Pd(II)-Catalyzed Cycloisomerization/Dipolar Cycloaddition Cascade of N-Arylnitrone Alkynes with Olefins

Article abstract of DOI:10.1021/acs.joc.5b00717

A cycloisomerization/dipolar cycloaddition tandem reaction of nitrone alkynes and electron-deficient olefins was described by employing a simple palladium catalyst. N-Arylnitrone alkynes, which were not well tolerated in previously reported methodologies, were successfully incorporated in the tandem reaction with generally good yields and moderate diastereoselectivities.

Full text of DOI:10.1021/acs.joc.5b00717

Note
pubs.acs.org/joc
Pd(II)-Catalyzed Cycloisomerization/Dipolar Cycloaddition Cascade
of N‑Arylnitrone Alkynes with Olefins
Yu-Liu Du, Yi-Fan Zhu, and Zhi-Yong Han*
Department of Chemistry, University of Science and Technology of China, Hefei 230026, China
*
S Supporting Information
ABSTRACT: A cycloisomerization/dipolar cycloaddition tan-
dem reaction of nitrone alkynes and electron-deficient olefins
was described by employing a simple palladium catalyst. N-
Arylnitrone alkynes, which were not well tolerated in
previously reported methodologies, were successfully incorpo-
rated in the tandem reaction with generally good yields and
moderate diastereoselectivities.
ransition-metal-catalyzed cascade reactions, for their high
efficiency and step-economy in constructing complex
the fact that the in situ generated imine could be further
incorporated into the reaction in a cascade manner. In the
8
T
molecules, have attracted increasing interest, providing a huge
number of versatile and important synthetic methodologies.
presence of different transition-metal catalysts, nitrone alkynes
could undergo versatile transformations. Shin and co-workers
reported that under the catalysis of cationic Au(I), isoindole
1
Nucleophilic attack on alkyne-triggered tandem reactions
represents a promising strategy in this discipline. In the cases
where nucleophiles are amine N-oxides, sulfoxides, nitrones,
and nitro groups, the cleavage of N−O σ bonds is usually
involved in the formation of highly active α-oxo metal carbenoid
2
5g
derivatives could be obtained efficiently (eq 2a). Pati and Liu
3
4
5
afforded α-pyridone derivatives through a ruthenium-catalyzed
6
5h
cycloisomerization of nitrone alkynes (eq 2b). Shin and co-
workers reported an AuCl -catalyzed tandem reaction of nitrone
3
intermediates, which could undergo versatile transformations
alkyne and diethyl acetylenedicarboxylate, obtaining the tricyclic
7
5i
5e
(eq 1). Significant interest has been placed on such internal
product with fair yield (eq 3). Li’s group found that the
9
redox processes as a valuable alternative approach to synthetic
useful metal carbenoid species.
azomethine ylide intermediates I, formed by the iridium-
catalyzed cycloisomerization of nitrone alkynes, could be
isolated or directly used for a one-pot [3 + 2] cycloaddition
10
reaction (eq 4). Interestingly, in all of these examples, N-
alkylnitrones were employed exclusively for the intramolecular
cycloisomerization reaction. Herein, we describe a palladium-
catalyzed cycloisomerization/dipolar cycloaddition cascade of
N-arylnitrone alkynes with electron-deficient olefins (eq 5).
As a starting point, we examined the reaction of N-arylnitrone
alkyne 1a and dimethyl fumarate 2a, as the dipolarophile, in the
presence of 10 mol % of AuCl , which displayed high efficiency
3
for the cascade reaction of N-alkylnitrone alkyne and diethyl
5i
but-2-ynedioate (eq 3). However, in our case, the reaction
resulted in a complex mixture with only a trace amount of the
desired product 3 observed (Table 1, entry 1). Other transition-
metal complexes, Ph PAuNTf, Cu(OTf) , and Rh (OAc) , also
3
2
2
4
failed to provide a significant amount of the cycloaddition
product (entries 2−4). [IrCp*Cl ] , which was the optimal
2
2
5e
catalyst for the reaction of N-alkylnitrone alkynes in Li’s work,
gave only 33% of 3 (entry 5). Surprisingly, PdCl proved to be a
2
better catalyst for the reaction, providing the desired product
with 41% yield and 1.7:1 diastereoselectivity (entry 6).
Screening of palladium(II) complexes showed that Pd(OAc)2
was the best catalyst, furnishing the product with 45% yield and
Comparatively speaking, employing nitrones as the nucleo-
phile holds unique advantages such as easy accessibility of the
substrates, mild reaction conditions for the redox process, and
Received: April 1, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b00717
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a
Table 1. Evaluation of Catalysts and Optimization of Reaction Conditions
entry
cat.
AuCl3
solvent
yield (%)
dr. (3/3′)
1
2
3
4
5
6
7
8
CH Cl2
trace
trace
trace
trace
33
2
Ph PAuNTf
3
CH Cl2
2
2
Cu(OTf)2
Rh (OAc)
CH Cl2
2
CH Cl2
2
4
2
[IrCp*Cl )]
PdCl2
CH Cl2
3.1:1
1.7:1
3.0:1
3.3:1
3.3:1
2.4:1
3.3:1
2.7:1
3.0:1
2.7:1
2.3:1
3.0:1
3.3:1
2
2
2
CH Cl2
41
2
Pd(CO CF )
CH Cl2
40
2
3
2
2
Pd(OAc)2
CH Cl2
45
2
b
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
CH Cl2
63
2
b
10
11
12
13
14
15
16
17
CHCl3
DCE
27
b
b
b
b
b
b
b
40
MeCN
toluene
THF
21
29
52
MeNO2
59
,
,
c
CH Cl2
66
2
d
CH Cl2
78
2
a
Unless indicated otherwise, the mixture of 1 (0.05 mmol), 2 (0.05 mmol), and Pd(OAc) (10 mol %) in CH Cl (0.8 mL) was stirred at 25 °C for
2
2
2
b
3
.5 h. A mixture of 1 (0.05 mmol) and 2 (0.05 mol) in CH Cl (0.3 mL) was added via a syringe pump over 0.5 h to Pd(OAc) (10 mol %) in 0.5
2 2 2
c d
mL of CH Cl ; the resulting mixture was then stirred at 25 °C for a further 3 h. 0.1 mmol of 2 was employed. 0.1 mmol of 1 was used.
2
2
3
.3:1 diastereoselectivity (entries 7 and 8). To further improve
In order to investigate the applicability of this methodology, a
larger scale (1.0 mmol) experiment was conducted. The desired
products were obtained with 62% yield and 3.1:1 diaster-
eoselectivity (Figure 1).
the yield, we added the substrates and catalyst in different
sequences. When dimethyl fumarate was added after the nitrone
alkyne 1a was stirred with Pd(OAc) , the reaction gave only a
trace amount of the cycloaddition product. On the other hand,
when the substrates (1 and 2) were added via a syringe pump
into a DCM solution of the palladium catalyst, we obtained 3a
with 63% yield without decline of the diastereoselectivity (entry
2
A deuterium-labeling experiment was carried out to probe the
mechanism of the Pd(II)-catalyzed cascade reaction of N-
arylnitrone alkynes and electron-deficient olefins. 1a-D, which
was 81% deuterated at the alkynyl position, and dimethyl
fumarate under the standard reaction conditions led to
deuterated product 3a-D, supporting a mechanism as shown
in Figure 2. The proposed reaction pathway is consistent with
9). Screening of the solvents showed that other solvents, such as
THF and MeNO , also provided acceptable yields (entries 10−
1
beneficial effect for the reaction and improved the yield to 78%
2
5). Tuning the ratio of substrates exhibited a significantly
5i
5e
(entries 16 and 17).
the mechanism brought up by Shin and Li. First, the Pd(II)
catalyst activates the C−C triple bond as a π-Lewis acid, leading
to a 6-exo-dig cyclization to form intermediate B. After an
internal N−O bond redox, palladium carbene species C is
We next investigated the substrate scope of this N-aryl nitrone
alkyne cycloisomerization/dipolar cycloaddition reaction (Table
). Nitrone alkynes with different N-aryl groups were first
2
examined. p-, m-, and o-methyl-substituted N-aryl groups were
well tolerated, providing the cyclic products with good yields
and moderate diastereoselectivities (3b−d). Substrates with an
electron-deficient N-aryl group also underwent the tandem
reaction smoothly, affording the corresponding products with
satisfying yields and diastereoselectivities (3e−h). Nitrone
alkynes with various substituents on the aryl core were
subsequently investigated. Generally, substrates with different
electron demands underwent the tandem reaction cleanly. For
example, methyl-, methoxy-, and fluoro-substituted substrates all
successfully afforded the tricyclic product with good yields (3i−
m). However, when more electron-rich nitrone alkyne 3n was
employed, only 38% yield was obtained. The structure of 3n was
further confirmed by single-crystal XRD analysis (see the
Supporting Information for details). Diethyl fumarate and N-
methylmaleimide also proved to be good dipolarophiles,
providing the dipolar cycloaddition products with good yields
and moderate diastereoselectivities (3o−p).
