Efficient synthesis of N-(buta-2,3-dienyl) amides from terminal N-propargyl amides and their synthetic potential towards oxazoline derivatives

Article abstract of DOI:10.1039/c2ob26291f

A series of N-allenyl amides was prepared conveniently from N-propargyl amides in good to excellent yields via a modified procedure developed in this group. The palladium-catalyzed coupling-cyclization of these prepared N-allenyl amides in the presence of

Full text of DOI:10.1039/c2ob26291f

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Organic &
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 8465
www.rsc.org/obc
PAPER
Efficient synthesis of N-(buta-2,3-dienyl) amides from terminal N-propargyl
amides and their synthetic potential towards oxazoline derivatives†
Bo Chen,a Nan Wang,b Wu Fanb and Shengming Ma*a,b
Received 6th July 2012, Accepted 5th September 2012
DOI: 10.1039/c2ob26291f
A series of N-allenyl amides was prepared conveniently from N-propargyl amides in good to excellent
yields via a modified procedure developed in this group. The palladium-catalyzed coupling–cyclization of
these prepared N-allenyl amides in the presence of organic iodides has been developed affording the
oxazoline derivatives efficiently.
Introduction
Results and discussion
In the past few decades, allene chemistry has experienced a veri-
table explosion.1 Many natural products and pharmaceuticals
with an allene moiety have also been identified.2 Thus, methods
for the synthesis of allenes from readily available starting
materials are of high interest.3 Among numerous methods devel-
oped, the reaction between terminal alkynes, aldehydes and
amines is one of the most convenient methods for the synthesis
of terminal or 1,3-disubstituted allenes.4 In our recent report,
many functional groups (such as hydroxyl group, ether, mesy-
late, alkylTsN-) may be introduced to terminal alkynes to
prepare the corresponding terminal allenes.4e Recently, Hashmi
synthesized the N-(buta-2,3-dienyl) amides under the i-Pr2NH/
CuBr conditions in very low yields (4–55%) (eqn (1)) for the
synthesis of 1,3-oxazines.5 We envisioned that the N-(buta-2,3-
dienyl) amides may be prepared in much higher yields by utiliz-
ing the Cy2NH/CuI protocol.4e Herein, we wish to report the
efficient synthesis of these N-(buta-2,3-dienyl) amides and their
application towards efficient synthesis of oxazolines6–8 under the
palladium catalysis.
In fact, by using the Cy2NH/CuI protocol, the N-(buta-2,3-
dienyl) amides 1 were efficiently synthesized from terminal N-
propargyl amides in good to excellent yields with a wide sub-
strate scope (Table 1). Different R1 groups such as aryl, alkyl,
benzyl groups may be tolerated (entries 1, 9 and 10). Electron-
withdrawing (CO2Et, halides) or electron-donating groups (Me,
MeO) may be introduced to the aromatic ring (entries 2–7): aryl-
containing substrates with electron-withdrawing groups afforded
the products 1b–e in higher yields (80–90%). A heteroaryl sub-
stituent such as 2-furanyl-substituted N-propargyl amide also
worked well under the current reaction conditions, thus affording
the N-(buta-2,3-dienyl) amide 1j in 82% yield (entry 10). In
Table 1 Synthesis of the N-(buta-2,3-dienyl) amides 1a
ð1Þ
Entries
R1
t (h)
Yieldb (%)
Reported in ref. 5
34
1
2
3
4
5
6
7
8
9
Ph–
9
85 (1a)
90 (1b)
80 (1c)
90 (1d)
81 (1e)
66 (1f)
76 (1g)
73 (1h)
65 (1i)
82 (1j)
p-FC6H4–
p-ClC6H4–
p-BrC6H4–
p-MeO2CC6H4–
p-MeC6H4–
p-MeOC6H4–
n-C4H9–
11.5
4.5
5.5
24
aState Key Laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, 345 Linglin Lu,
Shanghai 200032, P.R. China
6
1.2
2.7
2.7
9.7
bShanghai Key Laboratory of Green Chemistry and Chemical Process,
Department of Chemistry, East China Normal University, 3663 North
Zhongshan Lu, Shanghai 200062, P.R. China.
E-mail: masm@mail.sioc.ac.cn; Fax: (+86) 21-62609305
†Electronic supplementary information (ESI) available. CCDC 888586.
For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c2ob26291f
Bn–
2-Furyl–
10
55
a The reaction was carried out using 1 mmol of N-propargyl amide,
0.5 mmol of CuI, 2.5 mmol of (HCHO)n, 1.8 mmol Cy2NH in dioxane
(2 mL) at 100 °C in a Schlenk tube. b Yields of the isolated products.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 8465–8470 | 8465

View Article Online
Table 2 Optimization of the reaction conditionsa
addition, three examples of 10 or 15 mmol scale syntheses also
have been demonstrated (Scheme 1).
Entries
Solvent
t (h)
Base
3aab (%)
1
2
3
4
5
6
7
8
DMF
DMF
DMF
DMF
DMF
DMSO
DCE
DMA
CH3CN
Toluene
Dioxane
2
37
10.3
3
10.3
5.3
19
7.5
24
46
KOtBu
Li2CO3
Na2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
0
34c
74
90
87
82
23d
89
88
85
84
9
10
11
46
a The reaction was carried out using 0.2 mmol of 1a, 0.24 mmol of 2a,
Pd(PPh3)4 (5 mol%) and base (2 equiv.) in the indicated solvent (2 mL)
in a Schlenk tube. b The yields were determined by NMR using
mesitylene as an internal standard. c The substrate 1a was recovered by
23% NMR yield. d The substrate 1a was recovered by 62% NMR yield.
