Umpolung Strategy for Synthesis of β-Ketonitriles through Hypervalent Iodine-Promoted Cyanation of Silyl Enol Ethers

Article abstract of DOI:10.1021/acs.joc.5b01102

An efficient method to synthesize β-ketonitriles from silyl enol ethers by an umploung hypervalent iodine(III)-CN species generated in situ from PhIO/BF₃·Et₂O/TMSCN has been developed for the first time. This method can be applied to structurally diverse aromatic and aliphatic substrates and further extended to preparation of bioactive compounds like 5-aminopyrazole and 5-aminoisoxazole.

Full text of DOI:10.1021/acs.joc.5b01102

Subscriber access provided by NEW YORK UNIV
Article
An Umpolung Strategy for Synthesis of beta-Ketonitriles through
Hypervalent Iodine-Promoted Cyanation of Silyl Enol Ethers
Hang Shen, Jiaqiang Li, Qing Liu, Jing Pan, Ruofeng Huang, and Yan Xiong
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 11 Jun 2015
Downloaded from http://pubs.acs.org on June 12, 2015
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
An Umpolung Strategy for Synthesis of β-Ketonitriles
through Hypervalent Iodine-Promoted Cyanation of Silyl
Enol Ethers
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Hang Shen,† Jiaqiang Li,† Qing Liu,† Jing Pan,† Ruofeng Huang,† and Yan Xiong*,†,‡
† School of Chemistry and Chemical Engineering, Chongqing University, Chongqing
400044, China
‡ State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin
300071, China
Email: xiong@cqu.edu.cn
ABSTRACT: An efficient method to synthesize β-ketonitriles from silyl enol ethers
by an umploung hypervalent iodine(III)-CN species generated in situ from
PhIO/BF3•Et2O/TMSCN has been developed for the first time. This method can be
applied to structurally diverse aromatic and aliphatic substrates and further extended
to preparation of bioactive compounds like 3-aminopyrazole and 3-aminoisoxazole.
INTRODUCTION
β-Ketonitriles are important intermediates to synthesize different
biologically
and
pharmacologically
active
heterocycles
including
aminopyrazoles,1 aminoisoxazoles,2 imidazoles,3 furans,4 thiophenes,5
2-pyridones6 and triazoles.7 Owing to their importance, a variety of methods
have been developed to access β-ketonitriles, such as coupling of acetonitriles
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 21
1
2
3
4
5
6
7
8
9
with esters,8 cyanide displacement reaction with α-bromo ketones,9 C-arylation
of resin-bound cyanoacetates,10 indium-mediated coupling of bromoacetonitriles
with aromatic acyl cyanides,11 Pd-catalyzed carbonylation of aryliodides with
trimethylsilylacetonitrile,12 transformation of enaminones via isoxazoles13 and
kinetic cyanations of ketone enolates using p-toluenesulfonyl cyanide (TsCN).14
Regardless of these progress, the development of direct α-cyanation of ketones
and their reactive enolates is still highly expected.15,16
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Design of Cyanation for Synthesis of β-Ketonitriles
Tautomerism of carbonyl compounds to more reactive enolates and their
derivatives such as silyl enol ethers made them preferable to serve as versatile
nucleophiles to react with different electrophiles.17 Recently, hypervalent iodine
reagents have been paid much attentions owing to their low toxicity, commercial
availability as well as environmental friendliness.18 Chen and Guo et. al. reported
trifluoromethylation of silyl enol ethers using Togni’s reagent through a free
radical addition in 2014 (Eq. 1, Scheme 1).19 This inspired us to design
cyanobenziodoxole (1a)-promoted cyanation to synthesize β-ketonitriles from
silyl enol ethers. However, 1a resulted in the failure of direct cyanation
companied with generation of 1,4-diketone (55% yield, R' = Ph and R'', R''' = H)
ACS Paragon Plus Environment

Page 3 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
through oxidative α-C slef-coupling of ketone (Eq. 2). After much literature
review, we found that hypervalent iodine reagents have been already used to
achieve umpolung of silyl enol ethers, on the basis of their high electrophilicity.20
Umpolung or polarity inversion of silyl enol ethers exactly provides an
alternative way to get target molecules that are hardly synthesized using routine
methods (Figure 1).21 The combination of trimethylsilyl cyanide (TMSCN) with
bis(trifluoracetoxy)iodobenzene (PIFA) or iodosobenzene (PhIO) have been
reported about in situ prepared hypervalent iodine(III)-CN intermediates, which
were already utilized to accomplish cyanation of heteroaromatics.22 So we
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
further
attempted
PIFA/TMSCN
and
and
PhIO/TMSCN
as
systems
to
(β-styryloxy)trimethylsilane,
fortunately
envisioned,
3-oxo-3-phenylpropanenitrile was assembled. It was also observed that direct
α-cyanation of acetophenone failed in our studies (Eq. 3).
Figure 1. Pathways of Cyanation to β-Ketonitrile.
RESULTS AND DISCUSSION
The optimization studies for cyanation were initiated by using
(β-styryloxy)trimethylsilane as model substrate, which was prepared freshly
from corresponding ketone in the presence of trimethylsilyl chloride, sodium
iodide and triethylamine, and trimethylsilyl cyanide (TMSCN) as cyanide source
along with hypervalent iodine reagents 1a-d as oxidants in CHCl3. As shown in
Table 1, the efficiencies of various hypervalent iodine reagents were firstly
examined, cyanobenziodoxole 1a and (diacetoxyiodo)benzene 1b did not furnish
the desired product (entries 1 and 2), while iodosobenzene 1d was proved to be
most effective and bis(trifluoracetoxy)iodobenzene 1c only gave a trace of
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 21
1
2
3
4
5
6
7
8
9
desired product (entries 3 and 4), where hypervalent iodines (except 1a) were
premixed with BF3•Et2O and TMSCN for preactivation of 40 min before adding
(β-styryloxy)trimethylsilane. Without BF3•Et2O, 1d was disabled to this
transformation (entry 5). Different amounts of 1d were then investigated and as
a result, 1.6 equivalents was found to be the most suitable (entries 6-7). The
reaction was also found to be sensitive to the solvent, and CH3CN afforded the
best result than others, including CHCl3, CH2Cl2, DCE, THF as well as DMF (entries
8-12).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Screening Oxidants and Solventsa
Entry
1
Solvent
DMF
BF3•Et2O (eq.)
