CuI-catalyzed cycloisomerization of propargyl amides

Article abstract of DOI:10.1039/c3ob42030b

The synthesis of substituted dihydrooxazoles by the CuI-catalyzed cycloisomerization of terminal propargyl amides is reported. The reaction has been shown to have good substrate scope and experiments to delineate the mechanism have been performed. Substrates containing a benzylic methylene were oxidized to the ketone under the reaction conditions.

Full text of DOI:10.1039/c3ob42030b

Organic &
Biomolecular Chemistry
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CuI-catalyzed cycloisomerization of propargyl
amides†
Cite this: Org. Biomol. Chem., 2014,
12, 795
Ali Alhalib and Wesley J. Moran*
Received 10th October 2013,
Accepted 29th November 2013
The synthesis of substituted dihydrooxazoles by the CuI-catalyzed cycloisomerization of terminal propar-
gyl amides is reported. The reaction has been shown to have good substrate scope and experiments to
delineate the mechanism have been performed. Substrates containing a benzylic methylene were oxi-
dized to the ketone under the reaction conditions.
DOI: 10.1039/c3ob42030b
www.rsc.org/obc
Intrigued by this process, we investigated the reaction con-
ditions for the cyclization of 1a (Table 1). To determine
Introduction
Oxazole and oxazoline rings are found in a multitude of whether the Cu or Pd catalysts were responsible for the cycliza-
natural and non-natural compounds with useful biological tion, each was tested individually. The Pd catalyst led to no
properties, such as antibacterial, antifungal, antiviral and anti- conversion of 1a (entry 1) whereas the CuI led to 13% conver-
proliferative activities.1 Oxazoles and oxazolines are also useful sion (entry 2). Changing the solvent from triethylamine to
as intermediates in organic synthesis,2 ligands for catalysts3 CH2Cl2 led to an improvement in conversion and complete
and as protecting groups.4
consumption of 1a was observed (entry 3). Using CuCl as cata-
A popular strategy for the construction of oxazole and oxa- lyst led to complete conversion (entry 4) and several Cu(II) salts
zoline rings is the cycloisomerization of propargyl amides.5–9 led to complete conversion also (entries 5–7). Using one equi-
Gold-catalysis has been shown to be particularly effective for valent of either NaI or KOt-Bu both led to about 20% conver-
this process,6 but catalytic systems employing silver,7 copper,8 sion (entries 8 and 9).
molybdenum9 and tungsten9 salts have also been reported.
It was decided to continue with CuI as it is cheap, air
stable, non-hygroscopic and easy to handle. With these con-
ditions in hand, the scope of this reaction was investigated
(Table 2). However, it soon became apparent that there were
significant reaction rate differences between substrates, so the
solvent was changed to the higher boiling 1,2-dichloroethane
and the reactions were heated to reflux in all cases. A variety of
substituted benzamides cyclized in very good yields (3a–3d),
however substrate 1d, bearing a nitro substituent, required
48 hours to reach completion. Unprotected indole derivative
Results and discussion
Whilst attempting to prepare disubstituted alkyne 2 by a Sonoga-
shira reaction on propargyl amide 1a, heterocycle 3a was isolated
in 20% yield (Scheme 1). Coupled product 2 was not observed in
the crude reaction mixture and the phenyl group from iodoben-
zene was not incorporated into the product. Jin and co-workers
reported a similar phenomenon in a series of steroids.8
Table 1 Optimization studies for formation of oxazoline 3a from 1aa
Entry
Catalyst
Solvent
Conversionb/%
1
2
3
4
5
6
7
8
9
0.5 mol% Pd(PPh3)4
10 mol% CuI
10 mol% CuI
10 mol% CuCl
10 mol% Cu(OAc)2
10 mol% Cu(OTf)2
10 mol% CuSO4
1 equiv. NaI
Et3N
Et3N
0
13
99
99
99
99
99
20
18
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Scheme 1 Unexpected cycloisomerization under Sonogashira cross-
coupling conditions.
