Investigations into competitive cycloaddition/cyclization or elimination from 1,1-dimethyl-propargylcarbamates of anilines

Article abstract of DOI:10.1071/CH10344

The copper-catalyzed reaction of 1,1-dimethyl-O-propargyl aniline carbamates was studied and revealed the unexpected formation of oxazolidin-2-ones and alkylamines. An in-depth study of the reaction conditions showed that the formation of these products was highly dependent on the solvent, copper catalyst and aniline substituents. The reaction can be oriented towards oxazolidinones in pyridine and alkylamines in ethanol, whereas cycloaddition can be achieved in dry tetrahydrofuran.

Full text of DOI:10.1071/CH10344

Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2011, 64, 166–173
www.publish.csiro.au/journals/ajc
Investigations into Competitive Cycloaddition/Cyclization
or Elimination from 1,1-Dimethyl-propargylcarbamates
of Anilines
A
A
B
Re´gis Delatouche, Aure´lien Lesage, Floraine Collette,
B
A C
,
Vale´rie He´roguez, and Philippe Bertrand
A
Laboratoire Synthe`se et Re´activite´ des Substances Naturelles, Unite´ Mixte de
Recherche, Centre National de la Recherche Scientifique (UMR CNRS) 6514,
40 Avenue du Recteur Pineau, 86022, Poitiers cedex, France.
B
Laboratoire de Chimie des Polyme`res Organiques, UMR CNRS 5629,
16 Avenue Pey Berland, 33607, Pessac cedex, France.
C
Corresponding author. Email: philippe.bertrand@univ-poitiers.fr
The copper-catalyzed reaction of 1,1-dimethyl-O-propargyl aniline carbamates was studied and revealed the unexpected
formation of oxazolidin-2-ones and alkylamines. An in-depth study of the reaction conditions showed that the formation of
these products was highly dependent on the solvent, copper catalyst and aniline substituents. The reaction can be oriented
towards oxazolidinones in pyridine and alkylamines in ethanol, whereas cycloaddition can be achieved in dry
tetrahydrofuran.
Manuscript received: 16 September 2010.
Manuscript accepted: 18 October 2010.
Introduction
O
H
(i)
N
O
Bn
ꢀ
N3 Rꢁ
Bn
O
The easy preparation of a large variety of propargyl alcohols
has made them convenient intermediates to access functional
propargylic compounds of greater value. Several preparations
of propargylamines from the corresponding alcohols have been
described. Propargyl alcohols were directly converted to pro-
pargylamines in a three-step synthesis[1] or in a single step under
rhenium catalysis.[2] Propargylic fluorides have been synthe-
sized from propargyl alcohols as intermediates to five-membered
heteroaromatic compounds.[3] O-Propargylcarbamates were
studied some decades ago as potential anticancer compounds[4]
and were recently involved in fungicide preparation[5] and their
cycloaddition with nitrile oxides reported.[6] Specific depro-
tection of propargylic carbonate with tetrathiomolybdate in
the presence of propagylic carbamates was described.[7] Several
copper-catalyzed reactions involving propargylcarbamates are
available.[8–10] Finally, propargylic compounds are now com-
monly used in the popular Huisgen [3 þ 2] cycloaddition of
terminal alkynes and azides, the so-called click chemistry
(also referred to as CuAAC: Cu-catalyzed azide–alkyne
cycloaddition).[11] Propargylcarbamates have been used in
such cycloadditions in different ways with unsubstituted
O-propargylcarbamate,[12] and N-propargyl[13] and N-
disubstituted propargylcarbamate.[14,15] Interested in the possi-
bility of preparing carbamate 1 to be reacted with azide 2 in
the copper-catalyzed Huisgen cycloaddition[16] (Scheme 1), we
observed different reaction products, illustrating the above-
mentioned versatile reactivity of propargylic derivatives. We
found that the cycloadduct 3 could be obtained in good yields
N
H
Rꢁ
Rꢁ
N
N
N
N
O
N
N
1
2
3
5
O
MeO
Bn
O
HO
Rꢁ
N
N
N
H
Rꢁ
Rꢁ ꢂ
N
N
N
O
N
4
6
Scheme 1. (i) Copper catalyst, solvent, see text.
with CuI as the catalyst and pyridine as the solvent. Under the
classical Sharpless conditions (tBuOH/H2O, CuSO4ꢀ5H2O,
sodium ascorbate), three other products 4, 5 and 6 were formed
after cycloaddition. The propargylamine 4 resulted from a new
and interesting rearrangement of the triazolyl carbamate, the
alkene 5 was produced by elimination from the carbamate, and
the alcohol 6 was obtained as a hydrolysis product. All these
compounds were expected to be formed from the cycloaddition
reaction, the carbamate 1 alone being found stable under all the
tested conditions. The reaction was studied with the nucleo-
philic benzylamine and the formation of several compounds
mainly attributed to a solvent effect having some influence on
the intermediate copper complex stability and reactivity.
It was envisioned to extend this study to the cycloaddition
of less nucleophilic aromatic amines like anilines. In order
to evaluate the influence of substituents on the aniline ring
and their possible effects on the ratio in rearranged products to
Ó CSIRO 2011
10.1071/CH10344
0004-9425/11/020166

Competitive Reactions with Aniline Propargyl Carbamate
167
O
C
BocHN
O
Oꢃ
Nꢀ
H
O
R
NH2
H
H
N
(i)
(ii)
N
O
O
N
H
HN
N
O
Rꢁ
OH
Rꢁ
Rꢁ
O
O
N
O
R
O
8a, 67%
8b, 65%
8e, 51%
8f, 72%
8c, 65%
(iii)
O
7a, 7b, 7e
O
8b
8d
BocHN
a Rꢂ H, Rꢁ ꢂMe
b Rꢂ NO2, Rꢁ ꢂMe
c Rꢂ NH2, Rꢁ ꢂMe
d Rꢂ NH-Gly-NHBoc, Rꢁ ꢂ Me
e Rꢂ CF3, Rꢁ ꢂMe
NH
H
N
Rꢁ
O
Fig. 1. Hypotheses of intramolecular hydrogen bonding for 8b and 8d.