Oxidant (eq.)
1a/1.2
TMSCN (eq.)
Yield (%)b
0
2
2
2
0
2
2
2
2
2
2
2
-
0c
0
2
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
DCE
1b/1.2
1c/1.2
3
3
3
3
3
3
3
3
3
3
3
3
trace
43
0
4
1d/1.2
1d/1.2
1d/1.6
1d/2.0
1d/1.6
1d/1.6
1d/1.6
1d/1.6
1d/1.6
5
6
60
50
48
56
19
78
48
7
8
9
10
11
12
THF
CH3CN
DMF
a
Reaction conditions: (β-styryloxy)trimethylsilane (0.5 mmol), oxidant (specified), TMSCN
ACS Paragon Plus Environment

Page 5 of 21
The Journal of Organic Chemistry
1
2
3
4
o
b
c
(specified), BF3•Et2O (specified), and solvent (3.0 mL) at -30 C for 3 h. Isolated yields.
5
6
7
8
BF3•Et2O was replaced by CuI at rt for 3 h, the same conditions for trifluoromethylation referred
to lit. 19. DCE = 1,2-dichloroethane.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Other influencing factors of the reaction such as amounts of TMSCN and
BF3•Et2O, preacitivation time and reaction concentration were then examined, with
results depicted in Table 2. Fixing 2.0 equivalents of BF3•Et2O, different amount of
TMSCN was screened and as a result, 3.0 equivalents of TMSCN was proved to be
most beneficial (Table 2, entries 1-3). With 3.0 equivalents of TMSCN, further
decreasing the amount of BF3•Et2O to 1.7 equivalents provided the best yield of 79%
(Table 2, entries 4-5). Preactivation time of 1d with BF3•Et2O and TMSCN, and
reaction time were also investigated, the results showed that either prolonging or
shortening preactivation and reaction time was unbeneficial to this reaction (entries
6-9). Increase or decrease of the concentration through adjusting amount of CH3CN
was found to be detrimental to this cyanation (entries 10-11). Moreover, a coupling
product 1,4-diketone 4 was generated when using CuCN as cyanide source, where the
yield is higher than the reported (Scheme 2).20a
Table 2. Optimization of Reaction Conditionsa
Entry
BF3•Et2O (eq.)
TMSCN (eq.)
Yield (%)b
1
2
3
4
5
6
7
2
3
2.5
3.5
3
78
56
2
2
78
1.7
1.5
1.7
1.7
79
3
65
3
56c
77d
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 21
1
2
3
4
5
6
7
8
9
8
9
1.7
1.7
1.7
1.7
3
3
3
3
60e
70f
69g
77h
10
11
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
Reaction conditions: (β-styryloxy)trimethylsilane (0.5 mmol), PhIO (0.8 mmol), TMSCN
b
(specified), BF3•Et2O (specified) and CH3CN (3.0 mL) at -30 °C for 3 h. Isolated yields.
cPreactivation for 0 hour. Preactivation for 1 hour. 4 h of reaction time. 2 h of reaction
d
e
f
time. g 4 mL of CH3CN. h 2mL of CH3CN.
Scheme 2. An Approach to 1,4-Diketone
With the optimal conditions in hand, we then generalized the protocol
developed for the oxidative cyanation. As described in Table 3, the reactions of
different silyl enol ethers bearing either electron-donating substituents, such as
methyl and methoxyl, or electron-withdrawing substituents, like halogen and
ester, on aromatic ring gave the corresponding cyanated products in moderate to
good isolated yields (3a-l). Meta-substituents and para-substituents were found
to be more favorable than ortho-substituents (3b-c vs 3d, 3i-j vs 3k) and the
ability of withdrawing electron of groups didn’t influence the reaction with
regularity (3f-i). In addition, heteroaryl-containing compounds were converted
into the corresponding β-ketonitriles in moderate yields (3m-n) and
naphthalene-containing substrate also led to 45% yield (3o). It is worthy to note
that cinnamyl-containing and aliphatic substrates smoothly afforded the
cyanation products with up to 76% yield (3p-r), and only terminal cyano
products were detected (also see Scheme 3). Likewise, silyl enol ether of
propiophenone 2s did not gave the desired cyanation product using this method,
whereas a highly substituted oxazole was produced when switching the feeding
order, namely adding TMSCN immediately after the mixture of PhIO, BF3•Et2O
and silyl enol ether in sequence, where the solvent CH3CN was involved into the
ACS Paragon Plus Environment

Page 7 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
reaction.23 However, the same procedure to 2a generated 3a in 60% yield as a
major product with relatively small amounts of oxazole 6 in 22%, which
suggested the early interaction of hypervalent iodine and solvent CH3CN before
TMSCN (Scheme 4).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 3. Substrate Scope a
3a, 79%
3d, 46%
3b, 60%
3e, 64%
3c, 60%
3f, 68%
3g, 35%
3h, 76%
3i, 39%
3j, 39%
3k, 30%
3n, 53%
3l, 35%
3o, 45%
3m, 27%
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 21
1
2
3
4
5
6
7
8
9
3p, 50%
3q, 60%b
3r, 76%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
Reaction conditions: silyl enol ether (0.5 mmol), PhIO (0.8 mmol), TMSCN (1.5 mmol),
b
BF •Et O (0.85 mmol), and CH CN (3.0 mL) at -30 C for 3 h; Isolated yields. The yield
°
3
2
3
was based on portion of terminal ene.
Scheme 3. Regioselectivity of the Method
Scheme 4. Approach to Synthesis of Oxazoles
We next moved toward the applications of β-Ketonitrile to the preparation
of two important intermediates, viz. 3-aminopyrazole and 3-aminoisoxazole,
which can be further converted into a variety of biologically active products.1,2 As
shown in Scheme 4, the reactions of 4-methoxybenzoylacetonitrile with
hydrazine hydrate1 and hydroxylamine hydrochloride2b can easily give
3-aminopyrazole and 3-aminoisoxazole with the good yields of 77% and 68%,
respectively (Scheme 5).