Department of Chemical & Biological Sciences, University of Huddersfield,
Queensgate, Huddersfield HD1 3DH, UK. E-mail: w.j.moran@hud.ac.uk
†Electronic supplementary information (ESI) available: Copies of 1H and
13C NMR spectra for new compounds. See DOI: 10.1039/c3ob42030b
1 equiv. KOt-Bu
a Reactions conducted at room temperature. b Conversion determined
by 1H NMR analysis of the crude reaction mixture.
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Table 2 Scope of cyclizationa
Scheme 2 Tandem CuI-catalyzed cyclization/benzylic oxidation.
Scheme 3 Deuterium labelling experiment.
In order to investigate the mechanism of the cyclization,
deuterated compound 1a′ was prepared and subjected to the
standard reaction conditions (Scheme 3).11 In the event, three
compounds were observed by 1H NMR analysis of the crude
reaction mixture in a 3 : 1 : 1 ratio. The major product was 3a
with the two mono-deuterated compounds 3a′ and 3a″ formed
in equal and minor amounts. This is in contrast to the analo-
gous experiment conducted under Au(III)-catalysis reported by
Hashmi and co-workers (3a′ would be major in this case).6f
These results along with the inability of 1n to cyclize led us
to postulate that the mechanism proceeds through formation
of a copper acetylide followed by cyclization, proton transfer
and protonation to regenerate the Cu(I) catalyst (Scheme 4).
The Cu-catalyzed azide alkyne cycloaddition reaction (click
reaction) is believed to proceed through copper acetylide
a Yields of pure isolated compounds. b Reaction performed at ambient
temperature.
1e, furan 1f and thiophene 1g all cyclized in good yields. Aceta-
mide 1h did not cyclize under the reaction conditions,
however 1i did. Spirocycles 3j, 3k, 3l and 3m were formed in
very good yields under these conditions. However, 1n, contain-
ing an internal alkyne, did not cyclize and 1o which lacks a
gem-dialkyl group did not cyclize either.
Interestingly, compounds 3i and 3p underwent slow oxi-
dation at the benzylic position to form ketones 4i and 4p
(Scheme 2). Compound 3i could be isolated in pure form;
however, 3p underwent faster benzylic oxidation and could not
be isolated in pure form. Control experiments showed that the
CuI was necessary for the oxidation to occur. The CuCl-cata-
lyzed oxidation of diarylmethanes to benzophenones has been
reported however an oxygen atmosphere and a dioxyl radical
mediating agent was necessary for efficient conversion.10
Addition of a radical inhibitor (galvinoxyl) to the reaction
mixture did not lead to any noticeable differences in yield or
rate for formation of 4p from 1p or 3a from 1a.
Scheme 4 Postulated mechanism of cyclization.
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General procedure for the synthesis of amides 1a–f, h and o
1,1-Dimethylpropargyl amine (0.96 mL, 9.1 mmol, 1 equiv.)
was dissolved in CH2Cl2 (10 mL) and the corresponding acyl
chloride (1.89 equiv.) and triethylamine (2 equiv.) were added.
The mixture was stirred overnight at room temperature.
A saturated solution of NaCl (10 mL) was added and the
mixture extracted with CH2Cl2 (10 mL × 2). The organic
layers were combined and dried with anhydrous magnesium
sulfate, filtered and concentrated under vacuum to give the
product.
Scheme 5 Formation of dihydrothiazoles.
4-Chloro-N-(1,1-dimethylprop-2-ynyl)benzamide (1b). White
solid; yield: 92%; mp: 146–149 °C; IR(neat): 3328 (w), 3284 (m),
formation and cyclization.12 However, we cannot completely
rule out the alternative mechanism of the Cu(I) catalyst activat-
ing the alkyne for cyclization with the CuI also causing H/D
scrambling before cyclization. Our attempts to alkylate the
Cu intermediates with iodomethane or allyl bromide were
unsuccessful.
2990 (w), 1644 (s) cm−1 1H: δ 1.76 (6H, s), 2.40 (1H, s),
;
6.15 (1H, s), 7.40 (2H, d, J = 8.5 Hz), 7.70 (2H, d, J = 8.5 Hz);
13C: δ 29.3, 48.5, 69.9, 87.3, 128.7, 129.1, 133.5, 138.1, 165.7;
HRMS: m/z calc’d for [M + Na] C12H12ClNNaO 244.0500, found
244.0489.
