Palladium-catalyzed carbonylative sonogashira coupling of aryl bromides via tert -butyl isocyanide insertion

Article abstract of DOI:10.1021/jo4001096

A simple and efficient palladium-catalyzed carbonylative Sonogashira coupling via tert-butyl isocyanide insertion has been developed, which demonstrates the utility of isocyanides in intermolecular C-C bond construction. This methodology provides a novel pathway for the synthesis of alkynyl imines which can undergo simple silica gel catalyzed hydrolysis to afford alkynones. The approach is tolerant of a wide range of substrates and applicable to library synthesis.

Full text of DOI:10.1021/jo4001096

Article
pubs.acs.org/joc
Palladium-Catalyzed Carbonylative Sonogashira Coupling of Aryl
Bromides via tert-Butyl Isocyanide Insertion
Ting Tang,† Xiang-Dong Fei,† Zhi-Yuan Ge,† Zhong Chen,† Yong-Ming Zhu,*,† and Shun-Jun Ji*,‡
‡
†College of Pharmaceutical Sciences and College of Chemistry, Chemical Engineering and Materials Science, Soochow University,
Suzhou 215123, People’s Republic of China
S
* Supporting Information
ABSTRACT: A simple and efficient palladium-catalyzed carbonylative Sonogashira coupling via tert-butyl isocyanide insertion
has been developed, which demonstrates the utility of isocyanides in intermolecular C−C bond construction. This methodology
provides a novel pathway for the synthesis of alkynyl imines which can undergo simple silica gel catalyzed hydrolysis to afford
alkynones. The approach is tolerant of a wide range of substrates and applicable to library synthesis.
Scheme 1. Strategy to Alkynones via tert-Butyl Isocyanide
Insertion
INTRODUCTION
■
Within the past few decades, isocyanides have emerged as
powerful building blocks in modern synthetic organic
chemistry, with deep implications in the construction of
important medicinal molecules and natural products.1 Since
the pioneering work of Passerini2 and Ugi,3 isocyanide insertion
reactions have attracted the attention of many chemists. A vast
number of articles including two-component reactions4 and
multicomponent reactions (MCRs)5 have been reported.
On the other hand, owing to the great influence of transition-
metal-catalyzed coupling reactions on organic synthesis,
carbonylative coupling incorporating carbon monoxide has
been well established. Also, crystalline CO-releasing molecules
(CORMs) have been investigated to liberate CO for
application in carbonylation reactions.6 Isocyanide, a stable
and economic liquid compound which is isoelectronic with
carbon monoxide, can be considered to replace carbon
monoxide in coupling reactions. So far, a number of
transition-metal-catalyzed coupling reactions via the insertion
of isocyanides to form C−N7,8 and C−O9 bonds have been
investigated. For example, Huang and co-workers have reported
a palladium-catalyzed cyclization reaction of isocyanides with o-
halobenzamides.7g Very recently, our group developed a simple
and facile method for the synthesis of substituted lactones with
1-(2-bromophenyl)ethanones and tert-butyl isocyanide, in
which isocyanide was easily coupled with an enolic oxygen
atom.9b Nevertheless, reactions via isocyanide insertion to form
C−C bonds have been rarely described. Only recently did the
groups of Chatani4b and Takemoto4e report related reactions
with isocyanides. On the basis of these findings, we surmised
that it might be possible for the insertion of isocyanides into
aryl bromides and terminal alkynes to construct intermolecular
C−C bonds to generate alkynones (Scheme 1). Herein, we
report a palladium-catalyzed coupling of aryl bromides and
terminal alkynes via tert-butyl isocyanide insertion, which
discloses the utility of isocyanides in intermolecular C−C bond
construction. To the best of our knowledge, there have been no
reports of carbonylative Sonogashira coupling from isocyanides.
Due to the importance of alkynones, they appear in various
biologically active molecules10 and also constitute key
intermediates in the synthesis of natural products.11 The
traditional route to prepare alkynones involves the reaction of
alkynes with acid chloride.12 An alternative approach is the
palladium-catalyzed carbonylative coupling of alkynes with aryl
halides,13,14 aryl triflates,15 or aryl amines16 in the presence of
carbon monoxide. However, the drawbacks of high toxicity,
harsh reaction conditions, and modest tolerance of functional
groups have limited their application. Hence, our methodology
may represent a valuable example for the synthesis of alkynones
because of the advantage over other methods of simple
handling, wide substrate scope, and mild conditions.
RESULTS AND DISCUSSION
■
In a pilot experiment, bromobenzene and phenylacetylene were
reacted with tert-butyl isocyanide in the presence of Pd(OAc)2
and DPEPhos with K2CO3 as base. When the reaction was
Received: January 17, 2013
Published: February 25, 2013
© 2013 American Chemical Society
3170
dx.doi.org/10.1021/jo4001096 | J. Org. Chem. 2013, 78, 3170−3175

The Journal of Organic Chemistry
Article
performed in DMF at 100 °C for 2 h, the desired product N-
(1,3-diphenylprop-2-ynylidene)-2-methylpropan-2-amine (3aa)
was formed in 52% yield (Table 1, entry 1). Then, the bases for
(Table 2, entries 1−10). To our delight, bromoarenes
containing sensitive functional groups such as p-Cl and p-
COOCH3 and strongly electron deficient groups such as p-CF3
and p-NO2 were all coupled smoothly (Table 2, entries 7−10).
In addition, disubstituted aryl bromides were also efficiently
transformed into the desired products (Table 2, entries 11 and
12). Furthermore, 2-bromonaphthalene, 4-bromobiphenyl, and
several heteroaromatic substrates were successfully converted
into the corresponding products in good yields (Table 2,
entries 13−18). In addition, 1,4-dibromobenzene bearing two
bromo substituents could undergo isocyanide insertion twice,
thus demonstrating the ultility of the present scaffold (Table 2,
entry 19).