8d, 65%
O
f Rꢂ NO2, Rꢁ ꢂH
O
R
O
H
(i)
N
O
N
H
O
Scheme 2. (i) Heptane, reflux, NEt3 catalyst, 3 h; (ii) SnCl2ꢀxH2O, EtOH,
ꢀ
ꢀ
N
O
NH2
R
reflux, 1 h; (iii) BOC-Gly-COOH, TBTU, HOBt, DIPEA, acetonitrile, 1 day.
O
Rꢁ N3
R
Rꢁ
N
R
2
N
N
8a, 8b
9a
10b
11a, 11b
O
O
O
3, 4, 5 or 6 ortho-substituted aniline carbamates were prepared
bearing either electron-donating or withdrawing groups. In
the present work are described our efforts to prepare several
triazolyl aniline carbamates. We report herein the unexpected
solvent- and substituent-dependent reactivity of these carba-
mates under copper catalysis with a mechanistic proposal.
a R ꢂ H, Rꢁ ꢂ Me
b R ꢂ NO2, Rꢁ ꢂ Me
O
ꢂ Rꢁ
Scheme 3. (i) CuI 5 mol-%, pyridine, 24 h, 208C.
seven-membered ring. For the CF3 derivative 8e, hydrogen
bonding is not possible and only the electron-withdrawing effect
affects the chemical shift, lowered compared with the amide 8d.
As expected, the H- and NH2-substituted products 8a and 8c
exhibited the smallest chemical shifts.
Results and Discussion
Several substituted aniline carbamates 8 were prepared
(Scheme 2) to monitor the substituent effect of the aniline ring
(R) and propargyl alcohols (R0). The nitroformiate strategy
previously described by us[16] for benzylamine carbamates
was not found suitable for the less nucleophilic anilines. Car-
bamates 8a, 8b were finally obtained in good yields by reacting
phenylisocyanates 7 with 2-methyl-but-1-yn-2-ol in refluxing
heptane and a catalytic amount of triethylamine as described by
Thorne.[17] Phenylisocyanate 7a provided carbamate 8a as an
example of an unsubstituted phenyl ring, whereas isocyanates
7b, 7e gave two examples of carbamates 8b, 8e with an electron-
withdrawing group. In order to have an example of a
carbamate with an electron-donating group, 8b was reduced
to 8c (SnCl2ꢀxH2O, EtOH, reflux).[18] The amide 8d was
prepared as another example of withdrawing group from 8c,
under peptide-coupling conditions (TBTU (tetrafluoroborate
Having successfully prepared the desired propargyl carba-
mates 8, Huisgen cycloaddition was investigated with the azide
2 under the conditions we had developed earlier (pyridine, CuI)
to avoid the formation of undesired products.[11] Starting with
carbamate 8a, the cycloadduct 9a was obtained in only 19%
yield. The free aniline 11a (Scheme 3) and the elimination
product 5a (Scheme 1) were obtained as side products. Com-
pared with the cycloaddition with benzylaminecarbamate 1,
these new results were clearly associated with the presence of
the aniline ring. It can be postulated that the more nucleophilic
benzylamine gave stronger carbamate bonds compared with the
corresponding aniline carbamate 9a owing to higher electron
density. Under the mild basic conditions used with pyridine,
the elimination is thus easier for 9a than for 1. This type of
elimination catalyzed by pyridine was observed during the
tosylation of alcohol 6, which directly gave the alkene 5.[16]
Unexpectedly, the nitro derivative 8b gave the oxazolidinone
10b as a major product and the free 2-nitroaniline 11b as a side
product without any trace of the desired cycloadduct 9b.
The synthesis of 4-methylene-oxazolidin-2-one has pre-
viously been described and O-propargylic carbamates have
thus received much attention for the preparation of antibacterial
1,3-oxazolidin-2-one.[21] Several syntheses of oxazolidinones
from propargylic alcohols are known. They can be reacted with
an amine and carbon dioxide under pressure with a phosphine
as a catalyst,[22] or with aryl isocyanates under strong base
catalysis (sodium acetate,[23] sodium methoxide[24]) or boiling
pyridine.[25] Alternatively, propargyl carbamates can be used
as starting material in boiling pyridine.[12] Recently, an
efficient method was developed to only convert non-substituted
and monosubstituted propargyl carbamates to 4-methylene
oxazolidin-2-one, using LiOH catalysis at room temperature.[26]
The synthesis of oxazolidinones from N-propargylcarbamates
under gold catalysis has been reported.[27] Only a few examples
of copper-catalyzed reactions can be found in the literature,
mostly applied to unsubstituted and 1-monosubstituted propar-
gylcarbamates. CuCl was used with ionic liquids[28] or with 10%
potassium tert-butylate at reflux in toluene or THF,[29] but in the
O-(benzotriazol-1-yl-1,1,3,3-tetramethyl)-uronium),
HOBt
(N-hydroxybenzotriazole), DIPEA (diisopropylethylamine),
ACN (acetonitrile)). Unfortunately, only the additional carba-
mate 8f could be prepared as an example of the diversely sub-
stituted propargyl moiety.
