Structural diversity through gold catalysis: Stereoselective synthesis of N-hydroxypyrrolines, dihydroisoxazoles, and dihydro-1,2-oxazines

Full text of DOI:10.1002/anie.200902355

Angewandte
Chemie
DOI: 10.1002/anie.200902355
Gold Catalysis
Structural Diversity through Gold Catalysis: Stereoselective
Synthesis of N-Hydroxypyrrolines, Dihydroisoxazoles, and
Dihydro-1,2-oxazines**
Christian Winter and Norbert Krause*
The gold-catalyzed endo- or exo-selective cycloisomerization
of functionalized allenes is a valuable method for the
synthesis of chiral heterocycles.[1] To date, these transforma-
tions have provided access to five- or six-membered oxy-
gen-,[2,3] nitrogen-,[4,5] or sulfur-containing[6] heterocycles.
Interestingly, the gold-catalyzed endo cycloisomerization of
a-hydroxyallenes[2a–d] is usually faster than that of the
corresponding aminoallenes;[4a,b] this behavior is possibly
due to the deactivation of the gold catalyst by the Lewis
basic amine. Furthermore, the endo cyclization of a-function-
alized allenes to five-membered heterocycles is normally
faster than the formation of dihydropyrans or dihydropyr-
idines from b-functionalized allenes[2c,d] (Scheme 1).
formation of the six-membered dihydrooxazine should be
disfavored (path a). On the other hand, nucleophilic attack of
the nitrogen atom should be slow, but formation of the five-
membered N-hydroxypyrrolines should be fast (path b). Since
the outcome of this competition between cyclizations is
uncertain, and since reports of gold-catalyzed cycloisomeri-
zations of allenic substrates are limited to the synthesis of
heterocycles that contain just one heteroatom,[7] we decided
to examine the cyclization of various allenic hydroxylamines
in detail.
We started our investigation with the allenic hydroxyl-
amine 1a, which was prepared from the corresponding
a-hydroxyallene[4a,b] by Mitsunobu inversion with N,O-Boc-
protected hydroxylamine[8] (Boc = tert-butoxycarbonyl) and
subsequent deprotection. Treatment of 1a with 5 mol%
AuCl3 in CH2Cl2 at room temperature led to a regioselective
5-endo-cyclization within 30 minutes to give N-hydroxypyrro-
line 2a[9] in 77% yield (Table 1, entry 1). Use of gold(I)
chloride resulted in an excellent yield of 94% (Table 1,
entry 2). A decrease of the catalyst loading to 1 mol% AuCl
gave almost the same yield of 2a after an extended reaction
time of 7 hours (Table 1, entry 3). In contrast, the use of the
cationic gold complexes A,[10] B,[10] or [AuCl(PPh3)]/AgBF4
(Table 1, entries 4–6) resulted in slower reactions and
decreased yields of 2a because of incomplete conversion
Scheme 1. Different reaction rates in the endo cycloisomerization of
functionalized allenes and possible consequences for the cyclization of
N-hydroxy-a-aminoallenes.
Table 1: Gold-catalyzed cycloisomerization of allenic hydroxylamine 1a
to N-hydroxypyrroline 2a.
This observation has interesting implications for the gold-
catalyzed endo cycloisomerization of allenes with two adja-
cent heteroatoms, for example, N-hydroxy-a-aminoallenes
(Scheme 1). On one hand, attack of the hydroxy group at the
allene terminus should be kinetically favored, whereas
Entry
Precatalyst
t [h]
Yield [%]
1
2
AuCl3
AuCl
AuCl
A
0.5
0.5
7
18
1
16
2
2
77
94
87
3[a]
4
40[b]
62[c]
43
5
6
B
[*] C. Winter, Prof. N. Krause
[AuCl(PPh3)]/AgBF4
AgBF4
HAuCl4/LiCl
Organic Chemistry, Dortmund University of Technology
Otto-Hahn-Strasse 6, 44227 Dortmund (Germany)
Fax: (+ 49)231-755-3884
7
88
64
8[d]
http://www.chemie.tu-dortmund.de/groups/krause/index.html
E-mail: norbert.krause@tu-dortmund.de
[a] 1 mol% of AuCl was used. [b] 7% starting material was recovered.
[c] 37% starting material was recovered. [d] Water was used as solvent.
[**] We thank the Konrad-Adenauer Stiftung for a scholarship to C.W.
and Prof. A. M. Echavarren (ICIQ Tarragona, Spain) for samples of
gold precatalysts A and B.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200902355.
