318.0 mg), tert-butyl
hydroxycarbamate (210 mg, 1.58 mmol), and Et4NIO4
(507 mg, 1.58 mmol) in CH2Cl2 (12 ml); reaction time 1.5 h.
Purification by flash chromatography (hexanes–AcOEt, 7:3,
Rf 0.12). Yield 157 mg (32%), yellow solid, mp 138–140°C.
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 7.42–7.32 (2H,
m, H Ph); 7.25–7.07 (3H, m, H Ph); 6.85–6.72 (1H, m) and
6.64 (1H dt, J = 9.9, J = 3.6, 7,8-CH); 6.54 (1H, dd,
J = 5.5, J = 1.6) and 6.48* (1H, dd, J = 5.4, J = 1.7, 4-CH,
rotamer ratio 55:45); 4.99–4.91 (1H, m, 1-CH); 4.07 (1H,
dd, J = 11.0, J = 2.8), 3.91* (1H, dd, J = 11.5, J = 3.2),
3.30 (1H, d, J = 11.3), and 3.20* (1H, d, J = 11.4, 6-СH2,
rotamer ratio 55:45); 1.50 (9H, s) and 1.48* (9H, s, C(CH3)3).
13C NMR spectrum (CDCl3), δ, ppm: 155.8; 153.0; 150.8;
130.5; 130.3 and 130.0*; 129.5* and 129.4; 125.7; 121.6
(2C); 83.2; 69.9* and 69.6; 61.3* and 60.7; 46.8 and 46.5*;
28.1 (2C). Found, m/z: 355.1268 [M+Na]+. C17H20N2NaO5.
Calculated, m/z: 355.1264.
Screening of reaction conditions for the hetero-Cope
rearrangement of nitroso Diels–Alder adducts of the
amide series (Table 2). A screw-capped test tube was
charged with compound 1a (0.1 mmol), the catalyst
(0.2 equiv), the specified solvent (0.66 ml), and α-methyl-
naphthalene (0.035 mmol, 5 µl). The reaction mixture was
allowed to react at the temperature and for the time speci-
fied in Table 2, filtered through silica gel (1.5 ml), and
concentrated under vacuum. The residue was analyzed by
NMR using the α-metilnaphthalene as internal stardard to
determine the conversion of starting material 1a and the
NMR yield of product 2a.
3-tert-Butyl 5-phenyl (1S*,4R*,6R*)-6-phenyl-2-oxa-
3,5-diazabicyclo[2.2.2]oct-7-ene-3,5-dicarboxylate (3d)
was obtained according to the general method II from
phenyl 2-phenylpyridine-1(2H)-carboxylate (5c) (141 mg,
0.5 mmol), tert-butyl hydroxycarbamate (73 mg, 0.55 mmol),
and Et4NIO4 (177 mg, 0.55 mmol) in CH2Cl2 (4.2 ml);
reaction time 5 h. Purification by flash chromatography
(hexanes–AcOEt, 9:1, Rf 0.04). Yield 173 mg (85%), white
1
solid, mp 59–61°C. H NMR spectrum (CDCl3), δ, ppm
(J, Hz): 7.42–7.07 (9H, m, H Ph); 6.93–6.69 (2H, m, H Ph,
7(8)-CH); 6.57–6.47 (1H, m, 8(7)-CH); 6.37–6.23 (1H, m,
4-CH); 5.44–5.20 (1H, m, 6-CH); 5.05–4.91 (1H, m,
1-CH); 1.51 (9H, s, C(CH3)3).13C NMR spectrum (CD3CN,
65°C), δ, ppm: 157.9; 157.3; 152.3; 138.8; 132.0; 131.8;
130.5; 129.8; 129.5; 129.4; 128.9; 128.8; 127.8; 126.8; 122.6;
83.8; 83.7; 78.5; 75.6; 61.6; 59.8; 57.7; 28.6. Found, m/z:
431.1580 [M+Na]+. C23H24N2NaO5. Calculated, m/z:
431.1577.