DMSO = dimethyl sulfoxide, DMF = N,N-dimethylformamide, DMA =
N,N-dimethyl acetamide, DCE = dichloroethane.
Scheme 1 The gram-scale preparation of 1.
Table 3 Palladium-catalyzed coupling–cyclization of N-(buta-2,3-
Recently, allenes have been used to synthesize various hetero-
cycles efficiently.1 To the best of our knowledge, very limited
reports used an N-(buta-2,3-dienyl) amide motif in transition-
metal-catalyzed reactions: Brummond et al.9a reported the cycli-
zation of N-(buta-2,3-dienyl) amides affording 1,3-oxazines cat-
alyzed by AgNO3 or AgBF4; Hashmi et al.5 also realized the
synthesis of 1,3-oxazines under the catalysis of Au(PPh3)Cl/
AgOTs/TsOH; Cook9b reported the palladium-catalyzed cycliza-
tion of N-(buta-2,3-dienyl) amides and aryl iodides affording
oxazoline derivatives using our early reported conditions (Pd-
(PPh3)4/K2CO3/TBAB) for the intramolecular coupling–cycliza-
tion reaction of organic iodides with 2-(2′,3′-dienyl) malonates,10
in which the N-(buta-2,3-dienyl) amides were prepared from
amino acid derivatives in three steps (26–44% yields overall). In
continuation of our work in this area,11 we treated N-(buta-2,3-
dienyl) amides 1a with iodobenzene 2a catalyzed by [Pd-
(PPh3)4] (5 mol%) in DMF at 80 °C with different bases. The
reaction is complicated with KOtBu as the base (Table 1, entry
1). Then we switched to weaker bases and found the desired
product 3aa was formed exclusively in 90% NMR yield in the
presence of K2CO3! Na2CO3, Cs2CO3 or Li2CO3 gave slightly
lower yields with longer reaction times (Table 1, entries 2–5).
After screening of the solvent effect, we found the reaction pro-
ceeded smoothly in almost all the solvents tested affording 3aa
in good yields. The reaction proceeds faster in the polar solvent
and DMF gave the best result (Table 2, entries 6–11). Thus, we
defined the reaction of 1a (1 equiv.) and 2a (1.2 equiv.) cata-
lyzed by [Pd(PPh3)4] (5 mol%) with K2CO3 (2 equiv.) as the
base in DMF at 80 °C as the standard conditions for further
study.
dienyl) amides and organic iodidesa
Entry R1 (1)
R2 (2)
Time (h) 3b (%)
1
2
3
4
5
6
7
8
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (2a)
3
8
9
80 (3aa)
69 (3ab)
66 (3ac)
83 (3ad)
82 (3ae)
71 (3af)
91 (3ag)
63 (3ah)
82 (3ai)
88 (3aj)
77 (3ak)
79 (3al)
94 (3am)
66 (3an)
79 (3ao)
66 (3ap)
58 (3aq)
77 (3ar)
73 (3ba)
72 (3ca)
89 (3da)
86 (3ea)
87 (3fa)
76 (3ga)
53 (3ha)
52 (3ia)
71 (3ja)
4-MeOC6H4 (2b)
4-MeC6H4 (2c)
4-BrC6H4 (2d)
4-FC6H4 (2e)
4-ClC6H4 (2f)
4-EtO2CC6H4 (2g)
4-CH3COC6H4 (2h)
4-O2NC6H4 (2i)
4-NCC6H4 (2j)
4-PhC6H4 (2k)
3-MeC6H4 (2l)
3-FC6H4 (2m)
2-MeC6H4 (2n)
3-Thienyl (2o)
17.5
10
17
9
45.5
24
22
5
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
6
10
28
9
N-Tosyl-3-indolyl (2p) 9.5
Ph (1a)
Ph (1a)
4-FC6H4 (1b)
4-ClC6H4 (1c)
4-BrC6H4 (1d)
(E)-PhCHvCH (2q)
(E)-nBuCHvCH (2r)
Ph (2a)
Ph (2a)
Ph (2a)
6.5
6.5
21
5
10
10
5
9
8
6.4
22
4-MeO2CC6H4 (1e) Ph (2a)
4-MeC6H4 (1f)
4-MeOC6H4 (1g)
nBu (1h)
Bn (1i)
2-Furanyl (1j)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
With the optimized protocol in hand, we turned to demonstrate
the generality of this reaction. As listed in Table 3, a variety of
oxazoline derivatives could be prepared by the reaction between
N-(buta-2,3-dienyl) amides and organic iodides. The aryl iodides
a The reaction was carried out using 0.2 mmol of 1, 0.24 mmol of 2, Pd-
(PPh3)4 (5 mol%) and K2CO3 (2 equiv.) in DMF (2 mL) at 80 °C in a
Schlenk tube. b Yields of the isolated products.
8466 | Org. Biomol. Chem., 2012, 10, 8465–8470
This journal is © The Royal Society of Chemistry 2012

View Article Online
Experimental section
Materials
Starting materials N-propargyl amides were prepared according
to known procedures.13
1. Experimental details for the results presented in Table 1
(1) Synthesis of N-(buta-2,3-dienyl) benzamide (1a).
