Efficient Route to Deuterated Aromatics by the Deamination of Anilines

Article abstract of DOI:10.1021/acs.orglett.6b01438

One-step replacement of NH₂ groups in ring-substituted anilines by deuterium is reported. Approaches comprising both solid-phase and solution-phase syntheses can be used on a large variety of substrates. The method uses diazotization in a mixture of water and either dichloromethane or chloroform, which serve as a source of hydrogen. This protocol can be used as a general method for fast and easy incorporation of deuterium into an aromatic system using deuterated chloroform.

Full text of DOI:10.1021/acs.orglett.6b01438

Letter
pubs.acs.org/OrgLett
Efficient Route to Deuterated Aromatics by the Deamination of
Anilines
Kristyna Burglova,† Sergei Okorochenkov,‡ and Jan Hlavac*,‡
†Institute of Molecular and Translation Medicine, Faculty of Medicine, Palacky University, Hnev
̌
otínska
́
5, 779 00 Olomouc, Czech
́
Republic
‡Department of Organic Chemistry, Faculty of Science, Palacky University, 771 46 Olomouc, Czech Republic
́
S
* Supporting Information
ABSTRACT: One-step replacement of NH2 groups in ring-substituted anilines
by deuterium is reported. Approaches comprising both solid-phase and solution-
phase syntheses can be used on a large variety of substrates. The method uses
diazotization in a mixture of water and either dichloromethane or chloroform,
which serve as a source of hydrogen. This protocol can be used as a general
method for fast and easy incorporation of deuterium into an aromatic system
using deuterated chloroform.
euterated compounds play significant roles in many areas
Dof chemical research, such as the study of reaction
mechanisms,1 as important internal standards in mass spectrom-
etry, or as additives in various NMR experiments. They are
irreplaceable in elucidation of biosynthetic pathways and may
enhance metabolic stability of drugs (so-called “heavy drugs”)2,3
when deuterium can be advantageously incorporated into active
pharmaceutical ingredients. Although the application of
deuterated compounds is very broad, current labeling
methods4−10 suffer from complexity, limited scope, and the use
of expensive reagents. Another drawback of currently known
methods is their incompatibility with the requirements of solid-
phase chemistry, an important tool in many applications,
including peptide synthesis. To the best of our knowledge, no
rapid, mild, quantitative, metal-free, and inexpensive method for
the labeling of aromatic compounds exists to date.
deamination principle with nondeuterated dichloromethane
with selected amines according to Scheme 1.
Scheme 1. General Principle of Deamination on Solid Phase
Herein, we report a fast, efficient one-step method for the
reductive deamination of aromatic amines either in solution or
on a solid support, which can serve as a tool for the removal of
amino groups and for the easy introduction of deuterium into the
system.
As a model system for one-step deamination, we suggest a
biphasic water/dichloromethane mixture. This mixture is
compatible with reactions in solution and was successfully
applied in reduction on a solid support.11 The water layer allows
easy diazotization via a standard application of nitrite; dichloro-
methane serves as a hydrogen donor similarly to H3PO2,12
LiAlH4,13 NaHSO3,14 DMF,15 or THF,16 application of which is
more complicated and/or use for deuterium insertion is almost
impossible. The biphasic system can also be advantageous for the
easy separation of final products from inorganic and unreacted
diazonium salts.
Various aromatic amines, substituted by electron-withdrawing
groups (anilines 1(1)−1(5)), electron-donating groups (anilines
1(6)−1(9)), and heterocyclic anilines (anilines 1(10)−1(12))
were immobilized on Rink resin (Scheme 1). As shown in Table
1, deamination proceeds for all aromatic anilines that we chose.
The yields of the reactions appear moderate; however, they
comprise the entire reaction sequence, including the con-
struction of starting compound 1, deamination, and final HPLC
Reaction on Solid Support
Before the study of deuteration, which may possibly be
Received: May 17, 2016
complicated by isotopic effects, we attempted to verify the
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01438
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Organic Letters
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Table 1. Crude Purities and Isolated Yields of Deaminated
Products
Scheme 3. Formation of Benzotriazinone Rings from
Diamines
substitution
purity of 1(R)
purity of 2(R)
yield of 2(R)
a
a
b
(R)
(%)
(%)
(%)
(1)
(2)
91
100
78
80
85
90
84
80
82
90
82
65
62
80
85
68
80
90
65
62
27
c
45
38
39
41
26
43
30
32
19
(3)
(4)
Scheme 4. Combination of Deamination and Triazole
Formation
(5)
(6)
(7)
(8)
(9)
(10)
(11)
(12)
c
c
a
a
b
Purity was determined after cleavage and is decreased due to
Determined by LC/MS directly after cleavage. Overall yield
formation of trifluoroacetyl derivatives.
calculated to the initial loading of the resin after cleavage and HPLC
purification. No conversion (1(10)) or decomposition (1(11) and
c
1(12)).