To further explore the scope and generality of this approach,
a variety of alkynes were investigated, and the results are
summarized in Table 3. Both aromatic and aliphatic alkynes
were successfully coupled with tert-butyl isocyanide (Table 3,
entries 1−6). Electron-rich and electron-poor substituents were
well tolerated and led to good yields (Table 3, entries 1−4).
But aliphatic alkynes resulted in lower yields of the desired
product (Table 3, entries 5 and 6). Note that the intermediate
alkynyl imines of o-bromotoluene (Table 2, entry 3) and
aliphatic alkynes (Table 3, entries 5 and 6) generated the
byproducts of C−C triple bond hydration in the hydrolysis
step, which led to diminished yields.
a
Table 1. Condition Optimizations
b
entry
catalyst
ligand
base
solvent
yield (%)
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
DPEPhos
DPEPhos
DPEPhos
DPEPhos
DPEPhos
DPEPhos
Xantphos
X-Phos
K2CO3
DMF
52
69
0
2
Cs2CO3
t-BuONa
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF
3
DMF
4
DMSO
dioxane
toluene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
96
56
71
75
41
84
trace
0
5
6
7
8
9
(R)-BINAP
DPPF
10
11
12
13
14
15
DPPP
BuPAd2
87
33
79
86
PCy3
A plausible mechanism for this reaction is depicted in
Scheme 2. Oxidative addition of 1a to the Pd(0) catalyst leads
to the palladium complex 5, followed by tert-butyl isocyanide
insertion to form 6. With the assistance of Cs2CO3, the
bromide is exchanged by phenylacetylide, which leads to the
generation of 7. Reductive elimination of 7 gives the
intermediate 3aa, which yields the terminal product 4aa by
silica gel catalyzed hydrolysis.
DPEPhos
DPEPhos
Pd2(dba)3
a
Reaction conditions: all reactions were performed with 1a (0.5
mmol), 2a (0.6 mmol), tert-butyl isocyanide (0.6 mmol), catalyst
(0.015 mmol), ligand (0.03 mmol), and base (1.0 mmol) in 2.0 mL of
solvent at 100 °C for 2 h. Abbreviations: DPEPhos = bis[(2-
diphenylphosphino)phenyl] ether, Xantphos
= 4,5-bis-
(diphenylphosphino)-9,9-dimethylxanthene, X-Phos =2-(dicyclohexyl-
phosphino)-2′,4′,6′-triisopropylbiphenyl, (R)-BINAP = (R)-2,2′-bis-
(diphenylphosphino)-1,1′-binaphthyl, DPPF = 1,1′-bis(diphenyl-
phosphino)ferrocene, DPPP = 1,3-bis(diphenylphosphino)propane.
CONCLUSIONS
■
b
In summary, we have developed a simple and efficient
palladium-catalyzed carbonylative Sonogashira coupling via
tert-butyl isocyanide insertion, which sets an example of
isocyanides as carbonyl sources in catalytic C−C bond
construction. This methodology provides a novel pathway for
the synthesis of alkynones via Pd(OAc)2/DPEPhos-catalyzed
coupling reactions and subsequent silica gel catalyzed
hydrolysis. Characterized by wide substrate scope, mild reaction
conditions, and good to excellent yields, this protocol may aid
the further development of the reactions incorporating
isocyanides. Related studies are underway in our laboratory.
Isolated by neutral alumina chromatography.
the activity of the reaction were examined. To our delight, the
yield was improved to 69% when Cs2CO3 was used (Table 1,
entries 2 and 3). Solvent screening revealed that DMSO
appeared to be the best solvent and the yield was significantly
increased to 96% (Table 1, entries 4−6). Other commercially
available mono- and bidentate ligands were also tested to
improve the yield further. However, none of them were found
to compete with DPEPhos (Table 1, entries 7−13). In
comparison with Pd(OAc)2, other palladium sources such as
PdCl2 or Pd2(dba)3 resulted in diminished yields (Table 1,
entries 14 and 15). As for the hydrolysis conditions, a stronger
acid led to the addition of a C−C triple bond in comparison to
silica gel. Therefore, the optimal reaction conditions were
Pd(OAc)2 (3 mol %) and DPEPhos (6 mol %) as the catalyst
system, with Cs2CO3 (2 equiv) as the base and DMSO as the
solvent. Subsequently, silica gel catalyzed hydrolysis of 3aa
afforded alkynone 4aa in high yield.
With the optimized reaction conditions in hand, we then
extended the protocol with a range of commercially available
aryl bromides. As illustrated in Table 2, most substrates shown
gave clean conversion with no competing formation of
Sonogashira products. Both electron-withdrawing as well as
electron-donating substituents in the para, meta, and ortho
positions were well tolerated and the corresponding 1,3-
diarylalkynones were isolated in moderate to excellent yields
EXPERIMENTAL SECTION
■
General Remarks. Chemicals and reagents were purchased from
commercial suppliers and used without special instructions. All
anhydrous solvents used in the reactions were dried and freshly
distilled. TLC was performed on silica HSGF254 plates. Melting
points were determined with a digital melting-point apparatus. 1H and
13C NMR spectra were obtained from a solution in CDCl3 with TMS
as internal standard using a 400/101 MHz (1H/13C) or 300/75 MHz
(1H/13C) spectrometer. Chemical shifts (δ) are given in ppm and J in
Hz. HRMS analyses were carried out on an electrospray ionization
(ESI) apparatus using time-of-flight (TOF) mass spectrometry.