5-Benzyl 3-tert-butyl (1S*,4R*)-2-oxa-3,5-diazabicyclo-
[2.2.2]oct-7-ene-3,5-dicarboxylate (3e) was obtained
according to the general method II from benzyl pyridine-
1(2H)-carboxylate (5d) (215 mg, 1.0 mmol), tert-butyl
hydroxycarbamate (146 mg, 1.1 mmol), and Et4NIO4 (353 mg,
1.1 mmol) in CH2Cl2 (8.3 ml); reaction time 3 h. Purifi-
cation by flash chromatography (hexanes–AcOEt, 5:5,
Rf 0.35). Yield 118 mg (34%), yellow amorphous solid.
1H NMR spectrum (CD3CN), δ, ppm (J, Hz): 7.53–7.23
(5H, m, H Ph); 6.78–6.69 (1H, m) and 6.64–6.57 (1H, m,
7,8-CH); 6.33 (1H dd, J = 5.5, J = 1.7, 4-CH); 5.16 (2H, s,
COOCH2Ph); 4.89–4.83 (1H, m, 1-CH); 3.74 (1H, d,
J = 11.2) and 3.09 (1H, d, J = 11.2, 6-CH2); 1.44 (9H, s,
C(CH3)3). 13C NMR spectrum (CD3CN), δ, ppm: 158.6;
155.4; 137.7; 131.2 and 131.1*; 131.0* and 130.9; 129.5;
129.1; 128.8; 128.6; 70.8* and 70.6; 68.0; 62.2* and 61.6;
Optimized procedure for the synthesis of dioxazine
derivatives 2a–k (General method). An oven-dried 10-ml
pyrex vial was charged with the specified inverse cyclo-
adduct of type 1a–k, copper(I) chloride (0.20 equiv), and
1,2-dichloroethane (to obtain 0.15 M of compound 1). The
resulting mixture was allowed to react at 75°C until no
465

Chemistry of Heterocyclic Compounds 2018, 54(4), 458–468
compound 1 was detected by TLC analysis. The reaction
1H NMR spectrum (CDCl3), δ, ppm (J, Hz) (rotamer ratio
45:55): 7.44–7.21 (5H, m, H Ph); 7.06* (1H, d, J = 7.7)
and 6.90 (1H, d, J = 7.8, 6-CH); 4.86* (1H, d, J = 7.7,
5-CH); 4.81–4.69 (2H, m, 4a,5-CH); 4.25–4.10 (1H, m,
8a-CH); 4.05–3.87 (1H, m, 8-CH2); 3.80 (3H, s, OCH3);
3.67 (1H, d, J = 13.9, 8-CH2); 3.52 (2H, s, PhCH2).
13C NMR spectrum (CDCl3), δ, ppm: 155.0; 153.9 and
153.6*; 135.4; 128.9; 128.7; 128.3; 127.2; 101.0 and 100.8*;
66.2 and 66.0; 64.9; 53.6; 42.2; 38.4. Found, m/z: 311.1007
[M+Na]+. C15H16N2O4Na. Calculated, m/z: 311.1002.
Methyl (4aR*,8S*,8aS*)-3-benzyl-8-phenyl-8,8a-dihydro-
pyrido[4,3-e][1,4,2]dioxazine-7(4aH)-carboxylate (2e) was
obtained from compound 1e (73 mg, 0.20 mmol) with
CuCl (4.0 mg, 0.04 mmol) and DCE (1.32 ml) in 15 h.
