A mild synthesis of13C-methanol

Article abstract of DOI:10.1055/s-2005-917070

The formation of oxazolidinon-2-ones from amino alcohols and carbon dioxide is well known. Until now it was not possible to reduce the fixed carbon dioxide to any basic chemical like formaldehyde or methanol, only the less interesting N-methyl compounds w

Full text of DOI:10.1055/s-2005-917070

2
522
LETTER
13
A Mild Synthesis of C-Methanol
13
A
J
Mild
S
y
ö
nthesis of
r
gn ol Fröhlich, Stefan Berger*
Institute of Analytical Chemistry, University Leipzig, Linnèstrasse 3, 04103 Leipzig, Germany
Fax +49(341)9711833; E-mail: stberger@rz.uni-leipzig.de
Received 19 July 2005
A catalytic process of the reaction of amino alcohols with
carbon dioxide to form these five-membered rings is also
available. Our goal was now to reduce the fixed carbon
Abstract: The formation of oxazolidinon-2-ones from amino alco-
hols and carbon dioxide is well known. Until now it was not possi-
ble to reduce the fixed carbon dioxide to any basic chemical like
formaldehyde or methanol, only the less interesting N-methyl com-
5
dioxide, ideally to methanol. The high stability of the
pounds were formed with lithium aluminium hydride. Here we heterocycle makes it currently necessary to use lithium
show the reduction of a oxazolidin-2-one derivative to methanol aluminum hydride as a strong reducing agent. However,
and the corresponding sulfone amide after introducing a sulfone
for R = H and alkyl attached to the nitrogen the reaction
group at the nitrogen. With selective labelling of the carbonyl
carbon it was possible to produce C-labelled methanol.
4b
gives only the N-methyl compounds 3 (Equation 2).
1
3
Key words: carbon dioxide, sulfonation, reduction, oxazolidin-2-
ones, methanol
O
H3C
LiAlH4,
1.1 equiv
O
N
R
HO
N
R
THF
One of the most exciting tasks for chemists since about
hundred years is the utilization of carbon dioxide. Carbon
dioxide is a thermodynamically extremely stable and inert
molecule. While the nature has many creative solutions,
chemists failed except a few famous exceptions. These are
3
R = H, Bn, Me
Equation 2
the formation of urea, salicylic acid and cyclic carbonates The supposed mechanism for the reaction is given in
as polymer building blocks. The catalytic hydrogenation Scheme 1. The iminium compound 4 is the key inter-
of carbon dioxide over heterogeneous catalysts is current- mediate. With the suppression of the formation of this in-
1
ly a very intense field of investigation. The economic and termediate, it should be possible to release the carbonyl
ecological problems are tremendous as long the hydrogen carbon as a reduced species.
is produced by the water gas shift reaction. Since it is
R1
R2
known that carbon dioxide is one of the greenhouse gases,
the reduction of carbon dioxide to basic chemicals be-
comes more and more important.
R2
R1
R2
R1
R3
O
N
R3
R3
O
N
O
N
H
H
While a lot of attempts deal with the activation of carbon
dioxide using transition metal complexes, our concept is
more classical. It is well known and very well investi-
H
O
O
O
H
AlH3
2
gated, that amino alcohols 1 are able to bind carbon di-
R3 = H, Me
oxide to form carbamates, respectively, carbamate salts
3
R1
R2
(
Equation 1). By converting the alcohol function to a bet-
R1
R2
R1
R2
ter leaving group it is possible to form cyclic carbamates
, the oxazolidin-2-ones, which are formally condensa-
tion products of an amino alcohol and carbon dioxide
2
) H–
R3
1
O
N
R3
R3
HO
N
+
O
N
H
2
) H /H2O
4
(
Scheme 1).
H3C
H2C
H
H
O
H
Al
O
H
4
Scheme 1 Supposed mechanism for reduction of oxazolidin-2-ones
with LiAlH4
CO2
H2O
HO
NH2
O
NH
1
2
We therefore introduced an electron-withdrawing group
at the nitrogen. This group should hinder the free electron
pair of the nitrogen to stabilize the iminium ion 4. Intro-
ducing a trifluoromethyl group at the nitrogen failed with
our methods. The second choice was a sulfone moiety as
Equation 1
SYNLETT 2005, No. 16, pp 2522–2524
0
4
.1
0
.2
0
0
5
6
Advanced online publication: 21.09.2005
DOI: 10.1055/s-2005-917070; Art ID: G23105ST
Georg Thieme Verlag Stuttgart · New York
an electron-withdrawing group. Four sulfone-containing
moieties were tested: the p-toluene sulfonyl group, the
©