General Procedure for the Synthesis of Alkynones. In a 15
mL sealed tube equipped with a magnetic stirring bar were added 1
(0.5 mmol), 2 (0.6 mmol), tert-butyl isocyanide (0.6 mmol, 68 μL),
Pd(OAc)2 (0.015 mmol, 3 mg), DPEPhos (0.03 mmol, 16 mg),
Cs2CO3 (1.0 mmol, 326 mg), and anhydrous DMSO (2.0 mL). The
tube was purged with argon, and the contents were stirred at 100 °C
3171
dx.doi.org/10.1021/jo4001096 | J. Org. Chem. 2013, 78, 3170−3175

The Journal of Organic Chemistry
Article
Table 2. Carbonylative Sonogashira Coupling of Various Aryl Bromides with Phenylacetylene via tert-Butyl Isocyanide
a
Insertion
a
All reactions were performed under argon on a 0.5 mmol scale, using aryl bromides (0.5 mmol), phenylacetylene (0.6 mmol), tert-butyl isocyanide
(0.6 mmol), Pd(OAc)2 (0.015 mmol), DPEPhos (0.03 mmol), and Cs2CO3 (1.0 mmol) in DMSO (2.0 mL) at 100 °C for 2 h, followed by stirring
b
in methylene dichloride with silica gel at room temperature overnight. Stirring with silica gel for 48 h.
for 2 h. After completion of the reaction as indicated by TLC, the
mixture was filtered through neutral aluminum oxide and the solvent
was removed under vacuum. Then, the residue was stirred with silica
gel in methylene dichloride at room temperature overnight. The
resulting mixture was filtered and concentrated, and then the crude
product was purified by column chromatography on silica gel using
petroleum ether/EtOAc as eluent to provide the pure target product.
N-(1,3-Diphenylprop-2-ynylidene)-2-methylpropan-2-amine
1358, 1313, 1283, 1202, 1017, 758, 692, 670 cm−1. HRMS (ESI): m/z
calcd for C19H19N [M + H]+, 262.1596; found, 262.1591.
1,3-Diphenylprop-2-yn-1-one (4aa).14 Yellow oil (97 mg, 94%).
1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 7.8 Hz, 2H), 7.71−7.66
(m, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.6 Hz, 2H), 7.47 (d, J =
7.4 Hz, 1H), 7.41 (t, J = 7.4 Hz, 2H). 13C NMR (101 MHz, CDCl3): δ
177.9, 136.7, 134.0, 133.0, 130.7, 129.5, 128.6, 128.5, 120.0, 93.0, 86.8.
LRMS (ESI): m/z calcd for C15H10O [M + H]+, 207.1; found, 207.1.
3-Phenyl-1-p-tolylprop-2-yn-1-one (4ab).17 Yellowish solid (85
mg, 77%); mp 63−65 °C. 1H NMR (400 MHz, CDCl3): δ 8.11 (d, J =
8.0 Hz, 2H), 7.68 (d, J = 7.2 Hz, 2H), 7.50−7.38 (m, 3H), 7.31 (d, J =
7.9 Hz, 2H), 2.44 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 177.7,
145.2, 134.6, 133.0, 130.6, 129.7, 129.3, 128.6, 120.2, 92.6, 86.9, 21.8.
LRMS (ESI): m/z calcd for C16H12O [M + H]+, 221.1; found, 221.1.
1
(3aa). White solid (125 mg, 96%); mp 59−61 °C. H NMR (400
MHz, CDCl3): δ 8.14−8.03 (m, 2H), 7.60 (dd, J = 7.4, 2.1 Hz, 2H),
7.47−7.38 (m, 6H), 1.56 (s, 9H). 13C NMR (101 MHz, CDCl3): δ
147.0, 139.4, 131.6, 130.0, 129.6, 128.6, 128.1, 127.2, 121.9, 98.9, 84.0,
56.9, 29.5. IR (KBr): ν 2965, 2201, 1599, 1591, 1569, 1488, 1445,
3172
dx.doi.org/10.1021/jo4001096 | J. Org. Chem. 2013, 78, 3170−3175

The Journal of Organic Chemistry
Article
3-Phenyl-1-o-tolylprop-2-yn-1-one (4ac).17 Yellow oil (36 mg,
33%). H NMR (400 MHz, CDCl3): δ 8.31 (d, J = 7.5 Hz, 1H), 7.65
Table 3. Carbonylative Sonogashira Coupling of
1
Bromobenzene with Various Alkynes via tert-Butyl
a
(d, J = 7.0 Hz, 2H), 7.50−7.33 (m, 5H), 7.28 (d, J = 7.2 Hz, 1H), 2.68
(s, 3H). 13C NMR (101 MHz, CDCl3): δ 179.7, 140.5, 135.6, 133.2,
132.9, 132.1, 130.6, 128.6, 125.8, 120.3, 91.8, 88.3, 22.0. LRMS (ESI):
m/z calcd for C16H12O [M + H]+, 221.1; found, 221.1.
Isocyanide Insertion
1-(4-Methoxyphenyl)-3-phenylprop-2-yn-1-one (4ad).14 White
1
solid (93 mg, 79%); mp 91−93 °C. H NMR (400 MHz, CDCl3):
δ 8.19 (d, J = 8.6 Hz, 2H), 7.67 (d, J = 7.3 Hz, 2H), 7.49−7.37 (m,
3H), 6.98 (d, J = 8.6 Hz, 2H), 3.89 (s, 3H). 13C NMR (101 MHz,
CDCl3): δ 176.6, 164.4, 132.9, 131.9, 130.5, 130.2, 128.6, 120.3, 113.8,
92.3, 86.9, 55.6. LRMS (ESI): m/z calcd for C16H12O2 [M + H]+,
237.1; found, 237.1.