Purification by flash chromatography (hexanes–AcOEt, 8:2 +
+ 1% Et3N, Rf 0.11). Yield 55 mg (75%), white solid, mp
45–48°C. 1H NMR spectrum (CD3CN, 65°C), δ, ppm (J, Hz):
7.42–7.21 (10H, m, H Ph); 7.17–7.10 (1H, m, NCH=CH);
5.46 (1H, d, J = 2.9, NCHPh); 4.77–4.70 (1H, m,
NCH=CH); 4.55–4.50 (1H, m, CH=CHCH); 4.19–4.14
(1H, m, CHCHO); 3.70 (3H, s, OCH3); 3.48 (2H, s,
PhCH2). 13C NMR spectrum (CD3CN), δ, ppm: 156.5
151.2; 136.9 and 136.8*; 130.1; 130.0; 129.6; 129.5; 129.1;
128.1* and 127.9; 126.6; 122.4; 102.4; 69.0; 66.4; 58.7;
54.2; 38.5. Found, m/z: 387.1322 [M+Na]+. C21H20N2NaO4.
Calculated, m/z: 387.1315.
was quenched with water, the aqueous phase was extracted
with CH2Cl2, and the combined organic layers were dried
over MgSO4. Removal of the solvent gave a residue that
was purified by flash chromatography.
Phenyl (4aR*,8aS*)-3-benzyl-8,8a-dihydropyrido[4,3-e]-
[1,4,2]dioxazine-7(4aH)-carboxylate (2a) was obtained
from compound 1a (70.1 mg, 0.20 mmol) with CuCl
(4.0 mg, 0.04 mmol) and DCE (1.32 ml) in 18 h. Purifi-
cation by flash chromatography (hexanes–AcOEt, 7:3,
Rf 0.34). Yield 40 mg (59%), semisolid. 1H NMR spectrum
(CD3CN, 65°C), δ, ppm (J, Hz): 7.47–7.23 (8H, m, H Ph);
7.22–7.14 (2H, m, H Ph); 7.06 (1H, d, J = 6.3, 6-CH); 4.95–
4.86 (2H, m, 4a,5-CH); 4.26–4.19 (1H, m, 8a-CH); 4.11–
3.98 (1H, m) and 3.85–3.69 (1H, m, 8-CH2); 3.51 (2H, s,
PhCH2). 13C NMR spectrum (CD3CN), δ, ppm: 156.0;
153.1; 152.5* and 152.0; 136.9; 130.4; 129.7; 129.5;
128.7* and 128.6; 127.9; 126.9; 122.8; 103.9* and 103.3;
67.3 and 67.2*; 65.3* and 65.2; 44.0* and 43.7; 38.7.
Found, m/z: 373.1161 [M+Na]+. C20H18N2NaO4. Calcu-
lated, m/z: 373.1159.
Phenyl (4aR*,8aS*)-3-phenyl-8,8a-dihydropyrido[4,3-e]-
[1,4,2]dioxazine-7(4aH)-carboxylate (2b) was obtained
from compound 1b (67 mg, 0.20 mmol) with CuCl
(4.0 mg, 0.04 mmol) and DCE (1.32 ml) in 18 h. Purifica-
tion by flash chromatography (hexanes–AcOEt, 7:3, Rf 0.22).
1
Yield 31 mg (42%), white solid, mp 130–131°C. H NMR
1-((4aR*,8S*,8aS*)-3-Benzyl-8-phenyl-8,8a-dihydro-
pyrido[4,3-e][1,4,2]dioxazin-7(4aH)-yl)ethanone (2f) was
obtained from compound 1f (52 mg, 0.15 mmol), CuCl
(3.0 mg, 0.03 mmol) in DCE (1.00 ml) in 16 h. Purification
by flash chromatography (hexanes–AcOEt, 6:4, Rf 0.26).
Yield 36 mg (68%), white amorphous solid. 1H NMR
spectrum (CDCl3), δ, ppm (J, Hz) (rotamer ratio 60:40):
7.59* (1H, d, J = 9.1) and 6.89 (1H, d, J = 8.9, 6-CH); 7.42–
7.11 (10H, m, H Ph); 5.81 (1H, d, J = 2.5) and 5.23* (1H,
d, J = 2.5, 8-CH); 4.84* (1H, d, J = 8.7) and 4.75 (1H, d,
J = 8.5, 5-CH); 4.58 (s, 1H) and 4.51* (1H, s, 4a-CH); 4.09
(1H, br. s, 8a-CH): 3.48 (2H, s, PhCH2), 2.28 (3H, s), and
2.03* (3H, s, COCH3). 13C NMR spectrum (CD3CN),
δ, ppm: 169.9; 156.6; 137.0* and 136.8; 130.3; 129.9;
129.6; 129.5; 129.3; 128.9; 127.9; 126.8 and 126.6*;
103.8* and 102.7; 69.2; 66.9 and 66.6*; 56.9; 38.5; 21.9.
