Synthesis of 5-halo-4h-1,3-oxazine-6-amines by a copper-mediated domino reaction

Article abstract of DOI:10.1002/chem.201100423

Three become one! In one copper-mediated step, three simple components, including a propargylcarboxamide, a protected amine, and a source of chloride, assemble to give highly functionalized oxazines, which are interesting building blocks for the synthesis

Full text of DOI:10.1002/chem.201100423

COMMUNICATION
DOI: 10.1002/chem.201100423
Synthesis of 5-Halo-4H-1,3-oxazine-6-amines by a Copper-Mediated
Domino Reaction
A. Stephen K. Hashmi,*[a] Andreas M. Schuster,[a] Marc Zimmer,[a] and
Frank Rominger[a, b]
In ongoing work to expand the scope of the gold-cata-
lyzed[1] cyclization of propargylamides to their correspond-
ing oxazoles,[2] methyleneoxazolines,[3] or 1,3-oxazines,[4] we
intended to investigate new, higher functionalized substrates.
We considered ynamides derived from such propargylamides
to be an interesting target because ynamides are of increas-
ing importance for organic chemistry.[5] In this context a new
synthesis of ynamides recently published by Stahl et al.
seemed to apply perfectly to our plans.[6] This method pro-
vides direct access to ynamides starting from terminal al-
kynes using copper(II) as a catalyst. The reaction is per-
formed under an oxygen atmosphere to reoxidize the
copper catalyst, which is reduced under the reaction condi-
tions (Scheme 1). Recently, this kind of oxidative coupling
5-chloro-4H-1,3-oxazine-6-amine 2a (Scheme 2). The disap-
pearance of the amide proton at d=6.55 ppm and a shift of
the carbon NMR signal of the methylene group from d=
30.4 to 50.7 ppm indicated a 6-endo-dig cyclization. This
occurs due to attack of the nucleophilic oxygen of the amide
group at the more electrophilic position of the ynamide
triple bond. The formation of such a six-membered ring was
later confirmed by X-ray structure analyses (Figure 1 and
Figure 2). The low yield (16%) of 2a formed in this reaction
can be explained due to the fact that CuCl2 was applied
only in “catalytic” amounts (20 mol%) and the chloride
from the CuCl2 is consumed during the formation of 2a
(Scheme 2).
Scheme 1. Oxidative alkyne-N coupling by Stahl; R1 =aryl, alkyl, R2 =
alkyl, aryl, R3 =O2S-aryl.
reaction to terminal alkynes has been highlighted.[7] In addi-
tion, 1,3-oxazines are a well-known structural motif for bio-
logically active substances[8] and have a wide range of thera-
peutic use. Compounds with such a structure exhibit antifun-
gal,[9] antibiotic,[9–11] antiviral,[12] and antitumor[13] properties.
Besides these applications, they are also used as acetylcholi-
nesterase (AChE) inhibitors.[14]
A first test with N-propargylbenzamide 1a and N-methyl-
tosylamide did not yield the expected corresponding yna-
mide, but instead gave the cyclized and chlorinated product
Figure 1. Solid-state structures of 2b, 2e, 2g, and 2q.
[a] Prof. Dr. A. S. K. Hashmi, Dipl.-Chem. A. M. Schuster, M. Zimmer,
Dr. F. Rominger
Hereafter, to increase the yield, one equivalent of copper
salt was used. A series of different copper(II) salts were
then tested (Table 1). This screening clearly proved that the
halide ions were crucial for the reaction; only CuCl2 and
CuBr2 (Table 1, entries 1 and 2) led to product formation
(CuI2 is not a stable compound and thus could not be
Organisch-Chemisches Institut
Ruprecht-Karls-Universitꢀt Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax : (+49)6221-544205
E-mail: hashmi@hashmi.de
[b] Dr. F. Rominger
Crystallographic investigation.
tested). In all other cases, namely Cu
ACHTUNGTREN(UNNG OAc)2, CuF2, Cu-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100423.
A
E
E
ACHTUNGTRENNUNG
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Scheme 2. First test of Stahlꢂs reaction for the synthesis of the corresponding propargylamides resulted in a one-pot amination–halocyclization sequence;
X=Br, Cl.
Different N-propargylamides were then tested (Table 2).
For all these reactions, CuCl2 and N-methyltosylamide were
used (other acceptors on the amide were also investigated;
compare with Table 3). Aryl moieties like phenyl, 4-bromo-
phenyl, 2-furyl, and 2-thienyl were used (Table 2, entries 1–
4). The phenyl substrate gave 32% yield (Table 2, entry 1),
however with the 4-bromophenyl substituent a better yield
of 44% was obtained (Table 2, entry 2). Table 2 shows the
overall yields for both steps of the domino reaction. The
Table 2. Catalysis of substrates with different R groups
Entry
Starting
material
R
Product
Yield
[%]
Figure 2. Crystal structures of 2a, 2i, and 2j.
