Gold-Catalyzed Cyclization/Intermolecular Methylene Transfer Sequence of O-Propargylic Oximes Derived from Glyoxylates

Article abstract of DOI:10.1055/s-0037-1611640

We successfully extended our gold-catalyzed skeletal rearrangement reaction of O -propargylic oximes through C=N bond cleavage to include substrates having an ester group on the oxime moiety, affording the corresponding 2-isoxazolines having an alkoxycarb

Full text of DOI:10.1055/s-0037-1611640

SYNLETT
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Georg Thieme Verlag Stuttgart · New York
2018, 29, A–D
letter
A
en
Synlett
S. Gima et al.
Letter
Gold-Catalyzed Cyclization/Intermolecular Methylene Transfer
Sequence of O-Propargylic Oximes Derived from Glyoxylates
Shinya Gimaa
Keigo Shigaa
Masahiro Teradaa
CO2R
O
N
N
cationic Au(I) [cat.]
0
0
0
0-0
0
0
2-0
5
5
4-
8
6
5
2
O
R2
R1
Itaru Nakamura*b
0
0
0
0-0
0
0
2-1
4
5
2-5
9
8
9
cyclization/intermolecular
methylene transfer
R2
RO2C
R1
a
Department of Chemistry, Graduate School of Science, Tohoku University, 6-3
Aramaki Aza Aoba, Aoba-ku Sendai, 980-8578, Japan
1
R
= aryl, alkyl
13 examples
up to 83% yield
2
b
R
= aryl, alkyl, H
Research and Analytical Center for Giant Molecules, Graduate School of Science,
Tohoku University, 6-3 Aramaki Aza Aoba, Aoba-ku Sendai, 980-8578, Japan
itaru-n@tohoku.ac.jp
Published as part of the 30 Years SYNLETT – Pearl Anniversary Issue
Received: 25.09.2018
Accepted after revision: 18.11.2018
Published online: 06.12.2018
Gold-catalyzed skeletal-rearrangement reactions are
powerful methods for synthesizing highly functionalized
carbo- or heterocyclic compounds from readily available
starting materials in a single operation under mild condi-
DOI: 10.1055/s-0037-1611640; Art ID: st-2018-b0613-l
License terms:
1
tions with high functional-group compatibility. Earlier
2
Abstract We successfully extended our gold-catalyzed skeletal rear-
rangement reaction of O-propargylic oximes through C=N bond cleav-
age to include substrates having an ester group on the oxime moiety,
affording the corresponding 2-isoxazolines having an alkoxycarbonyl-
methylene group at the 4-position in good to high yields. Our mecha-
nistic studies indicated that the transfer of the alkoxycarbonylmethy-
lene group proceeded in an intermolecular manner, confirming that the
reaction proceeds through cyclization followed by intermolecular trans-
fer of the alkoxycarbonylmethylene group.
studies focused mainly on the use of 1,n-enynes or propar-
3
gylic esters as starting materials. We recently reported that
the gold-catalyzed skeletal rearrangement reactions of O-
3
propargylic formaldoximes 1 (R = H) proceed through C=N
bond cleavage, affording the corresponding 4-methylenated
4
2-isoxazolines 2 in good to excellent yields (Scheme 1).
Our mechanistic studies indicated that the methylene
group was transferred intermolecularly. We proposed that
the reaction proceeds through -acidic Au-promoted cy-
clization, followed by intermolecular C–C bond formation
between the iminium moiety of the cyclized vinylgold spe-
Key words gold catalysis, rearrangement, heterocycles, cyclization,
progargylic oximes, isoxazolines
R3
O
N
N
O
cationic Au(I) [cat.]
R2
R1
cyclization/intermolecular
methylene transfer
R2
R3
R1
Previous: R3 = H
This work: R3 = EWG
1
2
Au
Nu
R3
R3
O
N
Nu
N
R2
R1
N
R3
R3
O
R1
NuH
O
N
H
O
Au
–H
R2
R2
R1
R2
R1
R3
R3
–Au
O
N
Au
–NuH
Au
O N
R2
R1
A
R2
R1
B
Au
Au
Intermolecular C–C Bond Formation
Scheme 1 Au-catalyzed skeletal rearrangement of O-propargylic oximes
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

B
Synlett
S. Gima et al.
Letter
cies A and the enamine form B, generated in situ by attack
of a nucleophilic species (NuH), such as trace water, on an-
other vinylgold intermediate A. This intriguing rearrange-
ment reactions was, however, restricted to the use of sub-
Table 1 Optimization of the Reaction Conditionsa
CO2Et
O
N
N
[Au catalyst]
O
Ph
EtO2C
Ph
3
strates derived from formaldoxime (R = H); substrates that
CH2Cl2, 30 °C
Ph
possessed a substituent such as an alkyl and aryl group on
Ph
3
the oxime moiety (R ) did not undergo the transformation.
