Silver-catalyzed preparation of oxazolines from N-propargylamides

Article abstract of DOI:10.1055/s-2008-1078405

Treatment of N-propargylamides with 5 mol% of silver hexafluoroantimonate results in the rapid formation of oxazolines in essentially quantitative yield. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078405

LETTER
1399
Silver-Catalyzed Preparation of Oxazolines from N-Propargylamides
Oxazoline Formation ichael Harmata,* Chaofeng Huang
Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211, USA
Fax +1(573)8822754; E-mail: harmatam@missouri.edu
Received 3 March 2008
This paper is dedicated to Professor Scott E. Denmark on the occasion of his 55th birthday.
Heating 6 in a 1:1 mixture of benzene and triethylamine in
the presence of 10 mol% of CuI afforded 7 in 97% yield
(Equation 2).7 This compound could be obtained with an
equivalent in 84% yield upon treatment of 6 with one
equivalent of silver nitrate. Interestingly, the reaction of 8
with 0.2 mol% of silver nitrate in n-butyl acetate at 95 °C
for 30 minutes is reported to afford oxazoline 9 in 94%
yield (Scheme 2).8 Whether the high temperature could
have been avoided is not clear. However, many years ago
Easton and co-workers reported that several propargylic
amides could be converted into methylene oxazolines
upon treatment with 20 wt% (ca. 17 mol%) of silver ni-
trate in anhydrous DMF at room temperature.9 We assume
that such large amounts of silver ion catalyst were really
not necessary for the reaction to occur.
Abstract: Treatment of N-propargylamides with 5 mol% of silver
hexafluoroantimonate results in the rapid formation of oxazolines in
essentially quantitative yield.
Key words: N-propargylamides, silver, oxazolines, catalysis
The reaction of alkynes with metal ions of group 12 has a
long-standing and growing history.1 Copper, silver and
gold ions are increasingly of interest for the mild conver-
sion of alkynes into a variety of interesting and useful
products. Recently, we reported that the rapid rearrange-
ment of propargylic sulfinate esters to allenic sulfones
could be effected by exposure of the former to catalytic
amounts of silver cations.2 As part of our continuing inter-
est in silver ion catalyzed processes, we now report the
facile conversion of propargylic amides into alkylidene
oxazolines using silver ion catalysis.
F
O
Et
Et
Me
F
N
NH
Me
O
The reaction of propargylic amides with electrophilic
metal ions is known. Hashmi and co-workers reported the
conversion of propargylic amides 1 into the correspond-
ing oxazoles 3, via the intermediacy of methylidene ox-
azolines 2, which could be observed spectroscopically,
upon treatment with catalytic amounts of AuCl3
(Scheme 1).3 A gold(I) catalyst also promoted cyclization
of a propargylic amide to a methylene oxazoline, which
could be isolated before isomerization to the correspond-
ing oxazole.4 Alkylidene oxazolidinones have been pre-
pared via the gold(I)-catalyzed cyclization of Boc-
protected propargyl amines (Equation 1).5 A similar route
to carbonates using silver ion catalysis has also been pub-
lished.6
CuI (10 mol%)
C6H6/Et3N (1:1)
90 °C, 30 min
97%
7
6
O
Equation 2
O
Ph
AgNO3 (0.2 mol%)
HN
Ph
N
O
n-BuOAc, 95 °C, 30 min
94%
Me
Me
Me
Me
9
8
NaOH (0.5 N), toluene
Aliquat 336, reflux, 3 h
95%
O
O
Ph
Me
O
AuCl3 (5 mol%)
CH2Cl2, 20 °C
12 h, 95%
Ph
HN
N
Ph
Scheme 2
N
1
2
3
Palladium-catalyzed cyclizations of propargylic amides
have been conducted in the presence of CO and alcohols
to afford not simple cyclization products, but compounds
that have undergone an additional alkoxycarbonylation
(Equation 3).10
Scheme 1
O
OMe
O
(Ph3PAu)NTf2 (1.8 mol%)
CH2Cl2, 20 °C, 81%
