Catalytic aza-wittig reaction of acid anhydride for the synthesis of 4H-benzo[d][1,3]oxazin-4-ones and 4-benzylidene-2-aryloxazol-5(4H)-ones

Article abstract of DOI:10.1021/acscatal.6b00165

Compared to the aza-Wittig reaction of aldehydes, ketones, amides, and esters, the aza-Wittig reaction of acid anhydride was always overlooked, which should be an important part of Wittig reactions. Here, the aza-Wittig reaction of anhydride and catalytic aza-Wittig reaction of anhydride were both developed with high yields, which provides an efficient method to synthesize of 4H-benzo[d][1,3]oxazin-4-ones and 4-benzylidene-2-aryloxazol-5(4H)-ones. The strategy of copper-catalyzed reduction of phosphine oxide was used and found effective for this transformation. Additionally, the one-pot catalytic aza-Wittig reaction of carboxylic acids was achieved. Furthermore, NMR experiments and Hammett plot recorded the process of catalytic aza-Wittig reaction of anhydride, which provides direct proof that the copper-catalyzed reduction of waste phosphine oxide is the key step in this transformation.

Full text of DOI:10.1021/acscatal.6b00165

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Article
Catalytic aza-Wittig Reaction of Acid Anhydride for the Synthesis of 4H-
benzo[d][1,3]oxazin-4-ones and 4-benzylidene-2-aryloxazol-5(4H)-ones
Long Wang, Yi-Bi Xie, Nian-Yu Huang, Jia-Ying Yan, Wei-Min Hu, Ming-Guo Liu, and Ming-Wu Ding
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b00165 • Publication Date (Web): 16 May 2016
Downloaded from http://pubs.acs.org on May 19, 2016
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ACS Catalysis
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Catalytic aza-Wittig Reaction of Acid Anhydride for the Synthesis of
4H-benzo[d][1,3]oxazin-4-ones and 4-benzylidene-2-aryloxazol-
5(4H)-ones
†
Long Wang,†,‡, YiꢀBi Xie, NianꢀYu Huang,*,†,‡ JiaꢀYing Yan,† WeiꢀMin Hu,† MingꢀGuo Liu,†,‡ and Mingꢀ
§
Wu Ding*,†,
§
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† College of Materials and Chemical Engineering, China Three Gorges University, Yichang, Hubei 443002, China.
‡
Hubei Key Laboratory of Natural Products Research and Development, China Three Gorges University, Yichang, Hubei
443002, China.
§ Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Central China Normal University, Wuhan, Hubei
430079, China.
Abstract: Compared to the azaꢀWittig reaction of aldehydes, ketones, amides and esters, the azaꢀWittig reaction of
acid anhydride was always overlooked, which should be important part of Wittig reactions. Here, azaꢀWittig reaction
of anhydride and catalytic azaꢀWittig reaction of anhydride were both developed with high yields, which provides an
efficient method to synthesize of 4Hꢀbenzo[d][1,3]oxazinꢀ4ꢀones and 4ꢀbenzylideneꢀ2ꢀaryloxazolꢀ5(4H)ꢀones. The
strategy of copperꢀcatalyzed reduction of phosphine oxide was used and found effective for this transformation.
Additionally, the oneꢀpot catalytic azaꢀWittig reaction of carboxylic acids was achieved. Furthermore, NMR
experiments and Hammett plot recorded the process of catalytic azaꢀWittig reaction of anhydride, which provides
direct proof that the copperꢀcatalyzed reduction of waste phosphine oxide is the key step in this transformation.