In order to expand the scope of this process, we attempted
to prepare the thioamide analog of 1a for use in a subsequent
cyclization reaction. In the event, treatment of 1a with Lawes-
son’s reagent led to the direct formation of 5a in moderate
yield without any thioamide being observed or any copper
catalyst present (Scheme 5).13 Presumably, the thioamide is
formed but it undergoes facile cyclization under the reaction
conditions. Dihydrothiazole 5b was also prepared under
similar conditions.
N-(2-Methylbut-3-yn-2-yl)-4-nitrobenzamide (1d). Yellow
solid; yield: 39%; mp: 123–127 °C; IR(neat): 3278 (w), 2980 (m),
2184 (w), 1520 (m), 1343 (m) cm−1 1H: δ 1.77 (6H, s), 2.42
;
(1 H, s), 6.29 (1H, s), 7.91 (2H, d, J = 7.7 Hz), 8.26 (2H, d,
J = 7.1); 13C: δ 29.2, 48.9, 70.3, 86.9, 124.2, 128.5, 140.7, 150.0,
164.8; HRMS: m/z calc’d for [M + Na] C12H12N2NaO3 255.0740,
found 255.0741.
General procedure for the synthesis of amides 1g, 1i and 1p
Thionyl chloride (0.22 mL, 2.93 mmol, 3.4 equiv.) was added
to the corresponding carboxylic acid (2 equiv.) in CHCl3
(3 mL) and stirred overnight at room temperature. The
solvent was removed under vacuum to provide the acid chlor-
ide. 1,1-Dimethylpropargylamine (0.091 mL, 0.86 mmol,
1 equiv.) dissolved in CHCl3 (10 mL) was added to the freshly
prepared acid chloride followed by triethylamine (2 equiv.).
The mixture was stirred overnight, then quenched with NaOH
solution (3 M, 5 mL). The mixture was extracted with CH2Cl2
(10 mL × 2) and the organic layers were combined, dried with
anhydrous magnesium sulfate, filtered and concentrated
under vacuum. The residue was purified by flash chromato-
graphy (5 : 1 petroleum ether–EtOAc on silica gel) to give the
product.
Conclusions
The CuI-catalyzed cyclization of propargyl amides to dihy-
drooxazoles has been demonstrated. Mechanistic information
has been obtained and concomitant benzylic oxidation has
been observed in appropriate compounds. This reaction is
efficient, easy to carry out and has good scope.
In addition, Lawesson’s reagent has been shown to effect
direct cyclization of propargyl amides in to the analogous
dihydrothiazoles.
3-Bromo-N-(1,1-dimethylprop-2-ynyl)thiophene-2-carboxamide
(1g). Orange oil; yield: 23%; IR(neat): 3399 (w), 3295 (w), 3082 (w),
Experimental
General methods
2979 (w), 1647 (s), 1517 (s) cm−1 1H: δ 1.69 (6H, s), 2.34
;
1H NMR spectra were recorded at 400 MHz. Chemical shifts (1H, s), 6.95 (1H, d, J = 5.2 Hz), 7.17–7.25 (1H, m), 7.37 (1H, d,
are reported in ppm from tetramethylsilane with the solvent J = 5.2 Hz); 13C: δ 29.4, 48.6, 70.0, 86.9, 108.7, 130.6, 132.3,
resonance as the internal standard (CDCl3: 7.26 ppm). 13C 135.9, 159.6; HRMS: m/z calc’d for [M + Na] C10H10BrNNaOS
NMR were recorded with complete proton decoupling. Chemi- 293.9558, found 293.9559.