According to the Hammett constants, the carbamate N–H
bond acidity may be related to the electron-withdrawing char-
acter of the phenyl substituent, and should be correlated with
1
higher H NMR chemical shifts. These chemical shifts were
measured in CDCl3 and were as follows: 6.41, 6.54, 6.89, 8.52
and 9.81 ppm for, respectively, 8c (R ¼ NH2), 8a (R ¼ H), 8e
(R ¼ CF3), 8d (R ¼ NHCOR0) and 8b (R ¼ NO2). Compared
with the theoretical Hammet’s sp values,[19] an extremely large
chemical shift is observed for the nitro compound 8b
(9.81 ppm). This can be explained by the strong electron-
withdrawing property of the nitro group and by intramolecular
hydrogen bonding as described by Ringdahl for some propargyl
nitroanilines. In such cases, the formation of a six-membered
ring by hydrogen bonding between the nitro group in the ortho
position and the carbamate hydrogen is highly favoured
(Fig. 1).[20] The chemical shift of the carbamate proton in
the amide 8d was, surprisingly, observed at higher fields
than the equivalent proton in the CF3 analogue. This was
explained by hydrogen bonding between the amide carbonyl
and carbamate hydrogen in 8d (Fig. 1), forming a favoured

168
R. Delatouche et al.
Table 1. Catalyst effect on the ratio of formation of compounds 10:11
and unreacted carbamates 8 in pyridine
Table 2. Solvent effect on the ratio of products 10:11:12 and unreacted
carbamates 8
Compound 12 was not observed in this series of experiments
Entry
R
Catalyst [mol-%]
Solvent
10:11:12:8
Entry
R
Catalyst [mol-%]
10:11:8
1
2
H
CuI, 20
CuI, 20
CuI, 20
CuI, 5
CuI, 5
CuI, 5
CuI, 5
CuI, 5
CuI, 5
CuI, 5
DMF
0:100:0:0
0:100:0:0
0:100:0:0
0:100:0:0
1:99:0:0
1
2
3
4
5
6
7
8
9
H
–
0:0:100
0:0:100
0:100:0
63:37:0
0:100:0
72:28:0
72:28:0
53:47:0
77:23:0
H
Pyridine
DMF
NO2
H
–
3
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
CuI, 20
4
DMF
NO2
H
CuI, 20
5
Et3N
CuI, 5
6
Acetonitrile
PyridineA
Pyridine
EtOH
7:93:0:0
NO2
NO2
NO2
NO2
CuI, 5
7
86:14:0:0
72:28:0:0
2:33:36:26
0:0:0:100
CuI, 1
8
CuCl, 10
CuSO4ꢀ5H2O, 10;
sodium ascorbate, 20
9
10
THF/H2O
APyridine was freshly distilled over KOH.
O
N
3, 4). The reduction of the molar quantity of CuI catalyst to 5
and 1% (Table 1, entries 5–7) gave improved, similar yields of
oxazolidinone 10b, with again aniline 11b. For carbamate 8a,
the complete release of aniline was always observed. The
replacement of CuI by a CuSO4/sodium ascorbate combination
led to the formation of oxazolidinone 10b from carbamate 8b
with good conversion. CuCl was found less selective (Table 1,
entries 8, 9). Although CuSO4 and CuI gave equivalent results,
CuI was selected as the catalyst for further studies, in order to
remove water traces which could potentially favour side reac-
tions as previously observed.[16]
O
(i)
O
N
H
NH2
N
H
O
R
R
R
R
8a–8e
10a–10e
11a–11e
12a–12e
Scheme 4. (i) Copper catalyst, solvent, room temperature, overnight; see
Tables 1, 2 and 3.
latter case, CuCl was not critical. Mechanistic studies were
proposed with deuterated N-tosyl propargyl carbamates.[30]
The present work describes unprecedented conditions affording
oxazolidinones instead of the expected Huisgen cycloaddition
from propargylcarbamates of anilines bearing an electron-
withdrawing group. According to the literature mentioned
above and the proposed mechanism for gold catalysis,[27] the
more acidic the carbamate N–H bond, the easier its deprotona-
tion, even with mild bases. This process can lead to intramole-
cular cyclization if the alkyne bond is activated by chelating the
metal (copper, gold). In this respect, the nitrocarbamate 8b is
more prone to deprotonation than the unsubstituted aniline
compound 8a. Another point of interest in this work is the
use of 1,1-dimethylcarbamates, compared with literature data
where mainly unsubstituted or 1-monosubstituted carbamates
were used, particularly with a copper catalyst. This disubstitu-
tion introduced another difficulty owing to the possible forma-
tion of dimethylallene from carbamates 8 or an elimination
product like 5 (Scheme 1) when cycloaddition is favoured.
In order to find reaction conditions where competitive
cyclization or cyloaddition could be monitored, the carbamates
8a, 8b were reacted alone in pyridine with the different copper
salts involved in both reactions, i.e. CuI, CuCl and CuSO4
(Table 1, Scheme 4). If cyclization and elimination do not both
occur, and provided that the copper–alkyne insertion is realized,
it should be possible to have cycloaddition with azide 2. The
influence of catalyst quantity was also evaluated. After reaction,
the solvent was removed under vacuum and the crude mixture
was analyzed by 1H NMR in CDCl3 to calculate the conversion
based on the characteristic peaks of the 2-methylene-oxazolidin-
2-one (exo methylene signals at ,4 ppm), starting material
(terminal alkyne signal at ,2.5 ppm) and the released amine.
Compounds 8a, 8b in pyridine without catalyst gave no reaction,
underlining the essential role of the copper salts (Table 1, entries
1, 2). A 20% molar amount of CuI produced a complete release
of the aniline 11a from 8a, whereas the carbamate 8b gave the
cyclized product 10b with the nitroaniline 11b (Table 1, entries
The role of the solvent was investigated with carbamates 8a,
8b. At 20 mol-% CuI, pyridine or DMF again gave complete
release of aniline 11a from carbamate 8a (Table 2, entries 1, 2).
DMF was also able to promote complete release of aniline 8b at
5 or 20 mol-% CuI (Table 2, entries 3, 4), which was observed,
but incomplete, in pyridine (Table 1, entry 4). The key inter-
mediate 8b was reacted in other solvents. NEt3 and CH3CN
promoted the release of aniline 8b, as did DMF, even at 5 mol-%
CuI (Table 2, entries 5, 6). Pyridine appeared to be the best
solvent for the cyclization to oxazolidinone 11b. We also
checked the reactivity of our described propargyl benzylamine
carbamate 1 with CuI in different solvents and confirmed that no
reaction occurred in pyridine or ethanol but decomposition in
DMF gave quantitatively the corresponding symmetric diben-
zylurea, probably resulting from the release of the free benzyl-
amine, which attacked another molecule of carbamate 1.