Fig. 1 ORTEP representation of 3ah.
with electron-donating (MeO, Me) and electron-withdrawing (F,
Cl, Br, Ph, CO2Et, acetyl, NO2, CN) substituents in the para-,
ortho-, or meta-position of the aryl group are all suitable for this
transformation, affording corresponding oxazoline derivatives in
good to excellent yields (Table 3, entries 1–14). The reaction of
heterocyclic aromatic iodides such as 3-iodo-1-tosyl-1H-indole
or 3-iodothiophene also proceeded smoothly affording the
corresponding products 3ao or 3ap in 66% and 79% yields,
respectively (Table 3, entries 15 and 16). The reaction may also
be extended to 1-alkenyl iodides (Table 3, entries 17 and 18).
The structures of the products were unambiguously confirmed
by the X-ray single crystal diffraction study of compound 3ah
(Fig. 1).12 For R1, various substituted aryl groups may be accom-
modated to afford the oxazoline derivatives in good to excellent
yields (Table 3, entries 19–24); in addition, R1 may also be
2-furanyl or even an alkyl or benzyl group (Table 3, entries
25–27). Furthermore, the reaction may be easily conducted in a
scale of 1 g of the substrates catalyzed by 1 mol% or even
0.1 mol% Pd(PPh3)4 in 87% and 77% yields, respectively (eqn
(2) and (3)).
Typical procedure I: To an oven-dried reaction tube were added
CuI (54.9 mg, 0.5 mmol), paraformaldehyde (75.9 mg,
2.5 mmol), N-propargyl benzamide (158.4 mg, 1 mmol),
dioxane (2 mL), and dicyclohexylamine (0.36 mL, d = 0.916 g
mL−1, 326.4 mg, 1.8 mmol) sequentially under an argon atmos-
phere. The resulting mixture was then submerged in an oil bath
preheated to 100 °C. When the reaction was complete as moni-
tored by TLC, the mixture was cooled to rt, transferred with
ether (50 mL) and filtrated through a short pad (3 cm) of silica
gel. Evaporation and column chromatography on silica gel (pet-
roleum ether–ethyl acetate = 5 : 1) afforded 1a5 (146.4 mg,
1
85%): oil; H NMR (300 MHz, CDCl3) δ 7.83–7.74 (m, 2H,
ArH), 7.55–7.38 (m, 3H, ArH), 6.53 (bs, 1H, NH), 5.39–5.26
(m, 1H, CvCH), 4.90–4.84 (m, 2H, CvCH2), 4.06–3.97
(m, 2H, NCH2).
Gram-scale synthesis of 1a: To a 100 mL three-necked flask
equipped with a reflux condenser were added CuI (0.5491 g,
5 mmol), paraformaldehyde (0.7519 g, 25 mmol), dioxane
(20 mL), N-propargyl benzamide (1.6097 g, 10 mmol), and
dicyclohexylamine (3.6 mL, d = 0.916 g mL−1, 3.264 g,
18 mmol) sequentially. The resulting mixture was then sub-
merged in an oil bath preheated to 100 °C. After 14.5 h as moni-
tored by TLC, the resulting mixture was then cooled to room
temperature and concentrated under vacuum to a gummy
residue. The residue was diluted with 100 mL of ether, washed
sequentially with diluted (5%) hydrochloride acid (10 mL × 2),
brine (10 mL). The combined organic layer was dried over anhy-
drous MgSO4, filtrated and evaporated. Chromatography on
silica gel (petroleum ether–ethyl acetate = 5 : 1) afforded 1a5
ð2Þ
ð3Þ
1
(1.3945 g, 80%): oil; H NMR (300 MHz, CDCl3) δ 7.81–7.75
(m, 2H, ArH), 7.55–7.38 (m, 3H, ArH), 6.33 (bs, 1H, NH),
5.40–5.26 (m, 1H, CvCH), 4.98–4.84 (m, 2H, CvCH2),
4.10–4.00 (m, 2H, NCH2); 13C NMR (75 MHz, CDCl3) δ 207.9,
167.4, 134.3, 131.3, 128.4, 126.9, 87.9, 77.6, 37.8; IR (neat)
3271, 1952, 1627, 1603, 1577, 1545, 1490, 1435, 1329, 1305,
1250, 1063, 1032 cm−1; MS (EI) m/z (%) 173 (M+, 18.85), 105
(100).
Conclusion
In conclusion, we have presented a practical method for the syn-
thesis of N-(buta-2,3-dienyl) amides by applying dicyclohexyl-
amine/CuI and their synthetic potential towards oxazolines was
also disclosed. This method for the synthesis of oxazoline
derivatives has several advantages such as mild reaction con-
ditions, good functional group tolerance, low-catalyst loading
(up to 0.1 mol%), high yields, and easily accessible starting
materials with diversity, thus it will stimulate studies on the syn-
thesis of new oxazolines6,7 with promising potential in industrial
chemistry and asymmetric catalysis. Further studies on the devel-
opment of an asymmetric version are being actively pursued in
this laboratory.
The following compounds were prepared according to typical
procedure I.
(2) Synthesis of N-(buta-2,3-dienyl) 4-fluorobenzamide (1b).
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 8465–8470 | 8467

View Article Online
The reaction of CuI (54.9 mg, 0.5 mmol), paraformaldehyde
(75.1 mg, 2.5 mmol), N-propargyl 4-fluorobenzamide
(177.3 mg, 1 mmol), dicyclohexylamine (0.36 mL, d = 0.916 g
mL−1, 326.4 mg, 1.8 mmol), and dioxane (2 mL) afforded 1b
(171.6 mg, 90%) (eluent : petroleum ether–ethyl acetate = 5 : 1):
(M(81Br)+, 20.70), 251 (M(79Br)+, 26.75), 183 (100); anal. calcd
for C11H10BrNO: C, 52.41; H, 4.00; N, 5.56; found: C, 52.42;
H, 4.16; N, 5.47.
