Intramolecular oxidative Pd(II)-catalyzed alkoxylation of 3-aza-5-alkenols with O2 as sole oxidant: Mild conditions for the synthesis of 1,4-oxazine derivatives

Article abstract of DOI:10.1055/s-0030-1259295

Synthesis of 1,4-2H-oxazine derivatives was performed by Pd(II)-catalyzed aerobic oxidative cyclization of 3-aza-5-alkenols, prepared from easily available 1,2-amino alcohols. The reaction proceeds in very mild conditions with a simple catalytic system co

Full text of DOI:10.1055/s-0030-1259295

LETTER
227
Intramolecular Oxidative Pd(II)-Catalyzed Alkoxylation of 3-Aza-5-alkenols
with O2 as Sole Oxidant: Mild Conditions for the Synthesis of 1,4-Oxazine
Derivatives
S
ynthesis of 1,4-O
i
xazine
a
Derivativesnluigi Broggini,*a Egle M. Beccalli,b Elena Borsini,b Andrea Fasana,a Gaetano Zecchia
a
Dipartimento di Scienze Chimiche e Ambientali, Università degli Studi dell’Insubria, Via Valleggio 11, 22100 Como, Italy
Fax +39(031)2386449; E-mail: gianluigi.broggini@uninsubria.it
DISMAB, Sezione di Chimica Organica ‘A. Marchesini’, Università di Milano, Via Venezian 21, 20133 Milano, Italy
b
Received 17 October 2010
Dedicated to Professor Alberto Brandi on occasion of his 60th birthday
R1
R1
R1
Abstract: Synthesis of 1,4-2H-oxazine derivatives was performed
by Pd(II)-catalyzed aerobic oxidative cyclization of 3-aza-5-al-
kenols, prepared from easily available 1,2-amino alcohols. The
reaction proceeds in very mild conditions with a simple catalytic
system consisting of PdCl2(MeCN)2 in THF at room temperature
with molecular oxygen as the sole stoichiometric oxidant.
N
N
N
Pd(II)
O2
and/or
OH
O
O
R2
R2
R2
A
Scheme 1 Synthesis of 1,4-2H-oxazine derivatives by Pd(II)-cata-
lyzed aerobic oxidative cyclization of alkenols
Key words: palladium, heterocycles, alkenols, alkoxylation, mo-
lecular oxygen
well as from the potential use as building blocks in various
useful synthesis.9
The initial efforts to develop the desired reaction were
made on alkenol 4, prepared in satisfactory overall yields
starting from (N-acetyl)aminoethanol (1).10 After O-pro-
tection with TBDMSCl, the resulting amide 2 was func-
tionalized by reaction with allyl bromide in the presence
of NaH and KI to give 3. The subsequent removal of
TBDMS group in classical conditions (tetrabutylammoni-
um fluoride in THF) as final step furnished the target com-
pound 4 (Scheme 2).
Oxidative palladium(II) catalysis has gained a remarkable
role in functionalization of sp2-carbon atoms.1 Significant
success has been achieved for carbon–carbon2 and car-
bon–heteroatom3 bond formation either by inter- or in-
tramolecular reactions. In terms of versatility, economic
cost, and environmental impact, one of the key require-
ments for their success is played by the oxidant, essential
to restart a new catalytic cycle.4 A fruitful approach is the
use of procedures involved with a terminal oxidant such
as molecular oxygen. This offers both economical and
practical advantages, making attractive the challenge in
this field to use molecular oxygen as the sole oxidant
without any other co-oxidants.5,6
Ac
TBDMSCl
imidazole
Ac
Br
NH
NH
OH
N
NaH, KI
THF–DMF (4:1)
OTBDMS
DMF
1
2 (94%)
The intramolecular version of palladium-catalyzed oxida-
tive reactions has had a growing impact on heterocyclic
synthesis.7 Also in our laboratories some cyclization pro-
cedures have been previously performed as convenient
routes to access various heterocycle systems.8
Ac
Ac
N
TBAF
THF
OH
OTBDMS
4 (94%)
3 (82%)
Scheme 2 Synthesis of alkenol 4
Herein, we describe a practical procedure for the synthesis
of 2H-1,4-oxazine derivatives by palladium-catalyzed
aerobic oxidative cyclization of 3-aza-5-alkenols A
(Scheme 1), which are readily accessible from 1,2-amino
alcohols. This reaction was made possible by use of a very
Alkenol 4 was firstly tested under a number of conditions
potentially suitable for aerobic oxidative heterocycliza-
tion reactions (entries 1–8, Table 1). Pd(OAc)2 in THF
simple catalyst system consisting of PdCl2(MeCN)2 in and in DMSO afforded the desired 3,4-dihydro-2H-
THF, which is able to promote the cyclization at room oxazine 5 in 15% and 37% yield, respectively, beside un-
temperature with molecular oxygen as the sole stoichio- reacted or degradation materials (entries 1 and 2). Since a
metric oxidant.
better result was obtained by using PdCl2(MeCN)2 in
DMSO (entry 3), we privileged the use of the latter cata-
lyst and examined the influence of solvent and tempera-
ture on the product yield (entries 4–7). Disappointingly,
when the reaction took place with air as terminal oxidant,
compound 5 was formed in lower yield (entry 8). The re-
action was found to be feasible with other oxidant agents
such as Cu(OAc)2, 1,4-benzoquinone, H2O2, CuCl2/O2,
The interest towards 2H-1,4-oxazine skeleton arises from
its presence in compounds having biological activities as
SYNLETT 2011, No. 2, pp 0227–0230
Advanced online publication: 04.01.2011
DOI: 10.1055/s-0030-1259295; Art ID: G31210ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
1