cal shifts are reported in ppm from tetramethylsilane with the
N-(1,1-Dimethylprop-2-ynyl)-2-(2-thienyl)acetamide (1i). Yellow
solvent as the internal standard (CDCl3: 77.4 ppm). Mass spec- solid; yield: 53%; mp: 143–145 °C; IR(neat): 3304 (m), 3203 (m),
trometry (m/z) was performed in ESI mode, with only mole- 3009 (w), 2984 (w), 2935 (w), 1640 (s), 1548 (s) cm−1; 1H: δ 1.57
cular ions being reported. Infrared (IR) spectra νmax are (6H, s), 2.30 (1H, s), 3.55 (2H, s), 5.49 (1H, s), 6.99 (1H, dd, J =
reported in cm−1. Petroleum ether refers to the fraction boiling 5.1, 4.8 Hz), 7.13 (1H, d, J = 2.38 Hz), 7.32 (1H, dd, J = 4.9 Hz);
at 40–60 °C. All purchased reagents were used as received 13C: δ 29.2, 39.2, 48.0, 69.6, 87.3, 123.7, 127.1, 128.7, 135.2,
without further purification. All reactions were performed 169.9; HRMS: m/z calc’d for [M + Na] C11H13NNaOS 230.0611,
under a N2 atmosphere.
found 230.0615.
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General procedure for the synthesis of amides 1j–m
General procedure for the synthesis of dihydrooxazoles 3b–3m
1-Ethylcyclohexylamine (50 mg, 0.405 mmol, 1 equiv.) was The corresponding amide (50 mg, 1 equiv.) was dissolved in
dissolved in DMF (1 mL) and the corresponding acyl chloride
(2 equiv.) and triethylamine (2 equiv.) were added. The
mixture was stirred at 50 °C for an hour, then at room temp-
erature overnight. The solvent was removed under reduced
pressure and the residue was purified by flash chromatography
(5 : 1 petroleum ether–EtOAc with 5% Et3N on silica gel) to
give the product.
1,2-DCE (2 mL), and then CuI was added (10 mol%). The
mixture was heated at reflux overnight. After concentration
under vacuum, the residue was purified by flash chromato-
graphy (5 : 1 petroleum ether–EtOAc on silica gel) to provide
the product.
2-(4-Chloro-phenyl)-4,4-dimethyl-5-methylene-4,5-dihydro-
oxazole (3b). Yellow oil; yield: 88%; IR(neat): 2974 (w), 2928 (w),
1674 (m), 1309 (s) cm−1 1H: δ 1.47 (6H, s), 4.28 (1H, d, J =
;
N-(1-Ethynylcyclohexyl)-4-nitrobenzamide (1m). Light yellow
solid; yield: 99%; mp: 137–140 °C; IR(neat): 3301 (w), 3244 (w),
2.8 Hz), 4.76 (1H, d, J = 2.8 Hz), 7.42 (2H, d, J = 8.6 Hz), 7.94
(2H, d, J = 8.6 Hz); 13C: δ 30.1, 69.6, 83.2, 125.6, 129.2, 129.8,
138.4, 159.6, 167.9; HRMS: m/z calc’d for [M + H] C12H13ClNO
222.0680, found 222.0680.
2939 (w), 2853 (w), 1648 (s), 1522 (s), 1486 (s) cm−1 1H:
;
δ 1.21–1.33 (1H, m), 1.58–1.74 (5H, m), 1.83–1.89 (2H, m),
2.12–2.24 (2H, m), 2.45 (1H, s), 6.37 (1H, s), 7.88 (2H, d, J =
8.7 Hz), 8.19 (2H, d, J = 8.6 Hz); 13C: δ 22.9, 25.5, 37.2, 53.0,
72.5, 85.1, 124.1, 128.5, 140.9, 149.9, 164.7; HRMS: m/z calc’d
for [M + Na] C15H16N2NaO3 295.1053, found 295.1053.
2-(4-Methoxy-phenyl)-4,4-dimethyl-5-methylene-4,5-dihydro-
oxazole (3c). Colorless oil; yield: 93%; IR(neat): 2972 (w),
1
2930 (w), 1643 (m), 1609 (s) cm−1; H: δ 1.44 (6H, s), 3.84 (3H,
s), 4.22 (1H, d, J = 2.6 Hz), 4.71 (1H, d, J = 2.8 Hz), 6.92 (2H, d,
J = 9.1 Hz), 7.93 (2H, d, J = 9.0); 13C: δ 30.2, 55.7, 69.3, 82.3,
114.2, 119.7, 130.2, 160.0, 162.7, 168.4; HRMS: m/z calc’d for
[M + Na] C13H15NNaO2 240.0995, found 240.0995.