Keywords: catalytic azaꢀWittig reaction, anhydride, carboxylic acids
group showed that these compounds have good features
INTRODUCTION
that make them promising candidates for use as lightꢀ
activated switches in different applications.3a Therefore,
theirs synthesis has received extensive attention.4
4Hꢀbenzo[d][1,3]oxazinꢀ4ꢀones and 4ꢀbenzylideneꢀ2ꢀ
aryloxazolꢀ5(4H)ꢀones represent an important, widely
used structural motif in natural products, drugs and
biologically active compounds. For example, 4Hꢀ
benzo[d][1,3]oxazinꢀ4ꢀone is the key pharmacophore in
Cetilistat, which is a phaseꢀIII clinical trial drug.1 Some
others were found to display excellent antifungal,
antibacterial, herbicidal activities.2 Meanwhile, the
substances of 4ꢀbenzylideneꢀ2ꢀaryloxazolꢀ5(4H)ꢀones are
considered to be the potent inhibitor of deathꢀassociated
protein kinase (DAPK), which is a serine/threonine
protein kinase implicated in diverse programmed cell
death pathways. As the outstanding prospect target protein
for dealing with ischemic diseases, DAPK is mainly
adjusted cell death in response to external irritants, such
as cytokines, activation, etc. (Scheme 1).3 In 2010,
Okamoto et al identified several potent and selective
DAPK inhibitors efficiently by structureꢀbased virtual
screening and they pointed that 4ꢀbenzylideneꢀ2ꢀ
aryloxazolꢀ5(4H)ꢀones have potential to contribute to the
development of drug treatments for ischemic diseases.3b
Moreover, Bourguignon et al. found that 4ꢀbenzylideneꢀ2ꢀ
aryloxazolꢀ5(4H)ꢀones are very efficient fluorescence
resonance energy transfer (FRET) and will be useful for a
wide panel of biosensor applications.3d The Sampedro
Scheme 1. Several Bioactive Compounds.
The azaꢀWittig reaction was accepted as an excellent
tool in the construction of organic heterocycles by interꢀ
or intramolecular processes under very mild conditions.5
The azaꢀWittig reaction of aldehydes, ketones, amides and
esters were already used in the synthesis of many natural
1
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products and biologically active compounds,6 however, and carboxylic acids via PIII/PV =O redox cycling.7q
1
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8
azaꢀWittig reaction of acid anhydride was always
overlooked. As an important part of the azaꢀWittig
reaction, the expansion of the azaꢀWittig reaction of acid
anhydride is necessary and significant as a means to
enrich the azaꢀWittig reaction (Scheme 2).
Recently, we reported a catalytic classical azaꢀWittig
reaction by using the wasteꢀbyproduct triphenylphosphine
oxide as the catalyst.7c A series of quinazolinone
derivatives were very easily and convenient synthesized
using ring–close reaction caused by catalytic azaꢀWittig
reaction. Herein, azaꢀWittig reaction of anhydride and
catalytic azaꢀWittig reaction of anhydride were both
developed with the strategy of copperꢀcatalyzed reduction
of phosphine oxide, which provides an efficient method
for synthesis of 4Hꢀbenzo[d][1,3]oxazinꢀ4ꢀones and 4ꢀ
benzylideneꢀ2ꢀaryloxazolꢀ5(4H)ꢀones (Scheme 2).
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In the beginning, we found anhydrides (1) were very
easily prepared from the corresponding carboxylic acids
and acyl chlorides with high yields. Following their
synthesis, 2ꢀazidobenzoic benzoic anhydride (1a) was
chosen as the model substrate for the reaction attempt. We
firstly checked the effect of solvents on this reaction using
common triphenylphosphine as the yield precursor. As
shown in Table 1, the reaction was strongly solventꢀ
dependent. Low yields and longer reaction time were
obtained in DCM and THF. It was found that toluene was
the best solvent. Next, various phosphine reagents were
screened, with the results showing that nearly all the
phosphines could promote this transformation with
excellent yields.
Scheme 2. The azaꢀWittig Reaction of Aldehydes,
Ketones, Amides and Esters VS Acid Anhydride.