228
G. Broggini et al.
LETTER
and t-BuOOH (entries 9–13, Table 1). However, sizeable
amounts of degradation products were generally formed.
As a matter of fact, the overall account of the investigated
catalytic systems show as the most effective the mild con-
ditions of entry 5, namely PdCl2(MeCN)2 in THF at room
temperature in the presence of molecular oxygen.11
PdCl2(MeCN)2
(5 mol%)
CHO
O
O
N
N
N
+
O2, THF, r.t.
OH
O
6
7 (12%)
O
8 (53%)
Subsequently, we investigated the efficiency of molecular
oxygen to promote intramolecular alkoxylation of a few
differently N-substituted 3-aza-5-hexenols. When a tosyl
group replaced the acetyl group of compound 4, a satisfac-
tory reaction occurred providing the cyclization product
in higher yield (81% vs. 75% yield). Conversely, the reac-
tion of (N,N-diallyl)-2-aminoethanol (6) in the presence of
0.05 equivalents of PdCl2(MeCN)2 in THF under oxygen
atmosphere led to a synthetically useless mixture of the
bicyclic fused-ring product 7 and the acyclic compound 8
(Scheme 3). A tentative suggestion for the formation of 7
implies an insertion of the endocyclic olefin of B into a
Pd–H bond affording an intermediate which could evolve
through 5-endo cyclization, isomerization to an enamine,
adventitious water attack, and final oxidation. Converse-
ly, compound 8 plausibly arises by an oxidative degrada-
tion of the first-formed 3,4-dihydro-2H-1,4-oxazine B
through the intermediacy of the dioxetane species C sus-
ceptible to [2+2] retrocycloaddition.12
O
O
N
N
O
O
C
B
Scheme 3 Pd(II)-catalyzed reaction of (N,N-diallyl)aminoethanol 6
and (S)-2-aminobutanol, we synthesized the substrates
9a–g and transformed them into the optically active dihy-
drooxazines 10a–g in fair to good yields.
A plausible pathway accounting for the formation of the
1,4-oxazine product is depicted in Scheme 4. The first
formed Pd(II) coordination species E undergoes intramo-
lecular nucleophilic attack of the hydroxy group to gener-
ate the s-alkylpalladium complex F via a 6-exo-trig
cyclization process. Subsequent b-hydride elimination re-
sults in the formation of the exo-methylene compound G,
which isomerizes to the final product 5, and the complex
H which eliminates HCl giving the Pd(0) species I. At this
point, in the light of previous literature reports,5b,d the role
of molecular oxygen may be interpreted as follows. Oxy-
genation of I generates the dioxygen complex J, suscepti-
ble to protonation and ring opening to the Pd(II)-
At this stage of our study, we explored the scope of the in-
tramolecular alkoxylation procedure onto a variety of 2-
substituted 3-aza-alkenols. Starting from the easily avail-
able L-alaninol, L-valinol, L-leucinol, L-phenylalaninol,
Table 1 Optimization of Reaction Conditions
Ac
Ac
N
N
Pd(II)
OH
O
oxidant
4
5
Entry
1
Catalyst (5 mol%)
Pd(OAc)2
Oxidant
O2
Solvent
THF
Temp (°C)
Time (h)
Yield (%)
15
25
70
70
60
25
25
25
25
25
25
25
25
25
24
2
2
Pd(OAc)2
O2
DMSO
DMSO
THF
37
3
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
O2
4
61
4
O2
2
58
5
O2
THF
5
75
6
O2
1,4-dioxane
MeCN
THF
2
72
7
O2
2
52
8
air
24
24
1
45
a
9
Cu(OAc)2
1,4-BQa
THF
70
10
11
12
13
THF
38
a
H2O2
THF
3
25
CuCl2,b O2
THF
2
65
t-BuOOHa
THF
3
27
a 1.5 equiv.
b 10 mol%.
Synlett 2011, No. 2, 227–230 © Thieme Stuttgart · New York