Ar
HN
N
4
5
It should be mentioned that the conversion of propargylic
amides into alkylidene oxazolines does not require metal
catalysis at all. For example, treatment of 8 with 0.5 N
NaOH in toluene in the presence of a phase-transfer catal-
ysis resulted in the formation of 9 in 95% yield after three
hours at reflux (Scheme 2).11
Equation 1
SYNLETT 2008, No. 9, pp 1399–1401
Advanced online publication: 07.05.2008
DOI: 10.1055/s-2008-1078405; Art ID: S02208ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
0
8

1400
M. Harmata, C. Huang
LETTER
10% Pd/C, KI
MeOH, air, CO
heat, 66%
H
N
O
O
O
N
N
NH
O
CO2Me
10
MeO2C
11
Equation 3
We undertook our studies as a result of a failed attempt to We found that treatment of a variety of propargylic
generate an allenic sulfoximine. The reaction of 12 with amides with 5 mol% of silver hexafluoroantimonate in
benzoic anhydride and base afforded not the desired sulfi- dichloromethane at room temperature afforded excellent
namide 13 but 8 (Scheme 3), which was treated with sil- to nearly quantitative yields of cyclized product in five to
ver ion (before we knew we had prepared a simple ten minutes.14 This reaction presumably proceeds through
propargylic amide). This afforded 9 in very high yield. coordination of the silver cation to the alkyne followed by
Given that result, we decided to examine the preparation nucleophilic attack by the amide oxygen and proton trans-
of a number of different 4,4-dialkyl-5-methylene oxazo- fer to afford the product and regenerate the silver cation.
lines. The results are summarized in Table 1.13
At least three results among those shown are particularly
noteworthy. The crotonamide 20 cyclized successfully to
O
S
O
give 21 in high yield (Table 1, entry 5). A primary chlo-
ride is stable under the reaction conditions (Table 1, entry
6). Finally, blocking aromatization by dialkyl substitution
does not appear to be necessary, as evidenced by the iso-
lation of 2 in high yield. As pointed out by Hashmi,3 struc-
tures such as 2 are relatively rare, as they are prone to
aromatization except under the mildest of conditions.
Ph
HN
4-Tol
HN
Ph
AgSbF6 (5 mol%)
CH2Cl2, 5 min
97%
NaH
N
O
(PhCO)2O
Me
Me
Me
Me
12
Me
Me
8
9
O
O
S
Ph
N
4-Tol
Finally, given the reports of the gold-catalyzed synthesis
of alkylidene oxazolidinones starting from Boc-protected
propargylic amines,5 we decided to investigate the process
using silver ions. To our delight, treatment of 32 and 34
under our standard reaction conditions resulted in the for-
mation of 33 and 35 in 92% and 91% yields, respectively
(Equation 4).
13
Me
Me
Scheme 3
Table 1 Oxazolines from Propargylic Amides12
R3
O
R3
AgSbF6 (5 mol%)
HN
R1
N
O
O
O
CH2Cl2, r.t., 5–10 min
R1
AgSbF6 (5 mol%)
CH2Cl2, 5–10 min
NHBoc
R
R2
R2
NH
R
R
Entry Amide R1
R2
R3
Product Yield
(%)
R
32, R = Me, 92%
34, R–R = (CH2)5, 91%
33, R = Me, 92%
35, R–R = (CH2)5, 91%
1
2
3
4
14
8
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Bn
Et
15
9
98
97
97
96
Equation 4
In summary, we have shown that propargylic amides can
be rapidly cyclized to 5-methyleneoxazolines in high
yields at room temperature upon treatment with catalytic
amounts of silver hexafluoroantimonate.15 It is likely that
this chemistry can be extended to the synthesis of highly
substituted oxazoles. The investigation of this process and
other silver-catalyzed chemistry is in progress. New re-
sults will be reported in due course.
16
18
17
19
5
20
Me
Me
21
95
Me
6
7
22
24
26
28
30
1
Me
Me
Me
Et
Me
Me
Me
Et
(CH2)3Cl
23
25
27
29
31
2
89
96
94
96
97
91a
t-Bu
8
4-O2NC6H4
Acknowledgment
9
Ph
Ph
Ph
This work was supported by the National Science Foundation.
