Lewis Acid Mediated Tandem Reaction of Propargylic Alcohols with Hydroxylamine Hydrochloride to Give α,β-Unsaturated Amides and Alkenyl Nitriles

Article abstract of DOI:10.1021/acs.joc.5b01633

We have developed a highly selective method for the synthesis of α,β-unsaturated amides and alkenyl nitriles from readily available propargylic alcohols. The reaction proceeded smoothly under the neutral conditions with hydroxylamine hydrochloride (NH₂OH·HCl) as the nitrogen source. The development of these new strategies has significantly extended the application of hydroxylamine hydrochloride to the chemistry of propargylic alcohols. Moreover, both secondary and tertiary alcohols have been highly regioselectively transformed to the desired products with good functional group compatibility.

Full text of DOI:10.1021/acs.joc.5b01633

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Article
Lewis Acid-Mediated Tandem Reaction of Propargylic
Alcohols With Hydroxylamine Hydrochloride to give
alpha,beta-Unsaturated Amides and Alkenyl Nitriles
Ya-Ping Han, Xian-Rong Song, Yi-Feng Qiu, Xin-Hua Hao,
Jia Wang, Xin-Xing Wu, Xue-Yuan Liu, and Yong-Min Liang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01633 • Publication Date (Web): 28 Aug 2015
Downloaded from http://pubs.acs.org on August 29, 2015
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Lewis Acid-Mediated Tandem Reaction of Propargylic Alcohols With Hydroxylamine
Hydrochloride to give α,β-Unsaturated Amides and Alkenyl Nitriles
YaꢀPing Han, XianꢀRong Song, YiꢀFeng Qiu, XinꢀHua Hao, Jia Wang, XinꢀXing Wu,
XueꢀYuan Liu and YongꢀMin Liang*
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†State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000,
People’s Republic of China
liangym@lzu.edu.cn
Abstract:
We have developed a highly selective method for the synthesis of α,βꢀunsaturated amides
and alkenyl nitriles from readily available propargylic alcohols. The reaction proceeded
smoothly under the neutral conditions with hydroxylamine hydrochloride (NH2OH•HCl) as the
nitrogen source. The development of these new strategies has significantly extended the
application of hydroxylamine hydrochloride to the chemistry of propargylic alcohols. Moreover,
both secondary and tertiary alcohols have been highly regioselectivity transformed to the
desired products with good functional group compatibility.
Introduction
The nitrogenꢀcontaining compounds, as an important class of biological organic products,
have been studied to exist in many biological medicine such as antiꢀcancer drug, antioxidants,
and antimitotic agents.(1) Such compounds are also useful structural skeletons in a wide
variety of pharmaceuticals and functional materials.(2) Therefore, the development of atomꢀ
economical and versatile approaches to synthesize the nitrogenꢀcontaining compounds,
especially amides and nitriles, has attracted considerable attention.(3ꢀ6) The classical method
for the nitrogenation of alkynol and alkynes relies on the use of trimethylsilyl azide via
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nucleophilic substitution reaction. Recently, Zhan and Jiao groups have reported the
transformation of alkynols to alkenyl nitriles, respectively (Scheme 1a).(7) The transformation of
alkynes to amides has also been developed by Jiao group by using the AuꢀAgꢀTFA coꢀ
catalytic systems (Scheme 1b).(8) The high cost of nitrogen sources and catalysts, however,
reduce the potential for the further application. Very recently, Chiba and coꢀworkers disclosed
a BF3•OEt2 promoted transformation of vinyl azides to amides (Scheme 1c).(9) Nevertheless,
the difficulty in unstable substrate synthesis impose restrictions on the application in synthetic
chemistry. Whereas the addition of trimethylsilyl azide to alkynol and alkynes is wildly studied
for the synthesis of amides and nitriles, the reaction of related hydroxylamine hydrochloride as
the nitrogen source is to be disclosed.
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Scheme 1 Summary of the present studies and our new anticipation towards the nitrogenꢀ
containing compounds
a)
Zhan's and Jiao's work
OH
Ar1
Ar2
CN
FeCl3
Ar1
TMS
2
TsNHNH
+
CH3NO2
Ar2
R1
OH
H2SO4/NH4Br
CH3CN
R1
H
TMSN3
+
CN
Ph
R2
R2
b)
Jiao's work
Ph
H
Au/Ag/TFA
DCE
N
TMSN3
+
Ph
Ph
O
c)
Chiba's work
N3
E
H
NTs
R
O
BF3 OEt2
E / H2O
N
or
E =
R
R'
H
H
R
R
R'
O
d) this work
Ar1
Ar1
O
OH
Yb(OTf)3
CH3NO2
Ar1
TMSCl
CH3CN
NH2OH HCl
R
R
Ar2
N
CN
Ar2
R = H
Ar2
H
R = Aryl
Hydroxylamine hydrochloride has been extensively used as an important nucleophilic
reagent in organic synthesis due to its lower cost and high stability. The employment of
hydroxylamine hydrochloride as the nitrogenation reagents for the construction of nitrogenꢀ
containing compounds, such as pyrazoles,(10a) isoquinolines,(10b) pyridine Nꢀoxides,(10c) and
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isoxazoles(10d) has been widely investigated. Illuminated by these intriguing studies and our
recent success on the transformation of propargylic alcohols,(11) we paid attention to the
amidation and cyanation reactions of alkynols. Herein, we demonstrated a new method for the
synthesis of α,βꢀunsaturated amides and alkenylnitrile derivatives by the reaction of
propargylic alcohols and hydroxylamine hydrochloride.
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Results and Discussion
The initial exploration for our anticipation was started by employing compound 1a (0.1
mmol) as the model substrate to optimize the reaction conditions. To our delight, the expected
product 2a was obtained in 33% yield in the presence of NH2OH•HCl (3.0 equiv), Yb(OTf)3 (20
mol %) and H2O (6.0 equiv) in CH3NO2/CH3OH (1.5 mL, 2:1) at 80 ºC for 14 h (Table 1, entry
1). A subsequent investigation on the effect of temperature showed that the reaction gave the
best result at 100 ºC (Table 1, entries 2−4). Further studies revealed that the Yb(OTf)3 was the
most effective catalyst among various Lewis acids (Table 1, entries 5−7). No better result was
obtained by adjusting the amount of water (Table 1, entries 8−10). Reactions in other solvents
did not result in any improvement in the yield (Table 1, entries 11−14). After a series of
detailed investigations mentioned above, the optimal reaction conditions were eventually
finalized as the use of 1a (0.1 mmol), NH2OH•HCl (3.0 equiv) and H2O (6.0 equiv) in the
presence of Yb(OTf)3 (20 mol %) in CH3NO2/CH3OH (1.5 mL, 2:1) at 100 ºC for 14 h.