Synthesis of N-(1-(phenylethynyl)cyclohexyl)benzamide (1n)
1-Ethynylcyclohexylamine (100 g, 0.81 mmol, 1 equiv.) was dis-
solved in Et3N (5 mL) then CuI (16 mg, 0.081 mmol, 10 mol%),
PhI (91 µL, 0.81 mmol, 1 equiv.) and Pd(PPh3)4 (5 mg,
0.040 mmol, 0.5 mol%) were added. The mixture was left
stirring overnight at room temperature then concentrated
under reduced pressure. The residue was purified by flash
chromatography (5 : 1 : 0.005 petroleum ether–EtOAc–Et3N on
silica gel) to provide the product as a brown oil (0.064 g, 45%).
This was dissolved in DMF (5 mL) then benzoylchloride
(84 µL, 0.72 mmol, 2 equiv.) and Et3N (101 µL, 0.72 mmol,
2-(4-Nitro-phenyl)-4,4-dimethyl-5-methylene-4,5-dihydro-
oxazole (3d). Yellow solid; mp: 103–107 °C; yield: 88%; IR(neat)
:
3108 (w), 2974 (w), 1679 (m), 1644 (m), 1524 (s) cm−1 1H:
;
δ 1.46 (6H, s), 4.31 (1H, d, J = 3.0 Hz), 4.78 (1H, d, J = 3.1 Hz),
8.15 (2H, d, J = 8.9 Hz), 8.28 (2H, d, J = 9.0 Hz); 13C: δ 30.0,
70.0, 83.9, 124.0, 129.5, 133.2, 150.0, 158.6, 167.7; HRMS: m/z
calc’d for [M + H] C12H13N2O3 233.0921, found 233.0937.
2-(1H-Indol-2-yl)-4,4-dimethyl-5-methylene-4,5-dihydro-
2 equiv.) were added. The mixture was stirred overnight and oxazole (3e). Colorless oil; yield: 85%; IR(neat): 3126 (w), 3066
1
(w), 2968 (m), 1698 (m), 1650 (s) cm−1; H: δ 1.46 (6H, s), 4.29
concentrated under reduced pressure. The residue was purified
by flash chromatography (5 : 1 petroleum ether–EtOAc on silica
gel) to provide the product as a white solid; 0.096 g; yield:
84%; mp: 174–177 °C; IR(neat): 3285 (w), 3050 (w), 2913 (w),
(1H, d, J = 3.0 Hz), 4.78 (1H, d, J = 3.0 Hz), 7.13 (1H, s), 7.25
(1H, d, J = 7.5 Hz), 7.29 (1H, d, J = 7.3 Hz), 7.38 (1H, d, J = 8.2
Hz), 7.68 (1H, d, J = 8.0 Hz), 9.34 (1H, s); 13C: δ 30.2, 69.2, 83.3,
107.3, 111.9, 121.0, 122.4, 124.8, 125.1, 128.1, 137.5, 155.4,
167.7; HRMS: m/z calc’d for [M + H] C14H15N2O 227.1178,
found 227.1186.
2-(Furan-2-yl)-4,4-dimethyl-5-methylene-4,5-dihydrooxazole
(3f). Brown oil; yield: 76%; IR(neat): 3649 (w), 2981 (w),
2170 (w), 2156 (w), 2039 (m) cm−1; 1H: δ 1.26 (6H, s), 4.07 (1H,
d, J = 3.1 Hz), 4.54 (1H, d, J = 3.0 Hz), 6.32 (1H, dd, J = 3.4,
4.0 Hz), 6.82 (1H, d, J = 3.4 Hz), 7.38 (1H, d, J = 1.5); 13C:
δ 29.7, 69.0, 83.0, 111.7, 115.0, 142.1, 145.7, 152.4, 167.2;
HRMS: m/z calc’d for [M + Na] C10H11NNaO2 200.0682, found
200.0689.