Scheme 5. Applications of β-Ketonitrile
ACS Paragon Plus Environment

Page 9 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Based on our experimental results, a plausible mechanistic pathway for the
synthesis of β-ketonitriles was proposed to interpret the obsevered reactivities
(Figure 2). Active hypervalent iodine(III)-CH2CN species is firstly formed in situ
from the mixture of PhIO/BF3•Et2O/CH3CN. Then silyl enol ether 2 is oxidated by
hypervalent iodine(III)-CH2CN species to achieve umpolung and give
intermediate A. The CH2CN moiety in A is exchanged by CN- in the presence of
TMSCN to reach B. Through an intramolecular SN2 reaction and an electron
transfer in a three-membered ring transition state TS1, cyanation product 3a is
furnished, accompanied with the release of iodobenzene. Alternatively,
intermediate A can be converted into a five-membered ring transition state TS2
through nitrogen attack of cyano group and an oxazole 5 or 6 is formed
eventually through a decomposition of TS2, tautomerism of ketone C to enol D
and nucleophilic addition of hydroxyl. From our studies on cyantion of
(Z)-trimethyl(1-phenylprop-1-enyloxy)silane 2s where no cyanation product
was generated, we speculated rationally that methyl hindered the attack of CN in
intermediate E to form TS3.
Figure 2. Proposed Reaction Mechanisms.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 21
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In conclusion, we have developed a direct cyanation method of silyl enol
ethers to synthesize β-ketonitriles through umpolung strategy by
PhIO/BF3•Et2O/TMSCN system, in which diversely substituented aromatic,
heteroaromatic and aliphatic substrates worked well. Further studies about
synthetic utility of this versatile oxidative system and more mechanistic details
are presently pursued in our laboratories.
EXPERIMENTAL SECTION
General Information. 1H- and 13C-NMR spectra were recorded in CDCl3 or
DMSO-d6 on a 500 spectrometer (500 MHz for 1H, 125 MHz for 13C) at 20~25 °C.
1H NMR spectra were reported in parts per million using tetramethylsilane TMS
1
(δ = 0.00 ppm) as an internal standard. The data of H NMR are reported as
follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, quin = quintet, m = multiplet), coupling constants (J, Hz), and
integration. 13C NMR spectra were reported in parts per million using solvent
CDCl3 (δ = 77.2 ppm) or DMSO-d6 (δ = 39.5 ppm) as an internal standard, The
ACS Paragon Plus Environment

Page 11 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
data of 13C NMR are reported as follows: chemical shift, multiplicity (s = singlet, d
= doublet, t = triplet, q = quartet, quin = quintet, m = multiplet), and coupling
constants (J, Hz). High-resolution mass spectra (HRMS) electrospray ionization
(ESI) was carried out on a UPLC-Q-ToF MS spectrometer. Reactions were
monitored by TLC and column chromatography was performed using silica gel.
All solvents were purified by conventional methods, distilled before use.
Commercially available reagents were used without further purification unless
otherwise specified.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Procedure for Synthesis of cyanobenziodoxole (1a). 1a was synthesized
according to the reported method:24 1-acetoxy-1,2-benziodoxol-3(1H)-one (4.58
g, 15.0 mmol) were dissolved in dry dry CH2Cl2 (40 mL) under Ar atmosphere.
After the addition of Me3SiCN (4.3 mL, 30 mmol), the mixture was stirred for 24
h at room temperature. The crude product was filtered off, washed with CH2Cl2,
and dried at 40 ºC under vacuum to give white solid cyanobenziodoxole 1a; 70%
yield, 2.82 g. NMR data were in complete agreement with the reported ones.24
Procedure for Synthesis of Iodosylbenzene PhIO. PhIO was synthesized
according to the reported method:25 To (diacetoxyiodo)benzene (3.2 g, 10 mmol)
in a 100 mL Erlenmeyer flask was added 54 ml of sodium hydroxide solution
(1.88 M) dropwise at room temperature. The light yellow suspension appeared
slowly and the resulting mixture was stirred for three hours at room
temperature. The precipitate was filtered under high vacuum and washed with
water until the washing water got neutral to afford the slightly yellow solid
which was dried in the air and then mortared into fine powder for use.
General Procedure for Preparation of Silyl Enol Ether. Silyl enol ethers
were synthesized according to the reported method:26 The 100 mL-three-necked
flask loaded with a mixture of ketone (25 mmol) and sodium iodide (4.5 g, 30
mmol) was evacuated and filled with argon three times, then dry acetonitrile (30
mL) was added. The resulting solution was stirred for 5 min at room
temperature, and triethylamine (4.2 mL, 30 mmol) was added, followed by
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 21
1
2
3
4
5
6
7
8
9
chlorotrimethylsilane (3.82 mL, 30 mmol). The reaction mixture was then stirred
at 40 °C for overnight. The reaction was quenched by cold pentane (50 mL) and
ice water (50 mL). The organic phase was separated and the aqueous layer was
extracted with pentane (30 mL×2). The combined organics were washed with
brine, and then dried over anhydrous MgSO4. The solvents was removed firstly in
vacuo by rotatory evaporator, and the residue was distilled under reduced
pressure to provide pure silyl enol ether 2.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General Procedure for Preparation of β-Ketonitriles. For a sealed 50 mL
two-necked bottle filled with PhIO (176 mg, 0.8 mmol), argon replacement was
executed for three times in one hour and cooled to -30 °C. Dry solvent (3 mL),
BF3·Et2O (0.11 mL, 0.85 mmol) and TMSCN (0.19 mL, 1.5 mmol) were then added
successively under stirring conditions. After 40 min for preactivation, silyl enol
ether 2 (0.5 mmol) was added to the mixture slowly and reacted at -30 °C for 3 h.
The reaction was quenched by saturated sodium bicarbonate, sodium thiosulfate
solution and ethyl acetate. The organic phase was separated and the aqueous
layer was extracted with EtOAc (8 mL×3). The organic extract was combined,
dried with MgSO4 and filtered to get clear organic solution. The solvents were
removed under reduced pressure. The resulting residue was purified by column
chromatography using EtOAc-petroleum ether as eluent to give desired product
3.
