Copper-catalyzed N-aryl-β-enaminonitrile synthesis utilizing isocyanides as the nitrogen source

Article abstract of DOI:10.1002/adsc.201400973

A novel synthetic protocol for N-aryl-β-enaminonitriles, which are useful building blocks for heterocycle synthesis, was developed using isocyanides as the nitrogen source. Using copper-catalyzed one-step reactions between isocyanides and benzyl cyanides under mild conditions, diverse N-aryl-β-enaminonitriles could be synthesized in excellent yields and with high atom-efficiency. N-Alkyl-β-enaminonitriles were also synthesized in good yields. A mechanism involving an imidoyl-copper intermediate was proposed based on mechanistic studies and previous reports. In addition, we demonstrated that a synthesized N-aryl-β-enaminonitrile could be utilized for the synthesis of a β-keto nitrile compound and 3-aminopyrazole.

Full text of DOI:10.1002/adsc.201400973

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DOI: 10.1002/adsc.201400973
Copper-Catalyzed N-Aryl-b-enaminonitrile Synthesis Utilizing
Isocyanides as the Nitrogen Source
Seoksun Kima and Soon Hyeok Honga,*
a
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-742, Republic of Korea
Fax: (+82)-2-889-1568; phone: (+82)-2-880-6655; e-mail: soonhong@snu.ac.kr
Received: October 10, 2014; Revised: January 13, 2015; Published online: March 13, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400973.
Abstract: A novel synthetic protocol for N-aryl-b-en- nism involving an imidoyl-copper intermediate was
aminonitriles, which are useful building blocks for proposed based on mechanistic studies and previous
heterocycle synthesis, was developed using isocya- reports. In addition, we demonstrated that a synthe-
nides as the nitrogen source. Using copper-catalyzed sized N-aryl-b-enaminonitrile could be utilized for
one-step reactions between isocyanides and benzyl the synthesis of a b-keto nitrile compound and 3-
cyanides under mild conditions, diverse N-aryl-b-en- aminopyrazole.
aminonitriles could be synthesized in excellent yields
and with high atom-efficiency. N-Alkyl-b-enaminoni- Keywords: benzyl cyanide; copper; enaminonitriles;
triles were also synthesized in good yields. A mecha- formimidates; heterocycles; isocyanides
Introduction
stable poly(enaminonitrile)s[8] and in pharmaceutical
chemistry.[9] Because of its importance, diverse aspects
For several decades, the b-enaminonitrile group has of b-enaminonitriles have been studied, such as tauto-
been highlighted as a useful building block for the merization,[10] isomerization,[11] and photochemical re-
synthesis of heterocycles[1] such as pyrimidine,[2] pyri- actions.[12]
dine,[3] pyrazole,[4] pyrrole,[5] isothiazole,[6] and pyrroli-
Despite the importance of the b-enaminonitriles,
none[7] (Scheme 1). This building block has also been only limited methods have been reported for their
applied to the synthesis of polymers such as thermally synthesis. Traditionally, b-enaminonitriles have been
Scheme 1. Synthesis of diverse heterocycles from b-enaminonitriles.
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Copper-Catalyzed N-Aryl-b-enaminonitrile Synthesis Utilizing Isocyanides
of b-enaminonitriles is still poor, and nitrogen sources
were limited to formamides, amines, and nitriles. In
particular, examples of aryl-substituted enaminonitrile
synthesis are quite rare with a narrow substrate scope
and harsh reaction conditions.[10b,19]
To develop an efficient synthetic method for N-
aryl-b-enaminonitriles, we turned our attention to iso-
cyanides. Since the Ugi reaction was reported,[20] ex-
tensive studies have been carried out to utilize isocya-
nides in organic synthesis, such as heterocycle synthe-
sis.[21] Recently we developed a method for 1,4-diaryl-
imidazole synthesis[22] based on Cu-catalyzed formimi-
date formation from isocyanides.[23] Thus, we
envisioned a novel strategy for the synthesis of b-en-
aminonitriles from isocyanides as the nitrogen source
[Scheme 2, Eq. (7)]. To the best of our knowledge,
this is the first example of an N-aryl-b-enaminonitrile
synthesis using isocyanides as the nitrogen source.
Results and Discussion
We started our investigation by adapting the reaction
conditions involving the N-heterocyclic carbene
(NHC)-based Cu(I) species developed for 1,4-diaryl-
imidazole synthesis.[22] To our delight, the target com-
pound was obtained in 49% yield (Table 1, entry 1).