A particular feature of these reactions is the release of aniline.
Comparing cyclization and amine release, a proton source is
required in the latter case to equilibrate the reaction with the
transfer of two protons (one for the aniline, one for the allene).
Hattori et al.[24] showed in propargylamine syntheses that
proton[1] exchange should occur from the reaction mixture and
CuSO4ꢀ5H2O is thus a possible source. This is not possible for
CuI in pyridine, except if one considers the presence of water
traces in the solvent or the catalyst. The standard 99.5þ% pure
pyridine was then distilled over KOH, and a ratio increase to
86:14 of oxazolidinone 10b:11b was effectively obtained
(Table 2, entry 7). The very low quantity of catalyst required
for the cyclization with CuI and the mild reaction conditions
could make this procedure very attractive compared with others
using strong bases that are not suitable for all starting materials.
Finally, polar protic solvent conditions were evaluated. In the
case of EtOH, the unexpected N-propargylaniline 12b was
obtained as the major product (Table 2, entry 9) in modest and
variable yields, with free aniline 11b, starting material 8b and a

Competitive Reactions with Aniline Propargyl Carbamate
169
Table 3. Aniline substituent effect on the reactivity of carbamates 8 in
pyridine, with 5 mol-% CuI
n.d., not determined
Entry
R
10:11:12:8
Isolated yields in parentheses
are in mol-%
10f cis
10f trans
ꢃ40.71 kJ molꢃ1
ꢃ38.71 kJ molꢃ1
1
2
3
4
5
6
NO2
NO2
NHCOGlyBocA
HA
72:28:0:0
84 (67B):16:0:0
n.d. (67B):n.d.:n.d.:n.d.
0:100:0:0
A
Fig. 2. Hypothesis for two blocked atropoisomers of 10f with calculated
relative stabilities [kJ molꢁ1].
A
NH2
0:0:0:100
n.d. (46B):n.d.:n.d.:n.d.
A
CF3
NO2
APyridine was freshly distilled over KOH.
BIsolated yields.
O
(i)
NH
N
H
O
N3 Rꢁ
Rꢁ
N
NO2
N
N
O
small amount of oxazolidinone 10b. The variable yields could
be explained by the poor solubility of the substrate and catalyst
in ethanol and by the probable volatility of propargylamine 11b.
The rearrangement leading to the alkylamine was previously
observed with benzylamine carbamate 1, but after cycloaddi-
tion. To our knowledge, the rearrangement of propargylic
carbamates of anilines to propagylic anilines has not been
described previously. The combination of THF and H2O as
solvent gave no reaction, suggesting that the cycloaddition of
nitrocarbamate 8b with 2 should occur without side reactions
under these conditions, if the copper–alkyne insertion is
obtained.
The aniline substituent effect was investigated with carba-
mates 8c–8e, reacted with 5 mol-% CuI in pyridine, at room
temperature overnight (Table 3). Results from carbamates 8a,
8b are replicated from Table 2 for simplicity (Table 3, entries 1,
2, 4) with a 67% isolated yield for 8b. The less acidic character
of the carbamate N–H bond in the amino derivative 8c was
associated with no reaction whereas the amide 8d also gave
oxazolidinone 10d in 67% isolated yield. Additional hydrogen
bonding between the hydrogen atom of the carbamate group and
the ortho substituent for 8b, 8d may also increase acidity, as
observed from 1H NMR experiments.
8b
Rꢁ ꢂ
13b
O
O
O
Scheme 5. (i) CuI 5 mol-%, THF, room temperature, overnight.
The use of THF/H2O as solvent (Table 2, entry 10) gave
no reaction for 8b and thus these conditions were evaluated
for the cycloaddition of 8b with the azide 2 (Scheme 5). In
the presence of 5 mol-% CuI in dry THF, the rearranged
dimethyltriazolylmethylaniline 13b was obtained in a moderate
31% yield, as previously observed for carbamate 1 (Scheme 1).
In order to propose some rationale for the observed results,
the mechanistic aspects of this work were investigated. As
mentioned above, propargylic derivatives are prone to allene
formation, a reaction that is also catalyzed by copper
reagents.[33] Unfortunately, we were not able to detect such
compounds. The selection of the solvent is important for the
formation of solvent–copper–alkyne complexes[34,35] and a first
terminal alkyne copper(I) insertion is generally proposed. The
access to oxazolidinones 10 was rationalized[25,36] by the for-
mation of the intermediate alkyne complex 14 (Scheme 6).
The deprotonation of compounds 8b, 8d, 8e by the base gave
an anion able to attack the internal alkyne carbon atom, afford-
ing oxazolidinone via the complex 16. Stronger bases than
pyridine have been reported, like KOH, for the preparation of
oxazolidinones for unsubstituted aniline derivatives. In our case,
pyridine is sufficient to deprotonate the acidic aniline deriva-
tives bearing an electron-withdrawing group, as observed for
gold catalysis in NEt3 with N-tosylpropargylcarbamates.
Carbamates 8 being stable in pyridine with no catalyst, the
copper salt appeared critical to activate the alkyne bond. Direct
insertion of the copper ion as in complex 15 was proposed for
the copper-catalyzed Huisgen cycloaddition. This is not totally
in agreement with the mechanism proposed by Murahashi[8]
and Nishibayashi,[10] where complexes like 15 are involved in
propargylic amine formation. In such an intermediate 15, the
terminal copper complex can give allenylidene complex 17
by decarboxylation of the carbamate. This was apparently the
major process in DMF, where free amines were obtained in
all cases. The released amine can then be isolated (DMF) or
re-attack the carbocation 18 obtained from complex 17. An
important aspect in this proposed mechanism is the driving
force making the poorly nucleophilic aniline 8b attack the
carbocation 18 in conditions where no base or temperature are
The effect of the propargyl substituents on position 1 for the
nitroaniline carbamate was determined for the carbamate 8f and
gave a 52:48 ratio for compounds 10f:11f, from which 10f was
isolated in 46% yield. This should be compared with the 84:16
ratio obtained for 10b:11b. The latter result seems to indicate
that our procedure may be convenient for the synthesis of
oxazolidinones from 1,1-disubstituted N–H acidic propargyl-
carbamates. In the case of 10f, the isolated compound showed
1
more complex H NMR signals than its dimethyl counterpart
10b. This was attributed to the possible existence of two
inseparable atropoisomers (Fig. 2), where a trans and cis
relation may exist between the methyl group and the nitrophenyl
ring. The ortho positioning of the nitro group and the presence
of the carbonyl and methylene groups should block these two
isomers in two different particular conformations. To a lesser
extent, this atropoisomerism was also detected for the dimethyl-
nitro 10b, trifluoromethyl 10e and amide 10d analogues.