(5) Synthesis of N-(buta-2,3-dienyl) 4-carbomethoxy benzamide
(1e).
1
solid; mp 88–89 °C (petroleum ether–ethyl acetate); H NMR
(300 MHz, CDCl3) δ 7.85–7.72 (m, 2H, ArH), 7.10 (t, J =
8.3 Hz, 2H, ArH), 6.46 (bs, 1H, NH), 5.39–5.28 (m, 1H,
CvCH), 4.90–4.86 (m, 2H, CvCH2), 4.08–3.98 (m, 2H,
NCH2); 13C NMR (75 MHz, CDCl3) δ 207.9, 166.3, 164.6 (d, J
= 249.8 Hz), 130.5 (d, J = 3.2 Hz), 129.2 (d, J = 9.2 Hz), 115.5
(d, J = 21.1 Hz), 87.9, 77.8, 37.9; 19F NMR (CDCl3, 282 MHz)
−108.3; IR (neat) 3278, 1954, 1631, 1603, 1547, 1501, 1424,
1356, 1328, 1289, 1232, 1161, 1111, 1061, 1013 cm−1; MS (EI)
m/z (%) 191 (M+, 18.20), 123 (100); anal. calcd for
C11H10FNO2: C, 69.10; H, 5.27; N, 7.33; found: C, 69.03; H,
5.28; N, 7.32.
The reaction of CuI (54.4 mg, 0.5 mmol), paraformaldehyde
(75.3 mg, 2.5 mmol), N-propargyl 4-carbomethoxy benzamide
(217.2 mg, 1 mmol), dicyclohexylamine (0.36 mL, d = 0.916 g
mL−1, 326.4 mg, 1.8 mmol), and dioxane (2 mL) afforded 1e
(187.3 mg, 81%) (eluent : petroleum ether–ethyl acetate = 3 : 1):
solid; mp 126–127 °C (n-hexane–ethyl acetate); 1H NMR
(300 MHz, CDCl3) δ 8.10 (d, J = 8.4 Hz, 2H, ArH), 7.84 (d, J =
8.4 Hz, 2H, ArH), 6.36 (bs, 1H, NH), 5.40–5.26 (m, 1H,
CvCH), 4.99–4.85 (m, 2H, CvCH2), 4.15–4.02 (m, 2H,
NCH2), 3.95 (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3) δ
208.0, 166.5, 166.2, 138.2, 132.4, 129.5, 126.9, 87.7, 77.5,
52.2, 38.0; IR (neat) 3296, 2925, 2852, 1956, 1727, 1633, 1549,
1504, 1437, 1357, 1335, 1283, 1243, 1195, 1149, 1112, 1062,
1020 cm−1; MS (EI) m/z (%) 231 (M+, 38.15), 230 (M+ − 1,
3.52), 163 (100); anal. calcd for C13H13NO3: C, 67.52; H, 5.67;
N, 6.06; found: C, 67.49; H, 5.55; N, 6.12.
Gram scale synthesis of 1e: The reaction of CuI (0.830 g,
7.6 mmol), paraformaldehyde (1.126 g, 37.5 mmol), N-propar-
gyl 4-carbomethoxy benzamide (3.166 g, 14.6 mmol), dicyclo-
hexylamine (5.3 mL, d = 0.916 g mL−1, 4.9 g, 27 mmol) and
dioxane (40 mL) in 22 h afforded 1e (2.5644 g, 76%) (eluent:
petroleum ether–ethyl acetate = 10 : 1 to 1 : 1): solid; mp
126–127 °C (n-hexane–ethyl acetate); 1H NMR (300 MHz,
CDCl3) δ 8.04 (d, J = 8.4 Hz, 2H, ArH), 7.85 (d, J = 8.7 Hz,
2H, ArH), 7.10 (bs, 1H, NH), 5.36–5.25 (m, 1H, CvCH),
4.88–4.81 (m, 2H, CvCH2), 4.08–4.00 (m, 2H, NCH2), 3.93
(s, 3H, OCH3).
(3) Synthesis of N-(buta-2,3-dienyl) 4-chlorobenzamide (1c).
The reaction of CuI (54.8 mg, 0.5 mmol), paraformaldehyde
(74.7 mg, 2.5 mmol), N-propargyl 4-chlorobenzamide
(193.3 mg, 1 mmol), dicyclohexylamine (0.36 mL, d = 0.916 g
mL−1, 326.4 mg, 1.8 mmol), and dioxane (2 mL) afforded 1c
(165.0 mg, 80%) (eluent : petroleum ether–ethyl acetate = 5 : 1):
solid; mp 85–86 °C (n-hexane–ethyl acetate); 1H NMR
(300 MHz, CDCl3) δ 7.74 (d, J = 7.8 Hz, 2H, ArH), 7.34 (d, J =
7.8 Hz, 2H, ArH), 7.21 (bs, 1H, NH), 5.35–5.22 (m, 1H,
CvCH), 4.86–4.76 (m, 2H, CvCH2), 4.08–3.90 (m, 2H,
NCH2); 13C NMR (75 MHz, CDCl3) δ 208.0, 166.2, 137.7,
132.8, 128.8, 128.3, 87.9, 78.0, 37.9; IR (neat) 3281, 1953,
1630, 1596, 1543, 1486, 1422, 1325, 1292, 1277, 1244, 1183,
1148, 1114, 1092, 1061, 1013 cm−1; MS (EI) m/z (%) 209
(M(37Cl)+, 8.97), 207 (M(35Cl)+, 24.01), 139 (100); anal. calcd
for C11H10ClNO: C, 63.62; H, 4.85; N, 6.75; found: C, 63.52;
H, 4.93; N, 6.80.