The absolute configuration of the alkene was deter-
mined by X-ray crystallography (Figure 1).[24] Among
the solvents investigated, dimethoxyethane (DME)
resulted in the best yield (Table 1, entries 1–4). The
reaction worked well in the absence of the NHC
ligand and was optimized further without any addi-
tional ligand (Table 1, entry 5). A strong base such as
t-BuOK was essential for the reaction (Table 1, en-
tries 6 and 7). When Cu(I) halides were screened with
1.2 equiv. of t-BuOK, CuI resulted in quantitative
yield (Table 1, entries 7–9). The reaction without a Cu
catalyst also gave the desired product, but it exhibited
Scheme 2. Synthetic methods for b-enaminonitriles classified
according to nitrogen sources.
synthesized by the condensation of formamide with a much decreased yield (Table 1, entry 10). In this
arylformylacetonitriles [Scheme 2, Eq. (1)],[13] or am- case, a dimer of benzyl cyanide, (Z)-3-amino-2,4-di-
monia with cyanoacetophenone.[14] Moreover, amines phenylbut-2-enenitrile, from a Thorpe–Ziegler con-
and activated acetonitriles can serve as starting mate- densation was observed as the major by-product in
rials for the synthesis of b-enaminonitriles in the pres- 31% yield.[25]
ence of triethyl orthoformate [Scheme 2, Eq. (2)].[1b]
With the optimized reaction conditions in hand, we
However, the above-mentioned methods usually re- investigated the substrate scope of the reaction. First,
quire harsh conditions. Thorpe–Ziegler condensation the isocyanides used in the reaction were varied
[Scheme 2, Eq. (4)][15] and Gewald condensation (Table 2). In most of the cases, N-aryl-b-enaminoni-
[Scheme 2, Eq. (5)],[16] which use nitriles as the nitro- triles were obtained in good-to-excellent yields. The
gen source, require mild conditions; however, the sub- reaction worked well even with sterically hindered
strate scope is limited to N-unsubstituted b-enamino- isocyanides (3ca–3fa and 3a). Even stronger electron-
nitriles and thiophene derivatives. To broaden the withdrawing group-substituted isocyanides worked
substrate scope of b-enaminonitriles, Pd-catalyzed smoothly (3ga–3ka). The reaction showed good func-
tandem reactions [Scheme 2, Eq. (3)][17] and domino tional group tolerance to aryl-halogen bonds (3ga,
ring-opening cyclization reactions [Scheme 2, Eq. 3ha, and 3ma), ester group (3ia), nitrile group (3ja),
(6)][18] have been recently reported. Although various pyridine (3ka), and ether group (3la). 3-Pyridyl isocy-
synthetic methods are available, the substrate scope anide resulted in only a moderate yield, probably be-
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Seoksun Kim and Soon Hyeok Hong
Table 1. Optimization of the reaction conditions.[a]
Table 2. Substrate scope of isocyanides.[a]
Entry Catalyst Ligand Base
(equiv.)
Solvent Yield
[%][b]
1
2
3
4
5
6
7
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuBr
CuI
IPr·HCl 0.5
THF
DCM
benzene 29
DME
DME
DME
DME
DME
DME
DME
44
0
IPr·HCl 0.5
IPr·HCl 0.5
IPr·HCl 0.5
55
40
0
93
98
>99
60
–
–
–
–
–
–
0.5
0
1.2
1.2
1.2
1.2
8
9[c]
10
–
[a]
Reaction conditions: 1a (0.2 mmol, 1.0 equiv.), 2a
(0.28 mmol, 1.4 equiv.), precatalyst (0.01 mmol), ligand
(0.01 mmol), t-BuOK (x equiv.) in solvent (0.4 mL).
IPr·HCl=1,3-bis(2,6-diisopropylphenyl)imidazolium
chloride.
Yields were determined by HPLC using 2,6-diisopropyl-
aniline as the internal standard.
Reaction time: 8 h.
[b]
[c]
[a]
Reaction conditions: 1 (0.40 mmol), 2a (0.56 mmol), CuI
(0.02 mmol), t-BuOK (0.48 mmol) in DME (0.8 mL) at
558C.
Figure 1. Crystal structure of 3aa. ORTEP diagram showing
50% probability thermal ellipsoids.
Next, the scope of arylacetonitriles was investigated
(Table 3). Similar to isocyanides, arylacetonitriles
cause of its coordinating ability. Gratifyingly, alkyl showed a broad substrate scope with good-to-excel-
isocyanides also participated in the reaction (3oa– lent yields. 2-Naphthylacetonitrile afforded the corre-
3qa).
sponding product (3ab) in a very good yield. Elec-
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Copper-Catalyzed N-Aryl-b-enaminonitrile Synthesis Utilizing Isocyanides
Table 3. Substrate scope of arylacetonitriles.[a]
Table 4. Effect of catalyst and base.[a]
Entry
Variation from standard conditions
Yield [%][b,c]
1
2
none
without catalyst
>99
60
3
4
5
6
7
8
9
10
Sc(OTf)3 instead of CuI
AgOTf instead of CuI
BF3·OEt2 instead of CuI
FeBr2 instead of CuI
Cs2CO3 instead of t-BuOK
NaH instead of t-BuOK
KHMDS instead of t-BuOK
NaOMe instead of t-BuOK
45
61
53
56
14
59
55
57
[a]
Reaction conditions: 1a (0.2 mmol, 1.0 equiv.), 2a
(0.28 mmol, 1.4 equiv.), CuI (0.01 mmol), t-BuOK
(1.2 equiv,) in solvent (0.4 mL).
Yields of entries 1–6 were determined by HPLC using
2,6-diisopropylaniline as the internal standard.
Yields of entries 7–10 were determined by NMR using
mesitylene as the internal standard.
[b]
[c]
with CuI (Table 4, entries 8–10). These results indicat-
ed that t-BuOK has another role aside from simple
deprotonation of benzyl cyanides.