Molecular modelling was performed[31] and showed that in
both isomers, the nitro group tends to be orientated toward
the methylene group, the cis isomer being slightly more stable,
probably giving the lowest electronic interactions between
oxygen and nitrogen atoms. Anequivalent atropoisomerism was
found in the literature for oxazoline.[32]

170
R. Delatouche et al.
Scheme 6.
involved. The intermediate carbocation 18 may also be trapped
by the solvent in the case of EtOH, but the resulting ether was
not detected in the reaction. We previously proposed a reversed
chelation to explain an equivalent rearrangement.[16] Thus the
intermediate 19 could give 20, where the amine is maintained
near the reactive site by chelating the copper atom. After
carbamate decarboxylation, the amine can attack the carbo-
cation to give 12. The possible participation of the nitro group
for 8b (R ¼ NO2) can be suggested to stabilize complex 14
or 20 but was not determined. The presence of the two methyl
groups induces steric hindrance,[37] probably facilitating the
internal rearrangements. One should note that oxazolidinones
are essentially prepared from either unsubstituted or only
1-monosubstituted propargylcarbamates. However, 1,1-
disubstituted propargylamines are not often described. Thus
the preparation of compound 10 or 12 from 1,1-disubstituted
propargylcarbamates brings additional possibilities to this
chemistry.
conversion of propargylcarbamates to the interesting triazolyl-
alkylanilines should occur after the carbamate cycloaddition,
followed by rearrangement with CO2 loss. This suggested that
conditions may be found where such carbamates can be isolated.
A possible atropoisomerism has been detected in ortho-
substituted phenyl oxazolidinones 8b, 8d–8f that was not
reported earlier. These results highlighted the important impact
of the solvent and substituent on the aniline ring of aniline
propargylcarbamates, providing new insight into the reactivity
of these compounds. Work is in progress to optimize the
cycloaddition reaction observed in THF to develop access to
triazolylanilines.
Experimental
General
CH2Cl2 was distilled over P2O5, THF was distilled over sodium/
benzophenone under a nitrogen atmosphere. Pyridine was dis-
tilled over KOH under a nitrogen atmosphere. Silica (35–
70-mm) was used for flash chromatography and preparative
TLC. TLC was performed on aluminium plates coated with
silica gel (Merck silica gel 60 F254, thickness 0.2 mm). Visua-
lization was accomplished by UV light and the stains used were
ninhydrin and phosphomolybdic acid solutions. All reactions
were conducted under a nitrogen atmosphere, and solutions
were concentrated under reduced pressure using a rotary eva-
porator. Melting points were recorded on a Bu¨chi B-545 and are
Conclusion
Copper-catalyzed reactions involving propargylic anilines car-
bamates revealed unexpected reactivity of these derivatives
associated with the acidity of the carbamate N–H bond.
Electron-withdrawing substituents on the aniline ring of these
carbamates favoured deprotonation, leading to oxazolidinones
under very mild conditions with a small amount of copper
catalyst. When no substituent or electron-donating groups
are present on the aniline ring, the release of aniline may
be favoured, a process that can be potentially exploited for
the design of new protective groups. The expected Huisgen
cycloaddition was obtained when tetrahydrofuran was used as
the solvent, with a subsequent in situ rearrangement to alkyl-
aniline in moderate yields. Our results indicated that the
1
uncorrected. H NMR spectra were recorded on Bruker Ultra-
shield Plus 400 (400 MHz). The chemical shifts are reporter in d
[ppm] relative to chloroform (CDCl3, 7.26 ppm), acetone ([D6]
acetone, 2.05 ppm) and tetramethylsilane (TMS, 0.00 ppm)
as internal standards. The spectra were analysed by first order;
the coupling constants (J) are reported in Hertz [Hz] and refer
to apparent multiplicities and not true coupling constants: s,

Competitive Reactions with Aniline Propargyl Carbamate
171
singlet; bs, broad singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; bm, broad multiplet; dd, double doublet; dt, double
triplet; ddd, double double doublet. 13C NMR spectra were
recorded on a Bruker Ultrashield Plus 400 (100.6 MHz).
The chemical shifts are reported in d [ppm] relative to chloro-
form (CDCl3, 77 ppm), acetone ([D6]acetone, 29.84 ppm) and
tetramethylsilane (TMS, 0.00 ppm) as internal standards. 2D-
NMR spectra (COSY (Correlation spectroscopy), HETCORR
(Heteronuclear correlation), HSQCed (Heteronuclear Single
Quantum Coherence)) were recorded on a Bruker Ultrashield
Plus 400 (400 MHz). HRMS (High Resolution Mass Spectra)
were performed at the Centre Re´gional de Mesures Physiques
de l’Ouest (CRMPO), Rennes, France. Abbreviations used: PS
(petroleum spirit), EA (ethyl acetate), THF (tetrahydrofuran),
DCM (dichloromethane), DIPEA (diisopropylethylamine),
HOBt, TBTU.
evaporated under reduced pressure. The crude mixture was then
purified by flash chromatography, affording the amino carba-
mate 8c (0.279 g, 64%) as a brownish solid. Rf (EP/EA 1:1) 0.79.
dH (400 MHz, CDCl3) 7.33 (bd, 1H, J 6.4), 7.01 (dt, 1H, J 1.4,
7.7), 6.79 (m, 2H), 6.41 (s, 1H), 3.32 (bs, 2H), 2.57 (s, 1H), 1.75
(s, 1H). dC (100 MHz, CDCl3) 152.7, 139.5, 126.3, 124.6, 124.5,
119.9, 117.9, 84.9, 72.4, 72.4, 29.2. m/z (HRMS) 241.0952
(0 ppm). C12H14N2O2Na requires [M þ Na]þ 241.09530.