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Table 1. Optimization reaction conditions of 1a with hydroxylamine hydrochloride a.
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entry
1
catalyst (mol %)
Yb(OTf)3 (20)
Yb(OTf)3 (20)
Yb(OTf)3 (20)
Yb(OTf)3 (20)
Cu(OTf)2 (20)
LiOTf (20)
solvent (2:1)
CH3NO2/MeOH
CH3NO2/MeOH
CH3NO2/MeOH
CH3NO2/MeOH
CH3NO2/MeOH
CH3NO2/MeOH
CH3NO2/MeOH
CH3NO2/MeOH
CH3NO2/MeOH
CH3NO2/MeOH
CH3CN/MeOH
DCE/MeOH
T (ºC)
80
yieldb
33
71
66
69
32
41
0
2
100
120
130
100
100
100
100
100
100
100
100
100
100
3
4
5
6
7
pꢀTsOH (20)
Yb(OTf)3 (20)
Yb(OTf)3 (20)
Yb(OTf)3 (20)
Yb(OTf)3 (20)
Yb(OTf)3 (20)
Yb(OTf)3 (20)
Yb(OTf)3 (20)
8c
9d
10e
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14
47
53
62
64
44
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32
1,4ꢀdioxane/ MeOH
PhCH3/ MeOH
aUnless otherwise noted, all reactions were performed with 1a (0.1 mmol), NH2OH•HCl (3.0
equiv) and H2O (6.0 equiv) in the presence of Lewis acid in solvent (1.5 mL) under an air
b
c
atmosphere for 14 h. Yields are given for isolated products. This reaction was performed in
d
e
the absence of water. H2O (2.0 equiv) was used. H2O (4.0 equiv) was used. TMS:
trimethylsilyl, pꢀTsOH: pꢀtoluenesulfonic acid.
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With the optimized reaction conditions in hand, the scope of propargylic alcohols for this
transformation was subsequently examined. The results are summarized in Scheme 2. A
variety of tertiary propargylic alcohols were found to be compatible with this protocol and were
easily converted to the corresponding acrylamides in moderate to excellent yields (up to 98%).
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Both electronꢀdonating (OMe, Me, Et; 2a−2g) and electronꢀwithdrawing substituents (F, Cl, Br;
2i−2m) on the aromatic rings (R3) were tolerated. It is noteworthy that haloꢀsubstituted
propargylic alcohols worked smoothly and furnished the corresponding haloꢀsubstituted
amides, which are readily to be applied in various crossꢀcoupling coupling reactions (2k−2m).
Additionally, the substrates bearing electronꢀdonating and/or electronꢀwithdrawing groups on
the aromatic rings (R1, R2) were also employed, and the desired products were obtained in
moderate to good yields (2n−2q). However, when alkylꢀsubstituted (R3) tertiary propargylic
alcohols (1r, 1s) were used, no acrylamide products were detected. This might be attributed to
the reason that the alkyl group is hard to be migrated. (see Scheme 5). In the meantime, the
reactions of various secondary propargylic alcohols proceed smoothly to give the
corresponding α,βꢀunsaturated amides in high regioselectivity (2u−2w).
Scheme 2. Transformation of Propargylic Alcohols to α,βꢀUnsaturated Amidesa, b
HCl (3.0 equiv)
NH2OH
Yb(OTf)3 (0.2 equiv)
H2O (6.0 equiv)
R1
O
OH
R1
R2
R3
NH
R3
CH3NO2/CH3OH (2:1)
100 oC, 14 h
R2
1
2
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aUnless otherwise noted, all reactions were performed with substrate 1 (0.1 mmol),
NH2OH—HCl (3.0 equiv), Yb(OTf)3 (0.2 equiv) and H2O (6.0 equiv) in CH3NO2/CH3OH (1.5 mL,
2:1) at 100 ºC for 14 h. bYields are given for isolated products.
The nitrile product was obtained when terminal alkynol was used. Nitriles are important
structural moieties found in many natural products, biological compounds, interesting
materials and versatile building blocks in organic synthesis.(12ꢀ15) Herein, we also
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demonstrated an efficient and direct metalꢀfree transformation of terminal alkynols to
corresponding alkenyl nitriles.
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1ꢀ(2ꢀmethoxyphenyl) propꢀ2ꢀynꢀ1ꢀol (4a) was chosen as the model substrate to investigate
the exploration. Initially, the reaction was performed in the presence of NH2OH•HCl (3.0 equiv),
TFA (3.0 equiv) and NH4Cl (0.1 equiv) in CH3CN (2.0 mL) at 100 ºC, the desired product 3ꢀ(2ꢀ
ethoxyphenyl) acrylonitrile (5a) was obtained in 39% after 6.0 h (Table 2, entry 1). The acid
promoters were then investigated and a 70% yield of 5a was obtained when
trimethylchlorosilane (TMSCl) was used (Table 2, entries 2−5). Subsequent investigating the
effect of temperature revealed that the reaction at 120 ºC is the most suitable for this
transformation (Table 2, entries 5−7). Various representative solvents such as DCM, DMF,
CH3NO2, PhCH3 proved to be less effective (Table 2, entries 8−11). The use of 3.0 equiv of
TMSCl proved to be suitable and gave the desired product in 86% yield (Table 2, entries
12−14). Other additives including TBAB gave unsatisfactory yields of the desired product
(Table 2, entry 16). Ultimately, the optimal conditions for the generation of 5a were settled as
4a (0.2 mmol) and NH2OH•HCl (3.0 equiv), TMSCl (3.0 equiv), additive NH4Cl (0.1 equiv) in
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CH3CN
(2.0
mL)
under
an
air
atmosphere
at
120
ºC
for
6.0
h.