11
formed, which then undergoes an intramolecular nucleophilic
addition by the imine group, generating intermediate D.
Enolization of D leads to the key intermediate I-a, which
participates a [3 + 2] dipolar cycloaddition with electro-deficient
olefins to form the final product 3a. As supported by the results
of the deuterium-labeling experiment, in the entire process there
is no cleavage of the alkynyl C−H bond.
In summary, a cycloisomerization/dipolar cycloaddition
tandem reaction of nitrone alkynes and electron-deficient
olefins was revealed by employing a simple palladium(II)
catalyst. In previous studies, such N−O bond redox processes
were mainly catalyzed by gold, ruthenium, and iridium
complexes. More importantly, N-arylnitrone alkynes, which
were generally not tolerated in the reported methodologies,
were successfully incorporated in the tandem reaction with
generally good yields.
B
DOI: 10.1021/acs.joc.5b00717
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a c
Table 2. Scope of Substrates −
a
A mixture of 1 (0.10 mmol) and 2 (0.05 mol) in CH Cl (0.3 mL) was added via a syringe pump over 0.5 h to Pd(OAc) (10 mol %) in 0.5 mL of
2
2
2
b
c
1
CH Cl ; the resulting mixture was then stirred at 25 °C for a further 3 h. Combined yield of both diastereomers. The dr was determined by H
NMR.
2
2
Figure 1. 1.0 mmol scale reaction of 1a and 2a.
Figure 2. Proposed mechanism for the reaction.
C
DOI: 10.1021/acs.joc.5b00717
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1
458, 1399, 1166, 1079, 787, 761. HR-ESI: calcd for C H NO [M +
EXPERIMENTAL SECTION
16 13
■
H] 236.1075, found 236.1068.
Z)-N-(2-Ethynylbenzylidene)-2-methylaniline Oxide (1d). 452 mg.
Yield: 61%. Yellow oil. H NMR (400 MHz, CDCl ): δ 9.52 (d, J = 8.0
General Methods. NMR spectra were recorded on a 400 MHz
spectrometer. HRMS spectra were recorded on a TOF-Q mass
spectrometer. All starting materials, reagents, and solvents were
purchased from commercial suppliers and used as supplied unless
otherwise stated. Toluene and THF were dried over Na and distilled
prior to use. CH Cl was dried over CaH and distilled prior to use.
(
1
3
Hz, 1H), 8.18 (s, 1H), 7.58 (dd, J = 7.6, 1.0 Hz, 1H), 7.46−7.53 (m,
1
3
1
H), 7.44−7.37 (m, 2H), 7.36−7.24 (m, 3H), 3.37 (s, 1H), 2.44 (s,
13
H). C NMR (101 MHz, CDCl ): δ 149.1, 135.3, 133.1, 131.8, 131.6,
3
2
2
2
31.6, 130.2, 129.4, 129.4, 127.6, 126.8, 123.5, 121.6, 83.8, 80.9, 17.2.
For the synthesis procedure and characterization of alkyne nitrone
substrates, see the Supporting Information.
General Reaction Procedures. In a screw-capped vial, Pd(OAc)2
10 mol %) was flushed with argon and suspended in CH Cl (0.3 mL).
A mixture of substituted (2-ethynylbenzylidene)aniline oxide (0.1
mmol) and dienophile (0.05 mmol) was dissolved in CH Cl (0.5 mL)
before being added to the reaction by syringe pump over 30 min. The
resulting mixture was allowed to stir at 25 °C for another 3 h. After that,
the solvent was removed under reduced pressure, and the crude
product was purified through flash column chromatography on silica
gel (petroleum ether/ethyl acetate = 3:1).
General Procedures for the Synthesis of (2-Ethynylbenzyl-
idene)aniline Oxide Derivatives. A mixture of 2-bromobenzalde-
hyde derivative (10 mmol, 1.0 equiv), Pd(PPh ) Cl (140 mg, 0.2
IR: 2097, 1548, 1488, 1460, 1406, 1195, 1124, 1072, 765. HR-ESI:
calcd for C H NO [M + H] 236.1075, found 236.1069.
16
13
(Z)-4-Chloro-N-(2-ethynylbenzylidene)aniline Oxide (1e). 361 mg.
(
1
2
2
Yield: 72%. Yellow oil. H NMR (400 MHz, CDCl ): δ 9.53−9.45 (m,
1
3
H), 8.55 (s, 1H), 7.87−7.69 (m, 2H), 7.61 (dd, J = 7.6, 1.2 Hz, 1H),
2
2
7.54−7.44 (m, 3H), 7.42 (ddd, J = 7.6, 5.9, 1.3 Hz, 1H), 3.48 (s, 1H).
13
C NMR (101 MHz, CDCl ): δ 147.8, 136.0, 133.1, 132.3, 131.8,
3
1
1
2
30.5, 129.5, 129.4, 127.7, 123.1, 122.0, 84.0, 81.0. IR: 2098, 1483,
419, 1201, 1092, 1074, 760. HR-ESI: calcd for C H ClNO [M + H]
15
10
56.0529, found 256.0518.
Z)-3-Chloro-N-(2-ethynylbenzylidene)aniline Oxide (1f). 546 mg.
(
1
Yield: 64%. Yellow oil. H NMR (400 MHz, CDCl ): δ 9.49 (d, J = 8.1
3
Hz, 1H), 8.55 (s, 1H), 7.81−7.88 (m, 1H), 7.71−7.66 (m, 1H), 7.61
3
2
2
(dd, J = 7.6, 1.1 Hz, 1H), 7.55−7.49 (m, 1H), 7.48−7.39 (m, 3H), 3.48
(s, 1H). C NMR (101 MHz, CDCl ): δ 150.2, 135.1, 133.1, 132.6,
mmol), and CuI (19 mg, 0.1 mmol) was suspended in Et N (10 mL).
13
3
3
(
Trimethylsilyl)acetylene (1.68 mL, 12 mmol, 1.2 equiv) was added
into the reaction slowly, and then the mixture was stirred for 10 h at 60
C. Afterward, the mixture was filtered, and the solvent was removed
under reduced pressure. The crude product was purified through flash
column chromatography (petroleum ether/ethyl acetate = 50:1) to
obtain substituted 2-[(trimethylsilyl)ethynyl]benzaldehyde derivative.
To a mixture of substituted 2-[(trimethylsilyl)ethynyl]benzaldehyde
derivative (5.0 mmol, 1.0 equiv), nitrobenzene (0.56 mL, 5.5 mmol, 1.1
equiv), and ammonium chloride (344 mg, 6.5 mmol, 1.3 equiv) in
1
31.7, 130.6, 130.3, 130.2, 129.5, 127.8, 122.6, 122.1, 119.9, 84.0, 81.0.
IR: 2099, 1587, 1469, 1434, 1107, 760, 682. HR-ESI: calcd for
C H ClNO [M + H] 256.0529, found 256.0530.
°
15
10
(
Z)-N-(2-Ethynylbenzylidene)-4-fluoroaniline Oxide (1g). 298 mg.
1
Yield: 59%. Yellow oil. H NMR (400 MHz, CDCl ): δ 9.49 (d, J = 8.1
3
Hz, 1H), 8.53 (s, 1H), 7.86−7.77 (m, 2H), 7.60 (dd, J = 7.6, 1.0 Hz,
1
H), 7.47−7.55 (m, 1H), 7.38−7.44 (m, 1H), 7.22−7.14 (m, 2H), 3.46
13
(s, 1H). C NMR (101 MHz, CDCl ): δ 163.2 (d, J = 250.8 Hz), 145.6
3
(d, J = 2.8 Hz), 133.1, 132.1, 131.9, 130.3, 129.5, 127.7, 123.8 (d, J = 8.9
EtOH (10 mL) and H O (5 mL) was added Zn powder (650 mg, 10
2
Hz), 121.9, 116.1 (d, J = 23.2 Hz), 83.8, 81.0. IR: 2097, 1500, 1235,
12
mmol, 2 equiv) slowly over 30 min at 0 °C. The mixture was then
warmed to room temperature and stirred overnight. The reaction
mixture was filtered through Celite, extracted by CH Cl , and dried
1
200, 1074, 760. HR-ESI: calcd for C H FNO [M + H] 240.0825,
15 10
found 240.0818.
2
2
(Z)-N-(2-Ethynylbenzylidene)-3-(trifluoromethyl)aniline Oxide
1
over Na SO , and then the solvent as removed under reduced pressure.