2a
(E)-1a
(
Z/E = ca 9:1)
This drawback is presumably because these functional
groups interrupt the intermolecular C–C bond-forming pro-
cess, not only by steric repulsion, but also through low elec-
trophilicity. Accordingly, we envisioned that less-bulky and
more-electron-withdrawing functional groups might be
compatible as substituents on the oxime moiety, improving
the synthetic utility of the present cascade reactions. Here,
we report that Au-catalyzed skeletal rearrangement reac-
b
Entry
Au catalyst (mol %)
Time (h)
Yield (%)
1
Ph
Ph
Ph
Ph
Ph
3
3
3
3
3
PAuNTf
2
2
(5)
(5)
8
46
10
41
44
42
26
50
62
4
2c
PAuNTf
24
24
8
3
PAuCl (5), AgOTf (5)
PAuCl (5), AgBF (5)
PAuCl (5), AgClO (5)
4
4
5
4
8
tions of O-propargylic oximes derived from glyoxylates 1
3
6
Ph PAuCl (5), AgSbF (5)
8
(
R = CO R) afford the corresponding isoxazolines 2 in good
3
6
2
to high yields (Scheme 2).
7
(4-FC H ) PAuNTf (5)
8
6
4
3
2
8
(4-F
3
CC
6
H
4
)
3
PAuNTf
2
(5)
8
CO2R
9
(C
6
F
5
)
3
PAuNTf
2
(5)
8
O
N
N
cationic Au(I) [cat.]
O
R2
R1
10
11
(4-MeOC H ) PAuNTf (5)
8
28
6
4
3
2
cyclization/intermolecular
methylene transfer
R2
Ph
3
PAuNTf
2
(10)
2
76
R1
RO2C
(81)d
12
(4-F
3
CC
6
H
4
)
3
PAuNTf
2
(10)
2
1
2
a
b
c
Reaction conditions: (E)-1a (0.2 mmol), gold catalyst, CH
2
Cl
2
(0.4 mL), 30 °C.
Scheme 2 Au-catalyzed cyclization/intermolecular methylene transfer
sequence of O-propargylic oximes 1 derived from glyoxylates
1
2 2
Determined by H NMR with CH Br as an internal standard.
(
Z)-1a was used instead of (E)-1a.
d
Isolated yield.
Initially, the reaction of the (E)-oxime (E)-1a having an
ethoxycarbonyl group on the oxime moiety afforded the de-
sired product 2a in a moderate chemical yield (46%) under
our previous reaction conditions by using 5 mol% of
Ph PAuNTf in CH Cl at 30 °C (Table 1, entry 1). In contrast,
Next, the scope of substrates 1 was examined (Scheme
3). The efficiency of our reaction depended on the bulkiness
of the ester group; the methyl ester 1b and the ethyl ester
1a were converted into the corresponding products 2b and
2a (see also Table 1, entry 12), respectively, in good yields,
whereas the tert-butyl ester 1d required a prolonged reac-
tion time to be fully consumed, affording the desired prod-
uct 2d in low yield. It should be noted that the Z/E selectivi-
ty at the exo-olefin moiety of products 2a–d was not influ-
enced by the bulkiness of the ester group. The reaction of
substrate 1e, having a dimethylcarbamoyl group instead of
an ester group, gave the desired product 2e in poor yield
3
2
2
2
the reaction of the (Z)-oxime (Z)-1a resulted in a poor
chemical yield (entry 2), due to decomposition of the start-
5
ing material. The use of triflate, tetrafluoroborate, or per-
chlorate as a counteranion gave comparable result to that of
the triflic imide (entries 3–5), whereas the use of hexafluo-
roantimonate resulted in a lower yield (entry 6). The cata-
lytic activity depended on the electronic character of the
phosphine ligand (entries 7–10), in that the use of relatively
electron-deficient triarylphosphines improved the chemi-
cal yield (entries 7 and 8). In particular, the reaction using
7
(4%). Substrate 1f, having an electron-rich 4-anisyl group
1
at the alkyne terminus (R ) was converted into the corre-
sponding product 2f in 63% yield, whereas the reaction of
1g having an electron-deficient 4-trifluoromethyl group re-
sulted in a lower chemical yield (47%). In terms of alkyl sub-
(
4-F CC H ) P gave 2a in a good yield (entry 8), whereas
3 6 4 3
(
C F ) P was inefficient (entry 9). The chemical yield was
6
5 3
1
significantly improved by doubling the loading of the gold
stitution at R , 1h, containing a propyl group was compati-
6
catalyst, to afford 2a in 81% isolated yield (entry 12). The
ble, whereas the reaction of 1i having a bulky cyclohexyl
8
use of CH Cl and MeCN was effective to afford 2a in good
group was sluggish. An electron-deficient aryl group was
2
2
2
yields, whereas the use of MeOH resulted in formation of
considerable amounts of nonmethylenated isoxazoline as a
byproduct [see the Supplementary Information (SI)]. It
should be noted that the Z/E stereoselectivity at the exo-
olefin moiety was not significantly affected by the reaction
conditions: the Z/E ratio was about 9:1 in all cases (see SI).