2851 (w), 1786 (w), 1639 (s) cm−1 1H: δ 1.30–1.39 (1H, m),
;
1.63–1.83 (5H, m), 2.08–2.22 (2H, m), 2.26–2.29 (2H, m), 6.22
(1H, s), 7.27–7.29 (3H, m), 7.40–7.50 (5 H, m), 7.77 (2 H, d, J =
7.3 Hz); 13C: δ 23.3, 25.7, 37.3, 53.6, 84.2, 91.4, 123.5, 127.3,
128.4, 128.5, 128.9, 131.7, 132.2, 135.7, 166.7; HRMS: m/z
calc’d for [M + Na] C21H21NNaO 326.1515, found 326.1508.
Synthesis of 4,4-dimethyl-5-methylene-2-phenyl-
4,5-dihydrooxazole (3a)14
N-(2,2-Dimethylpropyne)benzamide 1a (50 mg, 0.27 mmol,
1 equiv.) was dissolved in CH2Cl2 (5 mL). Then, copper(I)
iodide (10 mol%) was added and the mixture was stirred at
room temperature overnight. After concentration under
vacuum, the residue was purified by flash chromatography
(5 : 1 petroleum ether–EtOAc on silica gel) to give 3a as a
yellow oil (0.374 g, 73%); IR(neat): 2972.4 (w), 2971 (w),
2294 (w), 2851 (w), 1643 (m) cm−1; 1H: δ 1.47 (6H, s), 4.26 (1H,
d, J = 2.9), 4.76 (1H, d, J = 2.9), 7.42–7.46 (2H, m), 7.49–7.7.55
(1H, m), 7.99–8.02 (2H, m); 13C: δ 29.8, 69.1, 82.4, 127.1, 128.1,
128.5, 131.8, 160.0, 168.1; HRMS: m/z calc’d for [M + H]
C12H14NO 188.1070, found 188.1069.
2-(3-Bromothiophen-2-yl)-4,4-dimethyl-5-methylene-4,5-di-
hydrooxazole (3g). Brown oil; yield: 87%; IR(neat): 3082 (w),
1
2973 (w), 2927 (w), 1696 (w), 1637 (s) cm−1; H: δ 1.45 (6H, s),
4.25 (1H, d, J = 3.0 Hz), 4.75 (1H, d, J = 2.9 Hz), 7.06 (1H, d, J =
5.3 Hz), 7.40 (1H, d, J = 5.3 Hz); 13C: δ 26.1, 30.1, 69.6,
83.3, 114.2, 129.8, 133.1, 154.9, 167.6; HRMS: m/z calc’d for
[M + Na] C10H10BrNNaOS 293.9558, found 293.9524.
4,4-Dimethyl-5-methylene-2-(thiophen-2-ylmethyl)-4,5-di-
hydrooxazole (3i). Dark green oil; yield: 76%; IR(neat): 3108 (w),
2972 (m), 2927 (w), 1667 (s) cm−1 1H: δ 1.35 (6H, s), 3.71
;
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(2H, s), 4.15 (1H, d, J = 3.0 Hz), 4.57 (1H, d, J = 3.3 Hz), 7.04 128.9, 131.1, 134.8, 134.8, 155.9, 166.2, 182.8; HRMS: m/z
(1H, d, J = 5.0, Hz), 7.16 (1H, d, J = 1.8, Hz), 7.28 (1H, d, J = calc’d for [M + Na] C13H13NNaO2 238.0838, found 238.0841.
5.0,); 13C: δ 29.8, 29.9, 69.0, 82.5, 123.0, 126.3, 128.5, 134.4,
General procedure for the synthesis of thiazoles (5a–b)
162.0, 168.4; HRMS: m/z calc’d for [M + H] C11H14NOS
208.0790, found 208.0789.
The requisite benzamide (1.1 mmol, 1 equiv.) and Lawesson’s
reagent (1.1 mmol, 1 equiv.) were dissolved in dry toluene
(10 mL) and heated at 90 °C overnight. The solvent was
removed under vacuum and the residue was purified by flash
chromatography (5 : 1 petroleum ether–EtOAc on silica gel) to
give the product.