2
4
(1h). 375 mg. Yield: 64%. Yellow oil. H NMR (400 MHz, CDCl ):
3
Pure 2-(trimethylsilyl)ethynyl)benzylidene aniline oxide was obtained
after flash column chromatography (petroleum ether/ethyl acetate =
δ 9.50 (d, J = 8.0 Hz, 1H), 8.61 (s, 1H), 8.13 (s, 1H), 7.99 (d, J = 8.0
Hz, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.69−7.60 (m, 2H), 7.49−7.57 (m,
13
1
0:1).
A mixture of 2-(trimethylsilyl)ethynyl)benzylidene aniline oxide (3
mmol, 1 equiv) and K CO (1.23 g, 9 mmol, 3 equiv) was suspended in
1
H), 7.48−7.40 (m, 1H), 3.49 (s, 1H). C NMR (101 MHz, CDCl ):
3
δ 149.6, 133.2, 132.8, 132.0 (q, J = 33.4 Hz), 131.6, 130.7, 130.0, 129.5,
127.8, 126.8 (q, J = 7.2 Hz), 125.0, 123.3 (q, J = 272.8 Hz), 122.2, 119.4
(q, J = 4.0 Hz), 84.1, 80.9. IR: 2100, 1328, 1173, 1130, 1075, 761. HR-
ESI: calcd for C H F NO [M + H] 290.0793, found 290.0783.
2
3
MeOH (10 mL). After being stirred for 30 min, the crude mixture was
filtered. Then, the solvent was removed under reduced pressure before
the product was purified through flash column chromatography on
silica gel (petroleum ether/ethyl acetate = 10:1) to achieve the (2-
ethynylbenzylidene)aniline oxide derivative 1.
16
10 3
(Z)-N-(2-Ethynyl-5-methylbenzylidene)aniline Oxide (1i). 396 mg.
1
Yield: 75%. Yellow oil. H NMR (400 MHz, CDCl ): δ 9.38 (s, 1H),
3
8.56 (s, 1H), 7.83−7.77 (m, 2H), 7.55−7.45 (m, 4H), 7.23 (dd, J = 7.8,
0.9 Hz, 1H), 3.40 (s, 1H), 2.45 (s, 3H). 13C NMR (101 MHz, CDCl ):
Characterization of (2-Ethynylbenzylidene)aniline Oxide
3
Derivatives 1. (Z)-N-(2-Ethynylbenzylidene)aniline Oxide (1a). 352
δ 149.5, 139.8, 132.9, 132.5, 131.8, 131.2, 130.0, 129.2, 128.2, 121.8,
119.1, 83.0, 81.3. IR: 2096, 1485, 1460, 1407, 1204, 1071, 817, 757,
6
1
mg. Yield: 64%. Yellow oil. H NMR (400 MHz, CDCl ): δ 9.53 (dd, J
3
=
1
8.1, 0.5 Hz, 1H), 8.58 (s, 1H), 7.83−7.77 (m, 2H), 7.60 (dd, J = 7.6,
86. HR-ESI: calcd for C H NO [M + H] 236.1075, found 236.1065.
16 13
13
.2 Hz, 1H), 7.54−7.45 (m, 4H), 7.38−7.43 (m, 1H), 3.46 (s, 1H).
C
(
Z)-N-(2-Ethynyl-4-methylbenzylidene)aniline Oxide (1j). 653 mg.
1
NMR (101 MHz, CDCl ): δ 149.5, 133.1, 132.3, 132.1, 130.2, 130.1,
Yield: 73%. Yellow oil. H NMR (400 MHz, CDCl ): δ 9.43 (d, J = 8.3
Hz, 1H), 8.55 (s, 1H), 7.76−7.83 (m, 2H), 7.56−7.45 (m, 3H), 7.41−
7.44 (m, 1H), 7.32 (d, J = 8.7 Hz, 1H), 3.42 (s, 1H), 2.39 (s, 3H).
NMR (101 MHz, CDCl ): δ 149.4, 140.9, 133.7, 132.3, 130.3, 130.1,
129.9, 129.5, 129.2, 129.2, 127.8, 121.9, 121.8, 83.3, 81.2, 21.5. IR:
2097, 1597, 1486, 1460, 1190, 1074, 763. HR-ESI: calcd for C H NO
[M + H] 236.1075, found 236.1072.
3
3
1
1
2
29.5, 129.2, 127.7, 121.9, 121.9, 83.8, 81.1. IR: 2102, 1603, 1504, 1316,
060, 756, 692. HR-ESI: calcd for C H NO [M + H] 222.0919, found
1
3
15
11
C
22.0925.
Z)-N-(2-Ethynylbenzylidene)-4-methylaniline Oxide (1b). 510 mg.
3
(
1
Yield: 68%. Yellow oil. H NMR (400 MHz, CDCl ): δ 9.55−9.47 (m,
3
16 13
1
7
(
H), 8.56 (s, 1H), 7.73−7.65 (m, 2H), 7.59 (dd, J = 7.7, 1.0 Hz, 1H),
.46−7.53 (m, 1H), 7.36−7.42 (m, 1H), 7.28 (d, J = 8.1 Hz, 2H), 3.45
(Z)-N-(2-Ethynyl-5-methoxybenzylidene)aniline Oxide (1k). 755
s, 1H), 2.42 (s, 3H). 13C NMR (101 MHz, CDCl ): δ 147.2, 140.4,
1
3
mg. Yield: 69%. Yellow oil. H NMR (400 MHz, CDCl ): δ 9.23 (d, J =
3
1
2
33.0, 132.2, 131.8, 130.1, 129.7, 129.4, 127.7, 121.8, 121.6, 83.7, 81.1,
1.2. IR: 2096, 1543, 1502, 1458, 1419, 1200, 1075, 812, 761. HR-ESI:
2.7 Hz, 1H), 8.59 (s, 1H), 7.83−7.77 (m, 2H), 7.55−7.46 (m, 4H),
1
3
6.97 (dd, J = 8.6, 2.8 Hz, 1H), 3.92 (s, 3H), 3.38 (s, 1H). C NMR
calcd for C H NO [M + H] 236.1075, found 236.1074.
(101 MHz, CDCl ): δ 160.1, 149.4, 134.1, 133.4, 132.6, 130.1, 129.3,
16
13
3
(
Z)-N-(2-Ethynylbenzylidene)-3-methylaniline Oxide (1c). 515 mg.
121.8, 118.0, 114.4, 111.3, 82.4, 81.2, 55.6. IR: 2093, 1594, 1477, 1298,
1245, 1206, 1101, 1027. HR-ESI: calcd for C H NO [M + H]
1
Yield: 66%. Yellow oil. H NMR (400 MHz, CDCl ): δ 9.52 (dd, J =
3
16 13
2
8
7
.1, 0.5 Hz, 1H), 8.55 (s, 1H), 7.64−7.48 (m, 4H), 7.43−7.33 (m, 2H),
252.1024, found 252.1022.
.28 (d, J = 7.6 Hz, 1H), 3.45 (s, 1H), 2.45 (s, 3H). 13C NMR (101
(Z)-N-(2-Ethynyl-4-fluorobenzylidene)aniline Oxide (1l). 428 mg.
1
MHz, CDCl ): δ 149.5, 139.5, 133.0, 132.2, 132.1, 130.8, 130.1, 129.4,
Yield: 65%. Yellow oil. H NMR (400 MHz, CDCl ): δ 9.61 (dd, J =
3
3
1
28.9, 127.7, 122.6, 121.8, 118.8, 83.7, 81.1, 21.4. IR: 2098, 1682, 1487,
9.1, 6.1 Hz, 1H), 8.52 (s, 1H), 7.81−7.76 (m, 2H), 7.53−7.47 (m, 3H),
D
DOI: 10.1021/acs.joc.5b00717
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
7
.29 (dd, J = 8.8, 2.7 Hz, 1H), 7.17−7.24 (m, 1H), 3.51 (s, 1H). 13C
NMR (101 MHz, CDCl ): δ 162.6 (d, J = 253.9 Hz), 149.3, 131.2,
J = 7.9 Hz, 1H), 4.25 (dd, J = 7.8, 5.4 Hz, 1H), 3.82 (s, 3H), 3.69 (s,
3H), 3.61 (d, J = 5.3 Hz, 1H), 2.19 (s, 3H). 13C NMR (101 MHz,
3
1
9
30.1 (d, J = 8.5 Hz), 130.1, 129.3, 128.7 (d, J = 3.5 Hz), 124.2 (d, J =
.6 Hz), 121.8, 120.0 (d, J = 24.1 Hz), 116.8 (d, J = 21.1 Hz), 84.8, 79.9
CDCl ): δ 194.0, 172.1, 170.5, 144.9, 143.8, 139.2, 134.9, 130.2, 129.2,
128.4, 127.2, 126.0, 121.2, 117.3, 113.6, 68.7, 63.2, 53.0, 52.7, 52.2, 47.6,
3
(
d, J = 3.2 Hz). IR: 2095, 1545, 1455, 1400, 1255, 1073, 860, 763, 689.
