Intramolecular conversion of N,N-bis(2-picolyl)ureas to cyclic carbamates

Article abstract of DOI:10.1016/j.tetlet.2015.09.118

Herein, we present a new methodology for preparing 6-membered ring carbamates from a Cu^I-promoted cyclization of N,N-bis(2-picolyl)amine substituted ureas. The reactions work best in the presence of up to five-fold excess of CuCl at room temper

Full text of DOI:10.1016/j.tetlet.2015.09.118

Tetrahedron Letters 56 (2015) 6340–6344
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Intramolecular conversion of N,N-bis(2-picolyl)ureas to cyclic
carbamates
⇑
Uwe Jakob, Willi Bannwarth
Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg, Albertstrasse 21, 79104 Freiburg, Germany
a r t i c l e i n f o
a b s t r a c t
I
Article history:
Received 10 July 2015
Revised 23 September 2015
Accepted 25 September 2015
Available online 28 September 2015
Herein, we present a new methodology for preparing 6-membered ring carbamates from a Cu -promoted
cyclization of N,N-bis(2-picolyl)amine substituted ureas. The reactions work best in the presence of up to
five-fold excess of CuCl at room temperature in a non-nucleophilic solvent such as acetonitrile. Nine
examples of the syntheses are presented to yield products in good to excellent amounts.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Copper
Carbamates
Urea derivatives
Introduction
are largely toxic, there is a great interest of developing other
strategies for the preparation of cyclic carbamates. An alternative
is the preparation via Curtius- or similar rearrangements.2
0,21
In 1970, Houghton and Puttner reported on an unusual trans-
formation of N,N-bis(2-picolyl)amides (bpa-amides) into their
Nevertheless, examples of the synthesis of cyclic carbamates under
mild conditions are rare. Cyclic carbamates often have interest-
1
22
methyl esters in the presence of equimolar amounts CuCl
2
.
They
suggested that an unusual coordination mode of the amide
nitrogen is mediating the nucleophilic attack of methanol on the
carbonyl group. More than 25 years later, Cox et al. confirmed
ing properties. For example, Efavirenz is a Non-Nucleoside Reverse
Transcriptase Inhibitor (NNRTI) and gained attention in the treat-
2
3–26
ment of HIV infections.
Other benzoxazinones were found to
the proposed coordination mode and solved the crystal structure
be orally active nonsteroidal progesterone receptor antagonists
which are interesting for the therapy of hormone-dependent
2
2
of the CuCl -complex of N,N-bis(2-picolyl)benzamide. In the early
2
7,28
years of this century, various groups became interested in these
highly unusual amide complexes. Detailed studies about their
spectroscopic properties, structural data,3 the mechanism of
cancers.
have anticonvulsant activity.
Furthermore, various cyclic and acyclic carbamates
2
9,30
–8
9
–11
the transformation into methyl esters were published as well.
Our group was successful in elaborating and exploiting the syn-
Results and discussion
1
2–18
thetic potential of chelating amides in organic chemistry.
For the preparation of the urea precursors, we converted various
Their utility was demonstrated as linker molecules in solid-phase
chemistry and as orthogonal relay protecting groups. Moreover,
activation by CuCl allows for a transfer of various hydroxy amides
c
-keto carboxylic acids 5a–14a into derivatives 5b–14b using
3
1
diphenyl phosphoryl azide (DPPA) as the reagent. The keto func-
tions were reduced with NaBH yielding precursors 5c–14c
4
1
into their corresponding lactones 2 (Scheme 1). Recently, Belzile
(Scheme 2).
et al. reported that N,N-bis(2-picolyl)ureas are also prone to an
alcoholysis in the presence of metal salts—a reaction which pro-
Due to the large extinction coefficient of carbamate 8 at
2
54 nm, its formation was chosen as a benchmark reaction. The
1
9
ceeds in analogy to the methanolysis of bpa-derived amides.
solutions of various metal salts (CuCl
in MeCN; NiCl in H O/MeCN 1:1) were added to a solution of urea
c in MeCN and the reaction mixture was stirred at 25 °C in a ther-
momixer (Table 1).
After 24 h, the conversion was detected via HPLC. CuCl
OTf) , ZnCl and FeCl led only to conversions up to 20%. Only
NiCl showed a higher reactivity with a yield of 65% after 24 h. This
is an interesting result since ureases are Ni -dependent metallo
2 3 2 2
, FeCl , ZnCl and Cu(OTf)
Herein, we widened the scope of the reaction by converting
N,N-bis(2-picolyl)ureas intramolecularly into cyclic carbamates 4.
Cyclic carbamates are generally synthesized from amino alcohols
with phosgene or its synthetic equivalents but since those reagents
2
2
8
2
, Cu
(
2
2
3
⇑
Corresponding author. Tel.: +49 761 203 6073; fax: +49 761 203 8705.
E-mail address: willi.bannwarth@organik.chemie.uni-freiburg.de (W. Bannwarth).
2
II
http://dx.doi.org/10.1016/j.tetlet.2015.09.118
040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
0