1
2
1a
1b
2a
2b
32
44
Table 1. Screening of different copper(II) salts
3
4
1c
1d
2c
2d
56
35
Entry
CuX2
Product
Yield [%]
5
6
1e
1 f
2e
2 f
49
41
1
2
3
4
5
6
7
8
9
CuCl2
CuBr2
CuACHTUNGTRENNUNG(OAc)2
CuF2
Cu(Ph-sulfinate)2
2a
2q
32
32
–
–
–
–
–
–
–
7
1g
1h
1a
2g
2h
2q
51
–
Cu
CuTf2
Cu(NO3)2
CuSO4
A
A
8
H
9[a]
32
10[a]
11[a]
1c
1e
2r
2s
42
37
starting material decomposed and no defined product could
be isolated (Table 1, entries 3–9). Copper salts, such as Cu-
ACHTUNGTRENNUNG(BF4)2, which are not able to form the cyclized product,
were used in an attempt to isolate the ynamide but again all
the material decomposed.
[a] With CuBr2 instead of CuCl2.
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Synthesis of Novel 5-Halo-4H-1,3-oxazine-6-amines
COMMUNICATION
Table 3. Testing different RACTHNUTRGNEUGN(EWG)NH coupling partners.
substrates in the reaction than aromatic ones. Since vinyl
bromides are more reactive than vinyl chlorides and thus
would be more valuable substrates for subsequent function-
alization, we also conducted the reaction of three of the sub-
strates with CuBr2. A phenyl substituent gave 2q in 32%
yield (Table 2, entry 9), which is the same as the reaction
yield obtained with CuCl2 (entry 1). The heteroaromatic 2-
furyl derivative gave of product 2r in 42% yield (Table 2,
entry 10), which is somewhat less than the reaction with
CuCl2 (entry 3). The styryl substituent also gave the product
2s in a lower yield (37%, Table 2, entry 11), compared with
the reaction with CuCl2 (entry 5). Single crystals of products
2b, 2e, 2g, and 2q could be obtained by slow evaporation
from benzene, which were suitable for X-ray structure anal-
ysis (Figure 1).[15] These structures prove unambiguously
that the products contain the 5-halogen-4H-1,3-oxazine-6-
amine motif. For compound 2q we were able to obtain two
different types of crystals from one crystallization ap-
proach.[15] One type crystallizes in the triclinic crystal
system, the other in the monoclinic crystal system.
Starting
Entry
Product
Yield [%]
32
material
1
2
1a
1a
2a
2i
2j
31
28
3
4
1a
1a
2k
–
In addition to the products, byproducts were also isolated
from the reactions of 1c with 2r and 1e with 2s, respectively
(Table 2, entries 10 and 11). These byproducts resulted from
5
6
1a
1a
2k
2l
1[a]
40
the
direct
cyclization
of
the
N-propargyl-
amides (products 3r and 3s) and the cyclization of the cor-
responding alkynyl bromide (products 4r and 4s).
7
1a
2m
unselective
9[a]
8
9
1a
1a
2n
2o
[b]
–
10
1a
1a
2p
2a
59
52
11[c]
After using N-methyltosylamide for testing different R
moieties, variations of the amide component were tested
(Table 3). In addition to tosyl, the easily removable o-, m-,
and p-nosylated methylamine was also tested (Table 3, en-
tries 1–4). Tosyl (entry 1), p-nosyl (entry 2) and m-nosyl
(entry 3) all gave products in yields of about 30%, whereas
when o-nosyl was used as a substrate no product 2 was ob-
tained (Table 3, entry 4). The failure of the latter coupling is
probably caused by steric hindrance. Tosylated benzylamine
gave only about 1% yield of unstable product, which quick-
ly decomposes even when it is isolated in pure form
(Table 3, entry 5). Low yield and instability is possibly
caused by the instability of the benzyl group under an
oxygen atmosphere. Switching to the tosylated allylamine
gave the product 2l in a good yield of 40% (Table 3,
entry 6). N-tert-Butoxycarbonyl (N-Boc) methylamine gave
no isolable product, only an unselective conversion of the
starting material was observed (Table 3, entry 7). Oxazolidi-
[a] Product unstable, only 1H NMR data available; [b] starting material
reisolated; [c] reaction with CuCl2 (2 equiv) and pyridine (10 equiv).
heteroaromatic furyl substrate 1c gave the best yield of all
substrates to give 2c in 56% yield (Table 2, entry 3). 2-Thio-
phenyl gave 2d in 35% yield (Table 2, entry 4), which is
comparable to the phenyl substrate from Table 2 (entry 1).