21.6. Light yellow oil.
Compound 3d. Yield: 76% (14.4 mg). dr = 3.4/1. H NMR (400
1
HR-ESI: calcd for C H FNO [M + H] 240.0825, found 240.0821.
15
10
(
Z)-N-(2-Ethynyl-5-fluorobenzylidene)aniline Oxide (1m). 339 mg.
MHz, CDCl ): δ 7.93 (d, J = 7.6 Hz, 1H), 7.44 (t, J = 7.3 Hz, 1H), 7.31
3
1
Yield: 58%. Yellow oil. H NMR (400 MHz, CDCl ): δ 9.33 (dd, J =
1
5
NMR (101 MHz, CDCl ): δ 163.5 (d, J = 249.5 Hz), 150.2, 135.6 (d, J
=
=
Hz), 81.2. IR: 2100, 1595, 1570, 1485, 1466, 1273, 1202, 761, 166. HR-
ESI: calcd for C H FNO [M + H] 240.0825, found 240.0819.
(t, J = 7.6 Hz, 1H), 7.11 (d, J = 7.5 Hz, 1H), 7.04 (d, J = 6.8 Hz, 1H),
6.89−6.78 (m, 2H), 6.50 (d, J = 7.5 Hz, 1H), 5.07 (d, J = 6.5 Hz, 1H),
4.67 (s, 1H), 4.16 (dd, J = 6.5, 6.2 Hz, 1H), 3.72 (s, 3H), 3.48 (d, J = 6.2
3
1.0, 2.6 Hz, 1H), 8.58 (s, 1H), 7.76−7.82 (m, 2H), 7.57 (dd, J = 8.5,
13
.7 Hz, 1H), 7.46−7.52 (m, 3H), 7.06−7.15 (m, 1H), 3.44 (s, 1H).
C
Hz, 1H), 3.45 (s, 3H), 2.24 (s, 3H). 13C NMR (101 MHz, CDCl ): δ
3
3
8.6 Hz), 135.0 (d, J = 10.3 Hz), 132.4, 131.3, 130.2, 122.7, 118.7 (d, J
3.5 Hz), 118.3 (d, J = 23.1 Hz), 115.6 (d, J = 27.2 Hz), 84.4 (d, J = 1.5
194.0, 171.3, 169.1, 142.4, 139.8, 133.3, 130.8, 129.7, 128.7, 127.8,
126.2, 125.5, 125.4, 122.3, 118.0, 69.4, 63.3, 52.0, 51.2, 50.8, 45.1, 18.2.
IR: 1738, 1694, 1600, 1493, 1246, 1223, 1176, 759. HR-ESI: calcd for
C H NO [M + H] 380.1498, found 380.1489. Light yellow oil.
15
10
22 21
5
1
(
Z)-N-((6-Ethynylbenzo[d][1,3]dioxol-5-yl)methylene)aniline
Compound 3d′. H NMR (400 MHz, CDCl ): δ 7.94 (d, J = 7.7 Hz,
3
1
Oxide (1n). 201 mg. Yield: 51%. Yellow oil H NMR (400 MHz,
CDCl ): δ 9.15 (s, 1H), 8.52 (s, 1H), 7.89−7.68 (m, 2H), 7.56−7.41
(
1
H), 7.56 (t, J = 7.5 Hz, 1H), 7.41−7.30 (m, 2H), 7.09 (d, J = 6.9 Hz,
3
1H), 6.93−6.83 (m, 2H), 6.60−6.54 (m, 1H), 5.30 (s, 1H), 4.67 (d, J =
13
m, 3H), 7.03 (s, 1H), 6.07 (s, 2H), 3.41 (s, 1H). C NMR (101 MHz,
7
.7 Hz, 1H), 4.26 (dd, J = 7.7, 5.4 Hz, 1H), 3.80 (s, 3H), 3.69 (s, 3H),
CDCl ): δ 149.3, 149.0, 148.4, 132.3, 129.9, 129.2, 127.9, 121.7, 117.1,
13
3
3.59 (d, J = 5.3 Hz, 1H), 2.30 (d, J = 8.9 Hz, 3H). C NMR (101 MHz,
1
12.7, 107.9, 102.1, 82.9, 81.1. IR: 2097, 1484, 1346, 1287, 1040, 762.
CDCl ): δ 195.2, 172.3, 170.6, 143.9, 143.1, 135.1, 131.8, 130.6, 130.1,
3
HR-ESI: calcd for C H NO [M + H] 266.0817, found 266.0814.
16
11
3
128.4, 126.7, 126.4, 125.2, 123.3, 119.1, 70.4, 64.5, 53.0, 52.9, 52.7, 47.6,
Characterization of the Cycloaddition Products 3. Compound
1
9.2. Light yellow oil.
Compound 3e. Yield: 84% (16.8 mg). dr = 2.9/1. H NMR (400
MHz, CDCl ): δ 7.91 (d, J = 7.6 Hz, 1H), 7.50 (t, J = 7.4 Hz, 1H), 7.34
1
3
7
a. Yield: 78% (14.1 mg). dr = 3.3/1. H NMR (400 MHz, CDCl ): δ
1
3
.92−7.86 (m, 1H), 7.47 (td, J = 7.5, 1.4 Hz, 1H), 7.29 (td, J = 7.6, 1.2
3
Hz, 1H), 7.26−7.23 (m, 1H), 7.14−7.08 (m, 2H), 6.80−6.71 (m, 3H),
5
Hz, 1H), 3.79 (s, 3H), 3.61 (dd, J = 6.3, 0.9 Hz, 1H), 3.54 (s, 3H).
NMR (101 MHz, CDCl ): δ 194.3, 172.0, 170.0, 145.1, 140.3, 134.2,
1
5
(
(
t, J = 7.5 Hz, 1H), 7.29−7.21 (m, 1 H), 7.07 (d, J = 8.7 Hz, 2H), 6.69
d, J = 8.7 Hz, 2H), 5.37 (d, J = 6.5 Hz, 1H), 4.95 (s, 1H), 4.22 (dd, J =
.43 (d, J = 6.6 Hz, 1H), 5.01 (t, J = 1.0 Hz, 1H), 4.23 (dd, J = 6.6, 6.3
13
C
6
.5, 6.2 Hz, 1H), 3.82 (s, 3H), 3.61 (d, J = 6.2 Hz, 1H), 3.55 (s, 3H).
C NMR (101 MHz, CDCl ): δ 194.0, 171.9, 169.8, 143.7, 139.9,
3
13
3
29.9, 129.4, 128.9, 127.5, 127.5, 120.4, 116.5, 68.9, 62.8, 53.1, 52.3,
1.9, 45.7. IR: 1735, 1697, 1599, 1498, 1436, 1232, 755. HR-ESI: calcd
1
5
34.3, 129.7, 129.3, 129.1, 127.6, 127.5, 125.3, 117.8, 69.0, 62.9, 53.2,
2.4, 51.7, 45.6. IR: 1740, 1697, 1598, 1496, 1287, 1232, 821, 756. HR-
for C H NO [M + H] 366.1342, found 366.1332. Light yellow oil.
2
1
19
5
1
ESI: calcd for C21
yellow oil.
H
18ClNO [M + H] 400.0951, found 400.0949. Light
5
Compound 3a′. H NMR (400 MHz, CDCl ): δ 7.88−7.83 (m,
H), 7.54 (td, J = 7.5, 1.3 Hz, 1H), 7.46−7.41 (m, 1H), 7.29 (td, J = 7.6,
.2 Hz, 1H), 7.15−7.07 (m, 2H), 6.80−6.71 (m, 3H), 5.51 (s, 1H),
.97 (d, J = 7.9 Hz, 1H), 4.26 (dd, J = 7.9, 5.4 Hz, 1H), 3.82 (s, 3H),
3
1
1
4
3
1
1
1
Compound 3e′. H NMR (400 MHz, CDCl ): δ 7.88−7.84 (m,
3
1
H), 7.55 (td, J = 7.5, 1.3 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.32 (td, J =
13
7.6, 1.1 Hz, 1H), 7.09−7.03 (m, 2H), 6.71−6.66 (m, 2H), 5.45 (s, 1H),
.69 (s, 3H), 3.63 (d, J = 5.4 Hz, 1H). C NMR (101 MHz, CDCl ): δ
3
4
3
.90 (d, J = 7.9 Hz, 1H), 4.24 (dd, J = 7.9, 5.4 Hz, 1H), 3.83 (s, 3H),
93.9, 172.1, 170.4, 145.0, 143.7, 134.9, 130.2, 129.4, 128.4, 127.2,
.69 (s, 3H), 3.63 (d, J = 5.4 Hz, 1H). 13C NMR (101 MHz, CDCl ): δ
26.0, 120.3, 116.6, 68.8, 63.3, 53.0, 52.7, 52.3, 47.6. Light yellow oil.