Table 1. Screening of Reaction Conditions a
Very recently, catalytic azaꢀWittig reaction has
gradually aroused people's interest because it only needs
catalytic amount organophosphorus reagent, which shows
high atom efficiency and solves the problem of the
separation of the product from the byproduct
triphenylphosphine oxide.7 In 2008, Marsden and coꢀ
workers reported the first example of catalytic azaꢀWittig
reaction using carbonyl isocyanate derivatives that cyclize
to produce benzoxazoles and phenanthridines with a
special cyclic phosphorus oxide as the catalyst.7a Later,
Delft developed the catalytic Staudinger/azaꢀWittig
sequence through inꢀsitu phosphane oxide reduction.7b In
2009, O’Brien and Chass demonstrated the first catalytic
Wittig reaction at moderate to high yields, also using a
special cyclic phosphorus oxide as the catalyst.7j In 2010,
Zhou group developed tandem catalytic Wittig reactions
by using "waste as the catalyst/coꢀcatalyst" strategy.7s In
2012, Ashfeld and coworkers reported a redox phosphine
catalyzed Staudinger ligation that enables the direct
conversion of carboxylic acids to amides, which is the
first example PPh3 used as a catalyst with a stoichiometric
silane reductant for C–N bond formations.7m In addition,
they also reported many other meaningful works about
phosphonic catalytic.7wꢀ7z In 2014, Krenske and O’Brien
reported the first examples of catalytic Wittig reactions
with semiꢀstabilized and nonꢀstabilized yields.7e In 2015,
Milstein developed a catalytic and oxidantꢀfree coupling
of alcohols with nonꢀstabilized phosphorus ylides to form
olefins using Wittig reagents.7t In 2015, Plietker found
that dual [Fe+phosphine] catalyst could catalyze the
Wittig reaction at moderate to high yields with Z/E
mixtures in most cases.7u In 2015, Werner developed the
first baseꢀfree catalytic Wittig reaction with available
tributyl phosphate as the catalyst.7v In 2015, Radosevich
designed a elegant phosphonic catalyst which is found to
catalyze the deoxygenative condensation of αꢀketo esters
Yield
Entry
PR3
Solvent
T
[%]b
67
21
51
98
91
93
95
90
93
91
88
98
98
<5
1
2
3
4
5
6
7
8
9
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12
13
14
PPh3
PPh3
PPh3
CH2Cl2
MeOH
THF
rt
rt
rt
rt
rt
rt
rt
rt
rt
PPh3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
P(4ꢀClC6H4)3
P(4ꢀMeOC6H4)3
P(4ꢀMeC6H4)3
P(4ꢀFC6H4)3
MePPh2
Me2PPh
P(nꢀBu)3
PPh3
rt
rt
60 oC
reflux
rt
PPh3
none
a Conditions: 1a (0.5 mmol, 1.0 equiv.), 2 (0.55 mmol, 1.1
equiv.), 1 h. b Isolated yields.
In the presence of triphenylphosphine and toluene, a
variety of substituted substrates have been tested to
examine the reaction scope (Table 2). In most cases, the
anhydrides (2) were very smoothly converted to the
corresponding
4Hꢀbenzo[d][1,3]oxazinꢀ4ꢀones
with
moderate to high yields. However, the reaction of
substrates with the electronꢀwithdrawing group gave
slightly high yields than those with the electronꢀdonating
group.
2
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ACS Catalysis
Table 2. azaꢀWittig Reaction of Anhydride a
7
pꢀMeꢀ C6H4
pꢀMeꢀ C6H4
pꢀMeꢀ C6H4
pꢀMeꢀ C6H4
Ph
oꢀMeOꢀC6H4
pꢀMeOꢀC6H4
oꢀMeꢀC6H4
pꢀFꢀC6H4
Ph
62(5g)
73(5h)
63(5i)
83(5j)
85(5k)
81(5l)
1
2
3
4
5
6
7
8
8
9
10
11
12
Entry
1
R1
H
R2
Ph
Yield[%]b
98(3a)
9
Ph
pꢀMeꢀC6H4
2
3
H
H
H
H
H
H
H
H
H
pꢀClꢀC6H4
pꢀBrꢀC6H4
oꢀMeꢀC6H4
Me
98(3b)
95(3c)
84(3d)
73(3e)
88(3f)
79(3g)
71(3h)
82(3i)
94(3j)
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a Conditions: 4 (0.5 mmol, 1.0 equiv.), PPh3 (0.55 mmol,
1.1 equiv.), toluene (3 mL), 0.2ꢀ2 h. b Isolated yields.