Found, m/z: 371.1374 [M+Na]+. C21H20N2O3Na. Calcu-
lated, m/z: 371.1366.
spectrum (CDCl3), δ, ppm (J, Hz): 7.90–7.80 (2H m,
H Ph); 7.51–7.34 (5H, m, H Ph); 7.30–7.10 (4H, m, H Ph,
6-CH); 5.18* (1H, dd, J = 8.3, J = 3.0, 5-CH); 5.12–5.02
(2H, m, 4a,5-CH); 4.48–4.35 (1H, m, 8a-CH); 4.24–4.11
(1H, m, 8-CHaHb); 4.01* (1H, dd, J = 14.0, J = 3.1) and
3.83 (1H, dd, J = 14.1, J = 2.9, 8-CHaHb). 13C NMR
spectrum (CDCl3), δ, ppm: 152.1; 151.5; 150.8 and 150.6*;
130.7; 130.2; 129.6; 129.1; 128.4; 126.1; 125.9; 121.6;
102.3* and 101.9; 66.1 and 65.8*; 65.4* and 65.2; 42.6.
Found, m/z: 359.1005 [M+Na]+. C19H16N2NaO4. Calcu-
lated, m/z: 359.1002.
Benzyl (4aR*,8aS*)-3-benzyl-8,8a-dihydropyrido[4,3-e]-
[1,4,2]dioxazine-7(4aH)-carboxylate (2c) was obtained
from compound 1c (845 mg, 2.3 mmol) with CuCl (45.5 mg,
0.46 mmol) and DCE (15.2 ml) in 18 h. Purification by
flash chromatography (hexanes–AcOEt, 7:3, Rf 0.28).
1
Yield 268 mg (32%), white solid, mp 68–72°C. H NMR
spectrum (CD3CN, 65°C), δ, ppm (J, Hz): 7.46–7.25 (10H,
m, H Ph); 6.92 (1H, s, 6-CH); 5.17 (2H, s, COOCH2); 4.91–
4.69 (2H, m, 4a,5-CH); 4.12 (1H, s, 8a-CH); 3.94 (1H, dd,
J = 14.0, J = 5.4) and 3.60 (1H, t, J = 13.8, 8-CH2); 3.46
(2H, s, PhCH2). 13C NMR spectrum (CD3CN), δ, ppm:
155.8; 141.0; 137.3; 136.9; 129.6; 129.5 (2C); 129.2;
129.0; 128.6; 127.9; 102.7* and 102.2; 68.7; 67.3; 65.2;
43.4; 38.7. Found, m/z: 387.1325 [M+Na]+. C21H20N2NaO4.
Calculated, m/z: 387.1315.
1-((4aR*,8S*,8aS*)-3,8-Diphenyl-8,8a-dihydropyrido-
[4,3-e][1,4,2]dioxazin-7(4aH)-yl)ethanone
(2g)
was
obtained from compound 1g (29 mg, 0.09 mmol) with
CuCl (1.7 mg, 0.017 mmol) and DCE (0.57 ml) in 17 h.