3
1
193.5, 172.0, 170.2, 143.7, 143.3, 135.0, 130.1, 129.3, 128.6, 127.3,
Compound 3b. Yield: 78% (14.7 mg). dr = 2.9/1. H NMR (400
1
26.0, 125.3, 117.8, 69.0, 63.5, 53.1, 52.8, 52.2, 47.6. Light yellow oil.
MHz, CDCl ): δ 7.90 (d, J = 7.7 Hz, 1H), 7.48 (t, J = 7.3 Hz, 1H), 7.30
(
6
(
3
1
5
3
1
Compound 3f. Yield: 71% (14.2 mg). dr = 2.7/1. H NMR (400
t, J = 7.5 Hz, 1H), 7.24 (d, J = 7.5 Hz, 1H), 6.91 (d, J = 8.2 Hz, 2H),
.67 (d, J = 8.4 Hz, 2H), 5.39 (d, J = 6.6 Hz, 1H), 4.96 (s, 1H), 4.23
MHz, CDCl ): δ 7.93 (d, J = 7.6 Hz, 1H), 7.51 (t, J = 7.2 Hz, 1H), 7.35
3
(
t, J = 7.5 Hz, 1H), 7.30−7.25 (m, 1H), 7.04 (t, J = 8.1 Hz, 1H), 6.79−
dd, J = 6.6, 6.3 Hz, 1H), 3.81 (s, 3H), 3.60 (d, J = 6.3 Hz, 1H), 3.55 (s,
H), 2.14 (s, 3H). 13C NMR (101 MHz, CDCl ): δ 194.6, 172.0, 170.1,
6.75 (m, 1H), 6.72 (d, J = 7.9 Hz, 1H), 6.64 (dd, J = 8.3, 1.6 Hz, 1H),
3
5
3
.39 (d, J = 6.6 Hz, 1H), 4.97 (s, 1H), 4.21 (dd, J = 6.6, 6.2 Hz, 1H),
.82 (s, 3H), 3.61 (d, J = 6.2 Hz, 1H), 3.56 (s, 3H). 13C NMR (101
42.6, 140.3, 134.2, 129.9, 129.9, 129.6, 128.8, 127.4, 116.5, 69.0, 62.9,
3.1, 52.3, 51.8, 45.7, 20.4. IR: 1737, 1694, 1515, 1176, 1014. HR-ESI:
MHz, CDCl ): δ 193.7, 171.8, 169.7, 146.2, 139.9, 135.2, 134.3, 130.4,
calcd for C H NO [M + H] 380.1498, found 380.1493. Light yellow
oil.
3
22
21
5
1
29.6, 129.1, 127.7, 127.4, 120.4, 116.6, 114.5, 68.8, 62.7, 53.2, 52.4,
1
51.7, 45.5. IR: 1738, 1698, 1594, 1483, 1435, 1287, 1234, 993, 758. HR-
ESI: calcd for C H ClNO [M + H] 400.0951, found 400.0948. Light
Compound 3b′. H NMR (400 MHz, CDCl ): δ 7.84 (d, J = 7.7 Hz,
3
1
(
1
3
(
1
2
H), 7.54 (td, J = 7.5, 1.2 Hz, 1H), 7.42 (d, J = 7.4 Hz, 1H), 7.33−7.27
m, 1H), 6.91 (d, J = 8.3 Hz, 2H), 6.66 (d, J = 8.5 Hz, 2H), 5.47 (s,
21 18
1
5
yellow oil.
Compound 3f′. H NMR (400 MHz, CDCl ): δ 7.88 (d, J = 7.6 Hz,
H), 4.93 (d, J = 7.9 Hz, 1H), 4.26 (dd, J = 7.9, 5.4 Hz, 1H), 3.82 (s,
3
H), 3.69 (s, 3H), 3.61 (d, J = 5.4 Hz, 1H), 2.14 (s, 3H). 13C NMR
1
7
7
H), 7.57 (dt, J = 7.5, 3.8 Hz, 1H), 7.44 (d, J = 7.4 Hz, 1H), 7.34 (t, J =
.6 Hz, 1H), 7.03 (t, J = 8.1 Hz, 1H), 6.77−6.74 (m, 1H), 6.72 (d, J =
.9 Hz, 1H), 6.63 (dd, J = 8.3, 2.0 Hz, 1H), 5.46 (s, 1H), 4.93 (d, J = 7.9
101 MHz, CDCl ): δ 194.2, 172.1, 170.5, 143.7, 142.6, 134.9, 130.2,
3
29.9, 129.6, 128.3, 127.1, 126.0, 116.6, 69.0, 63.4, 53.0, 52.7, 52.3, 47.6,
0.4. Light yellow oil.
Hz, 1H), 4.24 (dd, J = 7.9, 5.4 Hz, 1H), 3.83 (s, 3H), 3.70 (s, 3H), 3.62
(d, J = 5.3 Hz, 1H). C NMR (101 MHz, CDCl ): δ 193.3, 171.9,
170.2, 146.2, 143.3, 135.1, 135.1, 130.4, 130.0, 128.6, 127.4, 126.0,
120.4, 116.6, 114.6, 68.7, 63.2, 53.1, 52.8, 52.2, 47.6. Light yellow oil.
Compound 3g. Yield: 74% (14.2 mg). dr = 2.9/1. H NMR (400
1
13
Compound 3c. Yield: 81% (15.4 mg). dr = 3.0/1. H NMR (400
3
MHz, CDCl ): δ 7.91 (d, J = 7.6 Hz, 1H), 7.48 (t, J = 7.3 Hz, 1H), 7.31
(
6
6
(
1
1
1
3
3
t, J = 7.5 Hz, 1H), 7.27−7.23 (m, 1H), 6.99 (t, J = 7.8 Hz, 1H), 6.63−
1
.53 (m, 3H), 5.43 (d, J = 6.6 Hz, 1H), 4.99 (s, 1H), 4.22 (dd, J = 6.6,
.2 Hz, 1H), 3.81 (s, 3H), 3.60 (d, J = 6.2 Hz, 1H), 3.55 (s, 3H), 2.20
MHz, CDCl ): δ 7.91 (d, J = 7.6 Hz, 1H), 7.50 (t, J = 7.2 Hz, 1H), 7.34
3
s, 3H). 13C NMR (101 MHz, CDCl ): δ 194.4, 172.0, 170.0, 145.0,
(t, J = 7.5 Hz, 1H), 7.26−7.22 (m, 1H), 6.86−6.78 (m, 2H), 6.74−6.67
(m, 2H), 5.35 (d, J = 6.6 Hz, 1H), 4.93 (s, 1H), 4.23 (dd, J = 6.6, 6.3
3
40.3, 139.2, 134.2, 129.8, 129.2, 128.8, 127.5, 127.4, 121.3, 117.2,
13.6, 68.7, 62.7, 53.1, 52.3, 51.7, 45.7, 21.6. IR: 1739, 1697, 1603,
494, 1227, 1180, 775. HR-ESI: calcd for C H NO [M + H]
1
3
Hz, 1H), 3.82 (s, 3H), 3.61 (d, J = 6.3 Hz, 1H), 3.55 (s, 3H). C NMR
(101 MHz, CDCl ): δ 194.3, 172.0, 169.9, 157.0 (d, J = 239.7 Hz),
22
21
5
3
80.1498, found 380.1497. Light yellow oil.
141.4 (d, J = 2.3 Hz), 139.9, 134.3, 129.8, 129.0, 127.5, 127.5, 117.7 (d,
J = 7.7 Hz), 116.0 (d, J = 22.4 Hz), 69.3, 63.2, 53.1, 52.3, 51.8, 45.7. IR:
1740, 1697, 1509, 1436, 1230, 826, 756. HR-ESI: calcd for
C H FNO [M + H] 384.1247, found 384.1239. Light yellow oil.
