Palladium-catalysed arylative cyclisation of N-allylacetamides with aryl halides yielding benzyl-substituted oxazolines

Article abstract of DOI:10.1039/b912895f

Treatment of N-allylacetamide with aryl halide in the presence of sodium t-butoxide and a palladium catalyst leads to arylative cyclisation to provide the corresponding benzyl-substituted oxazoline in high yield.

Full text of DOI:10.1039/b912895f

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Palladium-catalysed arylative cyclisation of N-allylacetamides with aryl
halides yielding benzyl-substituted oxazolineswz
Daishi Fujino, Sayuri Hayashi, Hideki Yorimitsu* and Koichiro Oshima*
Received (in Cambridge, UK) 30th June 2009, Accepted 21st August 2009
First published as an Advance Article on the web 3rd September 2009
DOI: 10.1039/b912895f
Treatment of N-allylacetamide with aryl halide in the presence
of sodium t-butoxide and a palladium catalyst leads to arylative
cyclisation to provide the corresponding benzyl-substituted
oxazoline in high yield.
biphenylyl phosphines are less effective (entries 4 and 5).
Xantphos and tri-t-butylphosphine were inferior in terms of
2a/3a selectivity (entries 6 and 7). After further fine tuning, the
use of SPhos with smaller amounts of t-BuONa, PhBr, and
toluene proved to be the best conditions in terms of both yield
of 2a and 2a/3a ratio (entry 8).9 The choice of sodium
t-butoxide is crucial. The use of sodium methoxide, sodium
hydroxide, potassium t-butoxide, potassium carbonate, or
caesium carbonate resulted in exclusive formation of 3a.10,11
Although other amides such as benzamide could undergo
similar transformations, yields of the corresponding oxazolines
were much lower, up to 30%.
Oxazoline is an important skeleton often found in biologically
interesting molecules,1 synthetic intermediates,2 and ligands
for transition metal complexes.3 Oxazolines are usually prepared
from carboxylic acid derivatives and b-aminoalcohols.2a,b
Oxidative cyclisation of N-allylamides is also a useful route
to oxazolines since the oxazolines thus formed can possess a
functionalised side chain at the 5-position (eqn (1)).4
The scope of aryl halides is summarised in Table 2. Aryl
chlorides as well as aryl bromides participated in the reaction
(entries 1, 7, and 8). Sterically demanding aryl bromides
reacted smoothly (entries 2, 3, and 10). Electron-deficient
ð1Þ
fluorinated aryl bromides were also reactive (entries
4
and 5). Aryl halides bearing a t-butoxycarbonyl, diethyl-
aminocarbonyl, or cyano group underwent the arylative
cyclisation to yield the corresponding products in good
yields (entries 6–8). The reaction of 1a with electron-rich
4-bromoanisole resulted in a modest yield of 2i and formation
of a significant amount of Mizoroki–Heck byproduct (entry 9).
On the other hand, the steric hindrance of 2-bromoanisole is
likely to retard the side reaction (entry 10). It is worth noting
that separation of 2 from 3 was readily performed on silica gel
in each case.9
We have developed palladium-catalysed intramolecular
arylative cyclisation reactions of N-allylanilines with aryl
halides to yield aziridines (Scheme 1, Z ¼ Ph).5 During the
course of the study, we found that a similar reaction of
N-allylacetamides resulted in the selective formation of
5-benzyl-substituted oxazolines without contamination by
the corresponding aziridines (Scheme 1, Z ¼ CH3CO). Here
we report the preliminary results of the arylative cyclisation
for the synthesis of oxazolines.6,7 This is regarded as a
new variant of the carboetherification reactions that Wolfe
and others recently developed to construct tetrahydrofuran
derivatives.8
Several N-allylacetamides that bear a stereogenic center
at the allylic position were prepared and subjected to the
arylative cyclisation reaction (Table 3). The reactions
proceeded smoothly with good diastereoselectivity. The major
isomers have the larger R group and the newly formed benzyl
group in a trans relationship. The relative stereochemistries of
4 and 5 were determined by NOE analysis.
Based on the previous results,5,8 a plausible reaction
mechanism is outlined in Scheme 2. Oxidative addition is
followed by exchange between the bromide and amide 1a
to yield 7. Intermediate 7 would undergo intramolecular
Treatment of N-allylacetamide 1a with bromobenzene
under the same conditions as reported previously5 afforded
benzyl-substituted oxazoline 2a in 75% yield (Table 1,
entry 1). The cyclisation reaction inevitably competed with
the Mizoroki–Heck reaction, which yielded 3a as the only
identifiable byproduct. Several ligands were screened (Fig. 1),
and bulky ligands are generally effective for the cyclisation.
SPhos and RuPhos are excellent (entries 1 and 2), while larger
XPhos showed no activity for the cyclisation (entry 3). Other
Department of Material Chemistry, Graduate School of Engineering,
Kyoto University, Kyoto-daigaku Katsura, Nishikyo-ku,
Kyoto 615-8510, Japan.
E-mail: yori@orgrxn.mbox.media.kyoto-u.ac.jp;
oshima@orgrxn.mbox.media.kyoto-u.ac.jp; Fax: þ81-75-383-2438;
Tel: þ81-75-383-2437
w This article is part of a ChemComm ‘Catalysis in Organic Synthesis’
web-theme issue showcasing high quality research in organic
chemistry. Please see our website (http://www.rsc.org/chemcomm/or
ganicwebtheme2009) to access the other papers in this issue.
z Electronic supplementary information (ESI) available: Characterization
data. See DOI: 10.1039/b912895f
Scheme 1 Palladium-catalysed reactions of allylamine derivatives
with aryl halides.
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This journal is The Royal Society of Chemistry 2009
5754 | Chem. Commun., 2009, 5754–5756