U. Jakob, W. Bannwarth / Tetrahedron Letters 56 (2015) 6340–6344
6341
enzymes.32–34 Substituted Cu or ZnII analogues were found to be
inactive enzymes.
II
Table 1
3
5,36
Transformation of urea derivative 8c into the cyclic carbamate 8
The use of 5 equiv of CuCl led to a formation
of carbamate 8 in a yield of 90% already after 90 min. Since there
were no side-products except of the highly polar Cu-complexes,
the carbamate was easily purified via column chromatography
(
silica gel, DCM ? DCM/MeOH 95:5).
Carrying out the reaction at elevated temperatures led to no
higher conversion. The use of 2.5 equiv or 1.2 equiv of CuCl led to
lower conversions (Fig. 1) as it was already observed in the
intramolecular lactonization process.16 Due to the fact that CuCl
is a cheap and non-toxic metal salt, we decided to use it for the
transformation of other urea precursors into cyclic carbamates.
Metal salt
CuCl
Cu(OTf)
ZnCl
Solvent
Timeb (h)
Yieldc (%)
a
2
MeCN
24
24
24
24
24
20
16
17
15
65
a
2
MeCN
a
3
,1-Benzoxazin-2-ones 7–12 were isolated in yields of 70–90%
after column chromatography. The phenyl-substituted carbamate
was only obtained in a yield of 44% after purification via column
chromatography which is similar to methyl-substituted derivative
. Nevertheless, neither the starting material nor any other side-
2
MeCN
a
FeCl
NiCl
3
MeCN
a
O (2:1)d
2
MeCN /H
2
5
a
b
c
HPLC-grade.
Reaction was carried out at 25 °C.
Determined via HPLC.
2 2
A MeCN/H O-mixture was used because of the poor solubility of NiCl in pure
6
product was isolated. In the literature, carbamate 5 was synthe-
sized from the pertinent amino alcohol with various synthetic
equivalents of phosgene and it was obtained in similar yields
d
MeCN.
between 30% and 47% which is comparable with our yield.37 Other
typical methods as the preparation via Hofmann-rearrangement
2
1
gave yields of 78%. The conversion of an analogous seven-mem-
bered ring derivative gave only a poor yield of about 5%. The low
yield is may due to an competitive intermolecular reaction since
we have not reisolated any starting material. The method enables
the synthesis of carbamates which are derived from tertiary alco-
hols. Carbamate 15 was obtained in a yield of 86%.
Conclusions
Herein, we present a new approach for synthesizing cyclic
urethanes from N,N-bis(2-picolyl)urea-derivatives. The reaction
proceeds in analogy compared to the recently reported lactoniza-
tion reaction and requires the presence of 5 equiv of CuCl. Since
there are various cyclic carbamates with potentially interesting
properties, we are convinced that this new method is interesting
for the synthesis of various cyclic carbamates. Nevertheless, only
carbamates of the 3,1-benzoxazin-2-one-type were obtained in
good yields whereas 4-substituted 1,3-oxazinan-2-ones 5 and 6
were only isolated in yields of 44% and 37%. The analogous 1,3-oxa-
zepan-2-one derivative 14 was only formed in traces (Table 2).
Scheme 1. Analogous transformation of hydroxy substituted N,N-bis(2-picolyl)
amides into lactams and N,N-bis(2-picolyl)urea derivatives into cyclic carbamates.
Scheme 2. Synthesis of the N,N-bis(2-picolyl)urea precursors. Reagents and conditions: (a) carboxylic acid 5a–13a (1.4 equiv), DPPA (1.4 equiv), Et
3
N (1.4 equiv), bpa
(
1.0 equiv), toluene, reflux, 1 h; (b) NaBH (2.0 equiv), Et
4
2
O/MeOH (1:1), rt, overnight; (c) MeLi (2.5 equiv), THF, ꢀ78 °C, 1 h.

6
342
U. Jakob, W. Bannwarth / Tetrahedron Letters 56 (2015) 6340–6344
Experimental section
General procedure for the preparation of urea derivatives 5b–
1
4b
The carboxylic acid (2.8 mmol, 1.4 equiv), Et
.8 mmol, 1.4 equiv) and phosphoric acid diphenyl azide (DPPA;
04 l, 2.8 mmol, 1.4 equiv) were dissolved in toluene (30 ml)
3
N (390 ll,
2
6
l
and the reaction mixture was refluxed for 30 min under argon.
After the addition of bis(2-picolyl)-amine (bpa), the reaction mix-
ture was refluxed for further 30 min. After cooling down to rt,
the reaction mixture was poured on EtOAc (60 ml) and washed
with satd aq NaHCO
3
(2 ꢁ 40 ml). The organic phase was dried
with Na SO and the solvent removed under reduced pressure.
2
4
The resulting crude product was then purified via column chro-
matography (silica gel, DCM ? DCM/MeOH-mixtures; exception
1
4b, which was recrystallized from Cyclohexane/EtOAc) and the
resulting urea derivatives were obtained as gums or solids.
4
General procedure for the reduction with NaBH (Preparation of
5
c–14c)
The ketone was solved in a mixture of MeOH/Et
2
O (1:1-ratio; p.
A.-grade). NaBH (2.0 equiv) was dissolved in water (circa 2 ml)
4
and added to the ketone derivative. The whole reaction mixture
was stirred at room temperature overnight. Finally, a half-satu-
3
rated solution of NaHCO was added and the aqueous phase was
extracted three times with DCM. The combined organic phases
Figure 1. Transformation of urea derivative 8c into the cyclic carbamate 8.
were dried over Na
2
SO
4
and the solvent was removed under
Table 2
Transformation of N,N-bis(2-picolyl)ureas into cyclic carbamates
Entry
Urea derivative
Carbamate (product)
Conversiona,b (%)
1
(±)-521
(±)-638
(±)-720
(±)-8
44
37
77
90
2
3
4
5
6
(±)-920
80
75
(±)-1039

U. Jakob, W. Bannwarth / Tetrahedron Letters 56 (2015) 6340–6344
6343
Table 2 (continued)
Entry
Urea derivative
Carbamate (product)
Conversiona,b (%)
7
8
(±)-1140
90
73
(±)-12
9
(±)-13
71
1
0
1
(±)-14
6
1
1541
86
a
Carbamate derivative, CuCl (5.0 equiv), MeCN, rt, 6 h.
Isolated yield.
b
reduced pressure. The alcohols 5c–14c were isolated without fur-
ther purification.
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