3-Oxo-3-phenylpropanenitrile (3a).12a Pale yellow solid; 79% yield, 57.5 mg;
mp 68-70 °C. 1H NMR (500 MHz, CDCl3) δ 7.93 (d, J = 8.0 Hz,, 2H), 7.68 (tt, J = 7.5,
1.0 Hz, 1H), 7.54 (t, J = 7.5 Hz, 2H), 4.10 (s, 2H). 13C NMR (125 MHz, CDCl3) δ
187.2, 134.9, 134.4, 129.3, 128.7, 113.9, 29.6. HRMS (ESI) calcd for C9H7NO
[M+H]+ 146.0599, found 146.0597.
3-Oxo-3-m-tolylpropanenitrile (3b).12a Pale yellow solid; 60% yield, 47.6 mg;
mp 65-67 °C. 1H NMR (500 MHz, CDCl3) δ 7.73 (s, 1H), 7.70 (d, J = 7.5 Hz, 1H),
7.47 (d, J = 7.0 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H), 4.09 (s, 2H), 2.43 (s, 3H). 13C NMR
ACS Paragon Plus Environment

Page 13 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
(125 MHz, CDCl3) δ 187.5, 139.3, 135.7, 134.4, 129.1, 129.0, 125.8, 114.1, 29.6,
21.4. HRMS (ESI) calcd for C10H9NO [M+H]+ 160.0757, found 160.0758.
7
3-Oxo-3-p-tolylpropanenitrile (3c).12a Pale yellow solid; 60% yield, 47.4 mg;
mp 94-96 °C. 1H NMR (500 MHz, CDCl3) δ 7.82 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.5
Hz, 2H), 4.05 (s, 2H), 2.44 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 186.8, 146.2,
132.0, 130.0, 128.8, 114.0, 29.4, 22.0. HRMS (ESI) calcd for C10H9NO [M+H]+
160.0757, found 160.0759.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-oxo-3-o-tolylpropanenitrile (3d).12a Pale yellow solid; 46% yield, 36.5 mg;
mp 68-70 °C. 1H NMR (500 MHz, CDCl3) δ 7.62 (d, J = 8 Hz, 1H), 7.49 (t, J = 7.5 Hz,
1H), 7.33-7.31 (m, 2H), 4.05 (s, 2H), 2.57 (s, 3H). 13C NMR (125 MHz, CDCl3) δ
189.5, 140.6, 134.0, 133.5, 130.0, 129.4, 126.3, 114.2, 31.6, 22.0. HRMS (ESI)
calcd for C10H9NO [M+H]+ 160.0757, found 160.0761.
3-(4-Methoxyphenyl)-3-oxopropanenitrile (3e).12a Pale yellow solid; 64%
yield, 55.8 mg; mp 119-121 °C. 1H NMR (500 MHz, CDCl3) δ 7.90 (d, J = 7.5 Hz,
2H), 6.98 (d, J = 8 Hz, 2H), 4.03 (s, 2H), 3.90 (s, 3H). 13C NMR (125 MHz, CDCl3) δ
185.6, 164.9, 131.1, 127.5, 114.5, 114.3, 55.9, 29.2. HRMS (ESI) calcd for
C10H9NO2 [M+H]+ 176.0706, found 176.0713.
3-(4-Fluorophenyl)-3-oxopropanenitrile (3f).12a Pale yellow solid; 68% yield,
55.6 mg; mp 75-77 °C. 1H NMR (500 MHz, CDCl3) δ 7.97 (t, J = 6.5 Hz, 2H), 7.21 (t,
J = 7.5 Hz, 2H), 4.07 (s, 2H). 13C NMR (125 MHz, CDCl3) δ 185.6, 166.8 (d, J =
262.5 Hz), 131.5 (d, J = 10 Hz), 130.9 (d, J = 2.5 Hz), 116.6 (d, J = 22.5 Hz), 113.7,
29.5. HRMS (ESI) calcd for C9H6FNO [M+H]+ 164.0506, found 164.0506.
3-(4-Iodophenyl)-3-oxopropanenitrile (3g).1d Yellow solid; 35% yield, 47 mg;
mp 173-175 °C. 1H NMR (500 MHz, CDCl3) δ 7.91 (d, J = 7.5 Hz, 2H), 7.63 (d, J = 8
Hz, 2H), 4.04 (s, 2H). 13C NMR (125 MHz, CDCl3) δ 186.5, 138.8, 133.7, 129.8,
113.5, 103.5, 29.5. HRMS (ESI) calcd for C9H6INO [M+H]+ 271.9567, found
271.9563.
3-(4-Bromophenyl)-3-oxopropanenitrile (3h).12a Pale yellow solid; 76% yield,
85.4 mg; mp 156-157 °C. 1H NMR (500 MHz, CDCl3) δ 7.79 (d, J = 8.5 Hz, 2H), 7.68
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 21
1
2
3
4
5
6
7
8
9
(d, J = 8.5 Hz, 2H), 4.05 (s, 2H). 13C NMR (125 MHz, CDCl3) δ 186.3, 133.2, 132.8,
130.5, 130.1, 113.5, 29.5. HRMS (ESI) calcd for C9H6BrNO [M+H]+ 223.9706,
found 223.9703.
3-(4-Chlorophenyl)-3-oxopropanenitrile (3i).12a Pale yellow solid; 39% yield,
35.4 mg; mp 121-123 °C. 1H NMR (500 MHz, CDCl3) δ 7.88 (d, J = 9 Hz, 2H), 7.51
(d, J = 8.5 Hz, 2H), 4.06 (s, 2H). 13C NMR (125 MHz, CDCl3) δ 186.1, 141.7, 132.7,
130.0, 129.8, 113.6, 29.6. HRMS (ESI) calcd for C9H6ClNO [M+H]+ 180.0211,
found 180.0215.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-(3-Chlorophenyl)-3-oxopropanenitrile (3j).27 Pale yellow solid; 39% yield,
35.3 mg; mp 72-73 °C. 1H NMR (500 MHz, CDCl3) δ 7.91(s, 1H), 7.80 (d, J = 8 Hz,
1H), 7.65 (d, J = 8 Hz, 1H), 7.49 (t, J = 8 Hz, 1H), 4.08 (s, 2H). 13C NMR (125 MHz,
CDCl3) δ 186.2, 135.9, 135.8, 134.9, 130.7, 128.7, 126.7, 113.5, 29.7. HRMS (ESI)
calcd for C9H6ClNO [M+H]+ 180.0211, found 180.0208.
