Deuterodehalogenation - A mild method for synthesising deuterated heterocycles

Article abstract of DOI:10.1016/j.tetlet.2014.04.025

We report a mild and efficient method for introducing deuterium into a range of heterocycles by reacting readily available halide analogues in a deuterodehalogenation reaction using D₈-IPA or Et₃SiD under palladium-catalysed conditions.

Full text of DOI:10.1016/j.tetlet.2014.04.025

Tetrahedron Letters 55 (2014) 3305–3307
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Deuterodehalogenation—a mild method for synthesising deuterated
heterocycles
⇑
Craig S. Donald , Thomas A. Moss, Gary M. Noonan, Bryan Roberts, Emma C. Durham
Oncology iMed, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
We report a mild and efficient method for introducing deuterium into a range of heterocycles by reacting
readily available halide analogues in a deuterodehalogenation reaction using D8-IPA or Et3SiD under
palladium-catalysed conditions.
Received 26 February 2014
Revised 24 March 2014
Accepted 8 April 2014
Available online 16 April 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Deuterium
Deuterodehalogenation
Heterocycles
Metabolism
Deuteration of drugs has been shown in some cases to improve
their pharmacokinetic properties1–5 and as such, interest in this
area has gathered momentum in recent years. Many approaches
to synthesise these compounds, however, rely upon introduction
of the deuterium atom(s) at an early stage of the synthesis by
incorporation of ready-deuterated building blocks.5 There are
alternative approaches which introduce deuterium via the corre-
sponding halide, however, typically they require the use of
reagents such as NaBD4 under palladium catalysis,6 D2SO4/Zn,7
Pd-catalysed reduction with D2 gas8,9 or lithium-halogen exchange
followed by a D2O quench.10–13 Some of these approaches require
harsh conditions which may not be compatible with certain func-
tional groups or heterocycles.
As part of a drug discovery programme we were interested in
investigating whether incorporating a deuterium atom into a com-
pound with a reactive metabolite liability could solve the issue. We
looked into some of the approaches mentioned above although
they involved rather lengthy syntheses or were not tolerant of
the functionality in our molecule. A group of co-workers had pre-
viously reported a mild hydrodehalogenation (HDH) method using
triethylsilane,14 and we wondered if a similar approach could be
used to introduce a deuterium atom into our compounds at a late
stage by substituting with Et3SiD. This strategy for introducing
deuterium late stage into a drug-like molecule proved successful
so we decided to explore the transformation further with a range
of halo-heterocycles and herein we report our findings.
N
N
Et3Si(D/H)
D
Br
S-Phos (0.1 eq)
Pd(dba)2 (0.05 eq)
1
13
base (2 eq)
solvent
Scheme 1.
3-Bromoquinoline (1) was used as a model substrate (Scheme 1)
to optimise the reaction conditions and the results are shown in
Table 1. 3-Bromoquinoline was chosen as we were able to observe
clearly the proton at the 3 position in the 1H NMR spectrum, and
therefore determine the percentage of deuterium incorporation
observed. Optimised conditions for the previously reported HDH
reaction employed five equivalents of triethylsilane, however,
due to cost considerations we investigated whether the number
of equivalents of Et3SiD could be reduced. With this in mind the
initial experiments (entries 1–6) were attempted using cheaper
Et3SiH to optimise the conversion from 3-bromoquinoline into
quinoline. Entry 1 shows that good conversion into the product
could be achieved using two equivalents of silane. Our results
showed that caesium carbonate and triethylamine were preferred
to other bases trialled, so these were investigated further looking
into deuterium incorporation. We also examined alternative sol-
vents and both acetonitrile and 1,4-dioxane were good choices
for this reaction, however, DMF resulted in poorer deuterium
incorporation.15
⇑
Corresponding author. Tel.: +44 7779458312.
E-mail address: craig.donald@astrazeneca.com (C.S. Donald).
http://dx.doi.org/10.1016/j.tetlet.2014.04.025
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