Table 2. Screening of the Reaction Conditionsa
entry
acid (equiv)
TFA (3.0)
T (ºC)
100
solvent
CH3CN
CH3CN
CH3CN
CH3CN
yieldb
39
1
2
3
4
TsOH (3.0)
100
57
CH3COOH (3.0)
HCOOH (3.0)
100
60
100
49
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TMSCl (3.0)
TMSCl (3.0)
TMSCl (3.0)
TMSCl (3.0)
TMSCl (3.0)
TMSCl (3.0)
TMSCl (3.0)
TMSCl (2.0)
TMSCl (4.0)
TMSCl (5.0)
TMSCl (3.0)
TMSCl (3.0)
100
80
CH3CN
CH3CN
CH3CN
DCE
70
60
86
0
7
120
120
120
120
120
120
120
120
120
120
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DMF
42
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0
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11
12
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15c
16d
CH3NO2
PhCH3
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
73
72
82
62
73
aUnless otherwise noted, all reactions were performed with 4a (0.2 mmol), NH2OH—HCl (3.0
equiv), additive (0.1 equiv) in solvent (2.0 mL) at 120 ºC for 6.0 h. bYields are given for isolated
c
d
products. NH2OH—HCl (2.0 equiv).was used. TBAB instead of NH4Cl was employed. TMS:
trimethylsilyl, TBAB: tetrabutylammomium bromide, TfOH: trifluoromethanesulfonic acid.
The scope of the transformation was then investigated under the standard conditions
outlined in Scheme 3. Various secondary and tertiary alkynols were easily converted to the
corresponding alkenyl nitriles in moderate to excellent yields. The structure of 5h was further
identified by the Xꢀray Crystal Structure Analysis (see the Supporting Information). When
secondary alkynols were employed, the (E)ꢀacrylonitriles were selectively obtained (5a−5k).
No matter electronꢀdonating substituent (OMe) attached on the orthoꢀ, metaꢀ, or paraꢀpositions
of the aryl group (Ar1), the reactions performed well and gave the desired products in good to
excellent yields (5a−5c). Satisfactorily, the reaction of cinnamyl alkynol 4i gave conjugated
diene nitrile 5i in 83% yield. In particular, the products with multiple rings group naphthyl 5j
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Scheme 3. Transformation of Propargylic Alcohols to alkenyl nitrilesa,b
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aUnless otherwise noted, all reactions were performed with 4 (0.2 mmol), and NH2OH—HCl
(3.0 equiv), TMSCl (3.0 equiv), additive NH4Cl (0.1 equiv) in CH3CN (2.0 mL) under an air
atmosphere at 120 ºC for 6.0 h. bYields are given for isolated products. cThe olefin isomer E/Z
ratios of 5l, 5m, 5n, and 5p are 2.03:1, 1.70:1, 1.44:1, and 1.13:1, respectively.
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and 5k were obtained in moderate yields as well. Notably, the reactions of various tertiary
propargylic alcohols proceed smoothly to give the corresponding alkenyl nitriles (5o−5r). It is
worth noting that the asymmetric tertiary alkynol was compatible with this transformation as
well (5p) and the substrate with two methyl substituents gave a satisfactory yield of 96% (5r).
However, the electronic effect was very distinct in this transformation, the substrates with
electronꢀwithdrawing (F) failed to give the desired product under the optimized conditions (5e,
5q).
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To probe the mechanism of this novel transformation, additional mechanistic studies with
possible key intermediates have been conducted (Scheme 4). One possible pathway for this
transformation is likely to generate an α,βꢀunsaturated ketone through Lewis acid mediated
Meyer−Schuster rearrangement of propargylic alcohol, followed by a subsequent Beckmann
rearrangement to form amide.(7b) Thereby, the reaction of 1ꢀ(4ꢀmethoxyphenyl)ꢀ3,3ꢀ
diphenylpropꢀ2ꢀenꢀ1ꢀone (3) was carried out under the standard conditions. Only 49% yield of
the desired product 2a was obtained. This indicated that this reaction pathway might be
partially contributed to the formation of desired product.
Scheme 4 Investigation of the Possible Key Intermediate
A plausible mechanism is then proposed on the basis of literature(11,16,17) (Scheme 5). The
dehydration of alkynol 1 generates propargyl cation A in the presence of Lewis acid, which
may involve in two paths to the subsequent transformation. In path a, the attack of
NH2OH•HCl onto allenyl cation B generates intermediate C, which will be captured by a proton
to afford intermediate D. the tautomerization of D forms intermediate E, which could eliminate
a molecule of water through Schimidtꢀtype rearrangement to afford the intermediate F. The
subsequent nucleophilic attack of H2O leads to G, which cloud undergo a keto–enol
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tautomerization to give the desired α,βꢀunsaturated amide 2. In path b, the substitution
reaction of allenyl cation B attack of H2O leads to the intermediate H. Then the rapid
tautomerization of H would lead to the α,βꢀunsaturated ketone I, which could react with
NH2OH•HCl to generate ketoxime J by eliminating a molecule of water, the desired product 2
could be obtained through Beckmann rearrangement in the presence of the acid as well.
Based on the above consequence, the mechanism of this transformation may involve two
paths at the same time. Terminal alkynols go through like the path a until the intermediate F.
Subsequently, the desired alkenyl nitriles 5 could be afforded through elimination of proton in
the intermediate F.
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Scheme 5 Proposed Mechanism for the Formation of α,β-Unsaturated Amides and
Alkenyl Nitriles
Conclusions
In summary, we have reported a novel and efficient Lewis acidꢀmediated tandem reaction of
propargylic alcohols with hydroxylamine hydrochloride as the nitrogen source to give α,βꢀ
unsaturated amides and alkenylnitrile derivatives, the products were formed through a CꢀH or
a CꢀC bond cleavages, and a CꢀN bond formation. The value of this reaction has been
reflected by its applicability to a wide range of alkynol substrates.
Experimental Section
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General Procedure for the synthesis of 2a
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The reaction of propargylic acohol 1a (31.4 mg, 0.1 mmol), NH2OH•HCl (3.0 equiv),
Yb(OTf)3 (0.2 equiv), and H2O (6.0 equiv) in CH3NO2/CH3OH (1.5 mL, 2:1) was conducted at
100 °C under an air atmosphere. The reaction was complete within 14.0 h by TLC monitoring.