4
To demonstrate the advantages of this reaction, we
challenged catalytic azaꢀWittig reaction together with the
upper two transformations, which could be great
breakthrough in atom efficiency.7 The key question in
regard to catalytic azaꢀWittig reaction is the reduction of
the byproduct phosphine oxide. According to the
literature, phosphine oxide could be reduced to phosphine
by trichlorosilane,8 lithium aluminum hydride,9
phosgene10 and silanes.11 Among these reducing agents,
silane is a much better choice as a mild and economic
reason.12 We attempted the catalytic azaꢀWittig reaction
with the TMDS(tetramethyldisiloxane, Me2HSiOSiMe2H),
which is easily obtained as an inexpensive byproduct from
the organoꢀsilicon industry as a reduction. To our
surprise, we found that the reaction occurred smoothly
over a longer time (4h) with 95% yield obtained (Table 4,
entry 1). Generally, all the 2ꢀazidobenzoic benzoic
anhydrides could be converted to the corresponding 4Hꢀ
benzo[d][1,3]oxazinꢀ4ꢀones with very good yields (Table
4). However, there are only 9% yield was obtained in the
absence of Cu(OTf)2 (Table 4, entry 10), and no 4Hꢀ
benzo[d][1,3]oxazinꢀ4ꢀone 3a was produced without PPh3
(Table 4, entry 11).
5
6
pꢀMeꢀC6H4
oꢀMeOꢀC6H4
Et
7
8
9
pꢀMeOꢀC6H4
pꢀFꢀC6H4
10
a
Conditions: 1 (0.5 mmol, 1.0 equiv.), PPh3 (0.55 mmol, 1.1
equiv.), toluene (3 mL), 0.2ꢀ2 h. b Isolated yields.
The core of 4ꢀbenzylideneꢀ2ꢀaryloxazolꢀ5(4H)ꢀones
represents a typical skeleton in natural molecules that
revealed excellent bioactivities, i.e. antifungal, herbicidal,
antibacterial, HSVꢀ1 protease inhibition, etc. Here, we
also attempted the azaꢀWittig reaction of anhydrides with
2ꢀazidoꢀ3ꢀarylacrylic benzoic anhydride derivatives under
the upper conditions. The results were summarized in
Table 3. Under the optimized reaction conditions, a
variety of 2ꢀazidoꢀ3ꢀarylacrylic benzoic anhydride
derivatives could successfully converted to their
Table 4. Catalytic azaꢀWittig Reaction a
corresponding
4ꢀbenzylideneꢀ2ꢀaryloxazolꢀ5(4H)ꢀone
derivatives. As illustrated in Table 3, moderate to high
yields were achieved for most of the substrates.