[a]
Reaction conditions: 1a (0.4 mmol), 2 (0.56 mmol), CuI
(0.02 mmol), t-BuOK (0.48 mmol) in DME (0.8 mL) at
Based on the experimental results and our previous
608C.
study,[22]
a
possible mechanism is suggested
(Scheme 3). Because of the enhancement in yields
tron-withdrawing substituents on the aryl group
showed s negligible effect on the yields (3ac–3ag),
while electron-donating substituents on the aryl group
resulted in reduced yields, probably because of desta-
bilization of the arylacetonitrile anion (3ah and 3ai).
As shown in Table 3, functional groups such as aryl-
halogen bonds (3ac–3ae), ester group (3ag), and Boc-
protected amine group (3ai) were well tolerated. In-
terestingly, 2-pyridylacetonitrile resulted in an excel-
lent yield, while 3-pyridylisocyanide resulted in a mod-
erate yield (3af and 3ka).
Effects of the Cu catalyst and the base were further
examined in order to obtain a mechanistic insight for
the reaction (Table 4). Several Lewis acids were
tested, and none of them exhibited enhanced reactivi-
ty even compared to the base-only reaction conditions
(Table 4, entries 2–5). The results suggest that CuI
does not act as a simple Lewis acid in this reaction.[26]
Various kinds of bases were also screened. Cesium
carbonate, which is not strong enough to deprotonate
the benzylic proton of benzyl cyanide, gave the prod-
uct in a poor yield of 14% (Table 4, entry 7). Other
strong bases exhibited only moderate yields, even Scheme 3. Proposed reaction mechanism.
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Seoksun Kim and Soon Hyeok Hong
Scheme 4. Reactions of formimidates.
when coordinating solvents, such as THF and DME, and D could work, especially under base only condi-
were used (Table 1) and the fact that the tions. However, in our Cu-catalyzed conditions, we
(DME)Cu(I) complex has been reported as a long- believe that the proposed formimidate mechanism is
lived stable complex,[27] (DME)Cu(I)(O-t-Bu) (A) is more reasonable judging from the observation of the
proposed as the active catalytic species in this reac- special effect of t-BuOK in Table 4.
tion. An isocyanide can coordinate to this species to
The synthesized b-enaminonitrile 3aa could be
form the 18-electron Cu(I) complex (B). Because of transformed to other synthetically useful products
the innate electrophilic character of an isocyanide- under simple reaction conditions (Scheme 5).[17] The
metal complex,[21b] tert-butoxide ligand can attack the para-toluidine group of 3aa could be hydrolyzed to
carbon atom of the isocyanide group of B to generate form a b-keto nitrile 4.[28] In addition, 3-aminopyra-
imidoyl-Cu complex, C. Deprotonated benzyl cyanide zole (5) could be synthesized from 3aa through an
(D), t-BuOH, and C react to afford intermediate E acid-catalyzed reaction with hydrazine.[19a]
with the regeneration of (DME)Cu(I)(O-t-Bu) (A),
thus completing the catalytic cycle. Finally, successive
tert-butoxide elimination and tautomerization afford Conclusions
the desired N-substituted b-enaminonitrile.
To confirm the mechanism further, readily available In conclusion, we have reported on a novel Cu-cata-
ethyl formimidate and in situ generated tert-butyl for- lyzed N-aryl-b-enaminonitrile synthesis from isocya-
mimidate were subjected to the reaction conditions. nides and nitriles. A broad range of N-aryl-b-enami-
The desired products were afforded in good yields, nonitriles, which were not easily accessible with previ-
supporting the proposed mechanism (Scheme 4). The ously reported synthetic methods utilizing other nitro-
slightly reduced yields than when starting from iso- gen sources, was obtained in good-to-excellent yields
cyanides are presumably due to the reactivity differ- under mild conditions. The optimized conditions were
ence between the in situ generated formimidate inter- also applicable to the synthesis of N-alkyl-b-enamino-
mediates that stay coordinated to Cu and free form- nitriles. This efficient, atom-economical, and operati-
imidates. The direct reaction between an isocyanide cally simple synthetic protocol for N-alkyl/aryl substi-
tuted b-enaminonitriles can be applied to the synthe-
sis of diverse of heterocycles.
Experimental Section
General Information
Unless otherwise noted, all reactions were carried out using
standard Schlenk techniques or in an argon-filled glove box.
All anhydrous solvents were purchased from commercial
suppliers and degassed with dry argon before usage. tert-
Butyl isocyanide and cyclohexyl isocyanide were purchased
from commercial suppliers and used as received without fur-
ther purification, and other aryl isocyanides were synthe-
Scheme 5. Transformation of b-enaminonitrile 3aa.
sized from the corresponding amines following the literature
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Copper-Catalyzed N-Aryl-b-enaminonitrile Synthesis Utilizing Isocyanides
procedures.[29] Compounds 1q,[22] 2b,[30] 2g,[30] and 2i[31] were
prepared by the methods reported in the literature, and all
other arylacetonitriles were purchased from commercial
suppliers. HR-MS analyses were performed at the National
Center for Inter-university Research Facilities (NCIRF) at
Seoul National University and at the Daegu Center of the
Korea Basic Science Institute (KBSI). The absolute configu-
ration of the product 3aa was determined by X-ray crystal-
lography performed at the Western Seoul Center of the
KBSI.
