Efficient Synthesis of O - Tert -Propargylic Oximes via Nicholas Reaction

Article abstract of DOI:10.1055/s-0040-1707191

A synthetic protocol to access O - tert -propargylic oximes derived from tertiary propargylic alcohols was established via Nicholas reaction. Thus, BF ₃·OEt ₂-mediated reaction between the dicobalt hexacarbonyl complex of tert -propargylic alcohols and p -nitrobenzaldoxime followed by decomplexation with cerium(IV) ammonium nitrate afforded the corresponding O - tert -propargylic oximes in good to high yields. The obtained O - tert -propargylic oximes were effectively converted into heterocycles, such as four-membered cyclic nitrones, oxazepines, and isoxazolines, by using π-Lewis acidic catalysts.

Full text of DOI:10.1055/s-0040-1707191

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–E
paper
A
en
I. Nakamura et al.
Paper
Synthesis
Efficient Synthesis of O-tert-Propargylic Oximes via Nicholas Reaction
Itaru Nakamura*a
Keigo Shigab
Mao Suzukib
0
0
0
0-0
0
0
2-1
4
5
2-
5
9
8
9
Ar
OH
N
O
R3
R2
heterocycles
R3
π-Lewis acid
via Nicholas
reaction
Masahiro Teradab
R1
R2
R1
tert-propargylic alcohols
O-tert-propargylic oximes
11 examples
up to 85% yield for 3 steps
a Research and Analytical Center for Giant Molecules, Graduate
School of Science, Tohoku University, 6-3 Aramaki Aza Aoba,
Aoba-ku, Sendai 980-8578, Japan
R1 = alkyl, aryl, TMS
R2, R3 = alkyl, aryl
itaru-n@tohoku.ac.jp
b Department of Chemistry, Graduate School of Science,
Tohoku University, 6-3 Aramaki Aza Aoba, Aoba-ku, Sendai
980-8578, Japan
Received: 26.05.2020
Accepted after revision: 09.06.2020
Published online: 21.07.2020
ry alkoxyamine derivatives, our preliminary attempts to
synthesize the O-tert-propargylic hydroxylamines by these
methods from tert-propargylic alcohols 1 were unsuccess-
ful, presumably due to instability of the alkyne moiety.
Thus, we envisioned that application of the Nicholas reac-
tion12 would be an effective way to substitute the hydroxy
group of the tert-propargylic alcohols with the aminooxy
group through protection of the alkyne moiety by ligation
with two cobalt atoms. Herein, we report an efficient pro-
tocol to access O-tert-propargylic oximes 2 from the corre-
sponding tertiary-propargyl alcohols 1 via Nicholas reac-
tion (Scheme 2d) and we summarize their reactivity in -
Lewis acidic metal-catalyzed reactions for heterocyclic syn-
thesis.
DOI: 10.1055/s-0040-1707191; Art ID: ss-2020-f0290-op
Abstract A synthetic protocol to access O-tert-propargylic oximes de-
rived from tertiary propargylic alcohols was established via Nicholas re-
action. Thus, BF3·OEt2-mediated reaction between the dicobalt hex-
acarbonyl
complex
of
tert-propargylic
alcohols
and
p-
nitrobenzaldoxime followed by decomplexation with cerium(IV) ammo-
nium nitrate afforded the corresponding O-tert-propargylic oximes in
good to high yields. The obtained O-tert-propargylic oximes were effec-
tively converted into heterocycles, such as four-membered cyclic ni-
trones, oxazepines, and isoxazolines, by using -Lewis acidic catalysts.