1-(3-Methoxyphenyl)-3-phenylprop-2-yn-1-one (4ae).12c Yellow
oil (83 mg, 70%). 1H NMR (400 MHz, CDCl3): δ 7.86 (d, J = 7.5 Hz,
1H), 7.72−7.65 (m, 3H), 7.51−7.38 (m, 4H), 7.20−7.15 (m, 1H),
3.87 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 177.7, 159.7, 138.1,
133.0, 130.8, 129.6, 128.6, 122.8, 120.9, 120.0, 112.7, 92.9, 86.9, 55.4.
LRMS (ESI): m/z calcd for C16H12O2 [M + H]+, 237.1; found, 237.1.
1-(4-Fluorophenyl)-3-phenylprop-2-yn-1-one (4af).14 Yellowish
1
solid (109 mg, 97%); mp 47−49 °C. H NMR (400 MHz, CDCl3):
δ 8.25 (dd, J = 8.1, 5.7 Hz, 2H), 7.68 (d, J = 7.4 Hz, 2H), 7.53−7.39
(m, 3H), 7.19 (t, J = 8.4 Hz, 2H). 13C NMR (101 MHz, CDCl3): δ
176.3, 167.7, 165.1, 133.3, 133.0, 132.2, 132.1, 130.9, 128.7, 119.9,
115.9, 115.7, 93.3, 86.5. LRMS (ESI): m/z calcd for C15H9FO [M +
H]+, 225.1; found, 225.1.
1-(4-Chlorophenyl)-3-phenylprop-2-yn-1-one (4ag).12c Yellow
1
solid (83 mg, 69%); mp 96−98 °C. H NMR (400 MHz, CDCl3):
δ 8.15 (d, J = 8.3 Hz, 2H), 7.68 (d, J = 7.3 Hz, 2H), 7.48 (d, J = 8.1
Hz, 3H), 7.42 (t, J = 7.4 Hz, 2H). 13C NMR (101 MHz, CDCl3): δ
176.6, 140.6, 135.2, 133.1, 130.9, 130.8, 128.9, 128.7, 119.8, 93.6, 86.5.
LRMS (ESI): m/z calcd for C15H9ClO [M + H]+, 241.0; found, 241.0.
3-Phenyl-1-(4-(trifluoromethyl)phenyl)prop-2-yn-1-one (4ah).17
1
White solid (123 mg, 90%); mp 64−66 °C. H NMR (400 MHz,
CDCl3): δ 8.33 (d, J = 7.9 Hz, 2H), 7.79 (d, J = 7.9 Hz, 2H), 7.70 (d, J
= 7.4 Hz, 2H), 7.55−7.49 (m, 1H), 7.45 (t, J = 7.3 Hz, 2H). 13C NMR
(75 MHz, CDCl3): δ 176.7, 139.3, 135.3, 134.9, 133.2, 131.2, 129.8,
128.8, 125.7, 125.6, 125.3, 119.6, 94.4, 86.5. LRMS (ESI): m/z calcd
for C16H9F3O [M + H]+, 275.1; found, 275.1.
Methyl 4-(3-phenylpropioloyl)benzoate (4ai).17 White solid (95
mg, 72%); mp 95−97 °C. 1H NMR (400 MHz, CDCl3): δ 8.25 (d, J =
8.2 Hz, 2H), 8.16 (d, J = 8.2 Hz, 2H), 7.68 (d, J = 7.3 Hz, 2H), 7.52−
7.39 (m, 3H), 3.95 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 177.1,
166.0, 139.8, 134.6, 133.1, 131.0, 129.7, 129.3, 128.7, 119.7, 94.1, 86.7,
52.5. LRMS (ESI): m/z calcd for C17H12O3 [M + H]+, 265.1; found,
265.1.
a
All reactions were performed under argon on a 0.5 mmol scale, using
bromobenzene (0.5 mmol), alkynes (0.6 mmol), tert-butyl isocyanide
(0.6 mmol), Pd(OAc)2 (0.015 mmol), DPEPhos (0.03 mmol), and
Cs2CO3 (1.0 mmol) in DMSO (2.0 mL) at 100 °C for 2 h, followed
by stirring in methylene dichloride with silica gel at room temperature
overnight.
1-(4-Nitrophenyl)-3-phenylprop-2-yn-1-one (4aj).12c Yellow solid
(69 mg, 55%); mp 151−153 °C. 1H NMR (400 MHz, CDCl3): δ 8.37
(s, 4H), 7.71 (d, J = 7.3 Hz, 2H), 7.58−7.50 (m, 1H), 7.46 (t, J = 7.4
Hz, 2H). 13C NMR (101 MHz, CDCl3): δ 175.9, 150.8, 140.9, 133.3,
131.4, 130.4, 128.8, 123.8, 119.3, 95.4, 86.5. LRMS (ESI): m/z calcd
for C15H9NO3 [M + H]+, 252.1; found, 252.1.
Scheme 2. Plausible Mechanism for the Synthesis of 4aa
1-(3,5-Dimethylphenyl)-3-phenylprop-2-yn-1-one (4ak). Yellow-
1
ish oil (87 mg, 74%). H NMR (400 MHz, CDCl3): δ 7.83 (s, 2H),
7.69 (d, J = 7.3 Hz, 2H), 7.52−7.39 (m, 3H), 7.26 (s, 1H), 2.41 (s,
6H). 13C NMR (101 MHz, CDCl3): δ 178.4, 138.3, 136.9, 135.9,
133.0, 130.6, 128.6, 127.3, 120.2, 92.6, 87.1, 21.2. IR (KBr): ν 2208,
1638, 1605, 1490, 1315, 1170, 1159, 1070, 760, 744, 688 cm−1. HRMS
(ESI): m/z calcd for C17H14O [M + H]+, 235.1123; found, 235.1118.