DMSO-d6) d=9.64 (d, J=12.8 Hz, 1H), 8.05 (d, J=13.0 Hz,
1H), 7.51 (d, J=7.5 Hz, 2H), 7.35 (t, J=7.7 Hz, 2H), 7.28
(d, J=8.5 Hz, 2H), 7.20–7.16 (m, 1H), 7.11 (d, J=8.3 Hz,
2H), 2.25 (s, 3H); 13C NMR (75 MHz, DMSO-d6): d=142.4,
138.8, 134.4, 131.4, 129.7, 128.8, 125.4, 123.6, 118.5, 116.4,
82.1, 20.3; HR-MS-FAB: m/z=233.1077 [MÀH]À, calcd. for
C16H13N2: 233.1084.
(Z)-2-Phenyl-3-(phenylamino)acrylonitrile (3ba):[19b] Light
yellow solid; yield: 83 mg (94%); 1H NMR (300 MHz,
DMSO-d6) d=9.70 (d, J=10.4 Hz, 1H), 8.10 (d, J=11.3 Hz,
1H), 7.52 (d, J=7.3 Hz, 2H), 7.43–7.34 (m, 4H), 7.32 (t, J=
8.5 Hz, 2H), 7.19 (t, J=7.2 Hz, 1H), 7.01 (t, J=7.2 Hz, 1H);
13C NMR (75 MHz, DMSO-d6): d=142.2, 141.2, 134.2,
129.3, 128.8, 125.6, 123.7, 122.4, 118.4, 116.4, 82.8; HR-MS-
FAB: m/z=219.0919 [MÀH]À, calcd. C15H11N2: 219.0928.
(Z)-3-(Mesitylamino)-2-phenylacrylonitrile (3ca): Light
General Procedure for N-Aryl/alkyl-b-enaminonitrile
Synthesis
To an oven-dried 4-mL vial equipped with a stirring bar,
CuI (3.8 mg, 0.02 mmol) and potassium tert-butoxide
(53.9 mg, 0.48 mmol) were added inside a glove box. Then,
the vial was sealed with a septum screw cap and taken out
of the box. Anhydrous DME (0.8 mL), 2 (0.56 mmol), and
1 (0.40 mmol) were added successively to the vial. If solid
1 or 2 was used, solutions of each substrate in DME were
prepared under inert conditions, and then added to the vial.
In those cases, the overall volume of solvent was maintained
as in the original procedure. The resulting reaction mixture
was stirred for 8–16 h at 558C. Crude products were purified
via silica gel column chromatography.
1
orange solid; yield: 93 mg (88%); H NMR (300 MHz, ace-
tone-d6): d=7.77 (d, J=12.8 Hz, 1H), 7.55 (d, J=13.0 Hz,
1H), 7.42 (d, J=7.3 Hz, 2H), 7.35–7.26 (m, 2H), 7.11 (tt,
J=7.2, 1.3 Hz, 1H), 6.95 (s, 2H), 2.31 (s, 6H), 2.27 (s, 3H);
13C NMR (75 MHz, acetone-d6): d=149.5, 137.2, 136.9,
135.9, 135.5, 130.0, 129.7, 125.9, 124.0, 118.7, 81.4, 21.0, 18.6;
HR-MS-FAB: m/z=261.1393 [MÀH]À, calcd. for C18H17N2,
261.1397.
(Z)-3-[(2,6-Diisopropylphenyl)amino]-2-phenylacryloni-
trile (3da): Light green solid; 104 mg (85%); 1H NMR
(400 MHz, DMSO-d6): d=8.95 (d, J=12.1 Hz, 1H), 7.57
(br. s., 1H), 7.36 (d, J=7.4 Hz, 2H), 7.34–7.24 (m, 3H), 7.19
(d, J=7.4 Hz, 2H), 7.07 (t, J=7.0 Hz, 1H), 3.21 (spt, J=
5.9 Hz, 2H), 1.19 (d, J=6.7 Hz, 12H); 13C NMR (75 MHz,
DMSO-d6): d=150.3 (br. s), 146.1, 136.5 (br. s), 134.7 (br.
s), 128.8, 128.0 (br. s), 124.5, 123.3, 122.7, 118.7 (br. s), 77.9
(br. s), 27.8, 23.4; HR-MS-FAB: m/z=303.1859 [MÀH]À,
calcd. for C21H23N2: 303.1867.
General Procedure for 3-Oxo-2-phenylpropanenitrile
(4) Synthesis
To a solution of 3aa (46.9 mg, 0.20 mmol) in THF (2 mL)
was added 7% HCl aqueous solution (3 mL). The reaction
mixture was stirred for 17 h at 408C. After cooling to room
temperature, the reaction mixture was extracted with
EtOAc. The organic layer was separated, dried over with
anhydrous MgSO4 and concentrated under reduced pres-
sure. Crude products were purified via silica gel column
chromatography.