Purification by chromatography (hexanes–AcOEt 7:3,
Rf 0.21). Yield 23 mg (75%), semisolid. 1H NMR spectrum
(CDCl3), δ, ppm (J, Hz) (rotamer ratio 60:40): 7.81–7.75
(2H, m, H Ph); 7.66* (1H, d, J = 8.7) and 6.97 (1H, d,
J = 8.6, 6-CH); 7.47–7.18 (8H, m, H Ph); 5.92 (1H, d,
J = 2.8) and 5.33* (1H, d, J = 2.8, 8-CH); 5.06* (1H, dt,
J = 8.8, J = 2.0) and 4.97 (1H, dt, J = 8.7, J = 2.0, 5-CH);
4.88–4.84 (1H, m) and 4.81–4.76* (1H, m, 4a-CH); 4.32–
4.26 (1H, m, 8a-CH); 2.31 (3H, s) and 2.06* (3H, s,
COCH3). 13C NMR spectrum (CDCl3), δ, ppm: 169.0* and
168.5; 153.1* and 152.9; 135.7; 135.2; 130.7* and 130.7;
Methyl (4aR*,8aS*)-3-benzyl-8,8a-dihydropyrido[4,3-e]-
[1,4,2]dioxazine-7(4aH)-carboxylate (2d) was obtained
from compound 1d (54.0 mg, 0.19 mmol) with CuCl (3.7 mg,
0.037 mmol) and DCE (1.23 ml) in 18 h. Purification by
flash chromatography (hexanes–AcOEt, 7:3 + 2% Et3N,
Rf 0.20). Yield 18 mg (33%), white solid, mp 82–85°C.
466

Chemistry of Heterocyclic Compounds 2018, 54(4), 458–468
130.2 and 130.1*; 129.7; 129.3; 129.0; 128.4 and 128.3*;
6-CH); 5.55 (1H, br. s, 8-CH); 5.34–5.25 (1H, m, 4a-CH);
4.83 (1H, dt, J = 8.5, J = 2.0, 5-CH); 4.33–4.23 (1H, m,
8a-CH); 3.53 (2H, s, PhCH2). 13C NMR spectrum
(CD3CN), δ, ppm: 170.1; 156.8; 136.72; 134.9; 132.8;
132.0; 130.3; 129.7 (2 signals); 129.6 (2 signals); 128.8;
128.0; 122.4; 104.1; 85.6; 83.2; 67.6; 66.9; 47.5; 38.5.
Found, m/z: 457.1528 [M+Na]+. C28H22N2NaO3. Calcu-
lated, m/z: 457.1523.
126.3* and 125.8; 102.7* and 102.2; 69.2* and 69.0; 65.9*
and 65.7; 59.8; 56.4; 21.8 and 21.7*. Found, m/z: 357.1215
[M+Na]+. C20H18N2NaO3. Calculated, m/z: 357.1210.
Phenyl (4aR*,8S*,8aS*)-3-benzyl-8-phenyl-8,8a-dihydro-
pyrido[4,3-e][1,4,2]dioxazine-7(4aH)-carboxylate (2h)
was obtained from compound 1h (85 mg, 0.20 mmol) with
CuCl (4.0 mg, 0.04 mmol) and DCE (1.32 ml) in 18 h.
Purification by flash chromatography (hexanes–AcOEt,
(4aR*,8S*,8aS*)-7-Benzoyl-8-phenyl-4a,7,8,8a-tetra-
hydropyrido[4,3-e][1,4,2]dioxazin-3(2H)-one (6). A solu-
tion of compound 3d (51.0 mg, 0.13 mmol) in MeCN
(0.80 ml) and H2O (52 μl) was allowed to react at 75°C for
15 h. Removal of the solvent afforded a residue that was
subjected to flash chromatography (hexanes–AcOEt, 8:2,
Rf 0.12) to give the title compound. Yield 14 mg (32%).
1H NMR spectrum (CD3CN, 65°C), δ, ppm (J, Hz): 7.87–
7.71 (1H, m, NH); 7.61–7.28 (10H, m, H Ph); 7.07–6.91
(1H, m, NCH=CH); 5.78 (1H, br. s, NCHPh); 4.98 (1H, dd,
J = 8.5, J = 2.5, NCH=CH); 4.83 (1H, dd, J = 7.8, J = 3.0,
CH=CHCH); 4.41 (1H, dd, J = 7.8, J = 1.5, CH=CHCHCH).