Key words Nicholas reaction, alkynes, tertiary alcohols, heterocycles,
gold catalysts, spirocycles
R
N-Propargyloxyamine derivatives have been frequently
utilized as a synthetic intermediate of isoxazoline deriva-
tives1,2 via various transformations, such -Lewis acidic
metal-catalyzed reactions3 and iodocyclization reactions
(Scheme 1).4 Moreover, we have recently disclosed that O-
propargylic oximes serve as an intriguing platform for
unique heterocycles, such as azete-N-oxides5 and 1,4-oxaz-
epines,6 by the action of -Lewis acidic metal catalysts such
as Cu, Rh, and Au.7 In general, N-propargyloxyamines de-
rived from primary and secondary propargylic alcohols
have been prepared through Mitsunobu reaction between
the corresponding propargylic alcohols and N-hydroxyph-
thalimide (NHPI, Scheme 1).8 However, the protocol is prac-
tically inapplicable to propargyloxyamines derived from
tert-propargylic alcohols 1 due to severe steric repulsion in
the SN2 substitution (Scheme 2a). Thus, it is important to
develop efficient and robust approaches to the O-tert-prop-
argylic hydroxylamine derivatives for heterocyclic synthe-
sis.9 Although acid-mediated SN1-type reactions (Scheme
2b)10 as well as electrophilic amination reactions (Scheme
2c)11 have been typically utilized for the synthesis of tertia-
N
O
O
H
R
π-Lewis acid
I+
O
N
OH
R
R
OH
R1
N
O
R
O
heterocycles
R1
O
Mitsunobu reaction
R
(SN2)
primary- and secondary-
propargyl alcohols
N
R1
O
π-Lewis acid
R1
Scheme 1 Preparation of N-propargyloxyamines derived from primary
and secondary propargylic alcohols
Initially, alkyne 1 were efficiently reacted with Co2(CO)8
under standard conditions. As represented by the results of
1a–d, the corresponding dicobalt hexacarbonyl complex
3a–d were obtained in good to excellent yields (Scheme 3
and Table S1).
Next, Nicholas reactions between the alkyne-dicobalt
complex 3 and hydroxylamine derivatives 4 were exam-
ined, as summarized in Table 1. The reaction between 3a
and 3 equivalents of the oxime 4a, derived from p-nitro-
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
I. Nakamura et al.
Paper
Synthesis
Table 1 Nicholas Reaction of 3 with Hydroxylamine Derivatives 4a
(a) Mitsunobu reaction
R
N
(b) acid-mediated reaction
(c) electrophilic amination
O
R
R
N
OH
R3
R2
2.5 equiv BF3·OEt2
CH2Cl2, –10 °C
R
OH
O
R
Co2(CO)6
R1
R3
R2
+
HO
N
R1
R4
Co2(CO)6
R3
R2
R3
R
R2
R1
R1
4
tert-propargylic alcohols
3
5
N
(3 equiv)
(d) via Nicholas reaction
This work
1
O
OH
O
R3
R2
N
Co2(CO)6
Ph
R1
R4
Me
HO
N
O-tert-propargylic oximes
4a R4 = p-O2NC6H4
4b R4 = p-MeOC6H4
4c R4 = cyclohexyl
2
O
4d
byproduct 6a
Scheme 2 Synthesis of N-propargyloxyamines derived from tertiary
propargylic alcohols via Nicholas reaction
Entry
3
R1
Ph
R2, R3
4
Time (h)
2.5
5
Yield (%)b
1
3a
3a
3a
3a
3b
3c
3d
3e
3f
Me, Me,
Me, Me,
Me, Me,
Me, Me,
Ph, Me
4a
4b
4c
4d
4ad
4a
4a
4a
4a
4a
4a
4a
4a
5aa
5ab
5ac
5ad
5ba
5ca
5da
5ea
5fa
OH
91
53
47
<1c
95
OH
1.1 equiv Co2(CO)8
Co2(CO)6
Ph
R3
R2
R3
R2
2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
1.5
CH2Cl2, rt
2.5 h
Ph
3
0.75
1
3
1a R2 = R3 = Me
3a, 93%
3b, 69%
3c, quant.