2-Methylbut-3-yn-2-yl 2-(N-Boc-glycinamido)
phenylcarbamate 8d
To a solution of butyloxycarbonyl (BOC)-glycine (0.279 g,
1.59 mmol, 1.5 equiv.) in DCM (20 mL) at 08C were added
TBTU (0.512 g, 1.59 mmol, 1.5 equiv.), HOBt (0.244 g,
1.59 mmol, 1.5 equiv.) and DIPEA (0.53 mL, 3.19 mmol,
3 equiv.). The reaction was left at 08C for 30 min and
then 2-methyl-but-3-yn-2-yl 2-aminophenylcarbamate (0.232 g,
1.06 mmol, 1 equiv.) was added. After overnight stirring, the
reaction was diluted in EA and washed subsequently with 1 M
KHSO4, saturated NaHCO3 and brine. The organic phases were
combined, dried over MgSO4 and concentrated under reduced
pressure. The crude mixture was purified by flash chromato-
graphy on silica, affording 8d (0.215 g, 54%) as a viscous oil.
Rf (EP/EA 60:40) 0.23. dH (400 MHz, CDCl3) 8.52 (s, 1H), 7.61
(d, 1H, J 7.9), 7.38 (d, 1H, J 7.5), 7.32 (s, 1H), 7.21 (dt, 1H, J 1.3,
7.9), 7.13 (dt, 1H, J 1.4, 7.7), 5.39 (t, 1H, J 5.0), 3.92 (d, 2H,
J 5.7), 2.62 (s, 1H), 1.76 (s, 6H), 1.49 (s, 9H). dC (100 MHz,
CDCl3) 168.6, 161.2, 152.9, 130.8, 128.8, 126.7, 125.4, 124.2,
124.2, 84.9, 77.2, 72.6, 72.6, 45.0, 29.2, 28.3. m/z (HRMS)
398.1689 (1 ppm). C19H25N3O5Na requires [M þ Na]þ
398.16854.
2-Methylbut-3-yn-2-yl Phenylcarbamate 8a
To a solution of 2-methyl-but-3-yn-2-ol (0.58 mL, 5.61 mmol,
2 equiv.) in heptane (30 mL) was added NEt3 (0.391 mL,
2.81 mmol, 1 equiv.). The solution was refluxed and phenyl-
isocyanate was added (0.304 mL, 2.81 mmol, 1 equiv.). After
refluxing for 2 h, the solution was cooled to room temperature,
dissolved in Et2O and washed with 1 M KHSO4 and brine, dried
over MgSO4, filtrated and concentrated under reduced pressure.
The residue was purified (flash chromatography on silica gel,
PE/EA 9:1) and the collected fractions evaporated under
reduced pressure to afford 8a as a white solid (0.391 g,
1.88 mmol, 67%). dH (400 MHz, CDCl3) 7.37 (d, 2H, J 7.9), 7.26
(m, 2H), 7.03 (m, 1H), 6.54 (s, 1H), 2.56 (s, 1H), 1.73 (s, 6H).
dC (100 MHz, CDCl3) 151.6, 137.8, 129.0, 123.4, 118.6, 84.9,
72.4, 72.2, 29.2. m/z (HRMS) 226.0846. C12H13NO2Na requires
[M þ Na]þ 226.08440.
2-Methylbut-3-yn-2-yl 2-(Trifluoromethyl)
phenylcarbamate 8e
2-Methylbut-3-yn-2-yl 2-Nitrophenylcarbamate 8b
To a solution of 2-methyl-but-3-yn-2-ol (1.16 mL, 11.88 mmol,
1 equiv.) in heptane (20 mL) was added triethylamine (0.32 mL,
2.37 mmol, 0.2 equiv.). The solution was heated until refluxing
and 2-trifluoromethyl phenylisocyanate (1.79 mL, 11.88 mmol,
1 equiv.) was added. The solution was refluxed for 2 h under
stirring. After cooling to room temperature, the reaction mixture
was extracted with diethyl ether and washed with saturated
NaCl. The organic phase was dried with MgSO4, filtered and the
solvent removed under reduced pressure. The crude product was
separated by flash chromatography, affording 8e as a white solid
(1.640 g, 6.04 mmol, 51%), mp 508C. dH (400 MHz, CDCl3)
8.21 (d, 1H, J 8.4), 7.57 (d, 1H, J 8.3), 7.53 (t, 1H, J 7.9), 7.16
(t, 1H, J 7.7), 6.89 (s, 1H), 2.60 (s, 1H), 1.76 (s, 6H). dC
(100 MHz, CDCl3) 151.5, 135.7, 132.9, 126.0, 125.5, 123.3,
122.8, 122.3, 84.6, 72.9, 72.6, 29.2. dF (376 MHz, CDCl3)
ꢁ60.69. m/z (HRMS) 294.0714 (1 ppm). C13H12NO2F3Na
requires [M þ Na]þ 294.07123.