(Z)-3-(Naphthalen-1-ylamino)-2-phenylacrylonitrile (3ea):
1
Light yellow solid; yield: 92 mg (85%); H NMR (300 MHz,
DMSO-d6): d=9.67 (d, J=10.2 Hz, 1H), 8.27–8.18 (m, 1H),
8.06 (d, J=10.0 Hz, 1H), 7.99–7.90 (m, 1H), 7.73 (d, J=
7.7 Hz, 1H), 7.63–7.55 (m, 2H), 7.54–7.43 (m, 4H), 7.36 (t,
J=7.6 Hz, 2H), 7.18 (t, J=7.2 Hz, 1H); 13C NMR (75 MHz,
DMSO-d6): d=145.5, 137.5, 134.4, 133.9, 128.9, 128.1, 126.5,
126.3, 126.0, 125.9, 125.6, 124.4, 123.6, 122.7, 118.4, 116.6,
83.6; HR-MS-FAB: m/z=269.1076 [MÀH]À, calcd. for
C19H13N2: 269.1084.
General Procedure for 4-Phenyl-1H-pyrazol-3-amine
(5) Synthesis
3aa (93.7 mg, 0.40 mmol) was treated with N2H4·H2O
(38.8 mL, 0.80 mmol) and five drops of acetic acid in ethanol
(0.5 mL) then heated under the microwave irradiation for
4 min at 2508C. After cooling to room temperature, the re-
sulting mixture was diluted by EtOAc and a saturated solu-
tion of NaHCO3 was added. The reaction mixture was ex-
tracted with EtOAc. The organic layer was separated, dried
with anhydrous MgSO4 and concentrated under reduced
pressure. Crude products were purified via silica gel column
chromatography.
(Z)-3-([1,1’-Biphenyl]-2-ylamino)-2-phenylacrylonitrile
(3fa): Light green solid; yield: 83 mg (70%); 1H NMR
(300 MHz, DMSO-d6): d=8.27 (d, J=13.0 Hz, 1H), 8.00 (d,
J=13.2 Hz, 1H), 7.58 (t, J=7.5 Hz, 2H), 7.55–7.38 (m, 6H),
7.34–7.29 (m, 4H), 7.22 (d, J=7.3 Hz, 1H), 7.19–7.11 (m,
1H); 13C NMR (75 MHz, DMSO-d6): d=143.8, 137.9, 137.4,
133.6, 131.6, 130.8, 129.1, 129.0, 128.8, 128.7, 127.7, 125.6,
123.8, 123.4, 118.7, 117.8, 82.8; HR-MS-FAB: m/z=295.1235
[MÀH]À, calcd. for C21H15N2: 295.1241.
Characterization Data
(Z)-3-[(4-Bromophenyl)amino]-2-phenylacrylonitrile
(3ga): Light yellow solid; yield: 116 mg (97%); 1H NMR
(300 MHz, DMSO-d6): d=9.77 (d, J=12.6 Hz, 1H), 8.07 (d,
J=12.6 Hz, 1H), 7.53 (d, J=8.5 Hz, 2H), 7.46 (d, J=9.0 Hz,
2H), 7.42–7.32 (m, 4H), 7.19 (t, J=7.5 Hz, 1H); 13C NMR
(75 MHz, DMSO-d6): d=141.8, 140.6, 134.0, 131.9, 128.8,
125.8, 123.8, 118.4, 118.1, 114.0, 83.8; HR-MS-FAB: m/z=
297.0021 [MÀH]À, calcd. for C15H10BrN2: 297.0033.
Reactions for b-enaminonitriles were performed in
0.40 mmol scale. All compounds were identified by 1H,
13C NMR. All new compounds were further identified by
HR-MS. All reported compounds, 3ba,[19b] 3ha,[19b] 3la,[19b]
4,[32] and 5[19a] were also identified by spectral comparison
with literature data.
(Z)-2-Phenyl-3-(para-tolylamino)acrylonitrile (3aa): Light
yellow solid; yield: 88 mg (94%); 1H NMR (300 MHz,
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Seoksun Kim and Soon Hyeok Hong
(Z)-3-[(4-Chlorophenyl)amino]-2-phenylacrylonitrile
DMSO-d6): d=7.65 (d, J=14.1 Hz, 1H), 7.33 (d, J=7.3 Hz,
2H), 7.27 (t, J=8.1 Hz, 2H), 7.09–6.98 (m, 2H), 1.30 (s,
9H); 13C NMR (75 MHz, DMSO-d6): d=146.4, 135.4, 128.7,
124.1, 122.5, 119.4, 75.9, 52.9, 29.6; HR-MS-FAB: m/z=
223.1210 [M+H]À, calcd. for C13H16N2Na: 223.1206.
1
(3ha):[19b] Light brown solid; yield: 88 mg (86%); H NMR
(300 MHz, DMSO-d6): d=9.79 (d, J=12.6 Hz, 1H), 8.08 (d,
J=12.8 Hz, 1H), 7.53 (d, J=7.3 Hz, 2H), 7.43 (d, J=9.0 Hz,
2H), 7.39–7.30 (m, 4H), 7.18 (t, J=7.2 Hz, 1H); 13C NMR
(75 MHz, DMSO-d6): d=141.9, 140.2, 134.0, 129.0, 128.8,
126.1, 125.7, 123.8, 118.1, 117.9, 83.7; HR-MS-FAB: m/z=
253.0535 [MÀH]À, calcd. for C15H10ClN2: 253.0538.