The resulting mixture was cooled down to room temperature. The reaction mixture was then
diluted with ethyl acetate (2×15 mL), washed with a saturated aqueous solution of brine, dried
over Na2SO4, and evaporated under reduced pressure. The residue was further purified by
chromatography on silica gel (petroleum ether/ethyl acetate, 5:1) to afford 2a (23.4 mg).
Compounds 2a−2w(11a) are known compounds.
General Procedure for the synthesis of 5a
HCl (3.0 equiv)
NH2OH
OH
TMSCl (3.0 equiv)
NH4Cl (0.1 equiv)
CN
CH3CN
OMe
5a
120 oC, 6 h
OMe
4a
The reaction of propargylic acohol 4a (32.4 mg, 0.2 mmol), NH2OH•HCl (3.0 equiv), TMSCl
(3.0 equiv), in CH3CN (2.0 mL) was conducted at 120 °C under an air atmosphere. The
reaction was complete within 6.0 h by TLC monitoring. The resulting mixture was cooled down
to room temperature. The reaction mixture was then diluted with ethyl acetate (2×15 mL),
washed with a saturated aqueous solution of brine, dried over Na2SO4, and evaporated under
reduced pressure. The residue was further purified by chromatography on silica gel (petroleum
ether/ethyl acetate, 10:1) to afford 5a (27.4 mg). The crystal of 5h is very small colourless
block, the WR2 value of the date is 0.359 because of poor quality and disorder of the crystal.
Compounds 5a−5d, 5h, 5k−5o.(7a,13d,18) 5f,(19a) 5g, 5i,(19b) 5j,(19c) 5pꢀ5r,(19d) are known
compounds.
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Column chromatography was carried out on silica gel. H NMR spectra were recorded on
400 MHz in CDCl3 13C NMR spectra were recorded on 100 MHz in CDCl3. Chemical shifts
(ppm) were recorded with tetramethylsilane (TMS) as the internal reference standard.
Multiplicities are given as: s (singlet), d (doublet), t (triplet), dd (doublet of doublets), q (quartet)
or m (multiplet). Copies of their 1H NMR and 13C NMR spectra are provided in the Supporting
Information. Solvents were dried under standard method. Commercially available reagents
were used with further purification. THF was distilled immediately before use from
Na/benzophenone.
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Characterization data of 2a–2u
Nꢀ(4ꢀMethoxyphenyl)ꢀ3,3ꢀdiphenylacrylamide (2a):
The resultant residue was purified by flash silica gel column chromatography to afford 2a as a
1
white solid (23.4 mg, 71%); mp: 151–153 °C H NMR (400 MHz, CDCl3): 7.47–7.46 (m, 3H),
7.36–7.30 (m, 7H), 7.03 (d, J = 8.8 Hz, 2H), 6.85 (s, 1H), 6.75–6.73 (m, 2H), 6.50 (s, 1H), 3.74
(s, 3H). 13C{H} NMR (100 MHz, CDCl3): δ 164.2, 156.3, 150.1, 140.5, 138.3, 130.8, 129.6,
129.2, 129.0, 129.0, 128.5, 128.1, 123.2, 121.3, 114.0, 55.5.
Nꢀ(3ꢀMethoxyphenyl)ꢀ3,3ꢀdiphenylacrylamide (2b):
The resultant residue was purified by flash silica gel column chromatography to afford 2b as a
white solid (24.9 mg, 76%); mp: 116–118 °C 1H NMR (400 MHz, CDCl3): δ 7.49–7.47 (m, 3H),
7.37–7.32 (m, 7H), 7.08 (t, J = 8.0 Hz, 1H), 6.90 (d, J = 1.6 Hz, 2H), 6.59–6.50 (m, 3H), 3.74
(s, 3H). 13C{H} NMR (100 MHz, CDCl3): δ 164.3, 160.0, 150.5, 140.4, 138.8, 138.1, 129.5,
129.4, 129.2, 129.0, 128.5, 128.0, 123.0, 111.7, 110.0, 105.2, 55.2.
Nꢀ(2ꢀMethoxyphenyl)ꢀ3,3ꢀdiphenylacrylamide (2c):
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The resultant residue was purified by flash silica gel column chromatography to afford 2c as a
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colourless liquid (21.0 mg, 64%). H NMR (400 MHz, CDCl3): δ 8.39 (d, J = 7.6 Hz, 1H), 7.70
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(s, 1H), 7.41–7.40 (m, 3H), 7.34–7.29 (m, 7H), 6.98–6.87 (m, 2H), 6.72 (dd, J = 1.2, 8.0 Hz,
1H), 6.49 (s, 1H), 3.59 (s, 3H). 13C{H} NMR (100 MHz, CDCl3): δ 164.2, 150.6, 147.7, 141.1,
138.1, 129.7, 129.0, 128.6, 128.4, 128.2, 127.7, 123.4, 123.3, 120.9, 119.6, 109.6, 55.3.
3,3ꢀDiphenylꢀNꢀ(pꢀtolyl)acrylamide (2d):
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The resultant residue was purified by flash silica gel column chromatography to afford 2d as a
white solid (25.4 mg, 81%); mp: 154–156 °C 1H NMR (400 MHz, CDCl3): δ 7.46–7.45 (m, 3H),
7.35–7.30 (m, 7H), 7.00 (s, 4H), 6.90 (s, 1H), 6.50 (s, 1H), 2.25 (s, 3H). 13C{H} NMR (100 MHz,
CDCl3): δ 164.2, 150.2, 140.5, 138.2, 135.0, 133.7, 129.5, 129.3, 129.1, 129.0, 128.9, 128.5,
128.0, 123.2, 119.6, 20.8.