To a solution of 2-methyl-but-3-yn-2-ol (1.16 mL, 11.12 mmol,
1 equiv.) in toluene (50 mL) in a two-necked flask under a
nitrogen atmosphere was added NEt3 (0.313 mL, 2.24 mmol,
0.2 equiv.). The solution was heated until reflux and a solution of
2-nitrophenylisocyanate (1.0 g, 6.09 mmol, 0.54 equiv.) in THF
(few mL) was added. After 1 h, a precipitate was observed. The
solution was cooled to room temperature, diluted with Et2O and
washed several times with water and brine. The organic phase
was dried over MgSO4 and concentrated under vacuum. The
crude material was purified (flash chromatography on silica gel,
PE/EA 9:1) affording 8b as a yellow powder (0.983 g, 65%
yield), mp 1088C. The product can be easily crystallized from a
mixture of PE/EA. Rf (PS/EA 85:15) 0.72. dH (400 MHz,
CDCl3) 9.81 (s, 1H), 8.61 (d, 1H, J 8.6), 8.20 (d, 1H, J 8.5), 7.62
(dd, 1H, J 7.6), 7.13 (dd, 1H, J 7.5, 8.2), 2.62 (s, 1H), 1.78
(s, 6H). dC (100 MHz, CDCl3) 151.3, 136.1, 135.9, 135.4, 125.9,
122.3, 120.8, 84.4, 73.2, 72.9, 29.1. m/z (HRMS) 271.0696
(0 ppm). C12H12N2O4Na requires [M þ Na]þ 271.06948.
But-3-yn-2-yl 2-Nitrophenylcarbamate 8f
To a solution of but-3-yn-2-ol (0.56 mL, 7.13 mmol, 1 equiv.) in
heptane (40 mL) in a two-necked flask under nitrogen was added
triethylamine (0.99 mL, 7.13 mmol, 1 equiv.). The mixture was
heated until refluxing and 2-nitrophenylisocyanate (1.17 g,
7.13 mmol, 1 equiv.) diluted in a few mL THF was added. The
reaction was stirred for 2 h. After cooling, the mixture was
diluted in diethyl ether and washed with brine. The organic
phase was dried over MgSO4, filtered and the solvent evapo-
rated using a rotary evaporator. The crude solid was then pur-
ified by gradient flash chromatography with PS/EA 95:5 to
2-Methylbut-3-yn-2-yl 2-Aminophenylcarbamate 8c
To a solution of 2-methylbut-3-yn-2-yl 2-nitrophenylcarbamate
(0.500 g, 2.01 mmol, 1 equiv.) in absolute ethanol (50 mL)
was added SnCl2 hydrate (0.802 g, 4.23 mmol, 2.1 equiv.). The
solution was refluxed for 2 h. While refluxing, the colour of the
solution changed from yellow to deep red. The solution was then
cooled to room temperature, diluted in EA and washed subse-
quently with water, saturated NaHCO3 and brine. The organic
phase was collected, dried over MgSO4 and the solvent was

172
R. Delatouche et al.
70:30, affording 8f as a yellow solid (1.209 g, 5.16 mmol, 72%),
mp 788C. dH (400 MHz, CDCl3) 9.90 (s, 1H), 8.58 (dd, 1H, J 1.3,
8.6), 8.21 (dd, 1H, J 1.5, 8.5), 7.64 (ddd, 1H, J 1.6, 7.1, 8.5), 7.15
(ddd, 1H, J 1.3, 7.2, 8.5), 5.48 (dq, 1H, J 2.1, 6.7), 2.53 (d, 1H,
J 2.1), 1.60 (d, 3H, J 6.7). dC (100 MHz, CDCl3) 152.0, 136.2,
135.9, 135.1, 125.9, 122.6, 120.8, 81.7, 73.6, 61.9, 21.3. m/z
(HRMS) 257.034 (0 ppm). C11H10N2O4Na requires [M þ Na]þ
257.0538.
(m, 1H), 1.64 (m, 3H). The complex mutiplicity of the CH
endocyclic proton, the methylene protons and the methyl pro-
tons are due to 4J and 5J couplings. dC (100 MHz, CDCl3) 154.6,
146.7, 134.7, 131.3, 131.1, 130.2, 127.5, 126.3, 82.0, 76.2,
20.9. m/z (HRMS) 257.034 (0 ppm). C11H10N2O4Na requires
[M þ Na]þ 257.0538.
2-Methoxyethyl 2-(4-(4-(2-(Phenylcarbamoyloxy)
propan-2-yl)-1H-1,2,3-triazol-1-yl)butoxy)benzoate 9a
General Procedure for the Catalyzed Cyclization
of Propargyl Carbamates 10
To a solution of 2-methylbut-3-yn-2-yl phenylcarbamate
(0.208 g, 1 mmol, 1 equiv.) and 2 (0.323 g, 1 mmol, 1 equiv.) in
pyridine (5 mL) was added copper iodide (38 mg, 0.2 mmol,
0.2 equiv.). The solution was stirred overnight and pyridine was
then evaporated under reduced pressure. The crude mixture was
separated by flash chromatography over silica gel, affording the
clicked carbamate 9a as a yellowish viscous oil (99 mg, 19%
yield). dH (400 MHz, [D6]acetone) 8.57 (s, 1H), 7.99 (s, 1H),
7.72 (dd, 1H, J 1.7, 7.7), 7.49 (m, 3H), 7.24 (m, 2H), 7.08 (dd,
1H, J 0.6, 8.5), 6.98 (m, 2H), 4.51 (t, 2H, J 7.1), 4.38 (m, 2H),
4.08 (t, 2H, J 6.0), 3.65 (m, 2H), 3.32 (s, 3H), 2.17 (m, 2H), 1.85
(s, 6H), 1.80 (m, 2H). dC (100 MHz, [D6]acetone) 167.8, 160.1,
154.1, 153.3, 141.4, 135.2, 132.9, 130.5, 124.1, 123.3, 122.7,
121.9, 120.0, 115.2, 78.3, 72.1, 69.7, 65.4, 59.8, 51.2, 29.0, 28.8,
27.8. m/z (HRMS) 519.2210 (1 ppm). C26H32N4O6Na requires
[M þ Na]þ 519.22195.
In solvent (4 mL) were added the propargyl carbamate (100 mg)
and a catalytic amount of copper catalyst (1, 5, 10 or 20 mol-%).