1-(3,5-Difluorophenyl)-3-phenylprop-2-yn-1-one (4al). Yellowish
solid (112 mg, 93%); mp 79−81 °C. 1H NMR (400 MHz, CDCl3): δ
7.76−7.65 (m, 4H), 7.51 (t, J = 7.3 Hz, 1H), 7.43 (t, J = 7.5 Hz, 2H),
7.07 (t, J = 8.3 Hz, 1H). 13C NMR (101 MHz, CDCl3): δ 175.1, 164.2,
164.1, 161.7, 161.6, 139.7, 139.6, 139.6, 133.2, 131.3, 128.8, 119.4,
112.4, 112.3, 112.2, 112.1, 109.5, 109.3, 109.0, 94.4, 86.1. IR (KBr): ν
2205, 1642, 1591, 1439, 1321, 1151, 1123, 984, 858, 760, 739, 688
cm−1. HRMS (ESI): m/z calcd for C15H8F2O [M + Na]+, 265.0441;
found, 265.0440.
1-(Biphenyl-4-yl)-3-phenylprop-2-yn-1-one (4am). Yellow solid
1
(107 mg, 76%); mp 133−135 °C. H NMR (400 MHz, CDCl3): δ
3173
dx.doi.org/10.1021/jo4001096 | J. Org. Chem. 2013, 78, 3170−3175

The Journal of Organic Chemistry
Article
8.31 (d, J = 7.8 Hz, 2H), 7.78−7.69 (m, 4H), 7.66 (d, J = 7.2 Hz, 2H),
7.46 (dd, J = 17.3, 10.0 Hz, 6H). 13C NMR (101 MHz, CDCl3): δ
177.5, 146.7, 139.6, 135.6, 133.0, 130.7, 130.1, 128.9, 128.6, 128.4,
127.3, 127.2, 120.1, 93.1, 86.9. IR (KBr): ν 2203, 1635, 1603, 1486,
1311, 1287, 1213, 1172, 1033, 1010, 995, 846, 764, 739, 689 cm−1.
HRMS (ESI): m/z calcd for C21H14O [M + Na]+, 305.0942; found,
305.0946.
31.0. LRMS (ESI): m/z calcd for C19H18O [M + H]+, 263.1; found,
263.1.
3-(4-Fluorophenyl)-1-phenylprop-2-yn-1-one (4bd).19 White solid
1
(104 mg, 93%); mp 73−75 °C. H NMR (400 MHz, CDCl3): δ 8.24
(d, J = 7.5 Hz, 1H), 8.19 (d, J = 7.5 Hz, 1H), 7.74−7.46 (m, 5H),
7.18−7.05 (m, 2H). 13C NMR (101 MHz, CDCl3): δ 177.7, 165.1,
162.6, 136.6, 135.3, 135.2, 134.1, 129.4, 128.5, 116.2, 116.1, 116.0,
91.9, 86.7. LRMS (ESI): m/z calcd for C15H9FO [M + H]+, 225.1;
found, 225.1.
1-(Naphthalen-2-yl)-3-phenylprop-2-yn-1-one (4an).18 Yellow
1
solid (92 mg, 72%); mp 81−83 °C. H NMR (400 MHz, CDCl3):
1-Phenylpentadec-2-yn-1-one (4be). Yellow oil (62 mg, 42%). 1H
NMR (400 MHz, CDCl3): δ 8.14 (d, J = 7.6 Hz, 2H), 7.60 (t, J = 7.3
Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 2.50 (t, J = 7.1 Hz, 2H), 1.73−1.63
(m, 2H), 1.51−1.43 (m, 2H), 1.36−1.22 (m, 16H), 0.88 (t, J = 6.5 Hz,
3H). 13C NMR (101 MHz, CDCl3): δ 178.2, 136.8, 133.8, 129.5,
128.4, 96.9, 79.6, 31.9, 29.6, 29.4, 29.3, 29.0, 28.9, 27.8, 22.7, 19.2,
14.1. IR (KBr): ν 2925, 2853, 2236, 2202, 1647, 1450, 1313, 1264,
799, 702 cm−1. HRMS (ESI): m/z calcd for C21H30O [M + Na]+,
321.2194; found, 321.2184.
δ 8.78 (s, 1H), 8.20 (d, J = 8.5 Hz, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.90
(t, J = 8.9 Hz, 2H), 7.73 (d, J = 7.4 Hz, 2H), 7.59 (dt, J = 14.7, 7.0 Hz,
2H), 7.54−7.42 (m, 3H). 13C NMR (101 MHz, CDCl3): δ 177.9,
136.1, 134.3, 133.0, 132.6, 132.3, 130.7, 129.8, 129.0, 128.7, 128.5,
127.9, 126.9, 123.9, 120.1, 93.0, 87.0. LRMS (ESI): m/z calcd for
C19H12O [M + H]+, 257.1; found, 257.1.
3-Phenyl-1-(thiophen-3-yl)prop-2-yn-1-one (4ao).18 Yellow oil
1
(71 mg, 67%). H NMR (400 MHz, CDCl3): δ 8.36 (d, J = 1.2 Hz,
1H), 7.69−7.62 (m, 3H), 7.51−7.45 (m, 1H), 7.41 (t, J = 7.3 Hz, 2H),
7.35 (dd, J = 4.4, 2.9 Hz, 1H). 13C NMR (101 MHz, CDCl3): δ 171.3,
142.9, 135.4, 132.9, 130.7, 128.6, 126.8, 126.7, 120.0, 91.3, 87.3. LRMS
(ESI): m/z calcd for C13H8OS [M + H]+, 213.0; found, 213.0.