Table 3. azaꢀWittig Reaction of Anhydride a
Entry
1
R1
H
R2
Ph
Yield[%]b
95(3a)
2
3
4
5
6
7
8
9
H
mꢀClꢀC6H4
iꢀPr
95(3k)
66(3l)
H
Entry
Ar1
Ar2
Yield[%]b
4ꢀCl
4ꢀCl
4ꢀCl
4ꢀCl
4ꢀCl
4ꢀCl
Ph
92(3m)
93(3n)
76(3o)
85(3p)
90(3q)
79(3r)
1
2
3
4
5
6
pꢀMeꢀC6H4
pꢀMeꢀ C6H4
pꢀMeꢀ C6H4
pꢀMeꢀ C6H4
pꢀMeꢀ C6H4
pꢀMeꢀ C6H4
Ph
81(5a)
87(5b)
72(5c)
85(5d)
76(5e)
70(5f)
pꢀClꢀC6H4
oꢀMeOꢀC6H4
pꢀMeꢀC6H4
pꢀFꢀC6H4
pꢀMeOꢀC6H4
pꢀClꢀC6H4
oꢀClꢀC6H4
pꢀBrꢀC6H4
pꢀMeꢀC6H4
oꢀFꢀC6H4
3
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10
11
H
H
Ph
Ph
9 (3a) c
0 (3a) d
no desired product was generated. However, when acyl
1
2
3
4
5
6
7
8
chloride was added to the reaction, a nearly quantitative
product was separated with only 10% triphenylphosphine
used as the catalyst. Most of carboxylic acids reacted
easily to give the 4Hꢀbenzo[d][1,3]oxazinꢀ4ꢀones inhigh
yields (Table 6).
a
Conditions: 1 (0.5 mmol, 1.0 equiv.), PPh3 (0.05 mmol, 0.1
equiv.), Cu(OTf)2 (0.05 mmol, 0.1 equiv.), TMDS (3 equiv.),
toluene (3 mL), 2ꢀ6 h. Isolated yields. c Without copper salt.
b
d
Without PPh3 .
Table 6. Direct OneꢀPot Catalytic azaꢀWittig Reaction of
Concurrently, we conducted the catalytic azaꢀWittig
reaction of 2ꢀazidoꢀ3ꢀarylacrylic benzoic anhydrides and
the results were summarized in Table 5. Under those
conditions, the reaction proceeded well and the
Carboxylic Acids a
9
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corresponding
were obtained with moderate to high yields (Table 5).
4ꢀbenzylideneꢀ2ꢀaryloxazolꢀ5(4H)ꢀones
Table 5. Catalytic azaꢀWittig Reaction a
Entry
1
R1
H
R2
Ph
Yield[%]b
98(3a)
2
3
H
H
pꢀClꢀC6H4
pꢀBrꢀC6H4
oꢀMeꢀC6H4
Me
98(3b)
95(3c)
84(3d)
73(3e)
88(3f)
79(3g)
71(3h)
82(3i)
94(3j)
95(3k)
67(3l)
94(3m)
95(3n)
77(3o)
87(3p)
91(3q)
78(3r)
Entry
Ar1
Ar2
Yield[%]b
4
H
1
2
pꢀMeꢀC6H4
Ph
Ph
62(5a)
69(5m)
63(5n)
72(5o)
62(5p)
63(5q)
67(5r)
60(5s)
54(5t)
58(5u)
73(5v)
70(5w)
66(5x)
56(5y)
71(5z)
5
H
pꢀMeOꢀC6H4
pꢀFꢀC6H4
Ph
6
H
pꢀMeꢀC6H4
oꢀMeOꢀC6H4
Et
3
Ph
7
H
4
pꢀFꢀC6H4
pꢀFꢀC6H4
pꢀFꢀC6H4
pꢀFꢀC6H4
pꢀMeOꢀC6H4
pꢀMeOꢀC6H4
pꢀMeOꢀC6H4
pꢀMeOꢀC6H4
oꢀFꢀC6H4
oꢀFꢀC6H4
oꢀFꢀC6H4
oꢀFꢀC6H4
8
H
5
pꢀMeOꢀC6H4
pꢀMeꢀC6H4
pꢀFꢀC6H4
Ph
9
H
pꢀMeOꢀC6H4
pꢀFꢀC6H4
mꢀClꢀC6H4
iꢀPr
6
10
11
12
13
14
15
16
17
18
H
7
H
8
H
9
pꢀMeꢀC6H4
pꢀMeOꢀC6H4
pꢀFꢀC6H4
Ph
4ꢀCl
4ꢀCl
4ꢀCl
4ꢀCl
4ꢀCl
4ꢀCl
Ph
10
11
12
13
14
15
pꢀClꢀC6H4
oꢀMeOꢀC6H4
pꢀMeꢀC6H4
pꢀFꢀC6H4
pꢀMeOꢀC6H4
pꢀMeꢀC6H4
pꢀMeOꢀC6H4
pꢀFꢀC6H4
a Conditions: 4 (0.5 mmol, 1.0 equiv.), PPh3 (0.05 mmol,
0.1 equiv.), Cu(OTf)2 (0.05 mmol, 0.1 equiv.), TMDS (3
equiv.), toluene (3 mL), 2ꢀ8 h. b Isolated yields.