(Z)-3-(Cyclohexylamino)-2-phenylacrylonitrile
(3pa):
White solid; yield: 60 mg 66%); 1H NMR (300 MHz, ace-
tone-d6): d=7.69 (d, J=13.6 Hz, 1H), 7.38–7.19 (m, 4H),
7.0(5 (tt, J=7.2, 1.3 Hz, 1H), 6.27 (br. s., 1H), 3.43–3.27 (m,
1H), 2.03–1.94 (m, 2H), 1.84–1.72 (m, 2H), 1.68–1.57 (m,
1H), 1.56–1.39 (m, 2H), 1.39–1.26 (m, 2H), 1.25–1.13 (m,
1H); 13C NMR (75 MHz, acetone-d6): d=149.1, 136.4, 129.5,
125.1, 123.4, 119.5, 78.2, 58.1, 34.7, 25.9, 25.8; HR-MS-FAB:
m/z=225.1392 [MÀH]À, calcd. for C15H17N2: 225.1397.
(Z)-3-(Octylamino)-2-phenylacrylonitrile (3qa): White
Ethyl
(Z)-4-((2-cyano-2-phenylvinyl)amino)benzoate
(3ia): Light yellow solid; yield: 90 mg (77%); 1H NMR
(300 MHz, DMSO-d6): d=10.03 (d, J=12.4 Hz, 1H), 8.16
(d, J=12.4 Hz, 1H), 7.88 (d, J=8.9 Hz, 2H), 7.58–7.48 (m,
4H), 7.38 (t, J=7.7 Hz, 2H), 7.22 (t, J=7.2 Hz, 1H), 4.28
(q, J=7.1 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H); 13C NMR
(75 MHz, DMSO-d6): d=165.4, 145.3, 140.9, 133.7, 130.6,
128.8, 126.2, 124.1, 123.0, 117.8, 115.6, 85.7, 60.3, 14.2; HR-
MS-FAB: m/z=291.1139 [MÀH]À, calcd. for C18H15N2O2:
291.1139.
1
solid; yield: 62 mg (60%); H NMR (300 MHz, acetone-d6):
d=7.64 (d, J=13.6 Hz, 1H), 7.33 (d, J=7.2 Hz, 2H), 7.26 (t,
J=7.2 Hz, 2H), 7.05 (tt, J=1.0, 7.2 Hz, 1H), 6.47 (s, 1H),
3.40 (q, J=6.8 Hz, 2H), 1.65 (quin, J=7.1 Hz, 2H), 1.47–
1.21 (m, 10H), 0.98–0.81 (m, 3H); 13C NMR (75 MHz, ace-
tone-d6): d=150.9, 136.4, 129.6, 125.1, 123.4, 119.6, 78.0,
49.0, 32.6, 32.1, 30.0, 30.0, 27.2, 23.3, 14.4; HR-MS-FAB:
m/z=279.1831 [MÀH]À, calcd. for C17H24N2Na: 279.1837.
(Z)-2-(Naphthalen-2-yl)-3-(para-tolylamino)acrylonitrile
(3ab): Light orange solid; yield: 101 mg (89%); 1H NMR
(499 MHz, DMSO-d6): d=9.73 (d, J=13.2 Hz, 1H), 8.24 (d,
J=12.7 Hz, 1H), 7.91 (s, 1H), 7.90–7.84 (m, 3H), 7.79 (dd,
J=8.8, 2.0 Hz, 1H), 7.49 (t, J=7.6 Hz, 1H), 7.42 (t, J=
7.6 Hz, 1H), 7.34 (d, J=8.3 Hz, 2H), 7.14 (d, J=8.3 Hz,
2H), 2.26 (s, 3H); 13C NMR (75 MHz, DMSO-d6): d=142.7,
138.8, 133.4, 132.0, 131.5, 131.2, 129.7, 128.3, 127.5, 127.3,
126.5, 125.1, 122.4, 121.0, 118.5, 116.5, 82.2, 20.3; HR-MS-
FAB: m/z=283.1241 [MÀH]À, calcd. for C20H15N2:
283.1241.
(Z)-2-(4-Bromophenyl)-3-(para-tolylamino)acrylonitrile
(3ac): Light yellow solid; 125 mg (>99%); 1H NMR
(499 MHz, DMSO-d6): d=9.72 (d, J=12.7 Hz, 1H), 8.11 (d,
J=13.2 Hz, 1H), 7.51 (d, J=7.8 Hz, 2H), 7.47–7.44 (m,
2H), 7.29 (d, J=8.3 Hz, 2H), 7.12 (d, J=8.3 Hz, 2H), 2.25
(s, 3H); 13C NMR (75 MHz, DMSO-d6): d=143.0, 138.6,
133.9, 131.6, 131.5, 129.6, 125.4, 118.1, 117.8, 116.6, 80.8,
20.3; HR-MS-FAB: m/z=311.0180 [MÀH]À, calcd. for
C16H12BrN2: 311.0189.