tolerated at the propargylic position (R ) to furnish the cor-
responding isoxazoline in a good yield. Because 2k having a
4-(trifluoromethyl)phenyl group at the 5-position of the
isoxazoline ring was partially isomerized to the isoxazole
3k during purification, the crude product 2k was treated
with DBU in one pot to obtain 3k as a single product in
good yield. In contrast, the substrate 1l, which had an elec-
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

C
Synlett
S. Gima et al.
Letter
2
tron-rich 4-anisyl group at the R position gave 2l in a low
chemical yield of 27%. Moreover, the reaction of 1m having
2
CO Et
2
CO Me
(4-F3CC6H4)3PAuNTf2
N
N
(0.02 mmol)
2
O
O
a less-bulky propyl group at R gave 2m with excellent Z-
+
CH2Cl2 (0.4 mL)
stereoselectivity. The substrate 1n, which did not possess
any substituents at R , was effectively converted into the
corresponding product 2n in 83% yield.
Ar
Ph
30 °C, 0.5 h
2
Ph
Ph
1
j
1b
(0.1 mmol)
(0.1 mmol)
(Ar = 4-ClC6H4)
CO2R
O
N
O
N
O
N
O
N
O
N
N
3 6 4 3 2
10 mol% (4-F CC H ) PAuNTf
R2
R1
O
Ar
EtO2C
Ph
Ph
Ph
Ar
Ph
Ph
+
Ph
+
+
CH2Cl2, 30 °C
R2
RO2C
MeO2C
MeO2C
EtO2C
R1
Ph
2j
2b
2o
2a
2
1
Normal
Crossover
O
N
75% yield
ca. 1:1:1:1
O
N
2
b (R = Me) 68% (0.5 h) Z/E = 87:13
c (R =iPr) 54% (3 h) Z/E = 86:14
2d (R =tBu) 18% (6 h) Z/E = 87:13
Ph
Ph
Ph
Scheme 4 Crossover experiment
2
Me2NOC
RO2C
2e
%a,b (5 h)
4
We therefore concluded that the present reaction pro-
ceeds through cyclization followed by intermolecular trans-
fer of the alkoxycarbonylmethylene group, sequentially lib-
erating the product 2, in the same manner of our previous
O
N
O
N
O
N
Ph
EtO2C
n-Pr
Ph
EtO2C
Ph
OMe
CF3
EtO2C
4a
reaction of O-propargylic formaldoximes. The present re-
2f
2g
2h
action selectively afforded the (Z)-isomer (Z)-2 (Scheme 3).
Presumably, because the exo-olefin and isoxazoline C=N
bond in the (E)-isomer are not coplanar due to steric repul-
6
3% (0.5 h)
47% (1 h)
Z/E = 92:8
50% (0.5 h)
Z/E = 95:5
Z/E = 94:6
O
N
O
N
O N
1
sion between the ester group and the substituent R de-
Ph
EtO2C
Cy
Ph
Ph
Cl
F3C
rived from the alkyne terminus of the starting material 1,
the more-stable (Z)-isomer was obtained with high stereo-
selectivity. It should be noted that the reactions of 1m,
which has a less-bulky propyl group at the propargylic po-
EtO2C
2j
74% (0.5 h)
Z/E = 93:7
2
EtO C
2i
3
kc
4% (1 h)
1
3%a (24 h)
Z/E = 91:9
6
2
O
N
sition, and of 1n, which lacks a substituent at R , exhibited
O
N
O
N
excellent stereoselectivity. These results also can be ex-
plained by relaxation of the steric repulsion between the
ester group and R in the (Z)-isomer. The use of the gold
Ph
Ph
n-Pr
Ph
MeO
EtO2C
2
EtO2C
EtO2C
2
l
2m
72% (0.5 h)
Z/E = >99:1
2n
catalyst with an electron-deficient phosphine ligand, such
as (4-F CC H ) P, gave a better result than that of a catalyst
2
7% (1 h)
Z/E = 87:13
83% yield (0.5 h)
Z/E = >99:1
3
6
4 3
having an electron-rich ligand (Table 1, entry 8 versus entry 10).