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Table 3: Gold-catalyzed cycloisomerization of allenic hydroxylamine ether 3a to dihydro-1,2-oxazine 4a
and dihydroisoxazole 5a.
and partial decomposition of the
substrate. The conversion of 1a to
2a was also catalyzed by AgBF4,
although the reaction took longer
and the yield was slightly lower
compared to the reaction with
AuCl (Table 1, entry 7). The cycli-
zation of 1a can also be carried out
efficiently in water using chloroau-
ric acid[11] (Table 1, entry 8). All
Entry
Precatalyst
t [h]
4a: Yield [%] (d.r.)
5a: Yield [%] (d.r.)
4a/5a
1
2
AuCl
AuCl3
AuCl3
AuCl3
[Au(PPh3)]BF4
A
2.5
2.5
3.0
62
1.5
1.5
47 (>99:1)
49 (>99:1)
35 (>97:3)
40 (>98:2)
3 (n.d.)[d]
19 (87:13)
15 (89:11)
16 (87:13)
26 (87:13)
69 (79:21)
81 (94:6)
71:29
77:23
69:31
61:39
4:96
3[a]
4[b]
5
cycloisomerizations
proceeded
[c]
with exclusive 5-endo regioselec-
tivity and complete axis-to-center
chirality transfer.
To examine the scope of the
reaction, we treated various sub-
6
3 (n.d.)[d]
4:96
[a] A stock solution of AuCl3 in MeCN was used. [b] Reaction performed in THF. [c] Prepared in situ from
[AuCl(PPh3)] and AgBF4. [d] Not determined.
stituted
N-hydroxy-a-aminoal-
lenes 1b–g with AuCl in CH2Cl2 and obtained the N-
hydroxy-3-pyrrolines 2b–g in high yields (Table 2). Substrate
1b, which is the diastereomer of 1a, selectively afforded the
Lewis acidity of the gold catalyst in the presence of
acetonitrile or by using THF as the solvent (Table 3,
entries 2–4) had only a slight effect on the product ratio and
caused only a small shift in favor of 5a. A highly regiose-
lective cyclization of the allenic hydroxylamine ether 3a to
4,5-dihydroisoxazole 5a could be achieved in the presence of
cationic gold(I) complexes [Au(PPh3)]BF4 or A[10] (Table 3,
entries 5 and 6). Here, the more reactive gold complex A gave
not only the highest yield of 81%, but also the best cis-
selectivity of 94:6.
Table 2: Gold-catalyzed synthesis of N-hydroxypyrrolines 2b–g.
R1
R2
R3
R4
2 (Yield [%])
Under these optimized conditions, various allenic hydrox-
ylamine ethers 3b–g were converted into the corresponding
dihydroisoxazoles 5b–g in high yields (Table 4). The reaction
Entry
1
1
2
3
4
1b
1c
1d
1e
1 f
1g
iPr
nBu
Ph
nBu
Me
iPr
Me
Me
Me
Me
H
H
CH2OBn
H
H
H
(CH2)2Ph
(CH2)2CO2Et
2b (76)
2c (80)
2d (73)
2e (67)
2 f (78)
2g (77)
CH2OBn
CH2OBn
CH2OH
H
Table 4: Gold-catalyzed synthesis of dihydroisoxazoles 5b–g.
5[a]
6
H
H
[a] 1 f was used as a diastereomeric mixture (1:1).
product 2b (Table 2, entry 1), thus demonstrating the high
level of stereocontrol in these cyclizations. The reaction
tolerates alkyl and aryl substituents at the allene groups, as
well as free hydroxy and ester groups (Table 2, entries 4 and 6,
respectively). The gold-catalyzed cyclization of substrate 1e,
which bears three nucleophilic groups in the a- and b-position
(Table 2, entry 4), is particularly noteworthy; of these func-
tionalities, only the amino group reacts to afford pyrroline 2e
in good yield.
Entry
3
R1
R2
R3
5 (Yield [%])
d.r.
1
2
3
4
5
6
3b
3c
3d
3e
3 f
3g
nBu
H
H
Me
Me
iPr
Me
Me
Me
H
H
H
CH2OBn
CH2OBn
CH2OTBS
(CH2)2Ph
Me
5b (77)
5c (72)
5d (78)
5e (87)
5 f (86)
5g (86)
95:5
95:5
51:49
(CH2)2CO2Et
Encouraged by the high regioselectivity in the gold-
catalyzed cyclization of N-hydroxy-a-aminoallenes 1, we next
examined allenic substrates in which the heteroatom positions
were exchanged. The hydroxylamine ether 3a was synthe-
sized by Mitsunobu reaction of the corresponding a-hydroxy-
allene[4a,b] with N-hydroxyphthalimide and subsequent hydra-
zinolysis.[12] Treatment of 3a with AuCl in CH2Cl2 at room
temperature afforded a mixture of the 3,6-dihydro-1,2-
oxazine 4a (47% yield) and the 4,5-dihydroisoxazole 5a
(19%; Table 3, entry 1). Again, both heterocycles were
formed by the nucleophilic attack of the nitrogen atom, and
the dihydrooxazine 4a was formed with complete chirality
transfer. Use of AuCl3 as the precatalyst, and a decrease of the
tolerates benzyl and silyl ethers (Table 4, entries 1–3) as well
as ester groups (entry 6) and terminal allenes (entries 2 and
3). It is interesting to note that the benzyl-protected
dihydroisoxazoles 5a–c were formed with high cis-selectivity
whereas the tert-butyldimethylsilyl (TBS) ether 5d (Table 4,
entry 3) was obtained as a 1:1 mixture of diastereomers. A
mechanistic model for the cis-selective formation of 5a–c is
shown in Scheme 2.