3d, 93%
4
16.5
1b R2 = Ph, R3 = Me
1c R2 = R3 = Ph
5
9
1d R2–R3 = –(CH2)3–
6
Ph, Ph
1.75
2
94
Scheme 3 Ligation of propargylic alcohols 1 with Co2(CO)8
7
-(CH2)3-
-(CH2)4-
-(CH2)5-
75
8
0.5
2
36
9
58
benzaldehyde in the presence of 2.5 equivalents of BF3·OEt2
at –10 °C, afforded the corresponding O-propargylic oxime-
dicobalt complex 5aa in good yield (entry 1). The reaction
using either p-anisaldoxime (4b) or cyclohexanecarbaldox-
ime (4c) resulted in lower chemical yields due to the forma-
tion of the elimination byproduct 6a (entries 2 and 3). The
use of NHPI 4d as a nucleophile was totally inefficient (en-
try 4). The Nicholas reaction was applicable to various tert-
propargylic alcohols 3a–j. For example, substrate 3c, having
geminal diphenyl groups at the propargylic position, was
efficiently converted into the corresponding product 5ca
(entry 6), while the use of 5 equivalents of 4a was effective
for the reaction of 3b, having phenyl and methyl groups
(entry 5). Substrates 3d–f, having a cycloalkyl moiety, re-
acted with 4a to afford the desired products 5da–fa, respec-
tively, in good to acceptable yields (entries 7–9). Substrates
3g and 3h, having an aryl group at the alkyne terminus, re-
acted with 4a to afford the desired product in excellent
yields, irrespective of its electronic character (entries 10
and 11). An alkyl substituent was tolerated at the alkyne
terminus (entry 12). In addition, a trimethylsilyl group was
tolerated at R1, affording the desired product 5ja in good
yield (entry 13).
10
11
12
13
3g
3h
3i
p-MeOC6H4 Me, Me
12.5
5ga
5ha
5ia
>99
>99
94
p-F3CC6H4
n-Hex
Me, Me
Me, Me
Me, Me
11.5
11.5
1
3j
Me3Si
5ja
64
a The reaction of 3 (0.4 mmol) and 4 (0.8 mmol) was carried out in the pres-
ence of BF3·OEt2 in CH2Cl2 at –10 °C for 0.5–16.5 h.
b Isolated yield.
c Compound 6a was obtained in 70% yield.
d Compound 4a (2.0 mmol, 5 equiv) was used.
should be noted that O-tert-propargylic oximes with a vari-
ety of aryl groups at the alkyne terminus are potentially ac-
cessible from 2ja via desilylation followed by Sonogashira
reaction (entry 5). Substrate 5ia, having an alkyl group at
the alkyne terminus, was readily decomplexed to afford the
desired product 2ia in excellent yield (entry 4), whereas
5ac, bearing an alkyl group at the oxime moiety, was not
converted into the desired product, but suffered decompo-
sition under the reaction conditions (entry 6).
Obtained O-tert-propargylic oximes 2 were employed
for -Lewis acidic metal-catalyzed reactions to synthesize
heterocycles. For example, the reaction of the propargylic
oximes 2ca in the presence of a catalytic amount of [Cu-
Cl(cod)]2 at 80 °C afforded the corresponding four-mem-
bered cyclic nitrone (azete-N-oxide) 7ca in good yield (Ta-
ble 3, entry 1). The reaction proceeds via [2,3]-rearrange-
ment from propargylic oxime 2 to N-allenylnitrone 9 via
the vinylmetal intermediate 8 followed by 4-electrocy-
clization. The substrate 2ba, having phenyl and methyl
groups at the propargylic position, afforded a ca. 1:1 mix-
ture of E/Z stereoisomers at the exo-olefin moiety (entry 2).
Decomplexation of 5aa, bearing a p-nitrophenyl group
at the oxime moiety (R4), was efficiently promoted by using
4 equivalents of cerium ammonium nitrate (CAN) to quan-
titatively afford the O-tert-propargylic oxime 2aa (Table 2,
entry 1; see also the Supporting Information). The propar-
gylic oxime 2ga, having an electron-rich p-anisyl group at
the alkyne terminus, was obtained by reducing the loading
amount of CAN (2 equiv), due to instability of the substrate
5ga under the oxidative conditions (entry 2). However, it
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–E