LETTER
Synthesis of 1,4-Oxazine Derivatives
229
wards dihydroalkoxylation reactions to directly produce
optically active variously substituted morpholines are
now in progress.
Table 2 Reaction Scope
R1
N
R1
R2
N
PdCl2(MeCN)2 (5 mol%)
O2, THF, r.t.
OH
9a–g
O
R2
10a–g
Acknowledgment
Entry
R1
R2
Yield of 10 (%)
The authors thank the Ministero dell’Università e della Ricerca for
financial support (PRIN 2008KRBX3B).
1
2
3
4
5
6
7
Ac
i-Bu
Et
75
63
63
82
75
74
67
Ac
References and Notes
Ac
Bn
i-Pr
Me
Et
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H2O2
HCl
OOH
PdII(L2)
4
Cl
L2PdCl2
K
HCl
D
O
O
PdII(L2)
Cl
J
Cl
Pd
L
Ac
O2
Pd0(L2)
N
OH
I
E
Cl
L
H
HCl
Pd
PdII(L2)
L
H
Cl
Ac
H
N
HCl
O
Ac
F
N
5
O
G
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Scheme 4 Proposed mechanism for the oxidative palladium(II)-
catalyzed heterocyclization
In conclusion, we have developed an intramolecular oxi-
dative alkoxycyclization of 3-aza-5-alkenols in very mild
conditions to give 3,4-dihydro-2H-1,4-oxazine products,
which are useful intermediates to access more complex
structures containing a morpholine ring. Investigations to-
Synlett 2011, No. 2, 227–230 © Thieme Stuttgart · New York

230
G. Broggini et al.
LETTER
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A solution of 4 (1.0 mmol), PdCl2(MeCN)2 (0.05 mmol, 13
mg), in THF (5 mL) was stirred under oxygen atmosphere
for 5 h at r.t.. The solvent was evaporated under reduced
pressure. The crude mixture was diluted with brine (10 mL)
and extracted with CH2Cl2 (2 × 25 mL). The organic layer
was dried over Na2SO4 and the solvent removed under
reduced pressure. The residue was chromatographed on a
silica gel column with light PE–EtOAc (5:1) as eluent to
give 5 (75%).
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Data for 4-Acetyl-6-methyl-3,4-dihydro-2H-1,4-oxazine
(5)
Colourless oil. IR (nujol): 1676 cm–1. 1H NMR (400 MHz,
CDCl3): d = 1.75 (3 H, s), 2.12 (3 H, s), 3.48 (2 H, t, J = 4.7
Hz), 3.55 (2 H, t, J = 4.7 Hz), 5.89 (1 H, s). 13C NMR (100
MHz, CDCl3): d = 17.9 (q), 22.0 (q), 43.1 (t), 64.1 (t), 98.9
(d), 137.9 (s), 163.7 (s). MS: m/z = 141 [M+]. Anal. Calcd for
C7H11NO2: C, 59.56; H, 7.85; N, 9.92. Found C, 59.33; H,
7.96; N, 9.88.
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