1
Compound 3c′. H NMR (400 MHz, CDCl ): δ 7.86 (d, J = 7.6 Hz,
3
1
1
H), 7.54 (t, J = 7.3 Hz, 1H), 7.46−7.40 (m, 1H), 7.30 (t, J = 7.5 Hz,
H), 6.99 (t, J = 7.8 Hz, 1H), 6.63−6.53 (m, 3H), 5.50 (s, 1H), 4.96 (d,
21
18
5
E
DOI: 10.1021/acs.joc.5b00717
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1
Compound 3g′. H NMR (400 MHz, CDCl ): δ 7.86 (d, J = 7.7 Hz,
5.45 (s, 1H), 4.91 (d, J = 7.8 Hz, 1H), 4.22 (dd, J = 7.7, 5.5 Hz, 1H),
3.86 (s, 3H), 3.82 (s, 3H), 3.70 (s, 3H), 3.63 (d, J = 5.4 Hz, 1H). C
3
1
3
1
H), 7.56 (t, J = 7.5 Hz, 1H), 7.42 (d, J = 7.5 Hz, 1H), 7.32 (t, J = 7.6
Hz, 1H), 6.86−6.78 (m, 2H), 6.75−6.67 (m, 2H), 5.43 (s, 1H), 4.88 (d,
J = 7.9 Hz, 1H), 4.25 (dd, J = 7.8, 5.4 Hz, 1H), 3.83 (s, 3H), 3.69 (s,
3
1
1
2
NMR (101 MHz, CDCl ): δ 192.6, 172.2, 170.5, 164.8, 146.1, 145.1,
3
129.8, 129.3, 123.3, 120.3, 116.6, 114.0, 111.0, 68.7, 63.5, 55.6, 53.0,
52.7, 52.2, 47.9. Light yellow oil.
H), 3.63 (d, J = 5.3 Hz, 1H). 13C NMR (101 MHz, CDCl ): δ 193.9,
3
1
72.1, 170.4, 157.0 (d, J = 239.6 Hz), 143.3 (d, J = 2.3 Hz), 141.3,
35.0, 130.1, 128.5, 127.2, 126.1, 117.8 (d, J = 7.7 Hz), 116.0 (d, J =
2.5 Hz), 69.3, 63.7, 53.1, 52.8, 52.3, 47.7. Light yellow oil.
Compound 3l. Yield: 74% (14.2 mg). dr = 2.4/1. H NMR (400
MHz, CDCl ): δ 7.56 (dd, J = 8.4, 2.6 Hz, 1H), 7.29−7.23 (m, 1H),
3
7.20−7.16 (m, 1H), 7.15−7.09 (m, 2H), 6.81−6.71 (m, 3H), 5.44 (d, J
= 6.6 Hz, 1H), 5.01 (s, 1H), 4.22 (dd, J = 6.6, 6.2 Hz, 1H), 3.80 (s, 3H),
1
Compound 3h. Yield: 82% (17.8 mg). dr = 2.6/1. H NMR (400
MHz, CDCl ): δ 7.93 (d, J = 7.6 Hz, 1H), 7.52 (t, J = 7.3 Hz, 1H), 7.35
3.59 (d, J = 6.2 Hz, 1H), 3.56 (s, 3H). 13C NMR (101 MHz, CDCl ): δ
3
3
(
t, J = 7.5 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.25−7.19 (m, 1H), 7.04−
193.4, 171.8, 169.9, 162.5 (d, J = 249.9 Hz), 144.8, 136.2 (d, J = 3.4
Hz), 131.9 (d, J = 6.6 Hz), 129.5, 128.1, 121.3 (d, J = 22.3 Hz), 120.6,
116.5, 114.0 (d, J = 22.5 Hz), 68.4, 62.2, 53.2, 52.4, 51.7, 45.5. IR: 1740,
1704, 1599, 1499, 1267, 1231, 754. HR-ESI: calcd for C H FNO [M
6
1
1
1
1
.95 (m, 2H), 6.92 (d, J = 8.2 Hz, 1H), 5.45 (d, J = 6.6 Hz, 1H), 5.03 (s,
H), 4.23 (dd, J = 6.6, 6.2 Hz, 1H), 3.83 (s, 3H), 3.64 (d, J = 6.2 Hz,
H), 3.57 (s, 3H). 13C NMR (101 MHz, CDCl ): δ 193.5, 171.8, 169.6,
3
21 18
5
45.5, 139.8, 134.4, 131,7 (q, J = 32.1 Hz), 130.0, 129.6, 129.2,
27.8,127.4, 123.9 (q, J = 272.5 Hz), 119.3, 116.9 (q, J = 3.8 Hz), 112.9
m), 68.9, 62.8, 53.2, 52.4, 51.8, 45.6. IR: 1723, 1455, 1378, 1167, 1124,
+ H] 384.1247, found 384.1242. Light yellow oil.
1
Compound 3l′. H NMR (400 MHz, CDCl ): δ 7.51 (dd, J = 8.4,
3
(
2.6 Hz, 1H), 7.43 (dd, J = 8.3, 4.8 Hz, 1H), 7.23 (td, J = 8.4, 2.7 Hz,
1H), 7.15−7.08 (m, 2H), 6.79−6.70 (m, 3H), 5.52 (s, 1H), 4.96 (d, J =
7.9 Hz, 1H), 4.26 (dd, J = 7.9, 5.3 Hz, 1H), 3.82 (s, 3H), 3.70 (s, 3H),
1
070, 759, 697. HR-ESI: calcd for C H F NO [M + H] 434.1215,
22 18 3 5
found 434.1217. Light yellow oil.
1
13
Compound 3h′. H NMR (400 MHz, CDCl ): δ 7.89−7.85 (m,
3.60 (d, J = 5.3 Hz, 1H). C NMR (101 MHz, CDCl ): δ 193.1, 171.9,
3
3
1
7
6
5
H), 7.57 (td, J = 7.5, 1.3 Hz, 1H), 7.46 (d, J = 7.4 Hz, 1H), 7.33 (td, J =
.6, 1.1 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 7.02−6.97 (m, 2H), 6.94−
.89 (m, 1H), 5.51 (s, 1H), 5.00 (d, J = 7.9 Hz, 1H), 4.26 (dd, J = 7.9,
170.4, 162.2 (d, J = 249.1 Hz), 144.7, 139.6 (d, J = 3.3 Hz), 132.2 (d, J =
6.6 Hz), 129.5, 128.1 (d, J = 7.4 Hz), 121.9 (d, J = 22.4 Hz), 120.6,
116.5, 113.7 (d, J = 22.5 Hz), 68.3, 62.7, 53.1, 52.8, 52.3, 47.5. Light
yellow oil.
.4 Hz, 1H), 3.84 (s, 3H), 3.70 (s, 3H), 3.65 (d, J = 5.3 Hz, 1H). 13
C
NMR (101 MHz, CDCl ): δ 193.1, 171.9, 170.1, 145.4, 143.3, 135.1,
Compound 3m and 3m′. Yield: 73% (14.0 mg). dr = 2.5/1.
3
1
1
2
5
32.7 (q, J = 32.0 Hz), 130.0, 129.9, 128.7, 127.5, 126.0, 123.8 (q, J =
72.5 Hz), 119.4, 116.9 (q, J = 3.6 Hz), 113.0 (m), 68.9, 63.2, 53.1,
2.8, 52.2, 47.6. Light yellow oil.
Compound 3m. H NMR (400 MHz, CDCl ): δ 7.94 (dd, J = 8.4, 5.7
3
Hz, 1H), 7.18−7.07 (m, 2H), 7.04−6.91 (m, 2H), 6.87−6.68 (m,
3H),5.41 (d, J = 6.7 Hz, 1H), 4.99 (s, 1H), 4.25 (dd, J = 6.7, 6.4 Hz,
1
Compound 3i. Yield: 84% (16.0 mg). dr = 2.8/1. H NMR (400
1H), 3.81 (s, 3H), 3.61 (d, J = 6.4 Hz, 1H), 3.60 (s, 3H). Compound
1
MHz, CDCl ): δ 7.79 (d, J = 7.9 Hz, 1H), 7.16−7.08 (m, 3H), 7.06−
3m′: H NMR (400 MHz, CDCl ): δ 7.89 (dd, J = 8.6, 5.6 Hz, 1H),
3
3
7
1
1
1
1
1
3
.01 (m, 1H), 6.81−6.69 (m, 3H), 5.38 (d, J = 6.6 Hz, 1H), 4.97 (s,
H), 4.22 (dd, J = 6.6, 6.2 Hz, 1H), 3.80 (s, 3H), 3.60 (d, J = 6.2 Hz,
7.60−7.54 (m, 1H), 7.54−7.49 (m, 1H), 7.18−7.07 (m, 1H), 7.01−
7.01 (m, 1H), 6.87−6.68 (m, 3H), 5.49 (s, 1H), 4.95 (d, J = 7.9 Hz,
1H), 4.25 (m, 1H), 3.82 (s, 3H), 3.70 (s, 3H), 3.65−3.55 (m, 1H).