a
Conditions: 6 (0.5 mmol, 1.0 equiv.), acyl chloride 8 (0.55
mmol, 1.1 equiv.), NEt3 (0.55 mmol, 1.1 equiv.), PPh3 (0.05
mmol, 0.1 equiv.), Cu(OTf)2 (0.05 mmol, 0.1 equiv.), TMDS (3
equiv.), toluene (3 mL), 2ꢀ6 h. b Isolated yields.
Subsequently, we selected carboxylic acids as substrate
to check this methodology for the reason that they
aremuch cheaper and common reagents than anhydrides.
For another reason is that carboxylic acids are easier to
store and transport than the corresponding anhydrides. the
catalytic azaꢀWittig reaction of 2ꢀazidobenzoic acid was
then carried on. To our disappointment, it was found that
Additionally, we conducted the catalytic azaꢀWittig
reaction of (Z)ꢀ2ꢀazidoꢀ3ꢀphenylacrylic acid and found
that the reaction also took place smoothly. Under the
above optimal conditions, we explored the scope of the
triphenylphosphineꢀcatalyzed
oneꢀpot
azaꢀWittig
4
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reaction of (Z)ꢀ2ꢀazidoꢀ3ꢀphenylacrylic acids and the
results were summarized in Table 7. Various (Z)ꢀ2ꢀazidoꢀ
3ꢀphenylacrylic acids could be used in this oneꢀpot
25
26
oꢀFꢀC6H4
oꢀFꢀC6H4
pꢀMeOꢀC6H4
pꢀFꢀC6H4
56(5y)
71(5z)
1
2
3
4
5
6
7
8
cyclization to
5(4H)ꢀones.
produce 4ꢀbenzylideneꢀ2ꢀaryloxazolꢀ
a
Conditions: 7 (0.5 mmol, 1.0 equiv.), acyl chloride 8
0.55 mmol, 1.1 equiv.), NEt3 (0.55 mmol, 1.1 equiv.),
PPh3 (0.05 mmol, 0.1 equiv.), Cu(OTf)2 (0.05 mmol, 0.1
equiv.), TMDS (3 equiv.), toluene (3 mL), 2ꢀ8 h.
Isolated yields.
(
b
Table 7. Direct OneꢀPot Catalytic azaꢀWittig Reaction of
Carboxylic Acids a
9
10
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12
13
14
15
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31
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33
34
35
36
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40
41
42
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Most of the natural products or pharmaceuticals
contained
4Hꢀbenzo[d][1,3]oxazinꢀ4ꢀones
and
4ꢀ
benzylideneꢀ2ꢀaryloxazolꢀ5(4H)ꢀones are functionalized
molecules. Therefore, substrates containing other
functional groups occurred in this catalytic azaꢀWittig
reaction of anhydride (Table 8). In fact, functionalized
anhydrides were very smoothly converted to the
corresponding 4Hꢀbenzo[d][1,3]oxazinꢀ4ꢀones and 4ꢀ
benzylideneꢀ2ꢀaryloxazolꢀ5(4H)ꢀones at good yields.
Notably, ester, nitrile, nitro, alkene, ketone and even
aldehyde are well tolerated in this reaction.