10
11
(CH2)5
H
H
a The reaction failed in CH2Cl2; MeNO2 was used as solvent.
Synlett 2008, No. 9, 1399–1401 © Thieme Stuttgart · New York

LETTER
Oxazoline Formation
1401
2.33 (s, 1 H), 2.17 (q, J = 12.5 Hz, 2 H), 1.64 (s, 6 H), 1.14
(t, J = 12.5 Hz, 3 H). 13C NMR (125.8 MHz, CDCl3): d =
177.8, 87.3, 68.9, 47.4, 30.1, 28.9, 9.4. IR (CH2Cl2): 3309,
3223, 2982, 2238, 2099, 1658, 1540, 898, 718 cm–1. HRMS:
m/z calcd for C8H13NONa+: 162.0889; found: 162.0887. 19:
solid; mp 118–120 °C. 1H NMR (500 MHz, CDCl3): d = 4.81
(d, J = 3.5 Hz, 1 H), 4.38 (d, J = 3.5 Hz, 1 H), 2.50 (q, J = 3.0
Hz, 2 H), 1.45 (s, 6 H), 1.32 (t, J = 3.0 Hz, 3 H). 13C NMR
(125.8 MHz, CDCl3): d = 171.6, 164.6, 86.0, 68.0, 30.1,
22.9, 9.7. IR (CH2Cl2): 3624, 3411, 2986, 1654, 1180, 665
cm–1. HRMS: m/z calcd for C8H13NOH+: 140.1070; found:
140.1068. 20: solid; mp 96–98 °C. 1H NMR (500 MHz,
CDCl3): d = 6.84 (dt, J = 9.0, 14.5 Hz, 1 H), 5.92 (s, 1 H),
5.81 (d, J = 14.5 Hz, 1 H), 2.34 (s, 1 H), 1.83 (d, J = 9.0 Hz,
3 H), 1.67 (s, 6 H). 13C NMR (125.8 MHz, CDCl3): d =
165.0, 139.9, 125.3, 87.2, 68.9, 47.3, 28.9, 17.5. IR
(CH2Cl2): 3293, 3239, 2974, 2108, 1634, 1540, 1233, 967
cm–1. HRMS: m/z calcd for C9H13NONa+: 174.0890; found:
174.0889. 21: oil. 1H NMR (500 MHz, CDCl3): d = 6.84 (dt,
J = 6.0, 15.5 Hz, 1 H), 6.07 (d, J = 15.5 Hz, 1 H), 4.72 (d,
J = 3.0 Hz, 1 H), 4.27 (d, J = 3.0 Hz, 1 H), 1.94 (d, J = 6.0
Hz, 3 H), 1.41 (s, 6 H). 13C NMR (125.8 MHz, CDCl3): d =
165.9, 161.3, 143.3, 117.6, 83.5, 68.1, 29.8, 18.5. IR
References and Notes
(1) (a) Hashmi, A. S. K.; Hutchings, G. J. Angew. Chem. Int. Ed.
2006, 45, 7896. (b) Oh, C. H.; Yi, H. J.; Lee, J. H. New J.
Chem. 2007, 31, 835. (c) D’Souza, D. M.; Mueller, T. J. J.
Chem. Soc. Rev. 2007, 36, 1095. (d) Yorimitsu, H.;Oshima,
K. Angew. Chem. Int. Ed. 2005, 44, 4435.
(2) Harmata, M.; Huang, C. Adv. Synth. Catal. 2008, 350, 972.
(3) Hashmi, A. S. K.; Weyrauch, J. P.; Frey, W.; Bats, J. W.
Org. Lett. 2004, 6, 4391.
(4) Hashmi, A. S. K.; Rudolph, M.; Schymura, S.; Visus, J.;
Frey, W. Eur. J. Org. Chem. 2006, 4905.
(5) (a) Lee, E.-S.; Yeom, H.-S.; Hwang, J.-H.; Shin, S. Eur. J.
Org. Chem. 2007, 3503. (b) Robles-Machín, R.; Adrio, J.;
Carretero, J. C. J. Org. Chem. 2006, 71, 5023. (c) Buzas,
A.; Gagosz, F. Synlett 2006, 2727.