13C NMR spectrum (CD3CN), δ, ppm: 171.0; 159.6; 136.8;
132.1; 129.9; 129.6; 129.5; 129.0; 127.4; 114.3; 103.4;
87.6; 66.8; 63.5; 55.3 and 54.6*. Found, m/z: 359.1007
[M+Na]+. C19H16N2NaO4. Calculated, m/z: 359.1002.
Phenyl (2S*,3S*,4R*)-3-(aminooxy)-4-hydroxy-2-phenyl-
3,4-dihydropyridine-1(2H)-carboxylate (7). A screw-
capped test tube was charged with a solution of cyclo-
adduct 3e (41.7 mg, 0.1 mmol) in MeCN (0.6 ml) and H2O
(0.04 ml), and Yb(OTf)3 (6.2 mg, 0.01mmol) was added.
The resulting solution was allowed to react 24 h when it
was diluted with a mixture of DCM and water. The
aqueous layer was extracted with DCM (3 × 3 ml), and the
combined organic phases were dried over MgSO4 and
concentrated. Separation by flash chromatography (hexanes–
AcOEt, 7:3, Rf 0.12) gave the title compound. Yield 21 mg
1
7:3, Rf 0.12). Yield 55 mg (65%), semisolid. H NMR
spectrum (CD3CN, 65°C), δ, ppm (J, Hz): 7.47–7.19 (14H,
m, H Ph, 6-CH); 7.03 (2H, d, J = 7.3, H Ph); 5.62 (1H, d,
J = 2.7, 8-CH); 4.88 (1H, dt, J = 8.6, J = 2.1, 5-CH); 4.61
(1H, dt, J = 3.6, J = 1.9, 4a-CH); 4.28–4.22 (1H, m,
8a-CH); 3.51 (2H, s, PhCH2).13C NMR spectrum (CD3CN),
δ, ppm: 156.9; 152.3; 137.2; 137.1; 130.6; 130.3; 129.9;
129.7; 129.5; 128.3; 128.1; 127.1; 127.0; 122.7; 104.2;
69.6; 66.8; 59.8; 38.8. Found, m/z: 449.1479 [M+Na]+.
C26H22N2NaO4. Calculated, m/z: 449.1472.
Methyl (4aR*,8S*,8aS*)-3-benzyl-8-ethyl-8,8a-dihydro-
pyrido[4,3-e][1,4,2]dioxazine-7(4aH)-carboxylate (2i) was
obtained from compound 1i (63.3 mg, 0.20 mmol) with
CuCl (4.0 mg, 0.04 mmol) and DCE (1.32 ml) in 15 h.
Purification by flash chromatography (hexanes–AcOEt, 8:2 +
1
+ 2% Et3N, Rf 0.22). Yield 33 mg (52%), oil. H NMR
spectrum (CD3CN, 65°C), δ, ppm (J, Hz): 7.39–7.22 (5H,
m, H Ph); 6.82 (1H, d, J = 8.5, 6-CH); 4.93–4.88 (1H, m,
4a-CH); 4.67 (1H, dt, J = 8.5, J = 2.1, 5-CH); 4.30 (1H, td,
J = 3.6, J = 1.9, 8-CH); 3.98 (1H, dd, J = 5.8, J = 3.3,
8a-CH); 3.75 (3H, s, OCH3); 3.48 (2H, s, PhCH2); 1.63–
1.43 (2H, m, CH2CH3); 0.96 (3H, t, J = 7.5, CH2CH3).
13C NMR spectrum (CD3CN, 65°C), δ, ppm: 156.6; 154.8;
137.0; 129.7; 129.5; 127.9; 126.9; 101.9; 67.3; 66.5; 56.8;
53.9; 38.7; 23.2; 10.6. Found, m/z: 339.1318 [M+Na]+.
C17H20N2NaO4. Calculated, m/z: 339.1315.