H), 3.55 (s, 3H), 2.35 (s, 3H). 13C NMR (101 MHz, CDCl ): δ 194.2,
3
13
72.1, 170.0, 145.4, 145.1, 140.3, 129.7, 129.4, 128.0, 127.6, 127.4,
20.3, 116.5, 68.8, 62.8, 53.1, 52.2, 51.8, 45.8, 21.9. IR: 1739, 1694,
606, 1497, 1233, 757. HR-ESI: calcd for C H NO [M + H]
Mixture of 3m and 3m′. C NMR (101 MHz, CDCl ): δ 192.9, 192.4,
3
171.8, 171.8, 170.4, 169.8, 166.5 (d, J = 258.6 Hz), 166.0 (d, J = 258.3
Hz), 146.8 (d, J = 8.1 Hz), 144.8, 144.7, 143.5 (d, J = 8.1 Hz), 130.7 (d,
J = 9.8 Hz), 130.4 (d. J = 9.9 Hz), 129.5, 129.5, 126.8 (d, J = 2.8 Hz),
126.4 (d, J = 3.0 Hz), 120.6, 120.6, 116.6, 116.5, 116.3 (d, J = 22.0 Hz),
115.9 (d, J = 22.0 Hz), 114.6 (d, J = 22.3 Hz), 113.2 (d, J = 22.2 Hz),
68.7, 68.6, 63.1, 62.6, 53.1, 53.1, 52.8, 52.4, 52.1, 51.7, 47.7, 45.7. IR:
1739, 1698, 1606, 1497, 1436, 1260, 758. HR-ESI: calcd for
C H FNO [M + H] 384.1247, found 384.1238. Light yellow oil.
22
21
5
80.1498, found 380.1496. Light yellow oil.
1
Compound 3i′. H NMR (400 MHz, CDCl ): δ 7.74 (d, J = 7.9 Hz,
3
1
H), 7.23−7.21 (m, 1H), 7.14−7.06 (m, 3H), 6.79−6.71 (m, 3H), 5.45
(
s, 1H), 4.93 (d, J = 7.9 Hz, 1H), 4.24 (dd, J = 7.9, 5.4 Hz, 1H), 3.82 (s,
3
(
H), 3.69 (s, 3H), 3.61 (d, J = 5.4 Hz, 1H), 2.38 (s, 3H). 13C NMR
101 MHz, CDCl ): δ 193.7, 172.2, 170.5, 146.1, 145.1, 143.8, 129.3,
3
21 18
5
1
1
2
29.3, 127.8, 127.3, 126.5, 120.3, 116.6, 68.8, 63.4, 53.0, 52.7, 52.3, 47.7,
2.0. Light yellow oil.
Compound 3j. Yield: 88% (16.7 mg). dr = 2.9/1. H NMR (400
Compound 3n. Yield: 38% (7.8 mg). dr = 2.1/1. H NMR (400
MHz, CDCl ): δ 7.30 (s, 1H), 7.17−7.10 (m, 2H), 6.80−6.73 (m, 3H),
3
1
6.68 (s, 1H), 6.02−5.94 (m, 2H), 5.34 (d, J = 6.5 Hz, 1H), 4.93 (s, 1H),
4.19 (dd, J = 6.5, 6.2 Hz, 1H), 3.80 (s, 3H), 3.63 (s, 3H), 3.57 (d, J = 6.2
MHz, CDCl ): δ 7.70 (s, 1H), 7.31−7.22 (m, 1H), 7.16−7.08 (m, 3H),
3
6
6
2
1
6
1
3
.79−6.71 (m, 3H), 5.40 (d, J = 6.6 Hz, 1H), 4.99 (s, 1H), 4.20 (dd, J =
Hz, 1H). 13C NMR (101 MHz, CDCl ): δ 192.9, 172.0, 170.0, 152.8,
3
.6, 6.4 Hz, 1H), 3.81 (s, 3H), 3.60 (d, J = 6.4 Hz, 1H), 3.57 (s, 3H),
148.2, 145.0, 137.1, 129.4, 124.7, 120.4, 116.6, 107.3, 106.8, 102.0, 68.5,
62.9, 53.1, 52.4, 51.7, 45.8. IR: 1738, 1682, 1600, 1498, 1479, 1300,
1261, 1035. HR-ESI: calcd for C H NO [M + H] 410.1239, found
.28 (s, 3H). 13C NMR (101 MHz, CDCl ): δ 194.7, 172.1, 170.1,
3
45.1, 138.8, 137.3, 135.0, 129.6, 129.4, 127.9, 127.3, 120.3, 116.5, 68.8,
2.5, 53.1, 52.3, 51.7, 45.7, 21.2. IR: 1739, 1697, 1598, 1499, 1233,
175, 755. HR-ESI: calcd for C H NO [M + H] 380.1498, found
22
19
7
410.1230. Light yellow oil.
1
Compound 3n′. H NMR (400 MHz, CDCl ): δ 7.27−7.24 (m,
22
21
5
3
80.1488. Light yellow oil.
1H), 7.13 (t, J = 7.8 Hz, 2H), 6.85 (s, 1H), 6.81−6.71 (m, 3H), 5.97 (d,
J = 6.4 Hz, 2H), 5.42 (s, 1H), 4.90 (d, J = 7.8 Hz, 1H), 4.21 (dd, J = 7.7,
5.4 Hz, 1H), 3.81 (s, 3H), 3.70 (s, 3H), 3.59 (d, J = 5.2 Hz, 1H). C
1
Compound 3j′. H NMR (400 MHz, CDCl ): δ 7.65 (s, 1H), 7.36−
3
1
3
7
4
3
.30 (m, 2H), 7.15−7.06 (m, 2H), 6.80−6.70 (m, 3H), 5.48 (s, 1H),
.95 (d, J = 7.9 Hz, 1H), 4.25 (dd, J = 7.8, 5.4 Hz, 1H), 3.81 (s, 3H),
NMR (101 MHz, CDCl ): δ 192.1, 172.1, 170.5, 153.3, 147.9, 145.0,
3
13
.70 (s, 3H), 3.60 (d, J = 5.2 Hz, 1H), 2.28 (s, 3H). C NMR (101
140.8, 129.4, 125.0, 120.4, 116.7, 106.4, 106.0, 102.0, 68.5, 63.5, 53.0,
MHz, CDCl ): δ 194.3, 172.2, 170.6, 145.1, 140.9, 138.3, 135.7, 129.9,
52.7, 52.2, 47.6. Light yellow oil.
Compound 3o. Yield: 79% (15.6 mg). dr = 3.2/1. H NMR (400
3
1
1
29.3, 127.5, 126.0, 120.2, 116.6, 68.8, 63.0, 53.0, 52.7, 52.3, 47.6, 21.1.
Light yellow oil.
MHz, CDCl ): δ 7.91 (d, J = 7.6 Hz, 1H), 7.47 (dd, J = 7.5, 6.6 Hz,
3
1
Compound 3k. Yield: 72% (14.2 mg). dr = 2.4/1. H NMR (400
1H), 7.36−7.27 (m, 2H), 7.12 (t, J = 7.9 Hz, 2H), 6.82−6.69 (m, 3H),
5.43 (d, J = 6.6 Hz, 1H), 5.00 (s, 1H), 4.32−4.17 (m, 3H), 4.08−3.87
(m, 2H), 3.59 (d, J = 6.2 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H), 1.16 (t, J =
MHz, CDCl ): δ 7.87 (d, J = 8.6 Hz, 1H), 7.16−7.09 (m, 2H), 6.81−
3
6
1
4
1
5
.74 (m, 4H), 6.74−6.70 (m, 1H), 5.37 (d, J = 6.6 Hz, 1H), 4.94 (s,
H), 4.22 (t, J = 6.5 Hz, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 3.57−3.62 (m,
7.1 Hz, 3H). 13C NMR (101 MHz, CDCl ): δ 194.5, 171.6, 169.5,
3
H). 13C NMR (101 MHz, CDCl ): δ 193.3, 172.1, 167.0, 164.3, 145.1,
42.6, 130.1, 129.4, 123.0, 120.3, 116.5, 113.9, 113.0, 68.7, 63.0, 55.6,
3.1, 52.3, 51.8, 45.9. IR: 1737, 1683, 1599, 1496, 1264. HR-ESI: calcd
145.1, 140.3, 134.0, 129.9, 129.4, 128.8, 127.7, 127.5, 120.3, 116.5, 69.0,
62.8, 62.1, 61.4, 51.8, 45.8, 14.2, 14.1. IR: 1733, 1694, 1599, 1498, 1183,
1029. HR-ESI: calcd for C H NO [M + H] 394.1655, found
3
23
23
5
for C H NO [M + H] 396.1447, found 396.1439. Light yellow oil.