Switching to the olefinic styryl substituent 1e gave the prod-
uct 2e in 49% yield (Table 2, entry 5). The yield for the ali-
phatic tert-butyl group was somewhat lower (41%, Table 2,
entry 6) but increased to 51% yield when it was substituted
for adamantyl (Table 2, entry 7). When N-propargylforma-
mide was used as a substrate, no product was obtained, only
decomposition was observed (Table 2, entry 8). It seems to
be that aliphatic moieties, in most cases, are slightly better
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A. S. K. Hashmi et al.
none, which was one of the best coupling partners in Stahlꢂs
publication,[6] delivered only the unstable product 2n in 9%
yield, which again quickly decomposed (Table 3, entry 8).
This leads to the assumption that the reaction might mainly
be limited by product stability rather than the reactivity of
the reagents. With benzotriazole no product was formed,
but the N-propargyl amide could be reisolated (Table 3,
entry 9). This is the only case in which the starting material
was recovered after a reaction that did not lead to the prod-
uct 2; thus benzotriazole must inhibit the copper catalyst.
An indole derivative gave the product 2p in the best overall
yield (59%, Table 3, entry 10). Since all yields were of a sim-
ilar magnitude, an additional test with two equivalents of
CuCl2 was performed. The reaction of 1a with two equiva-
lents of CuCl2 and 10 equivalents of pyridine led to an in-
creased yield of 52% (Table 3, entry 11). This also leads to
the conclusion that the limiting factor of this reaction is not
the reactivity of the starting materials, but the fast conver-
sion of the ynamide, which is supposed to be unstable. Con-
trol experiments with CuCl2 (20 mol%) and NaCl (2 equiv)
gave 2a in only about 16% yield; the same yield was ob-
tained with CuCl2 (20 mol%) and no NaCl. Hence, it seems
crucial to add a large excess of the halogen source (CuX2).
It should be kept in mind that one equivalent of CuX2
equals a double excess of the halogen demanded and two
equivalents will give four times more halogen than is con-
sumed by the product-forming step in this cyclization
(unless only one chloro ligand is transferred to the substrate,
for example, as is known from the chemistry of organocup-
rates). From these experiments, single crystals of the prod-
ucts 2a, 2i, and 2j were obtained by slow evaporation from
benzene[15] and the X-ray crystal structures were generated
(Figure 2).
of NRACTHNGUTERN(UNG EWG) (EWG=electron-withdrawing group) results
in complex II. After reductive elimination the ynamide III is
obtained (Scheme 3). The Cu(0) is then re-oxidized to CuII
by molecular oxygen. Ynamide III is activated by CuCl2
leading to the cyclization to V. Reductive elimination incor-
porates the halogen in position 5 of the oxazine product 2.
It should be mentioned that under these conditions (under
an oxygen atmosphere), a radical mechanism is also conceiv-
able. In control experiments, the radical inhibitor 3,4-di-tert-
butyl-4-hydroxytoluene (BHT) completely inhibits the con-
version, as did the exclusion of oxygen.
To show the relevance of these new compounds as build-
ing blocks for even more complex structures and potential
drugs, we performed a Sonogashira coupling reaction with
compound 2q and phenylacetylene, to give the coupling
product 5 in an excellent 99% yield (Scheme 4).
Scheme 4. Sonogashira coupling reaction of 2q with phenylacetylene.
Ts=tosyl.
This new method allows the synthesis of a new class of ox-
azine derivatives and enables diverse substitution with a
wide range of functional groups. In addition to the vinyl-
chloride or vinylbromide substructure, an amazingly stable
ketene aminoacetal is part of the structural motif. We were
also able to show that these new compounds can be easily
derivatized by palladium cross-coupling reactions. We are
now trying to extend the scope of this reaction to other sub-
strates, such as propargylimidates.[3a] We also assume that
the synthesized products of type 2, or their derivatives,
The mechanistic proposal of this tandem reaction in
Scheme 3 is based on the mechanism shown in the publica-
tion of Stahl et al.[6] Starting from CuCl2, which is presuma-
bly coordinated to pyridine, an acetylide complex I of the
propargylamide is first formed. An additional coordination
Scheme 3. Mechanistic proposal for the formation of 5-halogen-4H-1,3-oxazine-6-amines 2. R=Aryl, adamantyl, tert-butyl, R’=alkyl, Ln =coordinated
ligand.
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Synthesis of Novel 5-Halo-4H-1,3-oxazine-6-amines
COMMUNICATION
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cif.
Keywords: alkynes · amides · bromides · chlorides · copper ·
tosylamides
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Received: January 13, 2011
Published online: April 13, 2011
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