1
1-((4aR*,8S*,8aS*)-3-Benzyl-8-hexyl-8,8a-dihydro-
pyrido[4,3-e][1,4,2]dioxazin-7(4aH)-yl)ethanone (2j) was
obtained from compound 1j (71 mg, 0.20 mmol) with CuCl
(4.0 mg, 0.04 mmol) and DCE (1.32 ml) in 15 h. Purifi-
cation by flash chromatography (hexanes–AcOEt, 3:7,
(65%). H NMR spectrum (CD3CN, 65°C), δ, ppm (J, Hz)
(rotamer ratio 45:55): 7.73 (1H, br. s, OH); 7.54–7.06
(11H, m, H Ph, NCH=CH); 5.67 (1H, br. s) and 5.57* (1H,
br. s, NCHPh); 5.15 (1H, dd, J = 8.6, J = 2.8, NCH=CH);
4.89 (1H, ddd, J = 7.8, J = 2.9, J = 0.7, CH=CHCH); 4.38
(1H, d, J = 7.8, CH=CHCHCH). 13C NMR spectrum
(CD3CN), δ, ppm: 159.4; 152.0; 137.3* and 136.9; 134.3;
130.5; 130.3* and 130.1; 129.4; 129.3; 127.3 and 127.1*;
127.0; 122.6 and 122.4*; 104.2* and 103.7; 66.2; 63.0;
55.4* and 55.1. Found, m/z: 349.1164 [M+Na]+.
C18H18N2NaO4. Calculated, m/z: 349.1159.
1
Rf 0.54). Yield 21 mg (30%), amorphous solid. H NMR
spectrum (CDCl3), δ, ppm (J, Hz): major rotamer: 7.38–
7.22 (5H, m, H Ph); 6.67 (1H, dt, J = 8.5, J = 1.3, 6-CH);
4.97–4.88 (1H, m, 4a-CH); 4.77–4.62 (2H, m, 5,8a-CH);
3.96 (1H, q, J = 2.7, 8-CH); 3.46 (2H, s, PhCH2); 2.21 (3H,
s, COCH3); 1.39–1.21 (10H, m, (CH2)5CH3); 0.92–0.80
(3H, m, (CH2)5CH3). 13C NMR spectrum (CD3CN), δ, ppm:
major rotamer: 169.7; 156.7; 128.1; 127.5; 126.3; 103.4;
67.7; 66.7; 53.0; 50.2; 38.6; 32.3; 29.7; 26.4; 24.5; 14.4.
Found, m/z: 379.2000 [M+Na]+. C21H28N2NaO3. Calcu-
lated, m/z: 379.1992.
Quantum-chemical computations were carried out
with the Gaussian 09 set of programs10 at the density
functional theory level (B3LYP). The NBO population
analysis was performed from the SCF density matrix with
the 6-311++G(d,p) basis set on the previously optimized
structures with 6-31+G(d) basis set. Berny analytical
gradient optimization routines were applied for optimi-
zation of the minima on the PES. All minima were
characterized by the frequency calculation in order to
verify that they had no imaginary frequencies.
[(4aR*,8S*,8aS*)-3-Benzyl-8-(phenylethynyl)-8,8a-di-
hydropyrido[4,3-e][1,4,2]dioxazin-7(4aH)-yl](phenyl)-
methanone (2k) was obtained from compound 1k (33 mg,
0.075 mmol) with CuCl (1.5 mg, 0.015 mmol) and DCE
(0.50 ml) in 15 h. Purification by preparative TLC (hexanes–
AcOEt, 7:3, 2 runs). Yield 19 mg (56%), yellowish solid,
1
mp 50–55°C. H NMR spectrum (CD3CN, 65°C), δ, ppm
We gratefully acknowledge the financial support from
P.R.A. 2016_27 by the University of Pisa.