Table
cyclisation reaction of 1a and competitive Mizoroki–Heck reaction
1
Effect of ligands on palladium-catalysed phenylative
Table 3 Diastereoselective cyclisation
Entry
Liganda
2a (%)
3a (%)
Entry
1
R
Time/h Yield (%) 4/5
1
2
3
4
5
6
7
8b
SPhos
75
78
0
55
12
76
70
76
16
19
45
25
21
24
30
12
1
2
1b Ph
1c 1-naphthyl
10
12
61
68
4b/5b ¼ 73 : 27
4c/5c ¼ 84 : 16
RuPhos
XPhos
DavePhos
P1
Xantphos
t-Bu3P
SPhos
3
1d
10
66
4d/5d ¼ 73 : 27
a
b
See Fig. 1. 1.5 equiv. of t-BuONa, 1.2 equiv. of PhBr, and 1.5 mL
of toluene were used.
Fig. 1 Structures of ligands.
Table 2 Scope of aryl halides
Scheme 2 Plausible reaction mechanism.
equilibrium between 7 and palladium amide 9. However,
cyclisation of 9 that forms an aziridine skeleton could
not occur.
The stereoselectivity is rationalised by considering that
the larger R group would prefer locating at the pseudo-
equatorial position prior to cyclisation (Scheme 3). Inter-
mediate 7a would be thus more stable than 7b, and the
formation of oxazoline 8a predominated to lead to 4 with
high diastereoselectivity.
Entry
R
X
Time/h
2
Yield (%)a
1
H
2-Me
(1-naphthyl)
4-F
4-CF3
4-CO2-t-Bu
4-CONEt2
4-CN
4-MeO
2-MeO
Cl
Br
Br
Br
Br
Br
Cl
Cl
Br
Br
4
4
6
8
8
12
10
10
10
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
77 (7)
84 (5)
79 (6)
76 (6)
80 (4)
61 (6)
67 (15)
59 (3)
50 (24)
69 (9)
Finally, transformation of oxazoline 2a was examined
(Scheme 4). Methanolysis of 2a occurred under acidic
conditions12 to yield amino alcohol 11. Reduction of 2a
with diisobutylaluminium hydride provided N-ethyl amino
2b
3b
4
5
6
7
8
9
10
2j
a
Isolated yields of 2. The NMR yields of the corresponding
Mizoroki–Heck byproducts are in parentheses. The byproducts were
b
easily separable from 2 by chromatographic purification. RuPhos
was used instead of SPhos.
oxypalladation to give 8. Smooth reductive elimination with
the aid of the bulky phosphine ligand affords product 2a and
regenerates the initial palladium species. There can be an
Scheme 3 Origin of stereoselectivity.
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This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 5754–5756 | 5755