2-(4-Chlorophenyl)-4-methylene-3-oxa-1-azaspiro[4.5]dec-1-ene
(3k). Colorless oil; yield: 82%; IR(neat): 2929 (m), 2852 (w),
1
1654 (s), 1489 (m) cm−1; H: δ 1.47–1.89 (10H, m), 4.23 (1H, d,
J = 2.8 Hz), 4.72 (1H, d, J = 2.8 Hz), 7.38 (2H, d, J = 8.5 Hz),
7.91 (2H, d, J = 8.6 Hz); 13C: δ 22.5, 26.0, 39.5, 72.5, 83.2, 126.3,
129.1, 129.9, 138.0, 158.8, 168.5; HRMS: m/z calc’d for [M + H]
C15H17ClNO 262.0993, found 262.0991.
4,4-Dimethyl-5-methylene-2-phenyl-thiazole (5a). Yellow oil;
yield: 53%; IR(neat): 2972 (m), 2927 (w), 1604 (m), 1447 (m)
cm−1; 1H: δ 1.53 (6H, s), 5.18 (1H, d, J = 1.7 Hz), 5.27 (1H, d, J =
1.9 Hz), 7.39–7.45 (3H, m), 7.77–7.80 (2H, m); 13C: δ 29.8, 82.8,
103.2, 128.3, 128.9, 131.5, 133.5, 156.7, 161.0; HRMS: m/z
calc’d for [M + H] C12H14NS 203.0841, found 203.0853.
2-(4-Chlorophenyl)-4,4-dimethyl-5-methylene-thiazole (5b).
Yellow oil; yield: 63%; IR(neat): 2973 (m), 2928 (w), 1606 (m),
2-(4-Methoxyphenyl)-4-methylene-3-oxa-1-azaspiro[4.5]dec-
1-ene (3l). Colorless oil; yield: 99%; IR(neat): 2929 (m), 2852 (w),
1
1646 (s), 1510 (s) cm−1; H: δ 1.38–1.5 (10H, m), 3.84 (3H, s),
4.22 (1H, d, J = 2.4 Hz), 4.71 (1H, d, J = 2.7 Hz), 6.92 (2H, d, J =
9.1 Hz), 7.95 (2H, d, J = 9.0 Hz); 13C NMR: δ 22.5, 25.9, 39.5,
55.7, 72.1, 82.8, 114.1, 120.0, 130.2, 159.6, 162.5, 168.6; HRMS:
m/z calc’d for [M + H] C16H20NO2 258.1488, found 258.1488.
2-(4-Nitrophenyl)-4-methylene-3-oxa-1-azaspiro[4.5]dec-1-ene
(3m). brown solid; mp: 68–71 °C; yield: 89%; IR(neat): 3301 (w),
1
1489 (m) cm−1; H: δ 1.50 (6H, s), 5.17 (1H, d, J = 1.8 Hz), 5.25
(1H, d, J = 1.5 Hz), 7.34–7.38 (2H, m), 7.67–7.70 (2H, m);
13C: δ 29.7, 82.9, 103.5, 129.1, 129.6, 132.0, 137.6, 156.6, 159.6;
HRMS: m/z calc’d for [M + H] C12H13ClNS 238.0451, found
238.0459.
2932 (s), 2853 (m), 1708 (m) cm−1 1H: δ 1.68–1.90 (10H, m),
;
4.29 (1H, d, J = 3.0 Hz), 4.78 (1H, d, J = 3.0 Hz), 8.17 (2H, d, J =
8.7 Hz), 8.28 (2H, d, J = 9.7 Hz); 13C: δ 22.4, 25.9, 39.6, 73.0,
83.9, 123.9, 129.5, 133.6, 149.9, 157.9, 168.2; HRMS: m/z calc’d Synthesis of N-(2-methylbut-3-yn-2-yl)benzamide-d1 (1a′)
for [M + H] C15H17N2O3 273.1234, found 273.1239.