(6) Yamada, W.; Sugawara, Y.; Cheng, H. M.; Ikeno, T.;
Yamada, T. Eur. J. Org. Chem. 2007, 2604.
(7) (a) Jin, C.; Burgess, J. P.; Kepler, J. A.; Cook, C. E. Org.
Lett. 2007, 9, 1887. (b) Jin, C.; Manikumar, G.; Kepler, J.
A.; Cook, C. E.; Allan, G. F.; Kiddoe, M.; Bhattacharjee, S.;
Linton, O.; Lundeen, S. G.; Sui, Z. Bioorg. Med. Chem. Lett.
2007, 5754.
(8) Rayle, H. L. Eur. Patent Appl., 952143, 1999; Chem. Abstr.
1999, 131, 310350.
(9) Easton, N. R.; Cassady, D. R.; Dillard, R. D. J. Org. Chem.
1965, 30, 3084.
(10) (a) Bacchi, A.; Costa, M.; Cà, N. D.; Gabriele, B.; Salerno,
G.; Cassoni, S. J. Org. Chem. 2005, 70, 4971. (b) Bacchi,
A.; Costa, M.; Gabriele, B.; Pelizzi, G.; Salerno, G. J. Org.
Chem. 2002, 67, 4450.
(11) (a) Rayle, H. L.; Roemmele, R. C.; Stephens, R. W. U.S.
Patent, 5859254, 1999; Chem. Abstr. 1999, 130, 110255.
(b) Schmidt, E. Y.; Vasil’tsov, A. M.; Mikhaleva, A. I.;
Zaitsev, A. B.; Afonin, A. V.; Toryashinova, D. D.; Klyba,
L. V.; Arndt, J.-D.; Henkelmann, J. ARKIVOC 2003, (xiii),
35.
(CH2Cl2): 2970, 1674, 1307, 1184, 972, 661 cm–1. HRMS:
m/z calcd for C9H13NONa+: 174.0889; found: 174.0886. 22:
solid; mp 48–49 °C. 1H NMR (500 MHz, CDCl3): d = 5.81
(s, 1 H), 3.61 (t, J = 6.0 Hz, 2 H), 2.34 (t, J = 6.0 Hz, 2 H),
2.11 (tt, J = 6.0, 6.0 Hz, 2 H), 1.64 (s, 6 H). 13C NMR (125.8
MHz, CDCl3): d = 170.8, 86.9, 67.1, 47.5, 44.4, 33.5, 28.9,
27.9. IR (CH2Cl2): 3350, 3239, 2994, 2108, 1646, 1540,
1221 cm–1. HRMS: m/z calcd for C9H14ClNONa+: 210.0656;
found: 210.0651. 23: oil. 1H NMR (500 MHz, CDCl3): d =
4.60 (d, J = 3.0 Hz, 1 H), 4.10 (d, J = 3.0 Hz, 1 H), 3.63 (t,
J = 6.0 Hz, 2 H), 2.56 (t, J = 7.0 Hz, 2 H), 2.17 (tt, J = 6.0,
7.0 Hz, 2 H), 1.35 (s, 6 H). 13C NMR (125.8 MHz, CDCl3):
d = 167.5, 162.9, 82.2, 68.3, 43.8, 29.5, 28.2, 25.2. IR
(CH2Cl2): 2974, 2929, 1679, 1192, 1127, 963 cm–1. HRMS:
m/z calcd for C9H14ClNOH+: 188.0837; found: 188.1277.
24: solid; mp 106–107 °C. 1H NMR (500 MHz, CDCl3): d =
(12) General Procedure for the Preparation of Methylene
Oxazolines from N-Propargylamides:
5.67 (s, 1 H), 2.32 (s, 1 H), 1.66 (s, 6 H), 1.20 (s, 9 H). 13
C
The amide (1 mmol) was placed in a dry flask with CH2Cl2
(2 mL). AgSbF6 (5 mol%) was added in one portion with
magnetic stirring. After 5–10 min, TLC showed no starting
material. The reaction mixture was filtered through Celite
and washed with CH2Cl2. The filtrate was evaporated to
afford the pure (1H NMR) product.