(6) Synthesis of N-(buta-2,3-dienyl) 4-methyl benzamide (1f).
(4) Synthesis of N-(buta-2,3-dienyl) 4-bromobenzamide (1d).
The reaction of CuI (55.1 mg, 0.5 mmol), paraformaldehyde
(75.6 mg, 2.5 mmol), N-propargyl 4-methyl benzamide
(173.8 mg, 1 mmol), dicyclohexylamine (0.36 mL, d = 0.916 g
mL−1, 326.4 mg, 1.8 mmol), and dioxane (2 mL) afforded 1f
(124.3 mg, 66%) (eluent: petroleum ether–ethyl acetate = 5 : 1):
solid; mp 67–68 °C (n-hexane–ethyl acetate); 1H NMR
(300 MHz, CDCl3) δ 7.69 (d, J = 8.1 Hz, 2H, ArH), 7.20 (d, J =
8.1 Hz, 2H, ArH), 6.63 (bs, 1H, NH), 5.37–5.25 (m, 1H,
CvCH), 4.90–4.82 (m, 2H, CvCH2), 4.09–3.95 (m, 2H,
NCH2), 2.38 (s, 3H, ArCH3); 13C NMR (75 MHz, CDCl3) δ
208.0, 167.2, 141.8, 131.6, 129.2, 126.9, 88.1, 77.7, 37.8, 21.4;
IR (neat) 3285, 2917, 1955, 1624, 1545, 1507, 1424, 1352,
1287, 1241, 1193, 1149, 1123, 1061, 1021 cm−1; MS (EI) m/z
(%) 187 (M+, 31.03), 119 (100); anal. calcd for C12H13NO: C,
76.98; H, 7.00; N, 7.48; found: C, 76.88; H, 6.94; N, 7.42.
The reaction of CuI (54.7 mg, 0.5 mmol), paraformaldehyde
(75.4 mg, 2.5 mmol), N-propargyl 4-bromobenzamide
(237.8 mg, 1 mmol), dicyclohexylamine (0.36 mL, d = 0.916 g
mL−1, 326.4 mg, 1.8 mmol), and dioxane (2 mL) afforded 1d
(225.9 mg, 90%) (eluent : petroleum ether–ethyl acetate = 5 : 1):
solid; mp 90–91 °C (n-hexane–ethyl acetate); 1H NMR
(300 MHz, CDCl3) δ 7.65 (d, J = 8.4 Hz, 2H, ArH), 7.57 (d, J =
8.4 Hz, 2H, ArH), 6.34 (bs, 1H, NH), 5.41–5.28 (m, 1H,
CvCH), 4.95–4.84 (m, 2H, CvCH2), 4.09–3.95 (m, 2H,
NCH2); 13C NMR (75 MHz, CDCl3) δ 207.9, 166.3, 133.2,
131.8, 128.5, 126.2, 87.8, 78.0, 37.9; IR (neat) 3287, 2926,
1957, 1631, 1591, 1542, 1483, 1423, 1357, 1331, 1292, 1245,
1190, 1145, 1113, 1073, 1062, 1011 cm−1; MS (EI) m/z (%) 253
8468 | Org. Biomol. Chem., 2012, 10, 8465–8470
This journal is © The Royal Society of Chemistry 2012

View Article Online
CvCH2), 3.82–3.75 (m, 2H, NCH2), 3.57 (s, 2H, CH2Ph); 13C
NMR (75 MHz, CDCl3) δ 207.4, 170.7, 134.6, 129.5, 128.9,
127.3, 87.8, 77.8, 43.6, 37.2; IR (neat) 3269, 3084, 2922, 1961,
1643, 1562, 1492, 1438, 1421, 1332, 1319, 1266, 1193, 1164,
1030 cm−1; MS (EI) m/z (%) 187 (M+, 25.95), 91 (100); HRMS
calcd for C12H13NO (M+): 187.0997, found: 187.1000.
(7) Synthesis of N-(buta-2,3-dienyl) 4-methoxyl benzamide
(1g).
(10) Synthesis of N-(buta-2,3-dienyl) furan-2-carboxamide
(1j).
The reaction of CuI (54.8 mg, 0.5 mmol), paraformaldehyde
(75.3 mg, 2.5 mmol), N-propargyl 4-methoxyl benzamide
(188.7 mg, 1 mmol), dicyclohexylamine (0.36 mL, d = 0.916 g
mL−1, 326.4 mg, 1.8 mmol), and dioxane (2 mL) afforded 1g
(153.3 mg, 76%) (eluent: petroleum ether–ethyl acetate = 3 : 1):
solid; mp 90–92 °C (n-hexane–ethyl acetate); 1H NMR
(300 MHz, CDCl3) δ 7.75 (d, J = 8.4 Hz, 2H, ArH), 6.92 (d, J =
8.4 Hz, 2H, ArH), 6.34 (bs, 1H, NH), 5.39–5.26 (m, 1H,
CvCH), 4.93–4.82 (m, 2H, CvCH2), 4.08–3.97 (m, 2H,
NCH2), 3.84 (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3) δ
207.9, 166.8, 162.1, 128.7, 126.7, 113.7, 88.1, 77.7, 55.3, 37.8;
IR (neat) 3322, 2929, 2853, 1957, 1633, 1612, 1575, 1539,
1507, 1460, 1445, 1325, 1308, 1286, 1256, 1180, 1113, 1064,
1026 cm−1; MS (EI) m/z (%) 203 (M+, 27.34), 135 (100); anal.
calcd for C12H13NO2: C, 70.92; H, 6.45; N, 6.89; found: C,
71.17; H, 6.41; N, 6.85.