2006, 62, 12247; (f) T. Kato, K. Marubayashi, S. Takizawa and
H. Sasai, Tetrahedron: Asymmetry, 2004, 15, 3693.
5 S. Hayashi, H. Yorimitsu and K. Oshima, Angew. Chem., Int. Ed.,
2009, 48, DOI: 10.1002/anie.200903178, in press.
6 Cyclisation of N-(4-acetoxy-2-butenyl)benzamides and decarboxyla-
tive cyclisation of 3-acyl-5-vinyloxazolidinones were reported to
yield 5-vinyloxazolines via p-allylpalladium intermediates:
(a) K.-Y. Lee, Y.-H. Kim, M.-S. Park, C.-Y. Oh and
W.-H. Ham, J. Org. Chem., 1999, 64, 9450; (b) G. R. Cook and
P. S. Shanker, Tetrahedron Lett., 1998, 39, 3405.
7 Palladium-catalysed addition of aryl iodides to N-(2,3-butadienyl)-
benzamide followed by cyclisation was reported to afford
5-vinyloxazolines via p-allylpalladium intermediates: G. R. Cook
and W. Xu, Heterocycles, 2006, 67, 215.
8 (a) J. S. Nakhla, J. W. Kampf and J. P. Wolfe, J. Am. Chem. Soc.,
2006, 128, 2893; (b) M. B. Hay and J. P. Wolfe, J. Am. Chem. Soc.,
2005, 127, 16468; (c) M. B. Hay, A. R. Hardin and J. P. Wolfe,
J. Org. Chem., 2005, 70, 3099; (d) J. P. Wolfe and M. A. Rossi,
J. Am. Chem. Soc., 2004, 126, 1620; (e) D. Jiang, J. Peng and
Y. Chen, Org. Lett., 2008, 10, 1695; (f) K. G. Dongol
and B. Y. Tay, Tetrahedron Lett., 2006, 47, 927; (g) M. B. Hay
and J. P. Wolfe, Angew. Chem., Int. Ed., 2007, 46, 6492;
(h) D. Jiang, J. Peng and Y. Chen, Tetrahedron, 2008, 64, 1641.
Reviews: (i) J. P. Wolfe, Eur. J. Org. Chem., 2007, 571;
(j) J. P. Wolfe, Synlett, 2008, 2913.
Scheme 4 Transformation of oxazoline 2a.
alcohol 12. Oxazoline 2a was converted to acetamide 13 by
acidic hydrolysis with trifluoroacetic acid.13 The overall
transformation of 1a to 13 represents regioselective carbo-
hydroxylation of N-allylacetamide.
In summary, we have developed palladium-catalysed
carboetherification reactions of N-allylacetamides with aryl
halides. The reactions provided benzyl-substituted oxazolines
without the conceivable formation of aziridines.5 In light of
the importance of oxazolines, the method offers a useful tool
in organic synthesis. We are pursuing higher diastereo-
selectivity and asymmetric cyclization and mechanistic studies
are underway.
9 Experimental Procedure: Sodium t-butoxide (43 mg, 0.45 mmol)
was added to a 30-mL two-necked reaction flask equipped with a
Dimroth condenser and was dried in vacuo with heating by a hair
dryer for 1 min. Tris(dibenzylideneacetone)dipalladium (6.9 mg,
0.0075 mmol) and 2-dicyclohexylphosphino-20,60-dimethoxy-
biphenyl (SPhos, 6.2 mg, 0.015 mmol) were added to the flask, and
the flask was filled with argon by using the standard Schlenck
technique. Toluene (0.5 mL) was then added at room temperature.
After the suspension was stirred for 10 min, a mixture of 1a
(75.4 mg, 0.30 mmol) and bromobenzene (56.5 mg, 0.36 mmol)
dissolved in toluene (1.0 mL) was added to the flask at ambient
temperature. The mixture was heated at reflux for 4 h with an oil
bath. After the flask was cooled to room temperature, water
(20 mL) was added to quench the reaction. The mixture was
extracted with ethyl acetate three times. The combined organic
layer was dried over sodium sulfate and concentrated under
reduced pressure. The resulting residue was purified by silica gel
column chromatography (hexane/AcOEt ¼ 3/1) to provide 5-benzyl-
2-methyl-4,4-diphenyl-4,5-dihydrooxazole 2a (74.7 mg, 0.228 mmol,
76%, Rf ¼ 0.37). N-Cinnamylacetamide 3a appeared at Rf ¼ 0.20
(hexane/AcOEt ¼ 3/1). IR (nujol) 3024, 1665, 1448, 1258, 973, 758,
This work was supported by Grants-in-Aid for Scientific
Research and for GCOE Research from MEXT and
JSPS. S.H. acknowledges JSPS for financial support. H.Y.
acknowledges financial support from Eisai and Kyoto
University.
Notes and references
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700 cmꢁ1
;
1H NMR (CDCl3) d 2.16 (s, 3H), 2.32 (dd, J ¼ 15.0,
11.0 Hz, 1H), 2.57 (dd, J ¼ 15.0, 2.5 Hz, 1H), 5.34 (dd,
J ¼ 11.0, 2.5 Hz, 1H), 7.15–7.20 (m, 4H), 7.21–7.34 (m, 7H),
7.35–7.40 (m, 2H), 7.44–7.48 (m, 2H); 13C NMR (CDCl3) d 14.64,
39.81, 81.07, 88.45, 126.76, 127.11, 127.39, 127.45, 128.16, 128.18,
128.64, 128.73, 129.21, 138.60, 142.14, 145.78, 164.15; Found: C,
84.12; H, 6.58%. Calcd for C23H21NO: C, 84.37; H, 6.46%. m.p.
116.0–117.5 1C.
10 Exposure of 3a to the reaction conditions resulted in no reaction.
This result strongly suggests that 3a is not an intermediate en route
to 2a.
11 When the reaction was performed in the presence of silver salts,
yield of 2a was not improved.
12 M. Braun, R. Fleischer, B. Mai, M.-A. Schneider and
S. Lachenicht, Adv. Synth. Catal., 2004, 346, 474.
13 F. Benfatti, G. Cardillo, L. Gentilucci, A. Tolomelli, M. Monari
and F. Piccinelli, Adv. Synth. Catal., 2007, 349, 1256.
ꢀc
This journal is The Royal Society of Chemistry 2009
5756 | Chem. Commun., 2009, 5754–5756