3-Phenyl-1-(pyridin-3-yl)prop-2-yn-1-one (4ap).17 White solid (63
1-Phenyldec-2-yn-1-one (4bf). Yellow oil (34 mg, 30%). 1H NMR
(400 MHz, CDCl3): δ 8.14 (d, J = 7.8 Hz, 2H), 7.60 (t, J = 7.3 Hz,
1H), 7.48 (t, J = 7.6 Hz, 2H), 2.50 (t, J = 7.1 Hz, 2H), 1.73−1.63 (m,
2H), 1.52−1.43 (m, 2H), 1.39−1.24 (m, 6H), 0.90(t, J = 6.5 Hz, 3H).
13C NMR (75 MHz, CDCl3): δ 178.2, 136.9, 133.8, 129.5, 128.4, 96.9,
79.6, 31.6, 28.9, 28.7, 27.8, 22.6, 19.2, 14.1. IR (KBr): ν 2928, 2855,
2235, 2202, 1646, 1451, 1313, 1264, 800, 703 cm−1. HRMS (ESI): m/
z calcd for C16H20O [M + Na]+, 251.1412; found, 251.1403.
1
mg, 61%); mp 60−62 °C. H NMR (400 MHz, CDCl3): δ 9.47 (s,
1H), 8.86 (s, 1H), 8.45 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 7.4 Hz, 2H),
7.56−7.42 (m, 4H). 13C NMR (75 MHz, CDCl3): δ 176.4, 154.1,
151.4, 136.3, 133.3, 132.2, 131.3, 128.8, 123.6, 119.5, 94.8, 86.3. LRMS
(ESI): m/z calcd for C14H9NO [M + H]+, 208.1; found, 208.1.
3-Phenyl-1-(quinolin-6-yl)prop-2-yn-1-one (4aq). Yellow solid
ASSOCIATED CONTENT
■
1
(108 mg, 84%); mp 120−122 °C. H NMR (400 MHz, CDCl3): δ
S
* Supporting Information
9.03 (d, J = 2.1 Hz, 1H), 8.74 (s, 1H), 8.45 (d, J = 8.6 Hz, 1H), 8.33
(d, J = 8.1 Hz, 1H), 8.19 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 7.3 Hz, 2H),
7.53−7.41 (m, 4H). 13C NMR (101 MHz, CDCl3): δ 177.1, 153.0,
150.5, 137.7, 134.6, 133.1, 132.0, 130.9, 130.1, 128.7, 127.9, 127.4,
122.1, 119.9, 93.7, 86.8. IR (KBr): ν 2203, 1627, 1324, 1294, 1165,
1117, 910, 848, 803, 781, 760, 725, 688 cm−1. HRMS (ESI): m/z calcd
for C18H11NO [M + H]+, 258.0919; found, 258.0923.
1
Figures giving H and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*Y.-M.Z.: e-mail, zhuyongming@suda.edu.cn; fax, (+86)-512-
67166591. S.-J.J.: e-mail, shunjun@suda.edu.cn; fax, (+86)-512-
65880307.
1-(1-Methyl-1H-indol-5-yl)-3-phenylprop-2-yn-1-one (4ar). Crim-
son solid (93 mg, 72%); mp 102−104 °C. 1H NMR (400 MHz,
CDCl3): δ 8.60 (s, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 7.0 Hz,
2H), 7.50−7.39 (m, 3H), 7.35 (d, J = 8.6 Hz, 1H), 7.13 (d, J = 1.9 Hz,
1H), 6.66 (d, J = 1.6 Hz, 1H), 3.80 (s, 3H). 13C NMR (101 MHz,
CDCl3): δ 178.2, 139.7, 132.8, 130.7, 130.3, 129.3, 128.5, 127.9, 125.4,
122.4, 120.5, 109.2, 103.3, 91.6, 87.4, 33.0. IR (KBr): ν 2203, 1619,
1601, 1313, 1272, 1242, 1158, 1143, 1097, 995, 760, 744, 689 cm−1.
HRMS (ESI): m/z calcd for C18H13NO [M + Na]+, 282.0895; found,
282.0883.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support by the PAPD (A
Project Funded by the Priority Academic Program Develop-
ment of Jiangsu Higher Education Institutions) and NSFC
(National Nature Science Foundation of China, No.
21172162).
1,1′-(1, 4-Phenylene)bis(3-phenylprop-2-yn-1-one) (4as).12c Yel-
1
lowish solid (70 mg, 42%); mp 188−190 °C. H NMR (400 MHz,
CDCl3): δ 8.35 (s, 4H), 7.71 (d, J = 7.2 Hz, 4H), 7.55−7.49 (m, 2H),
7.45 (t, J = 7.2 Hz, 4H). 13C NMR (101 MHz, CDCl3): δ 177.0, 140.4,
133.2, 131.2, 129.6, 128.8, 119.6, 94.5, 86.8. LRMS (ESI): m/z calcd
for C24H14O2 [M + H]+, 335.1; found, 335.1.
REFERENCES
(1) (a) Janvier, P.; Bois-Choussy, M.; Bienayme,
■
1-Phenyl-3-p-tolylprop-2-yn-1-one (4ba).14 White solid (105 mg,
95%); mp 50−52 °C. 1H NMR (400 MHz, CDCl3): δ 8.23 (d, J = 7.6
Hz, 2H), 7.65−7.56 (m, 3H), 7.52 (t, J = 7.5 Hz, 2H), 7.23 (d, J = 7.8
Hz, 2H), 2.40 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 178.0, 141.5,
136.9, 134.0, 133.1, 129.5, 129.5, 128.6, 116.9, 93.8, 86.7, 21.8. LRMS
(ESI): m/z calcd for C16H12O [M + H]+, 221.1; found, 221.1.