N-(2,2-Dimethylpropyne)benzamide 1a (0.2 g, 1.06 mmol,
1 equiv.) was dissolved in MeCN (1 mL) and K2CO3 (0.22 g,
Synthesis of (4,4-dimethyl-5-methylene-oxazol-2-yl)-
(2-thienyl)methanone (4i)
1.59 mmol, 1.5 equiv.) was added to the mixture. After 30 min
of stirring, D2O (0.96 mL, 53 mmol, 50 equiv.) was added and
the mixture was stirred overnight at rt. The mixture was
extracted with CH2Cl2 (10 mL × 2) and the organic layers were
combined and dried with anhydrous magnesium sulfate,
filtered and concentrated under vacuum. The residue was
stirred with HCl (0.5 M, 2 mL) for 7 days, and then extracted
with CH2Cl2 (10 mL × 2). The organic layers were combined
and dried with anhydrous magnesium sulfate, filtered and
concentrated under vacuum to give the product as white solid;
yield: 0.132 g, 66%; mp: 155–158 °C; IR: 3485 (w), 3238 (w),
4,4-Dimethyl-5-methylene-2-(thiophen-2-ylmethyl)-4,5-dihydro-
oxazole 3i (30 mg, 0.14 mmol, 1 equiv.) was dissolved in 1,2-
DCE (2 mL) and CuI was added (3 mg, 10 mol%). The mixture
was heated at reflux overnight and then concentrated under
vacuum. The residue was purified by flash chromatography
(5 : 1 petroleum ether–EtOAc on silica gel) to provide the
product 4i as a yellow oil (18 mg, 58%) IR(neat): 2975 (w),
1
2930 (w), 2360 (w), 1671 (s), 1634 (m) cm−1; H: δ 1.48 (6H, s),
4.32 (1H, d, J = 3.2 Hz), 4.84 (1H, d, J = 2.9 Hz), 7.33 (1H, dd,
J = 5.2, 5.1), 7.81 (1H, dd, J = 5.2, 5.1), 8.90 (1H, dd, J = 2.9,
3.0); 13C: δ 27.7, 57.9, 95.3, 125.9, 127.6, 131.0, 136.2, 150.1,
154.1, 158.2; HRMS: m/z calc’d for [M + Na] C11H11NNaO2S
244.0402, found 244.0402.
1
2980 (w), 2583 (w), 1639 (s), 1514 (s) cm−1; H: δ 1.77 (6H, s),
6.13 (1H, s), 7.40–7.70 (3H, m), 7.75 (2H, d, J = 7.1 Hz); 13C:
δ 29.4, 48.4, 127.2, 128.9, 131.9, 135.2, 166.8; HRMS: m/z calc’d
for [M + Na] C12H12DNNaO 211.0952, found 211.0959.
Synthesis of (4,4-dimethyl-5-methylene-4,5-dihydrooxazol-2-yl)-
(phenyl)methanone (4p)
Acknowledgements
N-(2-Methylbut-3-yn-2-yl)-2-phenylacetamide 1p (50 mg,
0.25 mmol, 1 equiv.) was dissolved in 1,2-DCE (2 mL) and CuI
(5 mg, 10 mmol%) was added. The mixture was heated at
reflux for 48 h and then concentrated under vacuum. The
residue was purified by flash chromatography (5 : 1 petroleum
ether–EtOAc on silica gel) to provide the product 4p as a yellow
solid (38 mg, 71%); mp: 53–56 °C; IR(neat): 2975 (w), 2930 (w),
We thank the State of Libya for a graduate studentship (AA).
Notes and references
1 (a) D. C. Palmer and S. Venkatraman, Chemistry of Hetero-
cyclic Compounds, A Series of Monographs, Oxazoles: Syn-
thesis, Reactions, and Spectroscopy, Part A, ed. D. C. Palmer,
Wiley, NJ, 2003, vol. 60; (b) P. Wipf, Chem. Rev., 1995, 95,
2115.
1
2360 (w), 1671 (s), 1634 (m) cm−1; H: δ 1.50 (6H, s), 4.34 (1H,
d, J = 3.4 Hz), 4.84 (1H, d, J = 3.1 Hz), 7.47–7.51 (2H, m),
7.61–7.65 (1H, m), 8.28–8.31 (2H, m); 13C: δ 29.8, 70.9, 84.9,
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