Entry
Ar1
Ar2
Yield[%]b
1
2
pꢀMeꢀC6H4
pꢀMeꢀC6H4
pꢀMeꢀC6H4
pꢀMeꢀC6H4
pꢀMeꢀC6H4
pꢀMeꢀC6H4
pꢀMeꢀC6H4
pꢀMeꢀC6H4
pꢀMeꢀC6H4
pꢀMeꢀ C6H4
Ph
Ph
62(5a)
72(5b)
54(5c)
68(5d)
61(5e)
55(5f)
49(5g)
56(5h)
47(5i)
71(5j)
67(5k)
64(5l)
69(5m)
63(5n)
72(5o)
62(5p)
63(5q)
67(5r)
60(5s)
54(5t)
58(5u)
73(5v)
70(5w)
66(5x)
pꢀClꢀC6H4
oꢀClꢀC6H4
pꢀBrꢀC6H4
pꢀMeꢀC6H4
oꢀFꢀC6H4
oꢀMeOꢀC6H4
pꢀMeOꢀC6H4
oꢀMeꢀC6H4
pꢀFꢀC6H4
Ph
Table 8. Evaluation of the Chemoselectivity in the
Catalytic azaꢀWittig Reaction of Anhydride.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Ph
pꢀMeꢀC6H4
pꢀMeOꢀC6H4
pꢀFꢀC6H4
Ph
Ph
Ph
pꢀFꢀC6H4
pꢀFꢀC6H4
pꢀFꢀC6H4
pꢀFꢀC6H4
pꢀMeOꢀC6H4
pꢀMeOꢀC6H4
pꢀMeOꢀC6H4
pꢀMeOꢀC6H4
oꢀFꢀC6H4
oꢀFꢀC6H4
pꢀMeOꢀC6H4
pꢀMeꢀC6H4
pꢀFꢀC6H4
Ph
pꢀMeꢀC6H4
pꢀMeOꢀC6H4
pꢀFꢀC6H4
Ph
pꢀMeꢀC6H4
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R1
O
PPh3 (10 moi%)
1
2
3
4
5
6
7
8
N
O
N3
Cu(OTf)2 (10 moi%)
O
R1
O
O
TMDS (3 equiv)
Toluene, reflux, 4 h
3
5
or
entry
1
1 or 4
O
O
O
O
O
N
N3
O
NO2
1s
3s
, 89%
NO2
O
To better understand this catalytic process of azaꢀWittig
O
9
reaction, the 31P NMR experiments were carried on since
phosphine ligands were involved in this transformation,
and the results are shown in Scheme 4. It was showed that
chemical shift of reaction mixture was appeared in 28.91
ppm, which is due to triphenylphosphine oxide. No signal
of triphenylphosphine was checked, which might means
that once triphenylphosphine is generated it will
immediately be consumed in the next azaꢀWittig reaction.
O
N
2
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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30
31
32
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34
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46
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49
50
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52
53
54
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60
N3
CN
3t, 91%
1t
CN
O
O
O
O
N
O
3
4
5
N3
O
1u
3u, 87%
O
Cl
Cl
O
O
N
O
N3
O
O
3v,
85%
O
1v
O
O
O
O
PPh3
O
O
Cl
N
Ph3P O
Cl
N3
NO2
3w
, 88%
NO2
1w
O
O
O
5 min
O
6
7
O
N
N3
CHO
30 min
3x,
79%
O
1x
CHO
O
O
O
1 h
4 h
O
Cl
N
Cl
N3
O
CHO
3y
CHO
, 81%
O
1y
O
O
O
N
8
9
O
N3
Scheme 4. The 31P NMR Spectra of Reaction Process.