We assume that the cyclization process requires a higher -
acidity than that in the reaction of formaldoximes due to
steric repulsion between the ester group of the (E)-oxime
Scheme 3 Au-catalyzed reaction of 1b–m. Reaction conditions: 1 (0.2
mmol), (4-F CC H ) PAuNTf (10 mol %), CH Cl (0.4 mL), 30 °C. Isolat-
3
6
4
3
2
2
2
1
ed yields of (Z)-2 are reported. The Z/E ratio was determined by H NMR
of the crude product. Yield determined by H NMR with CH Br as inter-
nal standard. 1e was used as an E/Z mixture (91:9). The crude prod-
uct 2k was treated with DBU (1 equiv) in CH Cl at 30 °C for 1 h to
a
1
2
2
b
c
1
and the alkyne substituent R in the cyclization process
2
2
4a
from 1 to A (Scheme 1). In addition, the electronic charac-
afford the isoxazole 3k.
ter of the gold catalyst might affect the electrophilicity of
the iminium moiety of the vinylgold intermediate A
(Scheme 1) to facilitate intermolecular C–C bond formation.
Further mechanistic studies are still underway in our labo-
ratory.
The reaction of the two equally reactive substrates 1b
and 1j under the standard reaction conditions afforded
equal amounts of the normal products 2b and 2j and the
crossover products 2a and 2o (Scheme 4). Neither the prod-
ucts nor the substrates showed crossover reactions the
presence of gold catalysts (see SI), clearly indicating that
transfer of the alkoxycarbonylmethylene group took place
intermolecularly. In addition, the reaction of 1b or 1m in
the presence of ethyl glyoxylate or 3,5-diphenylisoxazoline
exclusively afforded 2b or 2m, derived from the starting
material (see SI).
In conclusion, we have successfully synthesized isoxazo-
lines having an alkoxycarbonylmethylene group at the 4-
position in an efficient manner. Because there are only a
limited number of methods for synthesizing 4-alkylidene-
9
substituted isoxazolines, the present method is useful for
constructing densely functionalized heterocycles.
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

D
Synlett
S. Gima et al.
Letter
Funding Information
Chem. Res. 2014, 47, 953. (e) Mauleon, P.; Toste, F. D. In Modern
Gold Catalyzed Synthesis, Chap. 4, Hashmi, S. K.; Toste, F. D., Ed.;
Wiley-VCH: Weinheim, 2012, 75.
This work was supported by JSPS KAKENHI Grant Number
JP16H00996 in Precisely Designed Catalysts with Customized Scaf-
(
(
(
4) (a) Nakamura, I.; Gima, S.; Kudo, Y.; Terada, M. Angew. Chem. Int.
Ed. 2015, 54, 7154. (b) Gima, S.; Nakamura, I.; Terada, M. Eur. J.
Org. Chem. 2017, 4375.
folding.
J
a
p
a
n
S
o
c
i
ety forth
e
Pro
m
oti
o
n
of
S
c
i
e
n
c
e
(J
P
1
6
H
0
0
9
9
6)
5) Identifiable byproducts were not obtained from the reaction of
Supporting Information
(
Z)-1a. It is therefore unclear at the present stage why the reac-
tion of (Z)-1a resulted in a low chemical yield.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611640.