The reaction of CuI (54.4 mg, 0.5 mmol), paraformaldehyde
(75.3 mg, 2.5 mmol), N-propargyl furan-2-carboxamide
(150.0 mg, 1 mmol), dioxane (2 mL), and dicyclohexylamine
(0.36 mL, d = 0.916 g mL−1, 326.4 mg, 1.8 mmol) afforded
1j5 (133.8 mg, 82%) (petroleum ether–ethyl acetate = 3 : l): oil,
1H NMR (300 MHz, CDCl3) δ 7.44 (s, 1H, ArH), 7.13–7.08 (m,
1H, ArH), 6.64 (bs, 1H, NH), 6.49 (s, 1H, ArH), 5.38–5.22 (m,
1H, CvCH), 4.90–4.81 (m, 2H, CvCH2), 4.07–3.95 (m, 2H,
NCH2).
Gram scale synthesis of 1j: The reaction of CuI (0.8370 g,
7.5 mmol), paraformaldehyde (1.1340 g, 37.5 mmol), N-propar-
gyl furan-2-carboxamide (2.2610 g, 15 mmol), dioxane
(8) Synthesis of N-(buta-2,3-dienyl) pentanamide (1h).
(40 mL), and dicyclohexylamine (5.3 mL, d = 0.916 g mL−1
,
4.8548 g, 27 mmol) in 16 h afforded 1j5 (1.7809 g, 72%) (pet-
roleum ether–ethyl acetate = 5 : l): oil, 1H NMR (300 MHz,
CDCl3) δ 7.46–7.42 (m, 1H, ArH), 7.12 (d, J = 3.6 Hz, 1H,
ArH), 6.57 (bs, 1H, NH), 6.52–6.46 (m, 1H, ArH), 5.41–5.23
(m, 1H, CvCH), 4.91–4.82 (m, 2H, CvCH2), 4.07–3.96 (m,
2H, NCH2); 13C NMR (75 MHz, CDCl3) δ 207.9, 158.1, 147.6,
143.8, 113.9, 111.8, 87.5, 77.3, 37.1; IR (neat) 3305, 1958,
1645, 1593, 1572, 1523, 1474, 1429, 1358, 1294, 1242, 1227,
1184, 1079, 1013 cm−1; MS (EI) m/z (%) 163 (M+, 100), 95
(100).
The reaction of CuI (54.6 mg, 0.5 mmol), paraformaldehyde
(75.5 mg, 2.5 mmol), N-propargyl pentanamide (140.0 mg,
1 mmol), dioxane (2 mL), and dicyclohexylamine (0.36 mL, d =
0.916 g mL−1, 326.4 mg, 1.8 mmol) afforded 1h (111.7 mg,
73%) (petroleum ether–ethyl acetate = 5 : l): oil, 1H NMR
(300 MHz, CDCl3) δ 5.82 (bs, 1H, NH), 5.28–5.18 (m, 1H,
CvCH), 4.88–4.81 (m, 2H, CvCH2), 3.89–3.81 (m, 2H,
NCH2), 2.20 (t, J = 7.7 Hz, 2H, COCH2), 1.68–1.54 (m, 2H,
CH2), 1.42–1.26 (m, 2H, CH2), 0.92 (t, J = 7.4 Hz, 3H, CH3);
13C NMR (75 MHz, CDCl3) δ 207.9, 173.0, 88.1, 77.6, 37.3,
36.4, 27.8, 22.4, 13.8; IR (neat) 3290, 3078, 2958, 2931, 2872,
2. Experimental details for the results presented in entry 1,
Table 3
Synthesis
(3aa).
of
2-phenyl-5-(1-phenylvinyl)-4,5-dihydrooxazole
1958, 1645, 1544, 1429, 1354, 1268, 1198, 1118, 1059 cm−1
;
MS (EI) m/z (%) 153 (M+, 71.49), 85 (100); HRMS calcd for
C9H15NO (M+): 153.1154, found: 153.1156.
(9) Synthesis of N-(buta-2,3-dienyl) 2-phenylacetamide (1i).