C
I. Nakamura et al.
Paper
Synthesis
Table 2 Decomplexation of 5a
Table 3 Synthesis of Azete-N-oxides 7 by Cu- and Au-Catalyzed Reac-
tions of 2a
R4
R4
Ar
4 equiv CAN
O
N
O
N
Ar
R3
O
Metal catalyst
M (Cu or Au)
N
N
Co2(CO)6
acetone, 0 °C
O
Me
Me
1 h
Me
R1
5
Me
R3
Ph
R1
R2
R2
2
Ph
2
7
Ar = p-O2NC6H4
Entry
5
R1
Ph
R4
p-O2NC6H4
2
Yield (%)b
M
1
2c
3
4
5
6
5aa
5ga
5ha
5ia
2aa
2ga
2ha
2ia
2ja
–
quant
25
Ar
Ph
O
•
N
Ar
O
N
p-MeOC6H4
p-F3CC6H4
n-Hex
p-O2NC6H4
p-O2NC6H4
p-O2NC6H4
p-O2NC6H4
Cy
R3
R2
R3
Ph
– M
58
M
8
R2
9
91
5ja
Me3Si
66
Entry
2
R2, R3
Catalyst (mol%)
7
Yield (%)b
5ac
Ph
<1
1
2ca
2ba
2aa
2aa
2ea
Ph, Ph
[CuCl(cod)]2 (5)
[CuCl(cod)]2 (5)
[CuCl(cod)]2 (5)
7ca
85
86c
30
56
52
a The reaction of 5 (0.1 mmol) was carried out in the presence of CAN (0.4
mmol) in acetone at 0 °C for 1 hour.
b Isolated yield.
2
Ph, Me
Me, Me
Me, Me
-(CH2)4-
7ba
7aa
7aa
7ea
c CAN (0.2 mmol) was used.
3
4
(PPh3)AuNTf2 (5)
(PPh3)AuNTf2 (5)
5d
The chemical yield of 7aa, derived from 2aa having two
methyl groups at the propargylic position, was improved by
using (PPh3)AuNTf2 instead of [CuCl(cod)]2 (entries 4 vs. 3).
We previously reported that Au catalysts did not promote
[2,3]-rearrangement of O-propargylic oximes derived from
secondary alcohols, presumably because the ring-opening
process from 8 to 9 involves cleavage of the C–Au bond,
which is much stronger than the C–Cu bond due to the rela-
tivistic nature of the gold atom.5 Accordingly, the present
results indicate that substitution by two alkyl groups at the
propargylic position facilitates the ring-opening process
even in the gold-catalyzed reaction.
a Reaction conditions for Cu catalysis: [CuCl(cod)]2 (0.01 mmol) in CH3CN
(0.2 mL) at 80 °C for 44 h. For Au catalysis: (PPh3)AuNTf2 (0.01 mmol) in
1,2-dichloroethane (0.2 mL) at 70 °C for 9 h.
b Isolated yield.
c A 44:56 mixture of E/Z isomers was obtained.
d At 80 °C.
Ar
Ar
O
O
H
H
N
5 mol% [CuCl(cod)]2
N
O
Me
N
Ph
+
N
Me
1,4-dioxane, 80 °C
24 h
O
Me
Me
Me
O
O
Ph
Me
11aa, 54%
2aa
10
(3 equiv)
Ar = p-O2NC6H4
We have previously reported that the Cu-catalyzed re-
action between O-secondary propargylic oxime and elec-
tron-deficient olefins, such as N-methylmaleimide 10, pro-
ceeded through [2,3]-rearrangement, [3+2] cycloaddition
between the N-allenylnitrone 9 that was generated in situ
and the maleimide, and [1,3]-oxygen rearrangement from
the nitrogen atom to the allene center carbon, affording the
corresponding 1,4-oxazepines (Scheme 4). Thus, the cop-
per-catalyzed cascade reaction was applied to the O-tert-
propargylic oxime 2aa. The reaction with N-methylma-
leimide 10 proceeded at 80 °C in dioxane, affording the cor-
responding oxazepine 11aa in good yield with excellent
anti-selectivity.6
Moreover, the gold-catalyzed reaction of 2aa in metha-
nol gave isoxazoline 12 in good yield (Scheme 5). In partic-
ular, the reaction of 2da, bearing a cyclobutyl moiety at the
propargylic position, was efficiently converted into the cor-
responding spirocyclic isooxazoline 12da.13 The reaction
proceeds via alcoholysis of the cyclized vinylgold interme-
diate 8′ with rapid protodeauration in methanol. In fact, the
reaction involved formation of the acetal 13, supporting the
proposed mechanism.