3-(4-Methoxyphenyl)-1-phenylprop-2-yn-1-one (4bb).14 White
́
H.; Zhu, J. Angew.
Chem., Int. Ed. 2003, 42, 811−814. (b) Pirali, T.; Tron, G. C.; Zhu, J.
Org. Lett. 2006, 8, 4145−4148. (c) Pirali, T.; Tron, G. C.; Masson, G.;
Zhu, J. Org. Lett. 2007, 9, 5275−5278. (d) Scheffelaar, R.; Paravidino,
M.; Muilwijk, D.; Lutz, M.; Spek, A. L.; de Kanter, F. J. J.; Orru, R. V.
A.; Ruijter, E. Org. Lett. 2009, 11, 125−128. (e) Mihara, H.; Xu, Y.;
Shepherd, N. E.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2009,
131, 8384−8385. (f) Lygin, A. V.; Meijere, A. Angew. Chem., Int. Ed.
2010, 49, 9094−9124.
1
solid (108 mg, 92%); mp 68−70 °C. H NMR (400 MHz, CDCl3):
δ 8.22 (d, J = 7.5 Hz, 2H), 7.67−7.59 (m, 3H), 7.51 (t, J = 7.5 Hz,
2H), 6.93 (d, J = 8.5 Hz, 2H), 3.85 (s, 3H). 13C NMR (101 MHz,
CDCl3): δ 178.0, 161.7, 137.0, 135.1, 133.9, 129.4, 128.5, 114.4, 111.8,
94.3, 86.8, 55.4. LRMS (ESI): m/z calcd for C16H12O2 [M + H]+,
237.1; found, 237.1.
(2) (a) Passerini, M.; Simone, L. Gazz. Chim. Ital. 1921, 51, 126−
129. (b) Passerini, M.; Ragni, G. Gazz. Chim. Ital. 1931, 61, 964−969.
(3) (a) Ugi, I.; Meyr, R.; Fetzer, U.; Steinbruckner, C. Angew. Chem.
̈
1959, 71, 386−387. (b) Ugi, I.; Steinbruckner, C. Angew. Chem. 1960,
̈
3-(4-tert-Butylphenyl)-1-phenylprop-2-yn-1-one (4bc).14 Yellow
72, 267−268. (c) Ugi, I. Angew. Chem., Int. Ed. 1962, 1, 8−21.
(4) (a) Zhang, W.-X.; Nishiura, M.; Hou, Z. Angew. Chem., Int. Ed.
2008, 47, 9700−9703. (b) Tobisu, M.; Imoto, S.; Ito, S.; Chatani, N. J.
Org. Chem. 2010, 75, 4835−4840. (c) Jiang, H.; Liu, B.; Li, Y.; Wang,
A.; Huang, H. Org. Lett. 2011, 13, 1028−1031. (d) Hu, Z.; Liang, D.;
1
oil (115 mg, 88%). H NMR (400 MHz, CDCl3): δ 8.24 (d, J = 7.6
Hz, 2H), 7.63 (t, J = 7.6 Hz, 3H), 7.52 (t, J = 7.5 Hz, 2H), 7.45 (d, J =
8.1 Hz, 2H), 1.34 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 178.0,
154.5, 136.9, 134.0, 133.0, 129.5, 128.5, 125.7, 116.9, 93.8, 86.7, 35.0,
3174
dx.doi.org/10.1021/jo4001096 | J. Org. Chem. 2013, 78, 3170−3175

The Journal of Organic Chemistry
Article
Zhao, J.; Huang, J.; Zhu, Q. Chem. Commun. 2012, 48, 7371−7373.
(e) Nanjo, T.; Tsukano, C.; Takemoto, Y. Org. Lett. 2012, 14, 4270−
4273.
(15) Wu, X.-F.; Sundararaju, B.; Neumann, H.; Dixneuf, P. H.; Beller,
M. Chem. Eur. J. 2011, 17, 106−110.
(16) Wu, X.-F.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed. 2011,
50, 11142−11146.
(5) (a) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168−
̈
(17) Park, A.; Park, K.; Kim, Y.; Lee, S. Org. Lett. 2011, 13, 944−947.
3210. (b) Kusebauch, U.; Beck, B.; Messer, K.; Herdtweck, E.;
́
(18) Blay, G.; Cardona, L.; Fernandez, I.; Pedro, J. R. Synthesis 2007,
Domling, A. Org. Lett. 2003, 5, 4021−4024. (c) Andreana, P. R.; Liu,
̈
21, 3329−3332.
C. C.; Schreiber, S. L. Org. Lett. 2004, 6, 4231−4233. (d) Pirrung, M.
C.; Sarma, K. D. Tetrahedron 2005, 61, 11456−11472. (e) Wang, S.-
X.; Wang, M.-X.; Wang, D.-X.; Zhu, J. Angew. Chem., Int. Ed. 2008, 47,
388−391.
(19) Shen, Q.; Huang, W.; Wang, J.; Zhou, X. Organometallics 2008,
27, 301−303.
(6) (a) Friis, S. D.; Taaning, R. H.; Lindhardt, A. T.; Skrydstrup, T. J.
Am. Chem. Soc. 2011, 133, 18114−18117. (b) Bjerglund, K.;
Lindhardt, A. T.; Skrydstrup, T. J. Org. Chem. 2012, 77, 3793−3799.
(c) Nielsen, D. U.; Neumann, K.; Taaning, R. H.; Lindhardt, A. T.;
Modvig, A.; Skrydstrup, T. J. Org. Chem. 2012, 77, 6155−6165.
(7) Coupling reactions via isocyanide insertion to form intra-
molecular C−N bonds: (a) Zhu, C.; Xie, W.; Falck, J. R. Chem. Eur. J.