3,3ꢀDiphenylꢀNꢀ(mꢀtolyl)acrylamide (2e):
The resultant residue was purified by flash silica gel column chromatography to afford 2e as a
1
white solid (29.5 mg, 94%); mp: 141–143 °C H NMR (400 MHz, CDCl3): δ 7.47–7.46 (d, J =
2.0 Hz, 3H), 7.35–7.32 (m, 7H), 7.09–7.05 (m, 2H), 6.89 (s, 1H), 6.85–6.80 (m, 2H), 6.50 (s,
13
1H), 2.26 (s, 3H). C{H} NMR (100 MHz, CDCl3): δ 164.3, 150.4, 140.5, 138.7, 138.2, 137.5,
129.5, 129.2, 129.0, 128.6, 128.5, 128.0, 124.9, 123.1, 120.2, 116.6, 21.4.
Nꢀ(4ꢀEthylphenyl)ꢀ3,3ꢀdiphenylacrylamide (2f):
The resultant residue was purified by flash silica gel column chromatography to afford 2f as a
white solid (25.2 mg, 77%); mp: 150–152 °C 1H NMR (400 MHz, CDCl3): δ 7.47–7.45 (m, 3H),
7.35–7.31 (m, 7H), 7.03 (s, 4H), 6.92 (s, 1H), 6.50 (s, 1H), 2.55 (q, J = 8.0 Hz, 2H), 1.17 (t, J =
7.6 Hz, 3H). 13C{H} NMR (100 MHz, CDCl3): δ 164.2, 150.2, 140.5, 140.2, 138.2, 135.2, 129.5,
129.1, 129.0, 128.9, 128.5, 128.1, 128.0, 123.1, 119.7, 28.2, 15.6.
Nꢀ(3,5ꢀDimethylphenyl)ꢀ3,3ꢀdiphenylacrylamide (2g):
The resultant residue was purified by flash silica gel column chromatography to afford 2g as a
white solid (21.2 mg, 65%); mp: 174–176 °C 1H NMR (400 MHz, CDCl3): δ 7.47–7.45 (m, 3H),
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7.35–7.31 (m, 7H), 6.88 (s, 1H), 6.76 (s, 2H), 6.67 (s, 1H), 6.48 (s, 1H), 2.21 (s, 6 H). C{H}
NMR (100 MHz, CDCl3): δ 164.2, 150.4, 140.5, 138.4, 138.2, 137.4, 129.5, 129.1, 128.9,
128.8, 128.4, 128.0, 125.8, 123.0, 117.3, 21.3.
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N,3,3ꢀTriphenylacrylamide (2h):
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The resultant residue was purified by flash silica gel column chromatography to afford 2h as a
white solid (26.1 mg, 86%); mp: 114–116 °C 1H NMR (400 MHz, CDCl3): δ 7.48–7.47 (m, 3H),
7.37–7.31 (m, 7H), 7.22–7.18 (m, 2H), 7.10 (d, J = 7.6 Hz, 2H), 7.02 (t, J = 7.6 Hz, 1H), 6.92
(s, 1H), 6.51 (s, 1H). 13C{H} NMR (100 MHz, CDCl3): δ 164.3, 150.4, 140.4, 138.1, 137.6,
129.5, 129.2, 129.1, 129.0, 128.8, 128.5, 128.0, 124.1, 123.1, 119.5.
Nꢀ(4ꢀFluorophenyl)ꢀ3,3ꢀdiphenylacrylamide (2i):
The resultant residue was purified by flash silica gel column chromatography to afford 2i as a
white solid (25.3 mg, 80%); mp: 134–136 °C 1H NMR (400 MHz, CDCl3): δ 7.50–7.48 (m, 3H),
7.37–7.33 (m, 7H), 7.07–7.03 (m, 2H), 6.92–6.87 (m, 2H), 6.84 (s, 1H), 6.50 (s, 1H). 13C{H}
NMR (100 MHz, CDCl3): δ 164.3, 160.4, 160.0, 150.7, 140.3, 138.1, 133.6, 129.5, 129.3,
129.0, 128.5, 128.0, 122.7, 121.3, 121.2, 115.5, 111.3.
Nꢀ(3ꢀFluorophenyl)ꢀ3,3ꢀdiphenylacrylamide (2j):
The resultant residue was purified by flash silica gel column chromatography to afford 2j as a
white solid (16.1 mg, 51%); mp: 131–133 °C 1H NMR (400 MHz, CDCl3): δ 7.51–7.49 (m, 3H),
7.37–7.30 (m, 7H), 7.16–7.09 (m, 2H), 6.95 (s, 1H), 6.74–6.69 (m, 1H), 6.65–6.24 (m, 1H),
6.50 (s, 1H). 13C{H} NMR (100 MHz, CDCl3): δ 164.3, 164.1, 161.6, 151.1, 140.2, 139.2, 139.1,
138.0, 129.9, 129.8, 129.4, 129.4, 129.1, 129.1, 128.5, 128.0, 122.6, 114.7, 110.8, 110.6,
107.1, 106.8.
Nꢀ(4ꢀChlorophenyl)ꢀ3,3ꢀdiphenylacrylamide (2k):
The resultant residue was purified by flash silica gel column chromatography to afford 2k as a
white solid (18.7 mg, 56%); mp: 190–192 °C 1H NMR (400 MHz, CDCl3): δ 7.50–7.48 (m, 3H),
7.36–7.34 (m, 7H), 7.16 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 6.87 (s, 1H), 6.50 (s, 1H).
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13C{H} NMR (100 MHz, CDCl3): δ 164.3, 150.9, 140.2, 138.1, 136.2, 129.5, 129.4, 129.1,
128.8, 128.5, 128.0, 122.7, 120.7.
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Nꢀ(3ꢀChlorophenyl)ꢀ3,3ꢀdiphenylacrylamide (2l):
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The resultant residue was purified by flash silica gel column chromatography to afford 2l as a
white solid (32.6 mg, 98%); mp: 162–164 °C 1H NMR (400 MHz, CDCl3): δ 7.49– 7.47(m, 3H),
7.37–7.29 (m, 8H), 7.09 (t, J = 8.0 Hz, 1H), 6.98 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.0 Hz, 1H),
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6.49 (s, 1H). 13C{H} NMR (100 MHz, CDCl3): δ 164.3, 151.2, 140.2, 138.7, 138.0, 134.5, 129.7,
129.4, 129.4, 129.1, 129.1, 128.5, 128.1, 124.1, 122.5, 119.6, 117.4.
