Tungsten and molybdenum catalyst-mediated cyclisation of N-propargyl amides

Article abstract of DOI:10.1039/c1ob05512g

Tungsten and molybdenum catalysts were employed to promote the cyclisation of N-propargylic amides to afford the corresponding oxazolines or oxazines via 5-exo-dig or 6-endo-dig mode.

Full text of DOI:10.1039/c1ob05512g

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Tungsten and molybdenum catalyst-mediated cyclisation of N-propargyl
amides†
Xiangjian Meng and Sunggak Kim*
Received 2nd April 2011, Accepted 28th April 2011
DOI: 10.1039/c1ob05512g
Tungsten and molybdenum catalysts were employed to pro-
mote the cyclisation of N-propargylic amides to afford the
corresponding oxazolines or oxazines via 5-exo-dig or 6-endo-
dig mode.
In contrast to the wide application of late transition metal
catalysts such as Pd, Au, In and Ru for new bond formation in
synthetic organic chemistry,1 related reactions promoted by early
Scheme 1
transition-metal complexes such as Mo and W have not been well
explored and have scarcely been reported owing to their relatively
low activity as efficient catalysts in organic transformations.2
Nevertheless, it would be interesting and highly desirable to
develop the synthetic usefulness of Group VI metals in organic
transformations due to their characteristic reactivities.
Scheme 2
Group VI metal carbonyl complexes have attracted a great
deal of attention due to their ability for electrophilic activation
this assumption, we studied the effectiveness of W and Mo
of alkyne functionality under photochemical conditions.3 During
catalysts in the cyclisation of propargylic amides. As shown in
the last two decades, McDonald et al. efficiently employed
Table 1, we began our studies with N-propynylbenzamide 7 using
Mo(CO)5·(Et3N) as a catalyst to promote the cyclisation of alkynyl
20 mol% W(CO)3(CH3CN)3.12 When the reaction was carried out
alcohols4 while Iwasawa et al. developed the cyclisation of various
silyl ethers using W(CO)5·(THF) catalyst and also investigated the
in refluxing toluene, no reaction occurred (entry 1). Similarly, no
reaction occurred using Mo catalysts in refluxing THF (entries
detailed mechanism of this kind of cyclisation reaction.5
3 and 4).13 When the reaction was carried out using W(CO)6
The cyclisations of propargylic amides with Au,6 Ag,7 Cu8 and
or Mo(CO)6 in the presence of Et3N in refluxing toluene, the
Pd9 catalysts are known to give oxazoline derivatives. According to
reaction did not proceed to an observable extent (entries 5 and
the previous report by Hashmi et al.,10 the mode of the cyclisation
depended on the nature of the propargylic amides as shown in
Scheme 1. The 6-endo-dig ring closure was observed for the alkyl-
substituted alkynes, whereas the 5-exo-dig ring closure was general
for terminal alkynes. In addition, the oxazolines are prone to
aromatization and their preparations require mild conditions.
6). However, when the similar reaction was carried out under
irradiation at 350 nm, the cyclisation proceeded but the oxazoline
product was isolated in 40% yield contrary to our expectations
(entry 7). In the absence of Et3N, only trace amounts (<5%) of
the desired cyclised product was detected along with the recovery
of the starting material (entry 8). It was found that DABCO (1,4-
As we were keen on expanding the application of W and
diazabicyclo[2.2.2]octane) turned out to be much more effective
Mo catalysts in organic synthesis, we studied the possibility of
than Et3N and gave better yields (entry 9).14 In addition, carrying
using Mo and W catalysts for the cyclisation of propargylic
amides to prepare oxazolines 2 and/or oxazines 4 via the 5-
exo mode and/or 6-endo mode. Since W and Mo catalysts are
out the reaction in toluene improved the yield further (entry 10).
It is noteworthy that Mo catalyst also catalyzed the cyclisation but
was less effective than W catalyst (entry 12). Finally, the cyclisation
known to form vinylidene carbene species with alkynes,11 oxazines
in the presence of DABCO alone in refluxing toluene did not occur
4 could be formed via intermediate 5 (Scheme 2). Based on
(entry 13).
To further improve the yield, when the reaction mixture was
Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University, Singapore
637371, Singapore. E-mail: sgkim@ntu.edu.sg; Fax: +65 6791 1961;
Tel: +65 6592 7765
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c1ob05512g
treated with trimethylamine N-oxide dihydrate for the oxidative
treatment of the W complex product,15 the yield was increased to
some extent (84%). Thus, the remaining reactions were carried out
using 20 mol% W(CO)6 in the presence of DABCO (1 equiv) in
toluene at 350 nm for 12 h and subsequent oxidative treatment with
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Table 1 M(CO)5(L)-Catalyzed cyclisation of propargyl amide 7
Entry
Cat.
Additive
Solvent
Condition
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
W(CO)3(CH3CN)3
W(CO)3(CH3CN)3
Mo(CO)3(CH3CN)3
Mo(CO)3(DMF)3
W(CO)6
Mo(CO)6
W(CO)6
W(CO)6
W(CO)6
W(CO)6
W(CO)6
—
—
—
—
Et3N
Et3N
Et3N
—
DABCO
DABCO
DABCO
DABCO
DABCO