6) Ethyl (2Z)-(3,5-Diphenylisoxazol-4(5H)-ylidene)acetate [(Z)-
S
u
p
p
orit
n
g Inform ati
o
n
S
u
p
p
orti
n
g Inform ati
o
n
2a]; Typical Procedure
Oxime (E)-1a (61.5 mg, 0.2 mmol) in CH Cl (0.4 mL) was added
2
2
to (4-F CC H ) PAuNTf (18.9 mg, 0.02 mmol) in a V-vial under
3
6
4
3
2
References and Notes
argon, and the mixture was stirred at 30 °C for 2 h. The mixture
was then passed through a short pad of silica gel, eluting with
CH Cl (50 mL). The solvents were evaporated in vacuo, and the
(1) For selected reviews on gold catalysis, see: (a) Li, Y.; Li, W.;
2
2
Zhang, J. Chem. Eur. J. 2017, 23, 467. (b) Harris, R. J.;
Widenhoefer, R. A. Chem. Soc. Rev. 2016, 45, 4533. (c) Yang, W.;
Hashmi, A. S. K. Chem. Soc. Rev. 2014, 43, 2941. (d) Obradors, C.;
Echavarren, A. M. Chem. Commun. 2014, 50, 16. (e) Hashmi, A. S.
K. Angew. Chem. Int. Ed. 2010, 49, 5232. (f) Adcock, H. V.; Davies,
P. W. Synthesis 2012, 44, 3401. (g) Bhunia, S.; Liu, R.-S. Pure Appl.
Chem. 2012, 84, 1749. (h) Lu, B.-L.; Dai, L.; Shi, M. Chem. Soc. Rev.
crude product was purified by flash column chromatography
silica gel, hexane–EtOAc (8:1)] to give a colorless liquid; yield:
[
50 mg (81%, Z/E = 90:10). IR (neat): 3063, 3033, 2981, 2939,
2
1
903, 1709, 1641, 1494, 1455, 1444, 1367, 1331, 1310, 1299,
269, 1199, 1130, 1096, 1077, 1035, 1007, 912, 899, 873 cm–1
.
1
H NMR (400 MHz, CDCl ):  = 7.67–7.62 (m, 2 H), 7.55–7.50 (m,
3
3
H), 7.39–7.31 (m, 5 H), 6.76 (d, J = 3.2 Hz, 1 H), 6.32 (d, J = 3.2
2012, 41, 3318. (i) Kirsch, S. F. Synthesis 2008, 3183. (j) Skouta,
13
Hz, 1 H), 4.06 (q, J = 7.3 Hz, 2 H), 1.14 (t, J = 7.3 Hz, 3 H). C NMR
100 MHz, CDCl ):  = 165.22, 157.47, 155.10, 137.69, 130.36,
R.; Li, C.-J. Tetrahedron 2008, 64, 4917. (k) Hashmi, A. S. K. Chem.
Rev. 2007, 107, 3180.
(
3
1
6
3
29.07, 128.70, 128.63, 128.33, 127.58, 127.39, 115.57, 88.03,
0.83, 14.01. HRMS (ESI): m/z [M + Na] calcd for C19H17NNaO3:
30.1101; found: 330.1100.
(
2) For pioneering works, see: (a) Trost, B. M.; Tanoury, G. J. J. Am.
Chem. Soc. 1988, 110, 1636. (b) Chatani, N.; Morimoto, T.; Muto,
T.; Murai, S. J. Am. Chem. Soc. 1994, 116, 6049. For reviews, see:
+
(
7) A substrate having a trichloromethyl group was not converted
into the desired product under the optimal reaction conditions;
(c) Wang, Q.; Shi, M. Synlett 2017, 28, 2230. (d) Dorel, R.;
Echavarren, A. M. J. Org. Chem. 2015, 80, 7321. (e) Michelet, V.
Top. Curr. Chem. 2015, 357, 95.
60% of the starting material was recovered. Preparations from
substrates having a cyano or keto group instead of an ester
group failed.
(3) For pioneering works, see: (a) Rautenstrauch, V. J. Org. Chem.
1
984, 49, 950. (b) Mainetti, E.; Mouriès, V.; Fensterbank, L.;
Malacria, M.; Marco-Contelles, J. Angew. Chem. Int. Ed. 2002, 41,
132. For reviews, see: (c) Boyle, J. W.; Zhao, Y.; Chan, P. W. H.
Synthesis 2018, 50, 1402. (d) Fensterbank, L.; Malacria, M. Acc.
(
8) The reaction of 1i at 50 °C afforded the desired product 2i in 12%
yield.
9) (a) Dunn, P. J.; Graham, A. B.; Grigg, R.; Higginson, P.; Sridharan,
V.; Thornton-Pett, M. Chem. Commun. 2001, 1968. (b) Broggini,
G.; Bruché, L.; Zecchi, G.; Pilati, T. J. Chem. Soc., Perkin Trans. 1
2
(
1990, 533.
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D