Nꢀ(4ꢀBromophenyl)ꢀ3,3ꢀdiphenylacrylamide (2m):
The resultant residue was purified by flash silica gel column chromatography to afford 2m as a
white solid (32.0 mg, 85%); mp: 190–192 °C 1H NMR (400 MHz, CDCl3): δ 7.50–7.48 (m, 3H),
7.37–7.29 (m, 9H), 6.99 (d, J = 8.8 Hz, 2H), 6.86 (s, 1H), 6.49 (s, 1H). 13C{H} NMR (100 MHz,
CDCl3): δ 164.3, 150.9, 140.2, 138.0, 136.7, 131.8, 129.5, 129.1, 128.5, 128.0, 122.7, 121.0.
Nꢀ(4ꢀMethoxyphenyl)ꢀ3,3ꢀdiꢀpꢀtolylacrylamide (2n):
The resultant residue was purified by flash silica gel column chromatography to afford 2n as a
faint yellow solid (13.3 mg, 37%); mp: 153–155 °C 1H NMR (400 MHz, CDCl3): δ 7.28 (s, 1H),
7.26–7.19 (m, 5H), 7.13 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 6.82 (s, 1H), 6.75 (d, J =
8.8 Hz, 2H), 6.44 (s, 1H), 3.75 (s, 3H), 2.42 (s, 3H), 2.36 (s, 3H). 13C{H} NMR (100 MHz,
CDCl3): δ 164.5, 156.2, 150.2, 139.2, 138.8, 137.9, 135.3, 131.0, 129.6, 129.5, 129.1, 128.0,
122.0, 121.3, 114.0, 55.4, 21.3, 21.2.
3,3ꢀBis(4ꢀchlorophenyl)ꢀNꢀ(4ꢀmethoxyphenyl)acrylamide (2o):
The resultant residue was purified by flash silica gel column chromatography to afford 2o as a
faint yellow solid (20.9 mg, 53%); mp: 200–202 °C 1H NMR (400 MHz, CDCl3): δ 7.40 (d, J =
8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 9.6 Hz, 2H), 7.21–7.15 (m, 4H), 6.95 (s, 1H),
6.79 (d, J = 8.8 Hz, 2H), 6.42 (s, 1H), 3.76 (s, 3H). 13C{H} NMR (100 MHz, CDCl3): δ 163.6,
156.6, 148.7, 139.0, 136.3, 135.5, 135.1, 130.9, 129.4, 129.0, 128.8, 123.1, 121.5, 114.2, 55.5.
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3,3ꢀBis(4ꢀchlorophenyl)ꢀNꢀphenylacrylamide (2p):
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The resultant residue was purified by flash silica gel column chromatography to afford 2p as a
white solid (32.3 mg, 88%); mp: 180–182 °C 1H NMR (400 MHz, CDCl3): δ 7.40 (d, J = 8.4 Hz,
2H), 7.33–7.29 (m, 4H), 7.24 (d, J = 5.6 Hz, 4H), 7.20 (d, J = 8.8 Hz, 2H), 7.08–7.05 (m, 2H),
6.42 (s, 1H). 13C{H} NMR (100 MHz, CDCl3): δ 163.7, 149.2, 141.9, 138.9, 137.4, 136.2, 135.6,
135.2, 133.6, 130.9, 129.4, 129.1, 129.0, 128.8, 128.7, 127.9, 124.5, 123.0, 119.7.
(Z)ꢀ3ꢀ(4ꢀFluorophenyl)ꢀ3ꢀ(4ꢀmethoxyphenyl)ꢀNꢀphenylacrylamide (2q):
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The resultant residue was purified by flash silica gel column chromatography to afford 2q as a
white solid (12.3 mg, 36%); 1H NMR (400 MHz, CDCl3): δ 7.29–7.24 (m, 4H), 7.22 (s,1H), 7.19
(t, J = 9.6 Hz, 3H), 7.09 (s, 1H), 7.02 (d, J = 8.4 Hz, 3H), 6.96 (d, J = 8.4 Hz, 2H), 6.36 (s, 1H),
3.84 (s, 3H). 13C{H} NMR (100 MHz, CDCl3): δ 164.6, 164.4, 162.1, 160.3, 149.5, 137.7, 137.2,
131.1, 130.1, 130.0, 129.8, 128.8, 124.1, 122.3, 119.6, 115.5, 115.3, 114.4, 55.4.
(E)ꢀ3ꢀ(3,4ꢀDimethylphenyl)ꢀNꢀ(4ꢀmethoxyphenyl)acrylamide (2u):
The resultant residue was purified by flash silica gel column chromatography to afford 2s as a
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white solid (14.6 mg, 52%); mp: 130–132 °C H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 15.6
Hz, 1H), 7.54–7.49 (m, 3H), 7.27 (s, 1H), 7.24 (s, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.87 (d, J = 8.8
13
Hz, 2H), 6.51 (d, J = 15.6 Hz, 1H), 3.79 (s, 3H), 2.27 (s, 3H), 2.25 (s, 3H). C{H} NMR (100
MHz, CDCl3): δ 164.3, 156.4, 142.0, 138.8, 137.0, 132.4, 131.4, 130.1, 129.2, 125.4, 121.8,
119.8, 114.2, 55.4, 19.7, 19.6.
Nꢀ(Mꢀtolyl)cinnamamide (2v):
The resultant residue was purified by flash silica gel column chromatography to afford 2t as a
colourless liquid (23.8 mg, 50%). 1H NMR (400 MHz, CDCl3): δ 7.66 (d, J = 16.8 Hz, 1H), 7.49
(d, J = 6.8 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.35–7.31 (m, 4H), 7.24 (d, J = 8.4 Hz, 2H), 6.82
(d, J = 16.8 Hz, 1H), 2.42 (s, 3H). 13C{H} NMR (100 MHz, CDCl3): δ 142.3, 139.0, 137.9, 134.7,
129.9, 128.9, 127.9, 125.3, 120.8, 117.1, 21.5.