́
̌
2011, 17, 12591−12595. (b) Van Baelen, G.; Kuijer, S.; Rycek, L.;
Sergeyev, S.; Janssen, E.; de Kanter, F. J. J.; Maes, B. U. W.; Ruijter, E.;
Orru, R. V. A. Chem. Eur. J. 2011, 17, 15039−15044. (c) Miura, T.;
Nishuda, Y.; Morimoto, M.; Yamauchi, M.; Murakami, M. Org. Lett.
2011, 13, 1429−1431. (d) Wang, Y.; Wang, H.; Peng, J.; Zhu, Q. Org.
Lett. 2011, 13, 4604−4607. (e) Tyagi, V.; Khan, S.; Giri, A.; Gauniyal,
H. M.; Sridhar, B.; Chauhan, P. M. S. Org. Lett. 2012, 14, 3126−3129.
(f) Wang, Y.; Zhu, Q. Adv. Synth. Catal. 2012, 354, 1902−1908.
(g) Liu, B.; Li, Y.; Jiang, H.; Yin, M.; Huang, H. Adv. Synth. Catal.
2012, 354, 2288−2300.
(8) Coupling reactions via isocyanide insertion to form intermo-
lecular C−N bonds: (a) Saluste, C. G.; Whitby, R. J.; Furber, M.
Angew. Chem., Int. Ed. 2000, 39, 4156−4158. (b) Boissarie, P. J.;
Hamilton, Z. E.; Lang, S.; Murphy, J. A.; Suckling, C. J. Org. Lett. 2011,
13, 6256−6259. (c) Vlaar, T.; Ruijter, E.; Znabet, A.; Janssen, E.; de
Kanter, F. J. J.; Maes, B. U. W.; Orru, R. V. A. Org. Lett. 2011, 13,
6496−6499.
(9) (a) Soeta, T.; Tamura, K.; Ukaji, Y. Org. Lett. 2012, 14, 1226−
1229. (b) Fei, X.-D.; Ge, Z.-Y.; Tang, T.; Zhu, Y.-M.; Ji, S.-J. J. Org.
Chem. 2012, 77, 10321−10328.
(10) (a) Imai, K. J. Pharm. Soc. Jpn. 1956, 76, 405−408. (b) Faweett,
C. H.; Firu, R. D.; Spencer, D. M. Physiol. Plant Pathol. 1971, 1, 163−
166. (c) Quesnelle, C. A.; Gill, P.; Dodier, M.; St. Laurent, D.;
Serrano-Wu, M.; Marinier, A.; Martel, A.; Mazzucco, C. E.; Stickle, T.
M.; Barrett, J. F.; Vyas, D. M.; Balasubramanian, B. N. Bioorg. Med.
Chem. Lett. 2003, 13, 519−524.
(11) (a) Vong, B. G.; Kim, S. H.; Abraham, S.; Theodorakis, E. A.
Angew. Chem., Int. Ed. 2004, 43, 3947−3951. (b) Karpov, A. S.;
Merkul, E.; Rominger, F.; Muller, T. J. J. Angew. Chem., Int. Ed. 2005,
̈
44, 6951−6956. (c) Forsyth, C. J.; Xu, J.; Nguyen, S. T.; Samdai, I. A.;
Briggs, L. R.; Rundberget, T.; Sandvik, M.; Miles, C. O. J. Am. Chem.
Soc. 2006, 128, 15114−15116. (d) Tietze, L. F.; Singidi, R. R.; Gericke,
K. M.; Bockemeier, H.; Laatsch, H. Eur. J. Org. Chem. 2007, 5875−
̈
5878. (e) D’Souza, D. M.; Muller, T. J. J. Nat. Protoc. 2008, 3, 1660−
̈
1665.
(12) (a) Jackson, M. M.; Leverett, C.; Toczko, J. F.; Roberts, J. C. J.
Org. Chem. 2002, 67, 5032−5035. (b) Chen, L.; Li, C. Org. Lett. 2004,
́
6, 3151−3153. (c) Alonso, D. A.; Najera, C.; Pacheco, M. C. J. Org.
Chem. 2004, 69, 1615−1619. (d) Wang, B.; Bonin, M.; Micouin, L. J.
Org. Chem. 2005, 70, 6126−6128. (e) Yim, S. J.; Kwon, C. H.; An, D.
K. Tetrahedron Lett. 2007, 48, 5393−5395.
(13) (a) Ahmed, M. S. M.; Mori, A. Org. Lett. 2003, 5, 3057−3060.
(b) Fukuyama, T.; Yamaura, R.; Ryu, I. Can. J. Chem. 2005, 83, 711−
715. (c) Liang, B.; Huang, M.; You, Z.; Xiong, Z.; Lu, K.; Fathi, R.;
Chen, J.; Yang, Z. J. Org. Chem. 2005, 70, 6097−6100. (d) Rahman, M.
T.; Fukuyama, T.; Kamata, N.; Sato, M.; Ryu, I. Chem. Commun. 2006,
2236−2238. (e) Liu, J.; Peng, X.; Sun, W.; Zhao, Y.; Xia, C. Org. Lett.
2008, 10, 3933−3936. (f) Fusano, A.; Fukuyama, T.; Nishitani, S.;
Inouye, T.; Ryu, I. Org. Lett. 2010, 12, 2410−2413. (g) Wang, Y.; Liu,
J.; Xia, C. Tetrahedron Lett. 2011, 52, 1587−1591.
(14) Wu, X.-F.; Neumann, H.; Beller, M. Chem. Eur. J. 2010, 16,
12104−12107.
3175
dx.doi.org/10.1021/jo4001096 | J. Org. Chem. 2013, 78, 3170−3175