LETTER
A Mild Synthesis of 13C-Methanol
2523
trifluoromethane sulfonyl group, the methane sulfonyl saturated ammonium chloride solution the broad signal
1
group and the free sulfonic acid (Table 1). The free became very sharp (C*) and shows a quadruplet in the H-
sulfonic acid turned out as bad choice for the project be- coupled carbon spectrum. This carbon signal shows a
cause of its poor solubility and low stability in DMSO. As correlation with a proton signal at d = 3.4 ppm. To further
oxazolidin-2-one we choose the 5-phenyl-oxazolidin-2- ascertain methanol as the product, the reaction mixture
one (5). The sulfonic groups were introduced by standard was analysed by GCMS. Here conformity of the retention
methods, using a strong base and the sulfonic acid time as well as the mass number was found. Because of
7
13
13
chloride as electrophile (Equation 3). The yields were the absence of any other C-labelled species in the
C
moderate up to excellent (Table 1).
NMR spectra, it is assumed that the carbonyl carbon is
completely reduced to methanol.9
O
O
O
S
1
. BuLi, –78 °C , THF
O
N
R
O
NH
2
. RSO2Cl
O
Ph
Ph
5
6
a–d
Equation 3
Table 1 Sulfonated Oxazolidin-2-ones
Entry
R
Yield (%)
6
6
6
6
aa
ba
c
–CH3
–C H CH
48
86
–b
6
5
3
–OH
dc
–CF3
19
a
b
c
Purified by recrystallization from EtOH.
Unstable product.
Purified by column chromatography (silica gel, EtOAc–MeOH,
:1).
7
The reduction of the N-sulfonated heterocycles with lithi-
um aluminium hydride gave exclusively the sulfone
8
amides 7 (Equation 4).
O
O
O
S
H
Figure 1 Reduction of 6b followed by 13C NMR spectroscopy: a)
1
3
LiAlH4, THF
HO
Ph
N
S
R
C-labelled 6b in THF-d at –80 °C; b) after addition of LiAlH
8
4
O
N
R
(
20 °C); c) after hydrolysis with NH Cl in D O; d) gated-decoupled-
4 2
O
spectrum of state c.
O
MeOH
Ph
The search for other reducing agents failed up to now. An
overview over several tested reducing systems is given in
Table 2. The formation of the sulfone amide with sodium
hydridoborate causes hydrolysis because of the high
basicity of the sodium hydridoborate in protic solvents as
the used alcohols. Very interesting is the last entry, were
a combination of the amino borane and boron trifluoride
as a Lewis acid gives the N-methyl compound 8b. This
behavior is not clear, because a predicted activation of the
carbonyl function could not be observed by a chemical
shift change of the carbonyl group by adding the Lewis
7
a–d
6
a–d
Equation 4
The more important fact is that the former carbonyl
carbon atom becomes the carbon of methanol during the
reduction. This could be confirmed by following the reac-
tion with NMR spectroscopy. A 5-phenyl-3-(toluene-4-
1
3
sulfonyl)-oxazolidin-2-one (6b), C-labelled at carbonyl
carbon, was reduced in the NMR tube and the reaction
was followed from –80 °C up to 20 °C (Figure 1). No in-
10
acid. The reducing agents LiEt BH, which is known to
1
13
3
termediates could be observed, either with H NMR or C
NMR spectroscopy. But the broad signal B* at d = 50 ppm
should indicate, for our understanding, aggregates of
methanolate. After hydrolysis of the reaction mixture with
reduce carbamates to the corresponding alcohol and
amine, did not react in the case of the cyclic carbamate.11
Synlett 2005, No. 16, 2522–2524 © Thieme Stuttgart · New York