Nꢀ(4ꢀFluorophenyl)cinnamamide (2w):
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The resultant residue was purified by flash silica gel column chromatography to afford 2u as a
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white solid (14.5 mg, 35%); mp: 138–140 °C H NMR (400 MHz, CDCl3): δ 7.66 (d, J = 16.8
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Hz, 1H), 7.52–7.49 (m, 4H), 7.35 (d, J = 7.6 Hz, 4H), 7.15–7.11 (m, 2H), 6.76 (d, J = 16.8 Hz,
1H). 13C{H} NMR (100 MHz, CDCl3): δ 164.1, 160.7, 158.2, 142.5, 134.5, 134.0, 130.0, 128.9,
127.9, 121.9, 120.6, 115.8, 115.6.
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Characterization data of 5a–5n
(E)ꢀ3ꢀ(2ꢀmethoxyphenyl)acrylonitrile (5a)
The resultant residue was purified by flash silica gel column chromatography to afford 5a (27.4
1
mg, 86%); H NMR (400 MHz, CDCl3): δ 7.62 (d, J = 16.8 Hz, 1H), 7.39 (t, J = 8.0 Hz, 2H),
6.05 (d, J = 16.8 Hz, 1H), 3.89 (s, 3H). 13C{H} NMR (100 MHz, CDCl3): δ
6.99–6.92 (m, 2H),
158.2, 146.4, 132.3, 128.9, 122.5, 120.8, 119.0, 111.2, 96.9, 55.5.
(E)ꢀ3ꢀ(3ꢀmethoxyphenyl)acrylonitrile (5b)
The resultant residue was purified by flash silica gel column chromatography to afford 5b (26.4
1
mg, 83%); H NMR (400 MHz, CDCl ): δ
6.91 (d, J = 8.8 Hz, 2H), 5.71 (d,
7.41–7.31 (m, 3H),
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J = 16.8 Hz, 1H), 3.85 (s, 3H). C{H} NMR (100 MHz, CDCl3): δ 160.0, 150.5, 134.8, 130.1,
119.9, 118.1, 116.8, 112.5, 96.6, 55.4.
(E)ꢀ3ꢀ(4ꢀmethoxyphenyl)acrylonitrile (5c)
The resultant residue was purified by flash silica gel column chromatography to afford 5c (25.3
1
mg, 80%); H NMR (400 MHz, CDCl3): δ 7.40 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 16.8 Hz, 1H),
5.71 (d, J = 16.8 Hz, 1H), 3.85 (s, 3H). 13C{H} NMR (100 MHz, CDCl3): δ
6.93–6.90 (m, 2H),
162.0, 150.0, 129.0, 126.3, 118.7, 114.5, 93.3, 55.4.
(E)ꢀ3ꢀ(pꢀtolyl)acrylonitrile (5d)
The resultant residue was purified by flash silica gel column chromatography to afford 5d (21.3
1
mg, 74%); H NMR (400 MHz, CDCl ): δ
7.21 (d, J = 8.0 Hz, 2H), 5.82 (d,
7.38–7.33 (m, 3H),
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J = 16.8 Hz, 1H), 2.38 (s, 3H). C{H} NMR (100 MHz, CDCl3): δ 150.5, 141.8, 130.9, 129.8,
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127.3, 118.4, 95.0, 21.5.
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(E)ꢀ3ꢀ(3.4ꢀdimethylphenyl)acrylonitrile (5f)
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The resultant residue was purified by flash silica gel column chromatography to afford 5f (23.7
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mg, 76%); 1H NMR (400 MHz, CDCl ): δ 7.32 (d, J = 16.4 Hz, 1H),
5.80 (d,
7.20–7.14 (m, 3H),
3
J = 16.8 Hz, 1H), 2.29 (s, 3H), 2.28 (s, 3H). 13C{H} NMR (100 MHz, CDCl3): δ 150.7, 140.5,
137.4, 131.2, 130.3, 128.4, 124.9, 118.5, 94.7, 19.8, 19.7.
(E)ꢀ3ꢀ(benzo[d][1,3]dioxolꢀ5ꢀyl)acrylonitrile (5g)
The resultant residue was purified by flash silica gel column chromatography to afford 5g (29.4
mg, 85%); 1H NMR (400 MHz, CDCl ): δ 7.28 (d, J = 14.4 Hz, 1H),
6.82 (d,
6.94–6.92 (m, 2H),
3
J = 8.8 Hz, 1H), 6.03 (s, 2H), 5.67 (d, J = 16.8 Hz, 1H). 13C{H} NMR (100 MHz, CDCl3): δ
150.4, 150.0, 148.6, 128.0, 124.1, 118.4, 108.6, 105.5, 101.8, 93.9.
(E)ꢀNꢀ(4ꢀ(2ꢀcyanovinyl)phenyl)ꢀN,4ꢀdimethylbenzenesulfonamide (5h)
The resultant residue was purified by flash silica gel column chromatography to afford 5h (19.5
1
mg, 63%); H NMR (400 MHz, CDCl ): δ
7.25 (d, J = 8.0 Hz, 2H), 7.18 (d,
7.43–7.34 (m, 5H),
3
J = 8.4 Hz, 2H), 5.85 (d, J = 16.8 Hz, 1H), 3.17 (s, 3H), 2.42, (s, 3H). 13C{H} NMR (100 MHz,
CDCl3): δ 149.3, 144.0, 143.9, 133.1, 131.9, 129.5, 127.8, 127.6, 126.4, 117.9, 96.7, 37.5, 21.5.
(2E,4E)ꢀ5ꢀphenylpentaꢀ2,4ꢀdienenitrile (5i)
The resultant residue was purified by flash silica gel column chromatography to afford 5i (26.8
mg, 75%); 1H NMR (400 MHz, CDCl ): δ
7.47–7.45 (m, 2H), 7.40–7.34 (m, 3H), 7.18–7.12 (m,
3
5.44 (d, J = 16.0 Hz, 1H). 13C{H} NMR (100 MHz, CDCl3): δ 150.3,
1H), 6.91–6.79 (m, 2H),
141.4, 135.3, 129.6, 128.9, 127.4, 125.4, 118.3, 98.3.