Toluene
CH3CN
THF
reflux
reflux
reflux
reflux
reflux
reflux
350 nm
350 nm
350 nm
350 nm
350 nm
350 nm
reflux
10
10
20
20
12
12
12
12
12
12
24
12
10
trace
0
0
THF
0
Toluene
Toluene
THF
THF
THF
Toluene
Toluene
Toluene
Toluene
trace
trace
40
trace
63
73
65
9
10
11
12
13
Mo(CO)6
—
45
0
Table 2 W(CO)6-Catalyzed cyclisation of unsubstituted and monosub-
of 10f and 11f (entry 6). The complete isomerization could be
achieved by treating with DBU at room temperature. For instance,
treatment of a 65 : 33 mixture of 10f and 11f with DBU (1 equiv) in
benzene at room temperature overnight afforded 11f in 97% yield.
In the case of n-butyl substituted propargylic amides 12a and 12b,
contrary to previous reports,10,16 they did not undergo cyclisation
to give 13 and/or 14 under the present conditions and the starting
propargylic amides were recovered unchanged.
stituted propargyl amidesa
Entry
R1
R2
Yield (%) (10 : 11)
1
2
3
4
5
6
7
8
9
9a: Ph
H
H
H
H
80 : 0
89 : 0
91 : 0
83 : 0
0
65 : 33
20 : 73
72 : 22
67 : 25
9b: 2-BrPh
9c: 2-MeOPh
9d: n-C7H15
9e: 4-NO2Ph
9f: Ph
H
Me
Me
Me
Me
9g: Bn
9h: 2-BrPh
9l: n-C7H15
We next studied the cyclisation of disubstituted propargylic
amides using W and Mo catalysts along with DABCO under
standard reaction conditions. As we anticipated at the onset of
this research, when 15 was subjected to the standard cyclisation
conditions using 20 mol% W(CO)6, oxazine 17 was obtained as a
major product along with oxazoline 16 in a ratio of 78 : 17 (entry
1) and the product ratio remained the same for a longer reaction
time (24 h). The use of Mo catalyst provided a similar result in
favor of oxazine 17 (85 : 10) (entry 2). However, oxazines were not
always obtained as a major product and the ratio of oxazolines
and oxazines were variable, as shown in Table 3, and seemed to be
dependent on the nature of the catalysts and the structure of the
propargyl amides.
We next studied the cyclisation of thiocarbamate 18 using
W(CO)6/Mo(CO)6 and DABCO (Scheme 3). When a toluene
solution of 18 with W(CO)6 and DABCO in toluene was irradiated
at 350 nm for 15 h, no reaction occurred and the starting material
was recovered unchanged. However, using Mo(CO)6–DABCO
under similar conditions the cyclisation proceeded cleanly, yielding
a 54 : 36 mixture of thiazolidine 19 and thiaoxazine 20. Further-
more, we also attempted the cyclisation of carbamate 21 and urea
a 1. W(CO)6 (0.2 equiv), DABCO (1 equiv), toluene (1 mL), N2, 350 nm,
20 h, r.t.; 2. Trimethylamine N-oxide dihydrate, THF.
trimethylamine N-oxide. In the present approach, two noteworthy
features are (i) 5-exo-dig ring closure to give an oxazoline without
any indication of 6-endo-dig ring closure and (ii) no further
isomerization to an oxazole due to the mildness of the reaction
conditions.
With the optimum conditions in hand, the scope and limitations
of the present method were investigated (Table 2). When a solution
of unsubstituted propargylic amides, W(CO)6 (0.2 equiv) and
DABCO (1 equiv) in toluene was irradiated at 350 nm for
20 h, oxazoline products were obtained in high yields (entries
1–4). However, 4-nitro-N-propynylbenzamide did not undergo
cyclisation, probably due to the strong electron-withdrawing
nature of the nitro group (entry 5). Concerning the isomerisation
of oxazolines to oxazoles, as we observed previously, oxazoline 10
(R2 = H) did not undergo isomerization to oxazole 11.
The cyclisation of monoalkyl substituted propargylic amide 9
(R2 = Me) afforded a mixture of 10 and 11 (entries 6–9). To
complete the isomerization of oxazolines to oxazoles, when a
toluene solution of a 65 : 33 mixture of oxazoline 10f and oxazole
11f in the presence of DABCO (2 equiv) was stirred at 80 ◦C for
12 h, the isomerization was incomplete, yielding a 46 : 47 mixture
Scheme 3
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Table 3 W(CO)6/Mo(CO)6 Catalyzed cyclisation of dimethyl substituted
studies on the W and Mo-mediated cyclisations are currently in
progress.
propargyl amidesa
Acknowledgements
We thank the Division of Chemistry and Biological Chemistry,
Nanyang Technological University for financial support.
Entry
R2
Cat.
(16 : 17) (%)
Notes and references
1
2
3
4
5
6
7
8
15a: Ph
Ph
15b: 2-BrPh
2-BrPh
15c: Bn
Bn
W
Mo
W
Mo
W
Mo
W
17 : 78
10 : 85
49 : 49
16 : 82
69 : 23
8 : 86
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vinylidene complex C (Scheme 4).11 Intramolecular nucleophilic
attack of the carbonyl oxygen on the amide of intermediate
B via 5-exo or 6-endo mode followed by the protonation of
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17 Deuterium exchange experiment in the presence of CH3OD (20
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incorporation in two exo-methylene hydrogens. The detailed studies
will be reported in due course.
Scheme 4
In conclusion, we have developed W and Mo catalyst mediated
cyclisation of propargylic amides to oxazolines and/or oxazines.
The ratio of oxazolines and oxazines depends very much on the
structure of the substrates and the nature of the catalysts. Further
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 4429–4431 | 4431
©