O
3z
, 82%
O
1z
O
O
Furthermore, the Hammett plot was considered as the
means to more fully describe this transformation, because
the Hammett plot is a useful technique for checking
reaction process and mechanism. Therefore, we explored
the effect of different phosphine catalysts, and the
equation was built in Scheme 5. The experiments revealed
that electionꢀrich phosphine catalysts resulted in faster
reaction rate, which is consistent with the results reported
by Beller.12a
O
N
O
N3
3za
, 85%
1za
O
O
O
O
10
11
O
N
N3
CN
NC
4za
5za
, 68%
O
O
O
O
O
N
N3
O
O
O
P(p-R-Ar)3 (10 moi%)
Cl
Cl
O
Cu(OTf)2 (10 moi%)
4zb
5zb
, 65%
O
O
TMDS (3 equiv)
Toluene, reflux, 0.5 h
N
F
O
O
N3
O
F
12
O
1a
3a
N
N3
CHO
OHC
4zc
5zc, 63%
In order to obtain more information of this reaction, the
competition experiments of 2ꢀazidoꢀ3ꢀphenylacrylic
benzoic anhydride with the electronꢀwithdrawing group
and that with the electronꢀdonating group were carried on.
Interestingly, we found that there is certain product rate
was observed in this transformation (Scheme 3).
Scheme 3. Intermolecular Competition Reaction.
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2ꢀazidobenzoic acid 6a (0.326 g, 2.0 mmol) was dissolved
1
2
3
4
5
6
7
8
in toluene (10 mL), and then NEt3 (0.242 g, 2.4 mmol),
acyl chloride (2 mmol), Cu(OTf)2 (0.072 g, 0.2 mmol),
TMDS (0.804 g, 6 mmol) and PPh3 (0.052 g, 0.2 mmol)
were added in the solution in order. The reaction mixture
was then stirred at 110 oC and monitored by TLC
(petroleum ether/ethyl acetate 6:1). After the reaction was
completed (6 h), the solvent was removed under reduced
pressure and the residue was purified by column
chromatography with petroleum ether/ethyl acetate (6:1)
as eluent to give 3a with 98% yield. White solid (yield
9
10
11
12
13
14
o
1
0.437 g 98%), mp 183ꢀ186 C; H NMR (CDCl3, 600
MHz) δ (ppm) 8.32 (d, J = 7.8 Hz, 2H, ArꢀH), 8.25 (d, J
= 7.8 Hz, 1H, ArꢀH), 7.83 (t, J = 7.8 Hz, 1H, ArꢀH), 7.70
(d, J = 7.8 Hz, 1H, ArꢀH), 7.58 (d, J = 7.2 Hz, 1H, ArꢀH),
7.52 (t, J = 7.2 Hz, 3H, ArꢀH); 13C NMR (CDCl3, 100
MHz) δ (ppm) 159.4, 156.9, 146.8, 136.4, 132.5, 130.0,
128.6, 128.4, 128.1, 127.1, 116.8.
Scheme 5. Hammett Pot of Various Phosphines.
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31
32
33
34
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41
42
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52
53
54
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59
60
A possible mechanism for the catalytic azaꢀWittig
reaction can be proposed (Scheme 6). (i) in situ formation
of the anhydride via nucleophilic substitution reaction of
carboxylic acids and acyl chloride (ii) a Staudinger
reaction of anhydride 1 or 4 with triphenylphosphine to
get the iminophosphorane 9 or 10 (iii) intramolecular azaꢀ
Wittig reaction of iminophosphorane 9 or 10 to produce
the products 3 or 5 and triphenylphosphine oxide; (iv)
reduction of triphenylphosphine oxide by the
TMDS/Cu(OTf)2 system to regenerate triphenylphosphine,
which enters a new catalytic cycle.
ASSOCIATED CONTECT
Supporting Information
1
Detailed experimental procedures, H NMR, 13C NMR
data for 3, 5. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Eꢀmail: hny115@126.com, mwding@mail.ccnu.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge financial support of this work
by the National Natural Science Foundation of China
(21172085, 21572075.) and Youth Talent Development
Foundation of China Three Gorges University.
Scheme 6. A possible mechanism for the catalytic azaꢀ
Wittig reaction.
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EXPERIMENTAL DETAILS
Representative Procedure: Preparation of 3a via
catalytic aza-Wittig reaction of carboxylic acids in
one-pot.
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