Coordination of the gold catalyst to the allenic double
bond adjacent to the hydroxylamine moiety affords p com-
plex A, which undergoes a 5-endo cyclization to the zwitter-
ionic species B. In this case, the bulky gold moiety is
preferentially situated trans to the group R3 in order to
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Angewandte
Chemie
catalyzed synthesis of heterocycles with two heteroatoms
from allenic precursors. In all cases, the nitrogen atom acts as
the nucleophile and attacks the allene in a 5- or 6-endo
cyclization. In the case of allenic hydroxylamine ethers, the
regioselectivity can be shifted either towards dihydroisoxa-
zoles by employing cationic gold precatalysts, or in favor of
dihydrooxazines by using N-Boc-protected precursors. Our
method is particularly versatile as all three types of hetero-
cycles can be obtained in a stereoselective manner from the
same a-hydroxyallene. We continue to expand the scope of
coinage-metal catalysis with allenic substrates and to apply
our methods in target-oriented synthesis.
Scheme 2. Proposed mechanism for the formation of cis-substituted
dihydroisoxazoles 5a–c.
Experimental Section
In an oven-dried Schlenk tube, allene 1a (60.0 mg, 230 mmol) was
dissolved in dry dichloromethane (4 mL) and treated with AuCl
(2.7 mg, 11.5 mmol). After complete conversion (30 min, monitored
by TLC), the solvent was removed under reduced pressure and the
crude product was purified by flash column chromatography (SiO2,
cyclohexane/ethyl acetate/triethylamine= 91:6:3), to afford 56.5 mg
(94%) of N-hydroxypyrroline 2a as a yellow oil.
minimize steric interactions. Protodeauration with retention
of configuration led to the exocyclic enamine C, which
isomerized to the more stable dihydroisoxazole. An alter-
native mechanism that involves coordination of the gold
catalyst at the allenic double bond distal to the hydroxylamine
moiety, followed by 5-exo cyclization, would also lead to the
dihydroisoxazoles 5, but does not give a suitable explanation
for the formation of the cis diastereomer.
Received: May 3, 2009
Published online: July 15, 2009
Having established a highly regio- and stereoselective
cyclization of allenic hydroxylamine ethers 3 to dihydroisox-
azoles 5, we returned to the corresponding 6-endo cyclo-
isomerization. Fortunately, use of the tert-butoxy carbamate
6a instead of the unprotected hydroxylamine ether 3a led to a
regio- and stereoselective formation of the Boc-protected
dihydrooxazine 7a upon treatment with 5 mol% AuCl in
CH2Cl2 at room temperature (Table 5, entry 1). Analogous
results were obtained with protected hydroxylamine ethers
6b–d. The low stability of the precursor for 6c means that this
allene could only be used in an impure form, and may explain
the rather low yield of the phenyl-substituted dihydrooxazine
7c (30%; Table 5, entry 3). In contrast to the reaction with
AuCl, use of AuCl3 gave only incomplete conversion, and
cationic gold complexes ([Au(PPh3)]BF4/AgBF4 or A) or
AgBF4 induced decomposition of the substrate.
Keywords: allenes · cycloisomerization · gold · heterocycles ·
homogeneous catalysis
.
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In conclusion, we have established new highly regio- and
stereoselective routes to three different chiral heterocycles—
N-hydroxy-3-pyrrolines, 4,5-dihydroisoxazoles, and 3,6-dihy-
dro-1,2-oxazines—by gold-catalyzed cycloisomerization of
allenic hydroxylamine derivatives. To the best of our knowl-
edge, these reactions represent the first examples for the gold-
Table 5: Gold-catalyzed cycloisomerization of allenic hydroxylamine
ethers 6 to dihydro-1,2-oxazines 7.
Entry
6
R1
R2
R3
7 (Yield [%])
1
2
3
4
6a
6b
6c
6d
iPr
nBu
Ph
H
H
H
Me
CH2OBn
CH2OBn
CH2OBn
CH2OMe
7a (75)
7b (85)
7c (30)
7d (82)
Me
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6341

Communications
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