The mixture was stirred overnight at room temperature. After
reaction, the solvent was removed under vacuum and the crude
1
mixture was analysed by H NMR in CDCl3 to calculate the
conversion based on the integration of the characteristic peaks of
the 2-methylene oxazolidin-2-one (methylene protons, doublets
,4 ppm), starting material (alkyne proton, singlet ,2.5 ppm)
and released amine (NH2 ,6 ppm, aromatic protons). Every
cyclized new compound was purified by either preparative TLC
or flash chromatography on silica gel, allowing calculation of
the isolated yield.
5,5-Dimethyl-4-methylene-3-(2-nitrophenyl)oxazolidin-
2-one 10b
Obtained as a yellow solid, mp 928C. dH (400 MHz, CDCl3) 8.16
(dd, 1H, J 1.5, 8.2), 7.77 (dt, 1H, J 1.5, 7.7), 7.62 (ddd, 1H, J 1.4,
7.6, 8.2), 7.51 (dd, 1H, J 1.3, 7.9), 4.06 (d, 1H, J 3.4), 3.90 (d, 1H,
J 3.4), 1.68 (s, 3H), 1.66 (s, 3H). dC (100 MHz, CDCl3) 153.8,
150.9, 145.8, 134.5, 131.2, 130.0, 127.7, 126.2, 83.9, 81.1, 27.9,
27.8. m/z (HRMS) 271.0690 (0 ppm). C12H12N2O4Na requires
[M þ Na]þ 271.06893.
2-Methoxyethyl 2-(4-(4-(2-(2-Nitrophenylcarbamoyloxy)
propan-2-yl)-1H-1,2,3-triazol-1-yl)butoxy)benzoate 13b
To a solution of 2-methylbut-3-yn-2-yl 2-nitrophenylcarbamate
(0.134 g, 0.54 mmol, 1 equiv.) and 2-methoxyethyl 2-(4-
azidobutoxy)benzoate (0.165 g, 0.54 mmol, 1 equiv.) in freshly
distilled THF (4 mL) was added copper iodide (20 mg,
0.108 mmol, 0.2 equiv.). The mixture was stirred at room tem-
perature overnight. The mixture was diluted in EA and washed
with saturated NH4Cl, and the organic phase was dried with
MgSO4, filtered and the solvent removed under reduced pres-
sure. The crude residue was then purified by flash chromato-
graphy, affording the clicked propargylamine 13b (83.2 mg,
0.167 mmol, 31%) as a yellow oil. dH (400 MHz, [D6]acetone)
8.47 (s, 1H), 7.95 (dd, 1H, J 1.6, 8.6), 7.84 (s, 1H), 7.59 (dd, 1H,
J 1.8, 7.7), 7.35 (ddd, 1H, J 1.8, 7.4, 8.5), 7.12 (ddd, 1H, J 1.5,
7.0, 8.6), 6.93 (d, 1H, J 8.4), 6.86 (dt, 1H, J 0.9, 7.6), 6.54 (dd,
1H, J 1.0, 8.8), 6.48 (ddd, 1H, J 1.1, 6.9, 8.3), 4.37 (t, 2H, J 7.0),
4.21 (m, 2H), 3.92 (t, 2H, J 6.0), 3.51 (m, 2H), 3.18 (s, 3H), 2.01
(m, 2H), 1.70 (s, 6H), 1.61 (qd, 2H, J 6.1, 12.4). dC (100 MHz,
[D6]acetone) 166.7, 159.1, 153.1, 144.7, 136.0, 134.2, 133.7,
132.0, 127.4, 122.3 121.7, 120.9, 117.5, 116.3, 114.2, 71.1, 68.7,
64.4, 58.8, 53.0, 50.4, 29.8, 27.7, 26.7. m/z (HRMS) 520.2167
(0 ppm). C25H31N5O6Na requires [M þ Na]þ 520.21665.
tert-Butyl 2-(2-(5,5-Dimethyl-4-methylene-
2-oxooxazolidin-3-yl)phenylamino)-
2-oxoethylcarbamate 10d
Obtained as a colourless viscous oil. dH (400 MHz, CDCl3) 8.45
(s, 1H), 8.05–8.03 (m, 1H), 7.42–7.38 (m, 1H), 7.22–7.21 (m,
2H), 5.26 (bs, 1H), 4.04 (d, 1H, J 3.1), 3.94 (dd, 1H, J 5.0, 17.5,
AB system, Gly CH2, broad signal), 3.90 (d, 1H, J 3.0), 3.73 (dd,
1H, J 5.7, 17.1, AB system, Gly CH2), 1.66 (s, 3H), 1.61 (s, 3H),
1.44 (s, 9H). dC (100 MHz, CDCl3) 168.2, 156.1, 154.9,
150.6, 134.5, 129.9, 128.4, 125.7, 124.5, 124.5, 83.7, 82.4,
80.5, 45.2, 28.3, 28.3, 27.9. m/z (HRMS) 398.1684 (1 ppm).
C19H25N3O5Na requires [M þ Na]þ 398.16864.
5,5-Dimethyl-4-methylene-3-(2-(trifluoromethyl)phenyl)
oxazolidin-2-one 10e
Obtained as a white solid. dH (400 MHz, CDCl3) 7.82 (d, 1H,
J 7.3), 7.71 (dt, 1H, J 1.0, 7.7), 7.60 (t, 1H, J 7.7), 7.37 (d, 1H,
J 7.8), 4.05 (d, 1H, J 3.1), 3.69 (d, 1H, J 3.1), 1.65 (s, 3H),
1.64 (s, 3H). dC (100 MHz, CDCl3) 154.2, 152.8, 133.6, 131.8,
131.5, 130.0, 127.9, 127.9, 124.3, 83.5, 81.8, 28.2, 27.5. dF
(376 MHz, CDCl3) ꢁ61.45. m/z (HRMS) 294.0710 (1 ppm).
C13H12NO2F3Na requires [M þ Na]þ 294.07123.
Acknowledgements
The authors thank CNRS and Agence National de la Recherche (ANR-08-
PCVI-030, grant to R.D., F.C.) for financial support.
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