(E)ꢀ3ꢀ(naphthalenꢀ1ꢀyl)acrylonitrile (5j)
The resultant residue was purified by flash silica gel column chromatography to afford 5j (16.9
mg, 47%); 1H NMR (400 MHz, CDCl3): δ 8.23 (d, J = 16.4 Hz, 1H), 8.04 (d,
J = 8.4 Hz, 1H), 7.95
(m, 2H), 7.66 (d, J = 7.2 Hz, 1H), 7.62–7.54 (m, 2H), 7.51
–7.88
–7.47
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5.97 (d, J = 16.4 Hz, 1H). 13C{H} NMR (100 MHz, CDCl3): δ 147.9, 133.6, 131.5,
(m, 1H),
3
4
5
6
7
130.9, 130.7, 128.9, 127.4, 126.5, 125.3, 124.6, 122.8, 118.2, 98.8.
(E)ꢀ3ꢀ(naphthalenꢀ2ꢀyl)acrylonitrile (5k)
8
9
The resultant residue was purified by flash silica gel column chromatography to afford 5k (26.8
10
11
12
13
14
15
16
17
18
19
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60
1
mg, 75%); H NMR (400 MHz, CDCl3): δ 7.86–7.83 (m, 4H), 7.55–7.51 (m, 4H), 5.96 (d, J =
16.4 Hz, 1H). 13C{H} NMR (100 MHz, CDCl3): δ 150.6, 134.5, 133.0, 130.9, 129.7, 129.1,
128.7, 127.8, 127.8, 127.1, 122.2, 118.3, 96.3.
(E)ꢀ3ꢀ(2ꢀmethoxyphenyl)butꢀ2ꢀenenitrile (5m)
The resultant residue was purified by flash silica gel column chromatography to afford 5m
(11.2mg); 1H NMR (400 MHz, CDCl3): δ 7.37–7.32 (m, 1H), 7.19–7.17 (m, 1H), 6.98–6.92 (m,
2H), 5.57 (d, J = 1.2 Hz, 1H), 3.85 (s,3H), 2.43 (d, J = 0.8 Hz, 3H). 13C{H} NMR (100 MHz,
CDCl3): δ 160.0, 156.6, 130.6, 128.8, 128.7, 120.7, 117.5, 111.2, 98.7, 55.5, 21.8.
(Z)ꢀ3ꢀ(2ꢀmethoxyphenyl)butꢀ2ꢀenenitrile (5m’)
The resultant residue was purified by flash silica gel column chromatography to afford 5m (6.6
mg); 1H NMR (400 MHz, CDCl3): δ 7.38–7.33 (m, 1H), 7.23–7.20 (m, 1H), 7.02–6.94 (m, 2H),
5.43 (d, J = 1.6 Hz, 1H), 3.85 (s,3H), 2.24 (d, J = 1.6 Hz, 3H). 13C{H} NMR (100 MHz, CDCl3):
δ 161.3, 155.9, 130.5, 128.8, 127.8, 120.7, 117.1, 111.2, 98.0, 55.4, 24.6.
(E)ꢀ3ꢀ(pꢀtolyl)butꢀ2ꢀenenitrile (5n)
The resultant residue was purified by flash silica gel column chromatography to afford 5n
(17.9mg, 57%); 1H NMR (400 MHz, CDCl3): δ 7.46 (d, J = 8.0 Hz, 1H), 5.37 (d, J = 8.4 Hz, 2H),
7.24–7.20 (m, 4H), 5.60 (s,1H), 5.35 (d, J = 1.2 Hz, 1H), 2.45 (s, 3H), 2.38 (s, 5H), 2.26 (d, J =
1.2 Hz, 2H). 13C{H} NMR (100 MHz, CDCl3): δ 160.8, 159.5, 140.6, 140.1, 135.3, 134.9, 129.5,
129.3, 127.0, 125.7, 117.9, 117.8, 94.6, 94.4, 24.6, 21.3, 21.3, 20.1.
3.3ꢀdiphenylacrylonitrile (5o)
The resultant residue was purified by flash silica gel column chromatography to afford 5l (27.4
mg, 67%); 1H NMR (400 MHz, CDCl3): δ 7.47–7.41 (m, 6 H), 7.39–7.35 (m, 2H), 7.31–7.28 (m,
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2H), 5.74 (s, 1H). 13C{H} NMR (100 MHz, CDCl3): δ 163.1, 138.9, 137.0, 130.4, 130.0, 129.5,
128.6, 128.5, 128.5, 117.9, 94.9.
5
6
7
3ꢀphenylꢀ3ꢀ(pꢀtolyl)acrylonitrile (5p)
8
9
The resultant residue was purified by flash silica gel column chromatography to afford 5m
(29.8 mg, 75%); 1H NMR (400 MHz, CDCl3): δ 7.46–7.41 (m, 6 H), 7.38–7.29 (m, 6 H), 7.24 (d,
J = 4.8 Hz, 2H), 7.18 (s, 4H), 5.69 (d, J = 15.6 Hz, 2H), 2.41 (s, 3H), 2.38 (s, 3H). 13C{H}
NMR (100 MHz, CDCl3): δ 163.2, 163.1, 140.9, 140.3, 139.2, 137.2, 136.0, 134.2, 130.3,
129.9, 129.5, 129.3, 129.2, 128.6, 128.5, 128.5, 128.4, 118.1, 94.2, 93.9, 21.4, 21.3.
3,3ꢀdiꢀpꢀtolylacrylonitrile (5r)
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The resultant residue was purified by flash silica gel column chromatography to afford 5n (22.3
1
mg, 96%); H NMR (400 MHz, CDCl3): δ 7.33–7.31 (m, 2H), 7.23 (s, 2H), 7.20–7.15 (m, 4H),
5.65 (s, 1H), 2.41 (s, 3H), 2.38 (s, 3H). 13C{H} NMR (100 MHz, CDCl3): δ 163.1, 140.7, 140.2,
136.3, 134.3, 129.5, 129.3, 129.1, 128.5, 118.3, 93.3, 21.4, 21.3.
Supporting Information
General remarks, crystal preparation and xꢀray diffraction analysis, 1H and 13C NMR spectra
of the products, and a CIF file. This material is available free of charge via the Internet at
http://pubs.acs.org
Acknowledgements
Acknowledgements Financial support was received from the National Science Foundation
(NSF21272101, NSF21472073, NSF21472074, and NSF21302076), the Program for
Changjiang Scholars and Innovative Research Team in University (IRT1138).
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