(J, Hz): 7.63–7.23 (15H, m, H Ph); 6.71 (1H, d, J = 8.3,
467

Chemistry of Heterocyclic Compounds 2018, 54(4), 458–468
9. Acevedo, O.; Armacost, K. J. Am. Chem. Soc. 2010, 132,
References
1966.
1. For a recent review see: Courant, T.; Dagousset, G.; Mason, G.
Synthesis 2015, 1799.
10. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.;
Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.;
Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.;
Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.;
Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.;
Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.;
Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.;
Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.;
Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.;
Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.;
Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.;
Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.;
Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.;
Fox, D. J. Gaussian 09, Revision D.01; Gaussian, Inc.:
Wallingford, 2009.
2. (a) Gigant, N.; Gillaizeau, I. Org. Lett. 2012, 14, 4622.
(b) Gigant, N.; Dequirez, G.; Retailleau, P.; Gillaizeau, I.;
Dauban, P. Chem.–Eur. J. 2012, 18, 90. (c) Lepifre, F.;
Claiver, S.; Bouyssou, P.; Coudert, G. Tetrahedron 2001, 57,
6969. (d) Kozak, J. A.; Dodd, J. M.; Harrison, T. J.;
Jardine, K. J.; Patrick, B. O.; Dake, G. R. J. Org. Chem. 2009,
74, 6929.
3. (a) Le Corre, L.; Kizirian, J.-C.; Levraud, C.; Boucher, J.-L.;
Bonnet, V.; Dhimane, H. Org. Biomol. Chem. 2008, 6, 3388.
(b) Moriyama, N.; Matsumura, Y.; Kuriyama, M.; Onomura, O.
Tetrahedron: Asymmetry 2009, 20, 2677. (c) Shono, T.;
Matsumara, Y.; Tsubata, K.; Sugihara, Y.; Yamane, S.-I;
Kanazawa, T.; Aoki, T. J. Am. Chem. Soc. 1982, 104, 6697.
4. (a) Quirion, J.-C. In Science of Synthesis; Molander, G. A., Ed.;
Georg Thieme Verlag: Stuttgart, 2006, vol. 33, p. 629. (b) Lei, C.-H.;
Wang, D.-X.; Zhao, L.; Zhu, J.; Wang, M.-X. Chem.–Eur. J.
2013, 19, 16981. (c) Tong, S.; Wang, D.-X.; Zhao, L.; Zhu, J.;
Wang, M.-X. Angew. Chem., Int. Ed. 2012, 51, 4417.
5. Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A. B.
Chem. Rev. 2012, 112, 2642.
6. (a) Dubey, S. K.; Knaus, E. E. J. Org. Chem. 1985, 50, 2080.
(b) Backenstrass, F.; Streith, J.; Tschamber, T. Tetrahedron
Lett. 1990, 31, 2139.
7. Crotti, S.; Berti, F.; Pineschi, M. Org. Lett. 2011, 13, 5152.
8. (a) Bodnar, B. S.; Miller, M. J. Angew. Chem., Int. Ed. 2011,
50, 5630. (b) Berti, F.; Di Bussolo, V.; Pineschi, M. J. Org.
Chem. 2013, 78, 7324. (c) Berti, F.; Di Bussolo, V.; Pineschi, M.
Synthesis 2015, 647.
11. Defoin, A.; Fritz, H.; Schmidlin, C.; Streith, J. Helv. Chim.
Acta 1987, 70, 554.
12. Comins, D. L.; Abdullah, A. H.; Mantlo, N. B. Tetrahedron
Lett. 1984, 25, 4867.
13. Sundberg, R. J.; Bloom, J. D. J. Org. Chem. 1981, 46, 4836.
14. Fowler, F. W. J. Org. Chem. 1972, 37, 1321.
15. Knaus, E. E.; Avasthi, K.; Giam, C. S. Can. J. Chem. 1980,
58, 2447.
16. Yamaguchi, R.; Nakazono, Y.; Kawanisi, M. Tetrahedron
Lett. 1983, 24, 1801.
17. Black, D. A.; Arndtsen, B. A. Org. Lett. 2004, 6, 1107.
468