Solid phase synthesis of selectively deuterated arenes

Article abstract of DOI:10.1039/c1cc12950c

A novel access to deuterated and D₃CO-substituted arenes has been developed using immobilized triazenes as precursors. The linker system and the deuterating cleavage methodology could be shown to be compatible with various functional groups and are therefore suitable for the synthesis of derivatives only hardly available via comparable protocols.

Full text of DOI:10.1039/c1cc12950c

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COMMUNICATION
Solid phase synthesis of selectively deuterated arenesw
a
Sylvia Vanderheiden,ab Bekir Bulat,ab Thomas Zevaco,c Nicole Jung*ab and Stefan Brase*
¨
Received 19th May 2011, Accepted 27th June 2011
DOI: 10.1039/c1cc12950c
A novel access to deuterated and D3CO-substituted arenes has
been developed using immobilized triazenes as precursors. The
linker system and the deuterating cleavage methodology could be
shown to be compatible with various functional groups and are
therefore suitable for the synthesis of derivatives only hardly
available via comparable protocols.
compounds have been isolated in good yields by replacement of
16
diazonium groups through deuterium using thiophenol-d1 or
deuterated dimethylformamide in combination with FeSO4.17 As
far as we know, there are no alternatives to the generation of
arenes bearing a D3CO-functionality which do not use MeI-d3 or
dimethylsulfate-d6 as reagent.
In this communication we describe a new, mild and non-toxic
alternative to known methods of D- and D3CO-introduction via
triazenes (Scheme 1). We focused on the development of advanced
dediazoniation protocols which generally allow the conversion
of molecules with various substitution patterns. The method
developed herein has several advantages in comparison with those
used until now: first we use only volatile solvents and reagents and
work free of metal salts, thus rendering isolation and purification
straightforward. Our reaction conditions do not require working
under a controlled atmosphere and are well-designed for a solid
phase chemistry strategy that should permit the generation of a
library of small deuterated building blocks. In addition, this
method is also suitable for solution phase chemistry.
Stable deuterated compounds are very important substances in
analytics,1 pharmacology,2 material sciences,3 and life sciences.4
Deuterated compounds, physicochemically nearly identical to
the non-deuterated ones, are used for NMR experiments and
mechanistic studies,5 neutron scattering,6 and Raman spectro-
scopy,7 reflecting the unique isotopic effects of deuterium.8 The
kinetic isotopic effect of deuterium9 in particular is used for the
synthesis of metabolically more stable active compounds yielding
drugs with identical pharmacodynamic effects but different
pharmacokinetics.10 Recently, a high demand for partly and fully
deuterated compounds was created for patent purposes; this is
also an increasingly common business model for newly established
companies.11 Due to the high demand for these compounds, many
high-yielding methods have been developed for their generation.
The synthesis of deuterated arenes is mostly based on halogen–
metal exchange reactions and subsequent quenching with heavy
water.12 Unfortunately, all effective methods suffer from harsh
reaction conditions and low selectivities, tolerating only a small
number of functional groups.
Synthesis of monodeuterated arenes: all reactions were performed
on triazenes in solution or on triazene-containing resins which are
readily accessible via reaction of benzylamine resin with amines.18
This well-established linker system is known to be easily cleavable
through the addition of acid, giving the corresponding diazonium
salts in situ. The resulting diazonium salts are thermally decom-
posed at 80 1C in THF-d8 or D3COD, yielding the deuterated
target compounds in a one-pot synthesis without requiring
isolation of the toxic and unstable diazonium salts.
Beyond the introduction of a single deuterium, many attempts
have been made to synthesize trideuterated substances via the
formation of D3CO-functionalities.13 The synthesis of D3CO-
substituted arenes is important with regard to drug derivation for
pharmacological14 and analytical purposes related to drug abuse
monitoring and quantitative detection of, for example, THC
derivatives.15
All substances could be isolated without further aqueous
workup after removal of the resin by filtration, evaporation of
the solvent and column chromatography. Table 1 summarizes our
The disadvantages of the existing protocols for deuterium or
D3CO-derivation such as harsh reaction conditions, low
selectivities and the use of toxic reagents are manifold, and many
attempts have been made to overcome them. Monodeuterated
a Institute of Organic Chemistry, KIT-Campus South,
Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany.
E-mail: braese@kit.edu; Fax: +49 721-608-48581
b IOC-ComPlat, KIT-Campus North, ITG, Hermann von Helmholtz
Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
c Institute of Catalysis Research and Technology, KIT-Campus North,
Hermann von Helmholtz Platz 1, 76344 Eggenstein-Leopoldshafen,
Germany
Scheme 1 Triazene decomposition and dediazoniation to the solvent-
controlled formation of deuterium or CD3O-substituted arenes 3 and 4.
w Electronic supplementary information (ESI) available: Experimental
section and spectroscopic data. See DOI: 10.1039/c1cc12950c
c
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Chem. Commun., 2011, 47, 9063–9065 9063