(Z)-4-[(2-Cyano-2-phenylvinyl)amino]benzonitrile (3ja):
1
Light yellow solid; yield: 74 mg (76%); H NMR (300 MHz,
DMSO-d6): d=10.07 (d, J=12.4 Hz, 1H), 8.18 (d, J=
12.2 Hz, 1H), 7.74 (d, J=8.7 Hz, 2H), 7.62–7.52 (m, 4H),
7.39 (t, J=7.7 Hz, 2H), 7.23 (t, J=7.2 Hz, 1H); 13C NMR
(75 MHz, DMSO-d6): d=145.1, 140.7, 133.6, 133.4, 128.9,
126.4, 124.2, 119.3, 117.6, 116.4, 103.4, 86.5; HR-MS-FAB:
m/z=244.0879 [MÀH]À, calcd. for C16H10N3: 244.0880.
(Z)-2-Phenyl-3-(pyridin-3-ylamino)acrylonitrile
(3ka):
1
Light yellow solid; yield: 40 mg (46%); H NMR (300 MHz,
DMSO-d6): d=9.79 (br. s., 1H), 8.67 (br. s. , 1H), 8.23–8.11
(m, 2H), 7.80 (dd, J=7.9, 2.1 Hz, 1H), 7.54 (d, J=7.9 Hz,
2H), 7.41–7.28 (m, 3H), 7.20 (t, J=7.2 Hz, 1H); 13C NMR
(75 MHz, DMSO-d6): d=143.2, 141.9, 138.8, 137.8, 133.8,
128.8, 125.9, 123.9, 123.8, 122.9, 118.0, 84.4; HR-MS-FAB:
m/z=220.0876 [MÀH]À, calcd. for C14H11N3: 220.0880.
(Z)-3-[(4-Methoxyphenyl)amino]-2-phenylacrylonitrile
1
(3la):[19b] Light yellow solid; yield: 82 mg (82%); H NMR
(499 MHz, DMSO-d6): d=9.56 (br. s. , 1H), 8.00 (s, 1H),
7.48 (d, J=7.8 Hz, 2H), 7.36–7.29 (m, 4H), 7.15 (t, J=
7.7 Hz, 1H), 6.90 (d, J=9.3 Hz, 2H), 3.73 (s, 3H); 13C NMR
(75 MHz, acetone-d6): d=156.7, 143.0, 135.4, 135.3, 129.6,
126.3, 124.4, 118.7, 118.6, 115.5, 83.7, 55.7; HR-MS-FAB:
m/z=249.1029 [MÀH]À, calcd. for C16H13N2O: 249.1033.
(Z)-3-[(2-Bromophenyl)amino]-2-phenylacrylonitrile
(3ma): Light green solid; yield: 83 mg (69%); 1H NMR
(300 MHz, acetone-d6): d=8.29 (d, J=13.0 Hz, 1H), 7.72 (d,
J=12.4 Hz, 1H), 7.63 (td, J=8.5, 1.4 Hz, 2H), 7.59–7.53 (m,
2H), 7.45–7.34 (m, 3H), 7.24 (tt, J=7.5, 1.9 Hz, 1H), 7.00
(td, J=7.7, 1.5 Hz, 1H); 13C NMR (75 MHz, acetone-d6):
d=140.8, 138.6, 133.9, 133.8, 130.0, 129.8, 127.4, 125.0, 124.7,
117.7, 116.8, 112.4, 88.5; HR-MS-FAB: m/z=297.0019
[MÀH]À, calcd. for C15H10BrN2: 297.0033.
(Z)-2-(4-Chlorophenyl)-3-(para-tolylamino)acrylonitrile
1
(3ad): Light yellow solid; 95 mg (88%); H NMR (499 MHz,
DMSO-d6): d=9.71 (d, J=13.2 Hz, 1H), 8.10 (d, J=
13.2 Hz, 1H), 7.54–7.50 (m, 2H), 7.40–7.36 (m, 2H), 7.29 (d,
J=8.8 Hz, 2H), 7.12 (d, J=8.3 Hz, 2H), 2.25 (s, 3H);
13C NMR (75 MHz, DMSO-d6): d=143.0, 138.6, 133.4,
131.6, 129.6, 129.5, 128.6, 125.0, 118.2, 116.6, 80.8, 20.3; HR-
MS-FAB: m/z=267.0689 [MÀH]À, calcd. for C16H12ClN2:
267.0694.
(Z)-3-[(2-Methoxyphenyl)amino]-2-phenylacrylonitrile
(3na): Light yellow solid; yield: 91 mg (90%); 1H NMR
(300 MHz, DMSO-d6): d=8.34 (d, J=13.4 Hz, 1H), 7.96 (d,
J=13.4 Hz, 1H), 7.58–7.49 (m, 3H), 7.36 (t, J=7.8 Hz, 2H),
7.18 (t, J=7.2 Hz, 1H), 7.10–6.92 (m, 3H), 3.89 (s, 3H);
13C NMR (75 MHz, DMSO-d6): d=147.6, 141.5, 133.3,
129.0, 128.9, 125.7, 123.5, 123.1, 121.0, 117.9, 115.2, 111.4,
83.8, 56.0; HR-MS-FAB: m/z=249.1029 [MÀH]À, calcd. for
C16H13N2O: 249.1033.