2
524
J. Fröhlich, S. Berger
LETTER
Table 2 Tested Borane Reducing Agents Combined with Lewis
Acids
(3) Suda, T.; Iwaki, T.; Mimura, T. Chem. Lett. 1996, 25, 777.
(4) (a) Hassner, A.; Burke, S. S. Tetrahedron 1974, 30, 2613.
(
b) Schlörer, E. PhD Thesis; Universität Leipzig: Germany,
Reducing agenta
Lewis acid Solvent
Result
2001.
(
(
5) Tominaga, K.; Sasaki, Y. Synlett 2002, 307.
6) We are indepted to Prof. K. Burger and Prof. H. Wilde
BH ·THF
–
THF
THF
THF
No reaction
No reaction
No reaction
No reaction
7bb
3
(
University Leipzig) for helpful suggestions.
tert-Butylamine borane
–
(
7) Sulfonation of Oxazolidin-2-one (5).
Oxazolidin-2-one (500 mg, 3.07 mmol) was dissolved in dry
NH ·BH3
–
3
THF (10 mL) under N atmosphere. At –80 °C n-BuLi (1.93
2
NH ·BH3
–
CH Cl
mL, 3.07 mmol, 1.6 M solution in THF) was added slowly to
the solution. After the solution was allowed to warm up to
–30 °C, p-toluenesulfonyl chloride (585 mg, 3.07 mmol) in
dry THF (5 mL) was added. After stirring at r.t. for 4 h, the
3
2
2
NaBH4
–
MeOH
EtOH
NaBH4
–
7bb
reaction mixture was hydrolyzed with sat. NH Cl solution,
4
Mixturec
extracted with EtOAc (4 × 20 mL), the organic layer was
NH ·BH3
TiCl4
CH Cl
3
2
2
dried (MgSO ) and the solvent evaporated. The residue was
4
NaBH4
BF ·OEt
CH Cl
No reaction
recrystallized from EtOH to yield the N-sulfonated
oxazolidin-2-one (6b, 836 mg, 86%); mp 122–124 °C. H
3
2
2
2
2
1
NH ·BH3
BF ·OEt
3
CH Cl
2
2
8b
3
NMR (400 MHz, CDCl , TMS): d = 2.47 (s, Ph–CH ), 3.89
3
3
2
3
a
(dd, J = 9.2 Hz, J = 7.8 Hz, CH –NH), 4.42 (dd,
HH HH A
Only 6b tested.
By hydrolysis.
No product isolable.
2
3
3
b
JHH = 9.2 Hz, J = 8.1 Hz, CH –NH), 5.52 (dd, J = 8.1
HH B HH
Hz, O–CH), 7.37 (m, Ph), 7.95 (d, J = 8.1 Hz, Ph). C
3
13
c
HH
NMR (100 MHz, CDCl , TMS): d = 21.7 (Ph–CH ), 51.6
3
3
(
1
CH –N), 75.3 (Ph–CH), 125.6, 128.3, 128.9, 129.1, 133.8,
36.2, 145.7 (Ph), 151.5 (C=O). MS (ES ): m/z = 318 [M ].
2
+
+
In this work we have shown that a small change of the
electronic properties of a molecule causes dramatic ef-
fects of its reactivity. It is, to our knowledge, the first time
that an oxazolidin-2-one was reduced to the sulfone amide
and methanol instead of the N-methyl compounds. This
(8) Reduction of Sulfonated Oxazolidin-2-one (6b)
Under an N atmosphere, LiAlH (15 mg, 0.39 mmol) was
dissolved in dry THF (5 mL). While cooling the suspension
0 °C), the N-tosyloxazolidin-2-one (200 mg, 0.63 mmol) in
THF (5 mL) was added slowly and refluxed for 2 h. After
2
4
(
cooling to r.t. the mixture was hydrolyzed with sat. NH Cl
1
3
4
method can be used to produce C-labelled methanol.
solution, extracted with Et O (4 × 15 mL) and the solvent
2
1
3
Also a combination of C-labelling and deuteration by
using lithium aluminum deuteride would be possible by
the described procedure. The drawback of the method is
removed to yield the sulfone amide 7b (149 mg, 81%); mp
115–117 °C.
1
H NMR (400 MHz, CDCl , TMS): d = 2.42 (s, Ph–CH ),
3
3
2
3
3
.03 (dd, J = 13.4 Hz, J = 8.5 Hz, CH –NH), 3.85 (dd,
the stoichiometric use of LiAlH , which can reduce car-
HH
HH
A
4
2
3
1
2
J
HH = 13.4 Hz, JHH = 3.5 Hz, CH
B
–NH), 4.80 (dd,
bon dioxide directly. But our technique seems to be
much less sensitive to the reaction conditions then in the
direct case.
3
3
JHH = 8.5 Hz = 3.5 Hz, CH–Ph), 7.29 (m, Ph), 7.72 (d,
13
JHH = 8.1 Hz, Ph). C NMR (100 MHz, CDCl , TMS):
3
d = 21.5 (Ph–CH ), 50.2 (CH –NH), 72.8 (CH–Ph), 125.8,
3
2
1
27.1, 128.3, 128.7, 129.8, 136.8, 140.8 and 143.6 (Ph). MS
In the future, the influence of the lithium ion will be inves-
tigated. Also a catalytic reduction of the heterocycle
would be very interesting and is a subject of current work.
+
+
(
ES ): m/z = 292 [M] .
(
9) Determination of the Yield of Methanol in the Unlabelled
Case.
The reaction was performed like described (200 mg, 0.63
mmol 6b). After hydrolysis the reaction mixture was filtered
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1
(
1) Inui, T. In Effective Conversion of CO to Valuable
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2
8
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(
2) Arakawa, H.; Aresta, M.; Armor, J. N.; Barteau, M. A.;
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Synlett 2005, No. 16, 2522–2524 © Thieme Stuttgart · New York