NMR (125.8 MHz, CDCl3): d = 177.4, 87.4, 68.8, 47.4, 38.9,
28.7, 27.4. IR (CH2Cl2): 3362, 3288, 2998, 1650, 1523,
1356, 1209 cm–1. HRMS: m/z calcd for C10H17NONa+:
190.1202; found: 190.1200. 25: oil. 1H NMR (500 MHz,
CDCl3): d = 4.56 (d, J = 2.5 Hz, 1 H), 4.10 (d, J = 2.5 Hz,
1 H), 1.33 (s, 6 H), 1.27 (s, 9 H). 13C NMR (125.8 MHz,
CDCl3): d = 169.6, 168.5, 80.9, 68.2, 32.9, 29.5, 27.4. IR
(CH2Cl2): 3419, 2974, 1646, 1180, 1094 cm–1. HRMS: m/z
calcd for C10H17NONa+: 190.1202; found: 190.1042. 26:
solid; mp 108–110 °C. 1H NMR (500 MHz, CDCl3): d = 8.23
(d, J = 9.0 Hz, 2 H), 7.93 (d, J = 9.0 Hz, 2 H), 5.57 (s, 1 H),
2.43 (s, 1 H), 1.78 (s, 6 H). 13C NMR (125.8 MHz, CDCl3):
d = 164.5, 149.4, 140.3, 128.1, 123.6, 86.4, 69.8, 49.3, 28.8.
IR (CH2Cl2): 3289, 2982, 1654, 1527, 1352, 845 cm–1.
HRMS: m/z calcd for C12H12N2O3Na+: 255.0740; found:
255.0738. 27: oil. 1H NMR (500 MHz, CDCl3): d = 8.30 (d,
J = 8.0 Hz, 2 H), 8.18 (d, J = 8.0 Hz, 2 H), 4.80 (d, J = 3.0
Hz, 1 H), 4.33 (d, J = 3.0 Hz, 1 H), 1.48 (s, 6 H). 13C NMR
(125.8 MHz, CDCl3): d = 167.2, 158.2, 149.6, 132.6, 129.1,
123.6, 83.5, 69.6, 29.5. IR (CH2Cl2): 3427, 3105, 2982,
1646, 1597, 1519, 1307, 1066 cm–1. HRMS: m/z calcd for
C12H12N2O3Na+: 255.0740; found: 255.0739.
(13) The starting amides were prepared by the reaction of amines
with acid chlorides.
(14) The conversion of 8 into 9 required 15 min with 2% catalyst,
1 h with 1% catalyst and 28 h with 0.1% catalyst, all
reactions being conducted at r.t.
(15) Data of selected compounds: 16: solid; mp 138–140 °C. 1H
NMR (500 MHz, CDCl3): d = 7.25–7.37 (m, 5 H), 5.55 (s, 1
H), 3.54 (s, 2 H), 2.31 (s, 1 H), 1.57 (s, 6 H). 13C NMR (125.8
MHz, CDCl3): d = 169.9, 134.8, 129.2, 128.9, 127.2, 87.5,
69.1, 47.6, 44.4, 28.7. IR (CH2Cl2): 3309, 3215, 2099, 1642,
1540, 1221, 722 cm–1. HRMS: m/z calcd for C13H15NONa+:
224.1043; found: 224.1043. 17: solid; mp 192–193 °C. 1H
NMR (500 MHz, CDCl3): d = 7.26–7.34 (m, 5 H), 4.57 (d,
J = 3.0 Hz, 1 H), 4.14 (d, J = 3.0 Hz, 1 H), 3.69 (s, 2 H), 1.35
(s, 6 H). 13C NMR (125.8 MHz, CDCl3): d = 167.7, 134.2,
128.8, 128.7, 127.1, 82.3, 68.5, 34.8, 29.4. IR (CH2Cl2):
2974, 2921, 1662, 1454, 1180, 1123 cm–1. HRMS: m/z calcd
for C13H15NONa+: 224.1043; found: 224.1044. 18: solid; mp
96–97 °C. 1H NMR (500 MHz, CDCl3): d = 5.65 (s, 1 H),
Synlett 2008, No. 9, 1399–1401 © Thieme Stuttgart · New York

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