3-(2-Chlorophenyl)-3-oxopropanenitrile (3k).27 Pale yellow solid; 30% yield,
27 mg; mp 95-97 °C. 1H NMR (500 MHz, CDCl3) δ 7.64 (d, J = 7.5 Hz, 1H),
7.51-7.47 (m, 2H), 7.41 (t, J = 7.5 Hz, 1H), 4.15 (s, 2H). 13C NMR (125 MHz, CDCl3)
δ 189.6, 135.9, 133.9, 131.9, 131.2, 130.6, 127.7, 113.5, 33.1. HRMS (ESI) calcd
for C9H6ClNO [M+H]+ 180.0211, found 180.0215.
Methyl-4-(2-cyanoacetyl)benzoate (3l).12a Pale yellow solid; 35% yield, 35.3
mg; mp 163-164 °C. 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8 Hz, 2H), 7.99 (d, J =
8 Hz, 2H), 4.12 (s, 2H), 3.97 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 186.9, 165.9,
137.5, 135.6, 130.5, 128.6, 113.5, 52.9, 29.9. HRMS (ESI) calcd for C11H9NO3
[M+H]+ 204.0655, found 204.0662.
3-(Pyridine-2-yl)-3-oxopropanenitrile (3m).1c Pale yellow solid; 27% yield,
19.4 mg; mp 94-96 °C. 1H NMR (500 MHz, CDCl3) δ 8.69 (d, J = 4.5 Hz, 1H), 8.11
(d, J = 8 Hz, 1H), 7.91 (td, J = 7.5, 1.5 Hz, 1H), 7.57 (ddd, J = 7.5, 5.0, 1.0 Hz 1H),
4.40 (s, 2H). 13C NMR (125 MHz, CDCl3) δ 189.6, 151.0, 149.5, 137.6, 128.7, 122.6,
114.6, 28.7. HRMS (ESI) calcd for C8H6N2O [M+H]+ 147.0553, found 147.0553.
ACS Paragon Plus Environment

Page 15 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
3-(Furan-2-yl)-3-oxopropanenitrile (3n).27 Pale yellow solid; 53% yield, 35.9
mg; mp 63-65 °C. 1H NMR (500 MHz, CDCl3) δ 7.67 (d, J = 0.5 Hz, 1H), 7.39 (dd, J =
3.5, 0.5 Hz, 1H), 6.65 (dd, J = 3.5, 1.5 Hz, 1H), 3.97 (s, 2H). 13C NMR (125 MHz,
CDCl3) δ 175.9, 150.7, 147.9, 119.5, 113.6, 113.5, 29.0. HRMS (ESI) calcd for
C7H5NO2 [M+H]+ 136.0393, found 136.0395.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-(Naphthalen-2-yl)-3-oxopropanenitrile (3o).27 Yellow solid; 45% yield, 43.5
mg; mp 107-108 °C. 1H NMR (500 MHz, CDCl3) δ 8.42 (s, 1H), 7.99-7.90 (m, 4H),
7.67 (t, J = 7 Hz, 1H), 7.61 (t, J = 7 Hz, 1H), 4.22 (s, 2H). 13C NMR (125 MHz, CDCl3)
δ 187.2, 136.4, 132.5, 131.8, 130.9, 129.9, 129.7, 129.4, 128.1, 127.6, 123.6,
114.0, 29.6. HRMS (ESI) calcd for C13H9NO [M+H]+ 196.0757, found 196.0758.
Cinnamoylacetonitrile (3p).28 Yellow solid; 50% yield, 43 mg; mp 94-95 °C.
1H NMR (500 MHz, CDCl3) δ 7.69 (d, J = 16 Hz, 1H), 7.59 (d, J = 7 Hz, 2H),
7.47-7.42 (m, 3H), 6.88 (d, J = 16 Hz, 1H), 3.72 (s, 2H). 13C NMR (125 MHz, CDCl3)
δ 186.5, 146.8, 133.6, 131.9, 129.4, 129.0, 122.6, 114.2, 31.0. HRMS (ESI) calcd
for C11H9NO [M+H]+ 172.0757, found 172.0753.
3-Oxoheptanenitrile (3q).29 White solid; 60% yield, 37.7 mg; decomposition
before melt. 1H NMR (500 MHz, CDCl3) δ 3.47 (s, 2H), 2.62 (t, J = 7 Hz, 2H),
1.63-1.59 (m, 2H), 1.37-1.33 (m, 2H), 0.93 (t, J = 7 Hz, 3H). 13C NMR (125 MHz,
CDCl3) δ 197.8, 114.0, 42.1, 32.1, 25.5, 22.2, 13.9. HRMS (ESI) calcd for C7H11NO
[M+H]+ 126.0914, found 126.0919.
1
3-Cyclohexyl-3-oxopropionitrile (3r). Pale yellow oil; 76% yield, 57.7 mg. H
NMR (500 MHz, CDCl3) δ 3.51 (s, 2H), 2.55 (tt, J = 11.0, 3.5 Hz, 1H), 1.92-1.89 (m,
2H), 1.83-1.79 (m, 2H), 1.71-1.68 (m, 1H), 1.42-1.20 (m, 5H). 13C NMR (125 MHz,
CDCl3) δ 200.6, 114.1, 50.2, 30.4, 28.3, 25.7, 25.4. HRMS (ESI) calcd for C9H13NO
[M+H]+ 152.1070, found 152.1066.