Typical procedure II: After the Schlenk tube containing K2CO3
(55.4 mg, 0.4 mmol) was flame-dried and filled with nitrogen,
Pd(PPh3)4 (11.7 mg, 0.01 mmol), 1a (34.9 mg, 0.2 mmol), 2a
(49.7 mg, 0.24 mmol), and DMF (2 mL) were added sequen-
tially. The resulting solution was stirred at 80 °C. When the reac-
tion was completed as monitored by TLC, the mixture was
diluted with diethyl ether (50 mL) and washed with water (5 mL
× 3). Then the combined organic layer was dried over anhydrous
Na2SO4, filtrated and evaporated. The residue was purified by
chromatography on silica gel (eluent: petroleum ether–ethyl
The reaction of CuI (54.8 mg, 0.5 mmol), paraformaldehyde
(74.9 mg, 2.5 mmol), N-propargyl 2-phenylacetamide
(172.8 mg, 1 mmol), dioxane (2 mL), and dicyclohexylamine
(0.36 mL, d = 0.916 g mL−1, 326.4 mg, 1.8 mmol) afforded 1i
(121.7 mg, 65%) (petroleum ether–ethyl acetate = 5 : l): oil, H
NMR (300 MHz, CDCl3) δ 7.40–7.20 (m, 5H, ArH), 5.88 (bs,
1H, NH), 5.19–5.08 (m, 1H, CvCH), 4.77–4.68 (m, 2H,
1
1
acetate = 10 : 1) to afford 3aa (40.3 mg, 80%): oil; H NMR
(300 MHz, CDCl3) δ 8.06–7.97 (m, 2H, ArH), 7.55–7.24
Org. Biomol. Chem., 2012, 10, 8465–8470 | 8469
This journal is © The Royal Society of Chemistry 2012

View Article Online
R. Lopes, P. T. Tran and P. Crabbé, J. Chem. Soc., Perkin Trans. 1, 1984,
747–751; (d) S. Ma, H. Hou, S. Zhao and G. Wang, Synthesis, 2002,
1643–1645; (e) J. Kuang and S. Ma, J. Org. Chem., 2009, 74, 1763–
1765; (f) J. Kuang and S. Ma, J. Am. Chem. Soc., 2010, 132, 1786–
1787.
(m, 8H, ArH), 5.61 (t, J = 9.0 Hz, 1H, OCH), 5.46 (s, 1H, one
proton in CvCH2), 5.42 (s, 1H, one proton in CvCH2), 4.29
(dd, J = 14.7, 10.2 Hz, 1H, one proton in NCH2), 3.80 (dd, J =
14.7, 7.8 Hz, 1H, one proton in NCH2) (for more detail about
1H NMR, see ESI†); 13C NMR (75 MHz, CDCl3) δ 163.7,
146.8, 137.9, 131.3, 128.5, 128.3, 128.1, 128.0, 127.6, 126.5,
112.4, 80.0, 61.0; IR (neat) 3059, 2927, 2870, 1652, 1579,
1495, 1448, 1335, 1257, 1177, 1082, 1062, 1025 cm−1; MS (EI)
m/z (%) 249 (M+, 21.13), 117 (100); HRMS calcd for
C17H15NO [M+]: 249.1154; found: 249.1152.
5 A. S. K. Hashmi, A. M. Schuster, S. Litters, F. Rominger and
M. Pernpointner, Chem.–Eur. J., 2011, 17, 5661–5667.
6 For reviews on oxazolines, see: (a) A. K. Ghosh, P. Mathivanan and
J. Cappiello, Tetrahedron: Asymmetry, 1998, 9, 1–45; (b) M. Gómez,
G. Muller and M. Rocamora, Coord. Chem. Rev., 1999, 193–195, 769–
835; (c) J. S. Johnson and D. A. Evans, Acc. Chem. Res., 2000, 33, 325–
335; (d) H. A. McManus and P. J. Guiry, Chem. Rev., 2004, 104, 4151–
4202; (e) G. Desimoni, G. Faita and K. A. Jørgensen, Chem. Rev., 2006,
106, 3561–3651; (f) G. C. Hargaden and P. J. Guiry, Chem. Rev., 2009,
109, 2505–2550.
7 For most recent reports on the synthesis of oxazolines, see:
(a) A. S. K. Hashmi, M. Rudolph, S. Schymura, J. Visus and W. Frey,
Eur. J. Org. Chem., 2006, 4905–4909; (b) A. S. K. Hashmi,
A. M. Schuster, S. Gaillard, L. Cavallo, A. Poater and S. P. Nolan, Orga-
nometallics, 2011, 30, 6328–6337; (c) A. S. K. Hashmi, A. M. Schuster,
M. Schmuck and F. Rominger, Eur. J. Org. Chem., 2011, 4595–4602;
(d) A. S. K. Hashmi, A. M. Schuster, M. Zimmer and F. Rominger,
Chem.–Eur. J., 2011, 17, 5511–5515.
8 For some recent reports on the biological activities of oxazolines, see:
(a) A. Araki, T. Kubota, K. Aoyama, Y. Mikami, J. Fromont and
J. Kobayashi, Org. Lett., 2009, 11, 1785–1788; (b) V. Akhmedzhanova,
D. Batsurén and R. Shakirov, Chem. Nat. Compd., 1993, 29, 778–780;
(c) X. Fu, T. Do, F. J. Schmitz, V. Andrusevich and M. H. Engel, J. Nat.
Prod., 1998, 61, 1547–1551; (d) P. N. Yadav, R. E. Beveridge, J. Blay,
A. R. Boyd, M. W. Chojnacka, A. Decken, A. A. Deshpande,
M. G. Gardiner, T. W. Hambley, M. J. Hughes, L. Jolly, J. A. Lavangie,
T. D. MacInnis, S. A. McFarland, E. J. New and R. A. Gossage, Med-
ChemComm, 2011, 2, 274–277.
Acknowledgements
Financial support from the Major State Basic Research Develop-
ment Program (2009CB825300) is greatly appreciated. We thank
Mr Guo Bingjie in this group for reproducing the results pres-
ented in entries 13, 17, 26 of Table 3 and Prof. Yu yihua for
helpful discussion.