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Table 1 Cleavage of monodeuterated arenes from triazene resins in THF-d8
No
Resin
R1
R2
R3
R4
Yield [%]
D [%]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
OAr (OMe, p-Me)
OAr (o-OEt)
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Br
Me
Me
H
H
NO2
OPh
Br
H
H
H
H
H
H
H
H
Cl
H
H
H
H
H
H
H
H
61
499
84
499
81
499
98
66
95
93
95b
95
96
94
96
95b
95b
91
96
94
95
97
91
94
94
OAr (m-CHO)
OAr (m-OMe)
OAr (m-iPr)
OAr (m-iPr)
O-Biphenyl
O-Ph
O-Ph
OMe
H
–CHCHCHCH–
H
F
H
F
9
56
10
11
12
13
14
15
16
17
499
57 (60)a
49
30
62
57
43
85
H
H
H
H
H
Ar (p-OMe)
Ar (p-OMe)
–CRC–Ph
–CRC–Ph
–CRC–Ar(p-OMe)
H
a
b
Yields in brackets refer to syntheses on the mmol scale. Rate of deuteration determined via NMR spectroscopy.
Table 2 Cleavage of monodeuterated arenes from triazene resins in
methanol-d4
results giving monodeuterated substances after reaction in THF-d8.
The majority of the yields given therein were determined over two
steps (one modification of on bead and deuterating cleavage) as the
conversion on bead after a metal-involving coupling reaction is
difficult to determine. Isolated yields over two steps are good to
very good proving that the deuterating cleavage is a very effective
method that can compete against known protocols.
The obtained yields of electron-rich and electron-deficient
arenes were comparably high, which are in accordance with the
supposed radical mechanism of the deuterating cleavage in THF
(Scheme 1).19 Reactions were frequently performed with ortho-
immobilized diaryl ethers because the synthesis of this substance
class on solid phases is well-established, and gives in most
cases good conversions and yields. During our investigations of
monodeuteration in different solvents, we observed that mono-
deuteration can also be achieved via conversion in deuterated
methanol in cases when ortho-immobilized ethers are cleaved
(entries 3 and 4, Table 2). Encouraged by these results, which
are obviously a consequence of an electronic effect on the cleaved
arenes, we could also achieve the effective deuteration of arenes in
methanol-d4 in the presence of TFA-d1 for other substrates.
Entries 1 and 2 (Table 2), which refer to alkyne-substituted arenes,
gave excellent results, rendering the method a very effective
alternative to the THF protocol (Table 1). The methanol
approach becomes very attractive regarding the cost effectiveness
of the reaction, especially upon increasing the scale (methanol-d4 is
cheaper than THF-d8 and polystyrene based resins do not swell in
methanol: less solvent is needed). The deuteration methodology
was also performed on the mmol scale.
No Resin R1
R2
Yield [%] D [%]
1
2
3
4
1o
1q
1b
1d
H
H
–CRC–Ph
–CRC–Ar(p-OMe) 499
H
H
499
93
99
90
92
OAr (o-OEt)
OAr (m-OMe)
39
30
procedure were the same, however, simply a change of the solvent
to methanol-d4 enabled the synthesis of D3CO- rather than
D-substituted products. Additionally, the D+/H+ source could
now be used in its non-deuterated form. Table 3 summarizes the
results achieved through addition of methanol-d4 and TFA to
triazene resins and reaction at 80 1C for 12 hours. As the reaction
is presumed to follow an ionic pathway, the results depend on the
electronic nature of the immobilized arenes. Arenes with electron-
donating substituents often gave lower yields of, or could not
be converted into, the corresponding D3CO-derivatives. These
substrates gave the monodeuterated compounds when reacted
according to Table 3 (see also Table 2).
To our knowledge, the method described herein is the first
allowing for the selective introduction of a D3CO-group into
arenes via conversion of triazenes, offering the possibility for the
synthesis of D3CO-modified molecules without the need of
deuterated methyl iodide or dimethylsulfate-d6. Due to the
synthesis via dediazoniation, one D3CO-group can be generated
Synthesis of D3CO-derivatives: the synthesis of D3CO-
substituted arenes was performed using some of the identical resin
bound triazenes converted in the monodeuterating syntheses, as
described in Table 1. The starting material and the cleavage
c
9064 Chem. Commun., 2011, 47, 9063–9065
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Table 3 Generation of D3CO-substituted arenes from triazene resins
in CD3OD
Scheme 2 Combination of protocols: synthesis of arenes with
deuterium and OCD3 substitution. (a) Pd/C, H2, MeOH, rt, 12 h,
(b) i. C5H11ONO, BF3ÁEt2O, THF, À20 1C; ii. pyridine, MeCN,
benzylamine resin, À20 1C–rt, 12 h.
No Resin R1
R2
R3
Br
R4
H
Yield [%]
carbonyl residues. By using methanol-d4, the cost-effectiveness
of the reaction can be improved in the case of electron-rich arenes.
Starting with the same triazene linker system, we also developed a
high-yielding method for the preparation of trideuterated
compounds. Without precedent, the synthesis of D3CO-bearing
derivatives in the presence of carboxylic acids and alcohols was
achieved independently of the use of toxic methylating agents.
Lastly, we have demonstrated that a combination of the methods
described herein can even be used for the synthesis of arenes
displaying more than one deuterium substitution.
1
2
3
4
5
6
7
8
9
1l
1m
1r
1s
1t
1u
1v
1w
1x
–CHCHCHCH–
H
H
Ph
H
56
55
71
76
51
52
36
H
H
H
Ar (p-OMe) H
Ph
H
H
H
H
H
H
CH2OH H
H
H
OMe
Cl
Me
Me
COCH3
H
H
H
H
H
H
Me
D
H
H
I
OMe
H
CO2Me 73 (82)a
H
H
H
H
H
62
44
10 1y
11 1z
12 1aa
36
Ph
H
79b
80b
t
13 1ab CHCHCO2 Bu H
Notes and references
a
b
Yields in brackets refer to syntheses in the mmol scale. Syntheses in
solution.
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of arenes with a twofold deuterium-substitution. Resin 1j was
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deuterated nitroarene 3j. After conversion into the corres-
ponding amine and immobilization on benzylamino resin (to
give 1z), the dediazoniation could be applied again success-
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ether functionality, the reaction yields over two steps the
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c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 9063–9065 9065