394.1647. Light yellow oil.
Compound 3o′. H NMR (400 MHz, CDCl ): δ 7.87−7.82 (m,
1H), 7.53 (td, J = 7.5, 1.4 Hz, 1H), 7.45−7.40 (m, 1H), 7.28 (td, J = 7.6,
22
21
6
1
1
Compound 3k′. H NMR (400 MHz, CDCl ): δ 7.82 (d, J = 8.6 Hz,
3
3
1
H), 7.15−7.08 (m, 2H), 6.88 (d, J = 2.2 Hz, 1H), 6.81−6.71 (m, 4H),
F
DOI: 10.1021/acs.joc.5b00717
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1
1
4
.2 Hz, 1H), 7.14−7.07 (m, 2H), 6.80−6.76 (m, 2H), 6.76−6.70 (m,
H), 5.50 (s, 1H), 4.97 (d, J = 7.9 Hz, 1H), 4.31−4.21 (m, 2H), 4.17−
.08 (m, 2H), 3.60 (d, J = 5.3 Hz, 1H), 1.33 (t, J = 7.1 Hz, 3H), 1.24 (t,
L. J. Am. Chem. Soc. 2009, 131, 8394. (i) Ye, L.; He, W.; Zhang, L. J. Am.
Chem. Soc. 2010, 132, 8550. (j) Ji, K.; Zheng, Z.; Wang, Z.; Zhang, L.
Angew. Chem., Int. Ed. 2015, 54, 1245.
(4) (a) Lu, B.; Li, Y.; Wang, Y.; Aue, D. H.; Luo, Y.; Zhang, L. J. Am.
Chem. Soc. 2013, 135, 8512. (b) Shapiro, N. D.; Toste, F. D. J. Am.
Chem. Soc. 2007, 129, 4160. (c) Li, G.; Zhang, L. Angew. Chem., Int. Ed.
2007, 46, 5156.
(5) (a) Li, G.-H.; Zhou, W.; Li, X.-X.; Bi, Q.-W.; Wang, Z.; Zhao, Z.-
G.; Hu, W.-X.; Chen, Z. Chem. Commun. 2013, 49, 4770. (b) Wang, L.;
Xie, X.; Liu, Y. Org. Lett. 2012, 14, 5848. (c) Qian, Y.; Xu, X.; Wang, X.;
Zavalij, P. J.; Hu, W.; Doyle, M. P. Angew. Chem., Int. Ed. 2012, 51,
5900. (d) Bhunia, S.; Chang, C.-J.; Liu, R.-S. Org. Lett. 2012, 14, 5522.
(e) Song, G.; Chen, D.; Su, Y.; Han, K.; Pan, C.-L.; Jia, A.; Li, X. Angew.
Chem., Int. Ed. 2011, 50, 7791. (f) Chen, D.; Song, G.; Jia, A.; Li, X. J.
Org. Chem. 2011, 76, 8488. (g) Yeom, H.-S.; Lee, Y.; Lee, J.-E.; Shin, S.
Org. Biomol. Chem. 2009, 7, 4744. (h) Pati, K.; Liu, R.-S. Chem.
Commun. 2009, 5233. (i) Yeom, H. S.; Lee, J. E.; Shin, S. Angew. Chem.,
Int. Ed. 2008, 47, 7040. (j) Jeong, J.; Yeom, H.-S.; Kwon, O.; Shin, S.
Chem. - Asian J. 2011, 6, 1977.
13
J = 7.1 Hz, 3H). C NMR (101 MHz, CDCl ): δ 193.8, 171.7, 167.0,
1
6
3
45.1, 143.9, 134.8, 130.4, 129.3, 128.3, 127.1, 126.0, 120.2, 116.5, 68.9,
3.3, 62.0, 61.8, 52.4, 47.6, 14.3, 14.1. Light yellow oil.1
Compound 3p. Yield: 84% (13.9 mg). dr = 2.4/1. H NMR (400
MHz, CDCl ): δ 7.83 (d, J = 7.7 Hz, 1H), 7.51 (td, J = 7.5, 1.3 Hz, 1H),
3
7
2
.37 (d, J = 7.4 Hz, 1H), 7.28 (td, J = 7.6, 1.0 Hz, 1H), 7.18−7.11 (m,
H), 6.82−6.75 (m, 3H), 5.48 (d, J = 6.9 Hz, 1H), 5.06 (dd, J = 8.5, 0.7
13
Hz, 1H), 4.20−4.07 (m, 2H), 2.44 (s, 3H). C NMR (101 MHz,
CDCl ): δ 192.0, 174.1, 174.0, 144.7, 139.1, 134.7, 130.5, 129.6, 129.0,
3
1
1
28.3, 127.1, 120.9, 116.4, 67.1, 61.5, 50.3, 46.4, 24.4. IR: 1713, 1599,
498, 1433, 1381, 1282, 1212, 994, 755. HR-ESI: calcd for C H N O
3
2
0
16
2
[
M + H] 333.1239, found 333.1231. Light yellow oil.
1
Compound 3p′. H NMR (400 MHz, CDCl ): δ 7.95−7.90 (m,
3
1
1
4
3
1
4
H), 7.58 (td, J = 7.5, 1.4 Hz, 1H), 7.51−7.47 (m, 1H), 7.34 (td, J = 7.6,
.2 Hz, 1H), 7.14−7.07 (m, 2H), 6.79−6.73 (m, 3H), 5.43 (s, 1H),
.94 (s, 1H), 3.43 (d, J = 7.5 Hz, 1H), 3.36 (d, J = 7.5 Hz, 1H), 3.05 (s,
H). 13C NMR (101 MHz, CDCl ): δ 193.2, 176.2, 175.6, 144.5, 142.4,
3
(6) (a) Cikotiene, I. Eur. J. Org. Chem. 2012, 2012, 2766. (b) Patel, P.;
Ramana, C. V. Org. Biomol. Chem. 2011, 9, 7327. (c) Soderberg, B. C.
̈
G.; Gorugantula, S. P.; Howerton, C. R.; Petersen, J. L.; Dantale, S. W.
Tetrahedron 2009, 65, 7357. (d) Asao, N.; Sato, K.; Yamamoto, Y.
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D.; Dorey, G.; Casara, P.; Spedding, M.; Halpern, H. J. J. Org. Chem.
35.3, 129.5, 129.3, 128.9, 127.7, 126.4, 120.9, 116.9, 68.7, 63.0, 52.4,
6.0, 25.8. Light yellow oil.
ASSOCIATED CONTENT
■
* Supporting Information
S
2
000, 65, 4460. (f) Ramana, C. V.; Patel, P.; Vanka, K.; Miao, B.;
Degterev, A. Eur. J. Org. Chem. 2010, 2010, 5955.
7) (a) Nakamura, I.; Terada, M. Heterocycles 2014, 89, 845.
b) Wang, Y.; Zhang, L. Synthesis 2015, 47, 289. (c) Zhang, L. Acc.
Chem. Res. 2014, 47, 877. (d) Yeom, H.-S.; Shin, S. Acc. Chem. Res.
014, 47, 966. (e) Xiao, J.; Li, X. Angew. Chem., Int. Ed. 2011, 50, 7226.
8) (a) Hamer, J.; Macaluso, A. Chem. Rev. 1964, 64, 473.
b) Tufariello, J. J. Acc. Chem. Res. 1979, 12, 396. (c) Freeman, J. P.
Chem. Rev. 1983, 83, 241.
9) (a) Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98, 863.
b) Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765. (c) Harwood,
NMR spectra and X-ray data for compound 3n (CIF). The
Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.joc.5b00717. Crys-
tallographic data for compound 3n (CCDC-1401612) can be
obtained free of charge from the Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(
(
2
(
(
AUTHOR INFORMATION
■
(
Corresponding Author
(
*
E-mail: hanzy2014@ustc.edu.cn.
L. M.; Vickers, R. J. In Synthetic Applications of 1,3-Dipolar Cycloaddition
Chemistry Toward Heterocycles and Natural Products; John Wiley &
Sons, Inc.: New York, 2003; p 169. (d) Adrio, J.; Carretero, J. C. Chem.
Commun. 2011, 47, 6784.
(10) Actually, this type of azomethine ylides, namely the 4-
oxidoisoquinolinium betaines, were previously synthesized and studied
as dipolar agents by Katritzky and others. (a) Dennis, N.; Katritzky, A.
R.; Takeuchi, Y. J. Chem. Soc., Perkin Trans. 1 1972, 2054. (b) Dennis,
N.; Ibrahim, B.; Katritzky, A. R.; Takeuchi, Y. J. Chem. Soc., Chem.
Commun. 1973, 292a. (c) Undheim, K.; Hansen, P. E. Chem. Scripta
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the Fundamental
Research Funds for the Central Universities (WK2060190041).
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DOI: 10.1021/acs.joc.5b00717
J. Org. Chem. XXXX, XXX, XXX−XXX