(Z)-2-(2-Fluorophenyl)-3-(para-tolylamino)acrylonitrile
1
(3ae): White solid; yield: 86 mg (86%); H NMR (300 MHz,
DMSO-d6): d=9.74 (d, J=13.0 Hz, 1H), 7.89 (d, J=
13.0 Hz, 1H), 7.54–7.43 (m, 1H), 7.32–7.16 (m, 5H), 7.11 (d,
J=8.7 Hz, 2H), 2.24 (s, 3H); 13C NMR (75 MHz, DMSO-
d6): d=158.5 (d, J=245.4 Hz), 145.8 (d, J=6.5 Hz), 138.6,
131.7, 129.7, 128.4 (d, J=2.4 Hz), 127.6 (d, J=8.1 Hz), 124.8
(d, J=3.2 Hz), 122.4 (d, J=11.3 Hz), 118.0, 116.5, 115.9 (d,
J=21.8 Hz), 75.8, 20.2; HR-MS-FAB: m/z=251.0989
[MÀH]À, calcd. for C16H12FN2: 251.0990.
(Z)-3-(tert-Butylamino)-2-phenylacrylonitrile (3oa): Light
yellow solid; yield: 58 mg (73%); 1H NMR (300 MHz,
1010
asc.wiley-vch.de
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Adv. Synth. Catal. 2015, 357, 1004 – 1012

FULL PAPERS
Copper-Catalyzed N-Aryl-b-enaminonitrile Synthesis Utilizing Isocyanides
(Z)-2-(Pyridin-2-yl)-3-(para-tolylamino)acrylonitrile (3af):
Light yellow solid; yield: 77 mg (86%); H NMR (300 MHz,
was supported by the National Research Foundation of
Korea (NRF-2014R1A2A1A11050028; NRF-2014S1A2-
1
DMSO-d6): major isomer: d=12.51 (d, J=12.6 Hz, 1H),
8.62 (d, J=4.1 Hz, 1H), 8.28 (d, J=12.4 Hz, 1H), 7.87 (td,
J=7.8, 1.7 Hz, 1H), 7.39 (d, J=8.3 Hz, 1H), 7.30 (d, J=
8.3 Hz, 2H), 7.22 (t, J=6.2 Hz, 1H), 7.17 (d, J=8.1 Hz,
2H), 2.27 (s, 3H); minor isomer: d=10.03 (d, J=13.6 Hz,
1H), 8.57 (d, J=13.8 Hz, 1H), 8.45 (d, J=4.7 Hz, 1H), 7.73
(td, J=8.5, 1.9 Hz, 1H), 7.43–7.36 (m, 1H), 7.27–7.07 (m,
5H), 2.27 (s, 3H); 13C NMR (75 MHz, DMSO-d6): d=155.0,
147.8, 145.1, 137.6, 137.2, 132.7, 130.0, 120.7, 119.9, 119.3,
116.4, 79.7, 20.3; HR-MS-FAB: m/z=236.1187 [MÀH]À,
calcd. for C15H14N3: 236.1182.
A2028156; NRF-2014R1A5A1011165, Center for New Direc-
tions in Organic Synthesis), funded by the Korean Govern-
ment.
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(Z)-2-(4-Methoxyphenyl)-3-(para-tolylamino)acrylonitrile
(3ah): Light yellow solid; yield: 82 mg (77%); 1H NMR
(300 MHz, DMSO-d6): d=9.45 (d, J=12.8 Hz, 1H), 7.90 (d,
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2H), 7.10 (d, J=8.3 Hz, 2H), 6.93 (d, J=8.9 Hz, 2H), 3.75
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157.5, 141.1, 139.0, 130.9, 129.6, 126.6, 125.0, 118.7, 116.1,
114.3, 82.0, 55.1, 20.2; HR-MS-FAB: m/z=264.1263 [M]+,
calcd. for C17H16N2O: 264.1263.
tert-Butyl (Z)-{4-[1-cyano-2-(para-tolylamino)vinyl]phe-
nyl}carbamate (3ai): Light yellow solid; yield: 78 mg (56%);
1H NMR (300 MHz, DMSO-d6): d=9.48 (d, J=12.8 Hz,
1H), 9.32 (s, 1H), 7.92 (d, J=12.8 Hz, 1H), 7.43 (d, J=
9.0 Hz, 2H), 7.37 (d, J=9.0 Hz, 2H), 7.24 (d, J=8.7 Hz,
2H), 7.10 (d, J=8.3 Hz, 2H), 2.25 (s, 3H), 1.47 (s, 9H);
13C NMR (75 MHz, DMSO-d6): d=152.7, 141.2, 138.9,
137.3, 131.0, 129.6, 127.9, 123.9, 118.5, 116.2, 82.1, 79.0, 28.1,
20.2; HR-MS-FAB: m/z=348.1716 [MÀH]À, calcd. for
C21H22N3O2: 348.1718.
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7.30 (m, 3.1H), 7.24 (q, J=7.2 Hz, 1H); 13C NMR (75 MHz,
DMSO-d6): d=159.5, 158.0, 132.2, 131.6, 128.9, 128.6, 126.8,
126.6, 126.5, 124.1, 120.2, 116.8, 89.8, 89.5.
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The Supporting Information contains spectroscopic data for
the new compounds.
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X-ray crystallography and helpful discussions. This research
Adv. Synth. Catal. 2015, 357, 1004 – 1012
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1011

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