[1,3]-oxygen
rearrangement
[2,3]-rearrangement
Me
N
O
O
O
N
Ar
H
H
10
exo-[3+2]
O
Ar
Me
•
Ph
N
Me
Me
•
Ph
12
(E)-9
Me
Scheme 4 Cu-catalyzed reaction between O-tert-propargylic oxime
2aa and N-methylmaleimide 10
Ar
Ar
Ph
O
N
O
N
5 mol% PPh3AuNTf2
N
R
O
R
Ph
R
R
MeOH, 50 °C
24 h
R
Au
8'
R
Ph
12
2
Ar = p-O2NC6H4
OMe
O
N
O
N
Ar
OMe
Me
Me
12aa, 73%
Ph
Ph
byproduct 13
71% yield in the reaction of 2aa
86% yield in the reaction of 2da
12da, 81%
Scheme 5 Au-catalyzed cyclization of 2 to 2-isoxazolines 12
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–E

D
I. Nakamura et al.
Paper
Synthesis
In conclusion, we have developed an efficient approach
to O-tert-propargylic oximes derived from tertiary propar-
gylic alcohols by using the Nicholas reaction. Given that the
oximes serve as a platform for catalytic rearrangement re-
actions and also as an equivalent of propargyloxyamines in
-acidic metal catalysis, the present protocol is useful for
the synthesis of highly functionalized heterocycles.
Yield: 7.57 g (12.7 mmol, 91%).
IR (neat): 3428, 3413, 3370, 3359, 2989, 2937, 2376, 2362, 2347,
2334, 2323, 2090, 2051, 2021, 1601, 1587, 1523, 1482, 1442, 1377,
1345, 1140, 1109, 962, 852, 795, 762, 691 cm–1
.
1H NMR (CDCl3, 400 MHz):  = 8.19–8.15 (m, 2 H), 8.11–8.10 (m, 1 H),
7.58–7.54 (m, 4 H), 7.36–7.34 (m, 3 H), 1.88 (s, 1 H).
13C NMR (CDCl3, 100 MHz):  = 199.58, 148.01, 138.64, 138.25,
129.73, 128.75, 127.50, 123.85, 102.45, 92.61, 83.65, 46.24, 29.15.
HRMS (FD): m/z [M + Na]+ calcd for C24H16Co2N2O9: 616.9412; found:
616.9412.
1H and 13C NMR spectra were recorded on a JEOL JNM-ECS400 (400
MHz for 1H and 100 MHz for 13C) spectrometer. Chemical shifts are
reported in ppm relative to CHCl3 (for 1H,  7.26), and CDCl3 (for 13C, 
77.00). Infrared (IR) spectra were recorded on a JASCO FT/IR- 4100
spectrophotometer. High-resolution mass spectra analysis was per-
formed on a Bruker Daltonics APEX III FT-ICR-MS spectrometer and
Bruker Daltonics solariX FT-ICR-MS spectrometer at Research and An-
alytical Center for Giant Molecules, Graduate School of Science, To-
hoku University. Flash column chromatography was performed on sil-
ica gel 60N (Merck 40-63 μm or Kanto 40-50 μm). Analytical thin lay-
er chromatography (TLC) was performed on Merck pre-coated TLC
plates (silica gel 60 F254).
Compound 2aa
To 5aa (4.87 g, 8.16 mmol) in acetone (81.6 mL) in a 200 mL round-
bottom flask was added CAN (17.9 g, 32.6 mmol) at 0 °C. After stirring
at 0 °C for 5 h, the reaction was quenched with water and the mixture
was extracted with ether. The organic layer was washed with water
and brine and dried over Na2SO4. After removing solvents in vacuo,
the residue was purified by silica gel column chromatography using
hexane/EtOAc (10:1) as eluent to obtain 2aa in analytically pure form.
Yield: 2.52 g (8.16 mmol, quant).
IR (neat): 2997, 2949, 1598, 1589, 1519, 1491, 1443, 1421, 1409,
1341, 1305, 1245, 1215, 1174, 1154, 1102, 1070, 1028, 1013, 947,
Acetone, hexane, CH3CN, 1,4-dioxane, 1,2-dichloroethane, and metha-
nol were purchased form Fujifilm Wako Pure Chemical Corporation.