Typical Procedure for Synthesis of 1,4-Diketone 4.20a For a sealed 50 mL
two-necked bottle filled with PhIO (176 mg, 0.8 mmol), argon replacement was
executed for three times in one hour and cooled to -30 °C. Dry CH3CN (3 mL),
BF3·Et2O (0.11 mL, 0.85 mmol) and CuCN (134 mg, 1.5 mmol) were then added
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 21
1
2
3
4
5
6
7
8
9
successively under stirring condition. After 40 min for preactivation, silyl enol
ether 2a (98 mg, 0.5 mmol) and TMSCN (0.19 mL, 1.5 mmol) was added to the
mixture slowly and reacted at -30 °C for 3 h. The reaction was quenched by
saturated sodium bicarbonate, sodium thiosulfate solution and ethyl acetate. The
organic phase was separated and the aqueous layer was extracted with EtOAc (8
mL×3). The organic extract was combined, dried with MgSO4 and filtered to get
clear organic solution. The solvents were removed under reduced pressure. The
resulting residue was purified by column chromatography using
EtOAc-petroleum ether as eluent to give white solid 1,4-Diphenyl-1,4-butadione
4; 70% yield, 42 mg; mp 142-143 °C. 1H NMR (500 MHz, CDCl3) δ 8.04 (d, J = 7.5
Hz,, 4H), 7.58 (t, J = 7.5 Hz, 2H), 7.48 (t, J = 8 Hz, 4H), 3.47 (s, 4H). 13C NMR (125
MHz, CDCl3) δ 198.9, 136.9, 133.3, 128.8, 128.3, 32.7. HRMS (ESI) calcd for
C16H14O2 [M+H]+ 239.1067, found 239.1074.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Typical Procedure for Synthesis of Oxazole 5.23c A dry 50 mL two-necked
bottle was charged with PhIO (176 mg, 0.8 mmol) and then evacuated and
backfilled with argon. After cooling to -30 °C, BF3·Et2O (0.11 mL, 0.85 mmol),
silyl enol ether 2s (103 mg, 0.5 mmol) and TMSCN (0.19 mL, 1.5 mmol) were
added subsequently. The reaction mixture was stirred for 3 h at -30 °C. The
reaction mixture was quenched with saturated sodium bicarbonate, sodium
thiosulfate solution and ethyl acetate. The organic phase was separated and the
aqueous layer was extracted with EtOAc (8 mL×3). The combined organic extract
was then concentrated and the resulting residue was purified by column
chromatography on silica gel to get white solid 2,4-dimethyl-5-phenyloxazole 5;
77% yield, 67 mg; mp 45-47 °C. 1H NMR (500 MHz, CDCl3) δ 7.57 (d, J = 7.5 Hz,
2H), 7.42 (t, J = 8 Hz, 2H), 7.29 (t, J = 7.5 Hz, 1H), 2.48 (s, 3H), 2.38 (s, 3H). 13C
NMR (125 MHz, CDCl3) δ 159.5, 145.3, 131.8, 129.5, 128.9, 127.5, 125.2, 14.1,
13.4 HRMS (ESI) calcd for C11H11NO [M+H]+ 174.0914, found 174.0907.
The
Similar
Procedure
for
Synthesis
of
Oxazole
6.
2-Methyl-5-phenyloxazole (6).23c Pale yellow solid; 22% yield, 17.6 mg; mp 55-58
ACS Paragon Plus Environment

Page 17 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
°C. 1H NMR (500 MHz, CDCl3) δ 7.60 (d, J = 7 Hz, 2H), 7.41 (t, J = 8 Hz, 2H), 7.31 (t,
J = 7 Hz, 1H), 7.18 (s, 1H), 2.52 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 161.2, 151.3,
129.0, 128.3, 124.7, 124.1, 121.9, 14.3. HRMS (ESI) calcd for C10H9NO [M+H]+
160.0757, found 160.0750.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Procedure for Preparation of 3-Aminopyrazole 7. 7 was synthesized
according to the reported method:30 To a solution of 3e (103 mg, 0.5 mmol) in 3
mL of ethanol in a 50 mL round-bottom flask was added hydrazine hydrate (0.08
mL, 2.5 mmol), and the resulting mixture was heated at 100 °C for 6 h. After
cooling to rt, the solvents were removed under reduced pressure and the
resulting residue was purified by column chromatography to give white solid
3-(4-methoxyphenyl)-5-amine-1H-pyrazol 7; 77% yield, 72 mg; mp 136-137 °C.
1H NMR (500 MHz, DMSO) δ 11.7 (br s, 1H ), 7.60 (d, J = 8.0 Hz, 2H), 6.96 (d, J =
8.5 Hz, 2H), 5.71 (s, 1H), 4.75 (br s, 2H), 3.78 (s, 3H). 13C NMR (125 MHz, DMSO)
δ 158.6, 126.1, 114.0, 55.1. HRMS (ESI) calcd for C10H11N3O [M+H]+ 190.0975,
found 190.0969.
Procedure for Preparation of 3-Aminoisoxazole 8. 8 was synthesized
according to the reported method:31 To a stirred solution of compound 3e (103
mg, 0.5 mmol) and sodium hydroxide (40 mg, 1 mmol) in water (1.5 mL) was
added hydroxylamine hydrochloride (34 mg, 0.5 mmol), and the resulting
mixture was heated at 100 °C for 2.5 h. After cooling to rt, the mixture was
diluted with CHCl3 and the organic layer was separated. The aqueous layer was
further extracted with CHCl3, and the combined organic layers were dried over
MgSO4 and then concentrated under reduced pressure to afford orange solid
3-(4-methoxyphenyl)-5-amine-isoxazol 8; 68% yield, 64 mg; mp 110-113 °C. 1H
NMR (500 MHz, CDCl3) δ 7.66 (d, J = 9 Hz, 2H), 6.93 (d, J = 8.5 Hz, 2H), 5.38 (s,
1H), 4.55 (brs, 2H), 3.83 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 168.8, 163.7, 161.0,
128.2, 122.4, 114.3, 78.2, 55.5. HRMS (ESI) calcd for C10H10N2O2 [M+H]+
191.0815, found 191.0818.
ACKNOWLEDGMENT
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 21
1
2
3
4
5
6
7
8
9
We gratefully acknowledge funding from the National Natural Science Foundation of
China (No. 21372265), the Natural Science Foundation Project of CQ CSTC (No.
cstc2013jcyjA0217), and the Fundamental Research Funds for the Central
Universities (No. CQDXWL-2013-Z012 and No. CDJZR14225502).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
SUPPORTING INFORMATION
Copies of NMR spectra of compounds 3, 4, 5, 6, 7, 8. This material is available free
of charge via the Internet at http://pubs.acs.org.