Notes and references
1 For most recent reviews on the chemistry of allenes, see: (a) S. Ma,
Chem. Rev., 2005, 105, 2829–2871; (b) S. Ma, Aldrichimica Acta, 2007,
40, 91–102; (c) M. Brasholz, H.-U. Reissig and R. Zimmer, Acc. Chem.
Res., 2008, 42, 45–56; (d) S. Ma, Acc. Chem. Res., 2009, 42, 1679–
1688; (e) B. Alcaide, P. Almendros and T. M. d. Campo, Chem.–Eur. J.,
2010, 16, 5836–5842; (f) C. Aubert, L. Fensterbank, P. Garcia,
M. Malacria and A. Simonneau, Chem. Rev., 2011, 111, 1954–1993;
(g) F. López and J. L. Mascareñas, Chem.–Eur. J., 2011, 17, 418–428;
(h) S. Yu and S. Ma, Angew. Chem., Int. Ed., 2012, 51, 3074–3112;
(i) M. Rudolph and A. S. K. Hashmi, Chem. Commun., 2011, 47, 6536–
6544.
2 For reviews on the natural products and pharmaceuticals containing
allene unit(s), see: (a) A. Hoffmann-Röder and N. Krause, Angew.
Chem., Int. Ed., 2004, 43, 1196–1216; (b) N. Krause and
A. S. K. Hashmi, Modern Allene Chemistry, Wiley-VCH, Weinheim,
2004. For some recent reports on the biological activities of allenes, see:
(c) S. Wang, W. Mao, Z. She, C. Li, D. Yang, Y. Lin and L. Fu, Bioorg.
Med. Chem. Lett., 2007, 17, 2785–2788; (d) H. S. Ban, S. Onagi,
M. Uno, W. Nabeyama and H. Nakamura, ChemMedChem, 2008, 3,
1094–1103.
3 For reviews on the synthesis of allenes, see: (a) L. K. Sydnes, Chem.
Rev., 2003, 103, 1133–1150; (b) N. Krause and A. Hoffmann-Röder,
Tetrahedron, 2004, 60, 11671–11694; (c) B. Mitasev and
K. M. Brummond, Synlett, 2006, 3100–3104; (d) K. M. Brummond and
J. E. DeForrest, Synthesis, 2007, 795–818; (e) M. Ogasawara, Tetra-
hedron: Asymmetry, 2009, 20, 259–271; (f) S. Yu and S. Ma, Chem.
Commun., 2011, 47, 5384–5418.
4 (a) P. Crabbé, D. André and H. Fillion, Tetrahedron Lett., 1979, 20, 893–
896; (b) P. Crabbé, H. Fillion, D. André and J.-L. Luche, J. Chem. Soc.,
Chem. Commun., 1979, 859–860; (c) S. Searles, Y. Li, B. Nassim, M.-T.
9 (a) B. Mitasv and K. M. Brummond, Synlett, 2006, 3100–3104;
(b) G. R. Cook and W. Xu, Heterocycles, 2006, 67, 215–232.
10 S. Ma and S. Zhao, Org. Lett., 2000, 2, 2495–2497.
11 For reviews on palladium-catalyzed reactions of allenes with a nucleophi-
lic functionality connected to the α-carbon atom, see: (a) S. Ma, Acc.
Chem. Res., 2003, 36, 701–712; For most recent examples, see:
(b) W. Shu, Q. Yu, G. Jia and S. Ma, Chem.–Eur. J., 2011, 17, 4720–
4723; (c) W. Shu, G. Jia and S. Ma, Org. Lett., 2009, 11, 117–120;
(d) S. Ma, Z. Zheng and X. Jiang, Org. Lett., 2007, 9, 529–531.
12 Crystal data for 4ai: C19H17NO2, MW = 291.34, triclinic; space group
ˉ
P1, final R indices [I > 2σ(I)], R1 = 0.0374, wR2 = 0.0934; a = 8.3211(5)
Å, b = 9.7981(6) Å, c = 10.1922(6) Å, α = 73.183(2), β = 70.006(2)°,
γ = 85.591(2)°, V = 747.28(8) A3, T = 173(2) K, Z = 2, reflections col-
lected/unique 8766/2612 [R(int) = 0.0222], number of observations
[>2σ(I)] 2115, parameters: 207. CCDC 888586 contains the supplemen-
tary crystallographic data for this paper.
13 (a) A. Arcadi, S. Cacchi, L. Cascia, G. Fabrizi and F. Marinelli, Org.
Lett., 2001, 3, 2501–2504; (b) A. S. K. Hashmi, J. P. Weyrauch, W. Frey
and J. W. Bats, Org. Lett., 2004, 6, 4391–4394; (c) P. Wipf, Y. Aoyama
and T. E. Benedum, Org. Lett., 2004, 6, 3593–3595; (d) A. Saito,
A. Matsumoto and Y. Hanzawa, Tetrahedron Lett., 2010, 51, 2247–2250;
(e) J. P. Weyrauch, A. S. K. Hashmi, A. Schuster, T. Hengst, S. Schetter,
A. Littmann, M. Rudolph, M. Hamzic, J. Visus, F. Rominger, W. Frey
and J. W. Bats, Chem.–Eur. J., 2010, 16, 956–963; (f) X. Meng and
S. Kim, Org. Biomol. Chem., 2011, 9, 4429–4431.
8470 | Org. Biomol. Chem., 2012, 10, 8465–8470
This journal is © The Royal Society of Chemistry 2012