CH2Cl2 was purchased from Kanto Chemical Co., Inc. Co2(CO)8,
BF3·OEt2, and CAN were purchased from TCI. These reagents were
used as received. [Cu(cod)]2 and (PPh3)AuNTf2 were prepared accord-
ing to reported procedures.14,15 CDCl3 was purchased from Merck. All
air- and moisture-sensitive manipulations were performed under ar-
gon atmosphere using oven-dried glassware, including glovebox tech-
niques.
851, 795, 757, 690, 642, 622 cm–1
.
1H NMR (CDCl3, 400 MHz):  = 8.25–8.23 (d, J = 8.7 Hz, 2 H), 8.17 (s,
1 H), 7.82–7.80 (d, J = 8.7 Hz, 2 H), 7.45–7.43 (m, 2 H), 7.31–7.29 (m,
3 H), 1.74 (s, 6 H).
13C NMR (CDCl3, 100 MHz):  = 148.29, 147.56, 138.40, 131.78,
128.35, 128.20, 127.81, 123.92, 122.62, 90.45, 84.87, 83.79, 77.89,
35.06, 14.04.
HRMS (FD): m/z [M + Na]+ calcd for C18H16N2O3: 331.1053; found:
331.1053.
Compound 3a
To a suspension of Co2(CO)8 (5.6 g, 16.5 mmol) in CH2Cl2 (150 mL) in a
300 mL three-neck flask was added 1a (15 mmol) at room tempera-
ture. The mixture was stirred at room temperature for 3 h, then the
solvents were removed in vacuo, the crude product was purified by
silica gel column chromatography using hexane/CH2Cl2 (1:2) as eluent
to afford 3a.
Funding Information
This work was supported by JSPS KAKENHI Grant Number
JP16H00996 in Precisely Designed Catalysts with Customized Scaf-
folding and JP20H02731 (Grant-in-Aid for Scientific Research (B))
Yield: 6.18 g (13.9 mmol, 93%).
from MEXT Japan.
J
a
p
a
n
S
o
c
i
etyforth
e
Pro
m
oti
o
n
of
S
c
i
e
n
c
e
(J
P
1
6
H
0
0
9
9
6)J
a
p
a
n
S
o
c
i
etyforth
e
Pro
m
oti
o
n
of
S
c
i
e
n
c
e
(J
P
2
0
H
0
2
7
3
1)
IR (neat): 3606, 3535, 3082, 2988, 2933, 2475, 2089, 2041, 2001,
1606, 1573, 1482, 1459, 1443, 1377, 1362, 1312, 1231, 1153, 1106,
1073, 1030, 998, 954, 918, 828, 761, 736, 691, 672, 621 cm–1
.
Supporting Information
1H NMR (CDCl3, 400 MHz):  = 7.61 (m, 2 H), 7.35 (m, 3 H), 1.72 (s,
Supporting information for this article is available online at
6 H).
https://doi.org/10.1055/s-0040-1707191.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orit
n
gInformati
o
n
13C NMR (CDCl3, 100 MHz):  = 199.59, 164.68, 137.71, 129.73,
128.83, 127.76, 106.99, 96.10, 91.69, 73.40, 32.44.
HRMS (FD): m/z [M + Na]+ calcd for C17H12Co2O7: 468.9139; found:
468.9139.
References
(1) Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. J. Med. Chem. 2014,
57, 5845.
Compound 5aa
(2) (a) Lipshutz, B. H. Chem. Rev. 1986, 86, 795. (b) Baraldi, P. G.;
Barco, A.; Benetti, S.; Pollini, G. P.; Simori, D. Synthesis 1987,
857.
(3) (a) Knight, D. W.; Proctor, A. P.; Clough, J. M. Synlett 2010, 628.
(b) Yeom, H.-S.; Lee, E.-S.; Shin, S. Synlett 2007, 2292.