REFERENCES
(1) (a) Kordik, C. P.; Luo, C.; Zanoni, B. C.; Dax, S. L.; McNally, J. J.; Lovenberg, T.
W.; Wilson, S. J.; Reitz, A. B. Bioorg. Med. Chem. Lett. 2001, 11, 2283-2286. (b)
Ranatunge, R. R.; Garvey, D. S.; Janero, D. R.; Letts, L. G.; Martino, A. M.; Murty,
M. G.; Richardson, S. K.; Young, D. V.; Zemetseva, I. S. Bioorg. Med. Chem. 2004,
12, 1357-1366. (c) Pask, C. M.; Camm, K. D.; Kilner, C. A.; Halcrow, M. A.
Tetrahedron Lett. 2006, 47, 2531-2534. (d) Fan, H.; Kotsikorou, E.; Hoffman, A. F.;
Ravert, H. T.; Holt, D.; Hurst, D. P.; Lupica, C. R.; Reggio, P. H.; Dannals, R. F.;
Horti, A. G. Eur. J. Med. Chem. 2014, 78, 294-303. (e) Bera, H.; Ojha, P. K.; Tan, B.
J.; Sun, L.; Dolzhenko, A. V.; Chui, W.; Chiu, G. N. C. Eur. J. Med. Chem. 2014, 78,
294-303.
(2) (a) Eddington, N. D.; Cox, D. S.; Roberts, R. R.; Butcher, R. J.; Edafiogho, I. O.;
Stables, J. P.; Cooke, N.; Goodwin, A. M.; Smith, C. A.; Scott, K. R. Eur. J. Med.
Chem. 2002, 37, 635-648. (b) Rowbottom, M. W.; Faraoni, R.; Chao, Q.; Campbell, B.
T.; Lai, A. G.; Setti, E.; Ezawa, M.; Sprankle, K. G.; Abraham, S.; Tran, L. et al. J.
Med. Chem. 2012, 55, 1082-1055.
(3) Laufer, S. A.; Zimmermann, W.; Ruff, K. J. J. Med. Chem. 2004, 47, 6311-6325.
(4) Hu, J.; Wei, Y.; Tong, X. Org. Lett. 2011, 13, 3068-3071.
(5) (a) Puterova, Z.; Andicsova, A.; Vegh, D. Tetrahedron 2008, 64, 11262-11269. (b)
Aurelio, L.; Valant, C.; Flynn, B. L.; Sexton, P. M.; Christopoulos, A.; Scammells, P.
J. J. Med. Chem. 2009, 52, 4543-4547.
(6) Hauser, C. R.; Eby, C. J. J. Am. Chem. Soc. 1957, 79, 728-731.
ACS Paragon Plus Environment

Page 19 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
(7) Danence, L. J. T.; Gao, Y.; Li, M.; Huang, Y.; Wang, J. Chem.-Eur. J. 2011, 17,
3584-3587.
7
(8) (a) Dorsch, J. B.; McElvain, S. M. J. Am. Chem. Soc. 1932, 54, 2960-2964. (b)
Long, R. S. J. Am. Chem. Soc. 1947, 69, 990-995. (c) Eby, C. J.; Hauser, C. R. J. Am.
Chem. Soc. 1957, 79, 723-725. (d) Ji, Y.; Trenkle, W. C.; Vowles, J. V. Org. Lett.
2006, 8, 1161-1163.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(9) (a) Gakhar, H. K.; Gill, G. S.; Multani, J. S. J. Indian Chem. Soc. 1971, 48,
953-956. (b) Kamila, S.; Zhu, D.; Biehl, E. R.; Hua, L. Org. Lett. 2006, 8, 4429.
(10) Sim, M. M.; Lee, C. L.; Ganesan, A. Tetrahedron Lett. 1998, 39, 2195-2198.
(11) Yoo, B. W.; Hwang, S. K.; Kim, D. Y.; Choi, J. W.; Ko, J. J.; Choi, K. I.; Kim, J.
H. Tetrahedron Lett. 2002, 43, 4813-4815.
(12) (a) Park, A.; Lee, S. Org. Lett. 2012, 14, 1118-1121. (b) Pro, A.; Park, A.; Jung,
H. M.; Lee, S. Synthesis 2012, 44, 2885-2888.
(13) (a) Al-Qalaf, F.; Mandani, F.; Abdelkhalik, M. M.; Bassam, A. A. Molecules
2009, 14, 78-88. (b) Levchenko, K. S.; Semenova, I. S.; Yarovenko, V. N.; Shmelin,
P. S.; Krayushkin, M. M. Tetrahedron Lett. 2012, 53, 3630-3632.
(14) Kahne, D.; Collum, D. B. Tetrahedron Lett. 1981, 22, 5011-5014.
(15) Selected references on cyanation: (a) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc.
2004, 126, 8106-8107. (b) Wen, Y.; Huang, X.; Huang, J.; Xiong, Y.; Qin, B.; Feng,
X. Synlett 2005, 16, 2445-2448. (c) Gou, S.; Chen, X.; Xiong, Y.; Feng, X. J. Org.
Chem. 2006, 71, 5732-5736. (d) Xiong, Y.; Huang, X.; Gou, S. ; Huang, J.; Wen, Y.;
Feng, X. Adv. Synth. Catal. 2006, 348, 538-544. (e) Wen, Y.; Xiong, Y.; Chang, L.;
Huang, J.; Liu, X.; Feng, X. J. Org. Chem. 2007, 72, 7715-7719. (f) Chen, G.; Wang,
Z.; Wu, J.; Ding, K. Org. Lett. 2008, 10, 4573-4576. (g) North, M.; Usanov, D. L.;
Young, C. Chem. Rev. 2008, 108, 5146-5226. (h) Mazet, C.; Jacobsen, E. N. Angew.
Chem. Int. Ed. 2008, 47, 1762-1765. (i) Zhang, Z.; Wang, Z.; Zhang, R.; Ding, K.
Angew. Chem. Int. Ed. 2010, 49, 6746–6750. (j) Tanaka, Y.; Kanai, M.; Shibasaki, M.