Table 2. Influence of the Deuterated Solvents on the Structure
of the Final Compound
purification with individual efficiency; therefore, the success of
the deamination step is evaluated as the change in purity between
starting compound 1 and product 2 (Table 1). This method
failed for the heterocyclic substrate 1(10), which did not undergo
diazotization, and derivatives 1(11) and 1(12), which decom-
posed. The problematic diazotization of heterocyclic amines
previously described in the literature17 and the low stability of
some diazonium salts limit this reaction.
To support our theory that the diazonium salt is the real
intermediate, we treated aniline 1(1) with NaNO2 in AcOH.
One part of the resin was reacted with SnCl2·2H2O in DMF
(Scheme 2, path A), and the second part was reacted with DCM
entry
chloroform
water
acetic acid
D/H (%)
1
2
3
CHCl3
CDCl3
CDCl3
D2O
H2O
D2O
CD3CO2D
CH3CO2H
CD3CO2D
0
75
75
These results indicate that the amino group was replaced by
the deuterium from chloroform. The reaction with CDCl3 was
then used for transfer of deuterium to the aromatic ring.
Although the reaction proceeded with the same purity, the
deuteration was incomplete (Scheme 5 and Table 3).
Scheme 5. General Principle of Deuteration on Solid Phase
Scheme 2. Direction of the Reaction toward Deamination
(Path A) or Reduction (Path B)
Table 3. Deuteration on a Solid Phase
entry
1(R)
D/H (%) in 6(R)
1
2
3
4
5
1(1)
1(2)
1(4)
1(8)
1(15)
38
75
68
38
46
and water (Scheme 2, path B). Treatment with SnCl2·2H2O
afforded expected hydrazine 3(1), which is evidence of
diazonium salt formation. Treating the diazonium salt with
DCM/water afforded a clearly deaminated product 2(1).
Additionally, compounds bearing two amino groups 1(13)
and 1(14) that are able to form a triazine ring via a competitive
intramolecular coupling reaction were chosen. These com-
pounds yielded only benzotriazinones 4(13) and 4(14),
respectively, verifying that the intramolecular cyclization
proceeds faster than diazo group substitution under this
experimental conditions (Scheme 3).
When three amine groups are introduced in one system, a
combination of competitive reactions occurred, and deaminated
triazole 5(15) formed (Scheme 4).
Consequently, two experiments with cheaper chloroform,
which works with the same efficiency as DCM, were carried out
to prove the source of the hydrogen formally replacing the amino
group (Table 2).
According to these results, we hypothesized that the
competitive source of hydrogen is the linker or polymeric
matrix. Significant difference between the same polymer
equipped with a different linker of similar loading (Table 4,
entries 2 and 4) confirms that the linker is a competitive donor of
hydrogen. Remarkable difference between two different polymer
supports with the same linker (Table 4, entries 2 and 5) confirms
that the polymeric support can be the competitive source of
hydrogen. Higher D/H ratio in the reaction of the same substrate
with a lower loading resin, in which the reactive sites are located
mainly on the surface and top part of the pores (Table 4, couples
of entries 1, 2 and 3, 4), can be explained by a diminishing
interaction of the substrate with the polymeric matrix in deeper
and tighter pore parts.
B
DOI: 10.1021/acs.orglett.6b01438
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Organic Letters
Letter
nondeuterated. Subsequently, the substrates were subjected to
the same reaction with deuterated chloroform. Purities and yields
of both products (protonated/deuterated) are summarized in
Table 6.
Table 4. Deuteration of 1-Methyl-2-aminoterephthalate on
Different Solid Supports
entry
resin (loading in mmol/g)
D/H (%) in 6(R)
a
1
2
3
4
5
Rink (0.60)
38
45
a
Rink (0.35)
Table 6. Deamination/Deuteration in Solution
a
Wang (0.85)
84
a
a
b
b
Wang (0.44)
>99
8
yield of 2(R)
yield of 6(R)
D/H in 6(R)
c
c
d
entry amine
(%)
(%)
(%)
TentaGel Rink (0.37)
a
1
2
3
4
5
6
7
8
1(21)
1(22)
1(23)
1(24)
1(25)
1(26)
1(27)
1(28)
e
Linker is bound to standard Merrifield resin.
e
66
87
70
58
60
51
43
50
e
>99
>99
>99
After evaluation of the contribution and efficiency of each of
the variables in the system, we chose the system that gave the best
resultslow-loading Wang linkerand investigated deutera-
tion of more substrates (Figure 1 and Table 5).