(c) Nakamura, I.; Onuma, T.; Kanazawa, R.; Nishigai, Y.; Terada,
M. Org. Lett. 2014, 16, 4198.
To a mixture of 3a (6.18 g, 13.9 mmol) and oxime 4a (6.94 g, 41.8
mmol) in CH2Cl2 (140 mL) was added BF3·OEt2 (4.42 mL, 35.2 mmol)
dropwise at –10 °C. After stirring at –10 °C for 2.5 h, the reaction was
quenched with aqueous NaHCO3 solution and the mixture was ex-
tracted with CH2Cl2. The organic layer was washed with water and
brine and dried over anhydrous sodium sulfate. After solvents were
removed in vacuo, the residue was purified by silica gel column chro-
matography using hexane/EtOAc (5:1) as eluent to obtain 5aa.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–E

E
I. Nakamura et al.
Paper
Synthesis
(4) (a) Foot, O. F.; Knight, D. W.; Low, A. C. L.; Li, Y. F. Tetrahedron
Lett. 2007, 48, 647. (b) Okitsu, T.; Sato, K.; Potewar, T. M.; Wada,
A. J. Org. Chem. 2011, 76, 3438.
(5) (a) Nakamura, I.; Araki, T.; Zhang, D.; Kudo, Y.; Kwon, E.; Terada,
M. Org. Lett. 2011, 13, 3616. (b) Nakamura, I.; Kudo, Y.; Araki, T.;
Zhang, D.; Kwon, E.; Terada, M. Synthesis 2012, 44, 1542.
(6) Nakamura, I.; Kudo, Y.; Terada, M. Angew. Chem. Int. Ed. 2013,
52, 7536.
(7) (a) Nakamura, I.; Zhang, D.; Terada, M. J. Am. Chem. Soc. 2010,
132, 7884. (b) Nakamura, I.; Okamoto, M.; Sato, Y.; Terada, M.
Angew. Chem. Int. Ed. 2012, 51, 10816. (c) Nakamura, I.; Sato, Y.;
Takeda, K.; Terada, M. Chem. Eur. J. 2014, 20, 10214.
(d) Nakamura, I.; Gima, S.; Kudo, Y.; Terada, M. Angew. Chem. Int.
Ed. 2015, 54, 7154. (e) Gima, S.; Nakamura, I.; Terada, M. Eur. J.
Org. Chem. 2017, 4375. (f) Gima, S.; Shiga, K.; Terada, M.;
Nakamura, I. Synlett 2019, 30, 393. (g) Shiga, K.; Terada, M.;
Nakamura, I. Chem. Sci. 2019, 10, 5283.
(9) (a) Gaudemer, F.; Gaudemer, A. Tetrahedron Lett. 1980, 21, 1445.
(b) Sabbasani, V.; Lee, D. Org. Lett. 2015, 17, 4878.
(10) (a) Reddy, C. R.; Radhika, L.; Kumar, T. P.; Chandrasekhar, S. Eur.
J. Org. Chem. 2011, 5967. (b) Ren, Z.; Mo, F.; Dong, G. J. Am.
Chem. Soc. 2012, 134, 16991. (c) Kang, T.; Kim, H.; Kim, J. G.;
Chang, S. Chem. Commun. 2014, 50, 12073.
(11) (a) Choong, I. C.; Ellman, J. A. J. Org. Chem. 1999, 64, 6528.
(b) Sun, R.; Li, Y.; Lü, M.; Xiong, L.; Wang, Q. Bioorg. Med. Chem.
Lett. 2010, 20, 4693.
(12) (a) Lockwood, R. F.; Nicholas, K. M. Tetrahedron Lett. 1977, 18,
4163. (b) Teobald, B. J. Tetrahedron 2002, 58, 4133. (c) Diaz, D.
D.; Betancort, J. M.; Martin, V. S. Synlett 2007, 343.
(13) Kotha, S.; Deb, A. C.; Lahiri, K.; Manivannan, E. Synthesis 2009,
165.
(14) Chi, K. M.; Shin, H.-K.; Hampden-Smith, M. J.; Duesler, E. N.;
Kodas, T. T. Polyhedron 1991, 10, 2293.
(15) Mézailles, N.; Ricard, L.; Gagosz, F. Org. Lett. 2005, 7, 4133.
(8) (a) Somanadhan, B.; Loke, W.-K.; Sim, M.-K.; Go, M.-L. Bioorg.
Med. Chem. 2002, 10, 207. (b) Proctor, A. J.; Beautement, K.;
Clough, J. M.; Knight, D. W.; Li, Y. Tetrahedron Lett. 2006, 47,
5151.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–E