J. Am. Chem. Soc. 2010, 132, 8862-8863. (k) Wang, J.; Liu, X.; Feng, X. Chem. Rev.
2011, 111, 6947-6983. (l) Shu, Z.; Ji, W.; Wang, X; Zhou, Y.; Zhang, Y.; Wang, J.
Angew. Chem. Int. Ed. 2014, 53, 2186-2189.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 21
1
2
3
4
5
6
7
8
9
(16) (a) Davis, W. A.; Cava, M. P. J. Org. Chem. 1983, 48, 2774-2775. (b) Hughes, T.
V.; Cava, M. P. J. Org. Chem. 1999, 64, 313-315. (c) Wu, Y.; Limburg, D. C.;
Wilkinson, D. E.; Hamilton, G. S. Org. Lett. 2000, 2, 795-797. (d) Anbarasan, P.;
Neumann, H.; Beller, M. Chem.-Eur. J. 2010, 16, 4725-4728. (e) Akula, R.; Xiong,
Y.; Ibrahim, H. RSC Adv. 2013, 3, 10731-10735.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(17) (a) Brownbridge, P. Synthesis 1983, 1-28. (b) Brownbridge, P. Synthesis 1983,
85-104. (c) Kuwajima, I.; Nakamura, E. Acc. Chem. Res. 1985, 18, 181-187. (d) Otera,
J. Modern Carbonyl Chemistry, Wiley-VCH, Weinheim, 2000. (e) Kobayashi, S.;
Manabe, K.; Ishitani, H.; Matsuo, J.-I. Science of Synthesis 2002, 4, 317-369. (f)
Sodeoka, M.; Hamashima, Y. Comprehensive Chirality 2012, 4, 210-213.
(18) (a) Zhdankin,V. V.;Stang, P. J. Chem. Rev. 2002, 102, 2523-2584. (b)
Zhdankin,V. V.;Stang, P. J. Chem. Rev. 2008, 108, 5299-5385. (c) Merritt, E. A.;
Olofsson, B. Synthesis 2011, 517−538. (d) Yu, J.; Liu, S.; Cui, J.; Hou, X.; Zhang, C.
Org. Lett. 2012, 14, 832-835. (e) Cui, J.; Jia, Q.; Feng, R.; Liu, S.; He, T.; Zhang, C.
Org. Lett. 2014, 16, 1442-1445. (f) Zhang, X.; Huang, R.; Marrot, J.; Coeffard, V.;
Xiong, Y. Tetrahedron 2015, 71, 700-708.
(19) Li, L.; Chen, Q.; Guo, Y. J. Org. Chem. 2014, 79, 5145-5152.
(20) (a) Moriarty, R. M.; Prakash, O.; Duncan, M. P. J. Chem. Soc., Chem. Commun.
1985, 420. (b) Moriarty, R. M.; Prakash, O.; Duncan, M. P. Synthesis 1985, 943-944.
(c) Moriarty, R. M.; Prakash, O.; Duncan, M. P.; Vaid, R. K. J. Org. Chem. 1987, 52,
150-153. (d) Magnus, P.; Lacour, J.; Evans, P. A.; Roe, M. B.; Hulme, C. J. Am.
Chem. Soc. 1996, 118, 3406-3418. (e) Prakash,O.; Kaur, H.; Batra, H.; Rani, N.;
Singh, S. P.; Moriarty, R. M. J. Org. Chem. 2001, 66, 2019-2023. (f) Mizar, P.; Wirth,
T. Angew. Chem. Int. Ed. 2014, 53, 5993-5997.
(21) Seebach, D. Angew. Chem. Int. Ed. Engl. 1979, 18, 239-258.
(22) (a) Zhdankin,V. V.; Tykwinski, R.; Williamson, B. L.; Stang, P. J. Tetrahedron
Lett. 1991, 32, 733-734. (b) Dohi, T.; Morimoto, K.; Takenaga, N.; Goto, A.;
Maruyama, A.; Kiyono, Y.; Tohma, H.; Kita, Y. J. Org. Chem. 2007, 72, 109-116.
ACS Paragon Plus Environment

Page 21 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(23) Related reports: (a) Lee, J. C.; Lee, Y. C. Bull. Korean Chem. Soc. 2003, 24,
893-894. (b) Ishiwata, Y.; Togo, H. Tetrahedron 2009, 65, 10720-10724. (c) Saito, A.;
Hyodo, N.; Hanzawa, Y. Molecules 2012, 17, 11046-11055.
(24) Akai, S.; Okuno, T.; Egi, M.; Takada, T.; Tohma, H.; Kita, Y. Heterocycles,
1996, 42, 47-51.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(25) Havare, N.; Plattner, D. A. Org. Lett., 2012, 14, 5078-5081.
(26) Cazeau, P.; Duoudin, f.; Moulines, F.; Babot, O.; Dunogues, J. Tetrahedron 1987,
43, 2075-2088.
(27) Shen, J.; Yang, D.; Liu, Y.; Qin, S.; Zhang, J.; Sun, J.; Liu, C.; Liu, C.; Zhao, X.;
Chu, C.;Liu, R. Org. Lett., 2014, 16, 350-353.
(28) Mamuye, A. D.; Castoldi, L.; Azzena, U.; Holzer, W.; Pace, V. Org. Biomol.
Chem. 2015, 13, 1969-1973.
(29) Miyamoto, Y.; Banno, Y.; Yamashita, T.; Fujimoto, T.; Oi, S.; Moritoh, Y.;
Asakawa, T.; Maezaki, H. et al. J. Med. Chem. 2011, 54, 831-850.
(30) Kima, I.; Song, J. W.; Park, C. M.; Jeong, J. W.; Kim, H. R.; Ha, J. R.; No, Z.;
Hyun, Y.-L.; Cho, Y. S.; Kang, N. S.; Jeon, D. J. Bioorg. Med. Chem. Lett. 2010, 20,
922-926.
(31) Rowbottom, M. W.; Faraoni, R.; Chao, Q.; Campbell, B. T.; Lai, A. G.; Setti, E.;
Ezawa, M.; Sprankle, K. G.; Abraham, S.; Tran, L. et al. J. Med. Chem. 2012, 55,
1082-1055.
ACS Paragon Plus Environment