49
60
>99
>99
a
b
c
Reaction with CHCl3. Reaction with CDCl3. Yield determined via
LC/MS analysis of the crude reaction mixture according to the
d
calibration curve of an appropriate standard. Determined by 1H
e
NMR. Complicated mixture of products formed.
In contrast to the solid phase, deamination in solution works
only for electron-poor substrates. On the other hand, those
substrates that undergo deamination are excellent starting
compounds for H/D exchange and give labeled compounds
Figure 1. Deamination of substrates on a Wang linker according to
Scheme 1.
1
Table 5. Deamination of Substrates on a Wang Linker
with >99% isotopic purity. Figure 2 displays the H NMR
entry
1(R)
D/H (%) in 6(R)
1
2
3
4
5
1(16)
1(17)
1(18)
1(19)
1(20)
64
60
36
60
18
It is obvious that there is no guarantee of quantitative
deuteration, and the structure−reactivity relationship is difficult
to determine. Isotopic purity is dependent on resin and the
structure of the substrate; therefore, high or complete isotopic
purity is only obtained when a specific combination of all factors
occurs. Although the deuteration is not quantitative for the
majority of substrates, the isotopic mixture could be further
purified by HPLC or GC depending on the substrate’s
nature.18,19
Figure 2. 1H NMR spectrum of crude 4-deuterated acetophenone
6(25) in comparison with the nondeuterated analogue 2(25).
Reaction in Solution
spectrum of the crude product 6(25) as an example of the
reaction using CDCl3 in comparison to CHCl3. Reaction also
proceeds smoothly with a pharmaceutically relevant Fmoc-
phenylalanine derivative 1(28), affording deuterated Fmoc-
phenylalanine, which is directly applicable in the solid-phase
synthesis of peptide drugs.
The reaction in solution was performed comparatively with
CHCl3 and CDCl3 (Scheme 6).
For this experiment, we chose simple and easily accessible
amines with various electronic properties (Scheme 6). First, we
performed deamination in solution in which all solvents were
The mechanism of the reaction can be explained by radical
decomposition of diazonium salt and halogenated hydrocarbon.
We tried to confirm it by addition of TEMPO as a radical
scavenger. Unfortunately, the application of TEMPO in the
solution-phase approach was unsuccessful because of its low
solubility in water, which contains the diazonium salt. Therefore,
we turned our attention to solid-phase reaction. Amine 1(1) was
treated with the usual deamination mixture in the presence of
TEMPO (Scheme 7, route A). Instead of the TEMPO-bound
adduct 30, phenol derivative 31 was isolated after cleavage from
the resin. The hypothesis for decomposition of TEMPO during
the cleavage of the substrate from the resin was successfully
confirmed by bonding of TEMPO adduct 29 to resin prepared in
Scheme 6. Deamination in Solution of Selected Amines
C
DOI: 10.1021/acs.orglett.6b01438
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Scheme 7. Deamination in the Presence of a TEMPO
Scavenger
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solution and its cleaving from the resin (Scheme 7, route B).
These results confirm the facile radical decomposition of
diazonium salts. Presumably, these radicals react with DCM or
chloroform in a subsequent step.
In conclusion, we developed a fast and efficient method for the
reductive deamination of anilines that is applicable in the
synthesis of deuterated compounds. This protocol is compatible
with solid-phase and solution-phase chemistry. Contrary to
solution chemistry, where only systems deactivated to electro-
philic substitution are applicable, solid-phase approaches enable
the deamination of a much wider scope of substrates. Solution
deamination offers great progress in the preparation of
deuterated compounds because the isotopic purity of its
products is >99%. Deuteration reaction proceeds under very
mild conditions (rt, catalytic amount of acid, no metal catalyst)
using cheap deuterated chloroform in a short reaction time.
Additionally, incorporation of deuterium into the aromatic
system is very selective; its position is given by the position of the
amine functionality and can be changed as demanded.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01438.
1
Experimental procedures, characterization, H and 13C
NMR spectra for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: hlavac@orgchem.upol.cz
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research project was supported by the Ministry of
Education, Youth and Sport of the Czech Republic (project
IGA_PrF_2016_020) and by the European Social Fund (project
CZ.1.07/2.3.00/20.0009). The infrastructure of this project
(Institute of Molecular and Translation Medicine) was
supported by the National Program of Sustainability (project
LO1304).
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D
DOI: 10.1021/acs.orglett.6b01438
Org. Lett. XXXX, XXX, XXX−XXX