3306
C. S. Donald et al. / Tetrahedron Letters 55 (2014) 3305–3307
Table 1
Table 2a (continued)
Substrate
Product
Yieldb (%)
Entry Solvent
Base
Time D/H
Conversiona
T
Deuteration
Br
D
(h)
source (%)
(°C) (%)
N
N
(equiv)
N
N
N
N
1
2
3
1,4-Dioxane Et3N
1,4-Dioxane None
1,4-Dioxane KF
1
2
3
3
1
3
1
1
1
1
1
1
2
2
2
2
8
2
2
2
2
2
2
2
2
2
2
3
5
3
3
3
>95
54
64
100
70
89
63
100
70
100
98
100
100
100
100
100 N/A
100 N/A
100 N/A
100 N/A
100 N/A
100 N/A
120 93
120 74
120 93
100 >90
100 >90
100 >90
120 92
120 80
120 92
80 >95
80 >95
95
N
O
N
O
O
O
4
1,4-Dioxane CsF
21
22
9
5
6
7
1,4-Dioxane DMAP
1,4-Dioxane Cs2CO3
1,4-Dioxane Cs2CO3
N
N
N
Cl
D
N
8
DMF
Cs2CO3
Cs2CO3
Et3N
Et3N
Et3N
Et3N
K3PO4
Et3N
K2CO3
K2CO3
91
79
9
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN-D3
D8-IPA
D8-IPA
10
11
12
13
14
15
16
17
10
Cl
D
N
N
Solvent 100
Solvent 97
N
N
a
Based on 1H NMR spectra of the crude reaction mixture.
11
23
O
O
Table 2a
Cl
D
O
O
90
Substrate
Product
Yieldb (%)
O
O
O
O
D
Br
12
24
72
72
N
N
a
Conditions used: Pd(dba)2, K2CO3, S-Phos, D8-IPA, MeCN, 100 °C (MW), 2.5 h.
% deuterium incorporation P95%.
13
1
b
N
S
N
Cl
D
S
O
O
2
14
In most cases, we observed some H incorporation into the prod-
Br
D
ucts and made attempts to improve this but were unsuccessful.
Reaction vessels were vacuum-dried and dry solvents (including
using molecular sieves) were used to eliminate the possibility of
water as the H source. Attempting the reaction in deuterated sol-
vent (entry 15) gave a comparative yield to the non-deuterated
example (entry 13), thus eliminating the solvent as the source of
hydrogen in this case. A potential explanation is that the hydrogen
is perhaps introduced due to b-hydride elimination of the palla-
dium–silane complex.16 We did not carry out the experiment with
59
30
52
91
S
S
3
NBoc
15
NBoc
N
N
N
N
N
Cl
N
D
D
4
5
16
17
Br
D16-triethylsilane due to availability, although this would likely
confirm or disprove our theory. Another potential source of hydro-
gen might be the base, but we observed low levels of hydrogen
incorporation with a range of bases including inorganic bases con-
taining no hydrogen atoms so this seems unlikely.
We then became aware of alternative HDH conditions using i-
PrOH17 as a source of hydrogen and investigated whether this
offered any improvement in deuterium incorporation levels. This
method has the added advantage that D8-IPA is significantly
cheaper than Et3SiD. Improved deuterium incorporation was
observed using these conditions (entries 16 and 17) so the reaction
was investigated further. A range of common halo-heterocyclic
compounds were subjected to the D8-IPA conditions and the find-
ings are summarised in Table 2.
Different bromo and chloro-heterocyclic substrates were
reacted under the optimised conditions to afford deuterated ana-
logues in reasonable yields. Generally, we found that high amounts
of deuterium incorporation (P95%) were achieved, and therefore
believe that it is a very useful method for making deuterated com-
pounds. A limitation of the D8-IPA reaction is that certain sub-
strates (with activated halides), for example, 2-chloropyrimidines
may undergo SnAR substitution with the alcohol solvent. In this
N
Boc
N
Boc
N
N
Ph
N
N
Cl
D
Ph
6
18
Br
N
D
O2N
O2N
N
N
N
74
68
PMB
PMB
7
19
N
N
N
N
Br
D
O
O
N
N
20
8

C. S. Donald et al. / Tetrahedron Letters 55 (2014) 3305–3307
3307
case, the triethylsilane method can be considered as a viable alter-
Acknowledgements
native. Another observation of the D8-IPA method was that the
reaction worked best when free NH and OH groups were protected.
Transesterification is also something to be aware of when using
ester-containing substrates, again neither of these issues are a con-
cern for the silane method. The versatility of the D8-IPA method is
such that examples of electron-rich and electron-deficient hetero-
cycles are successful substrates, therefore making this a particu-
larly attractive approach for chemists within the pharmaceutical
industry wishing to further explore the metabolic liabilities of their
compounds. To demonstrate the wide range of tolerability of this
chemistry we performed the reaction on two marketed drugs, Clo-
mipramine (11) and Tricor (12), both of which underwent deuter-
ation in good yield and with high D incorporation.
We thank Barry Hayter for discussions and the Alderley Park
iPASS group for purification and analytical support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.04.
025. These data include MOL files and InChiKeys of the most
important compounds described in this article.
References and notes
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In summary, we have described a versatile method for introduc-
ing deuterium into a range of heterocyclic compounds by a deute-
rodehalogenation method. We believe that this approach might be
of interest to those interested in studying isotope effects on the
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Example procedure. Preparation of 3-deuterioquinoline (13)
In a dried microwave reactor vessel were added 3-bromoquin-
oline (0.204 mL, 1.5 mmol), Pd(dba)2 (86 mg, 0.15 mmol), K2CO3
carbonate (415 mg, 3.00 mmol), S-Phos (185 mg, 0.45 mmol), dry
D8-IPA (0.500 mL) and MeCN (1 mL). The mixture was degassed
and placed under a nitrogen atmosphere. The sealed reaction tube
was heated to 100 °C in a microwave (BiotageÒ Initiator) for 2.5 h.
The solvents were removed under reduced pressure, the crude
material pre-loaded on to silica and purified using flash silica chro-
matography (15% EtOAc/heptane). The fractions containing the
desired compound were combined and evaporated to dryness to
afford 3-deuterioquinoline (140 mg, 72%); 1H NMR (400 MHz,
DMSO, 27 °C): d (ppm) 7.62 (ddd, J = 1.20, 6.89, 8.11 Hz, 1H), 7.77
(ddd, J = 1.50, 6.87, 8.43 Hz, 1H), 7.99 (dd, J = 1.33, 8.18 Hz, 1H),
8.03 (d, J = 8.41 Hz, 1H), 8.37 (s, 1H), 8.91 (d, J = 1.70 Hz, 1H); 13C
NMR (176 MHz, DMSO, 30 °C) 121.0, 126.4, 127.8, 128.0, 128.8,
129.3, 135.8, 147.7, 150.3; HRMS (EI): M+, found 130.0643,
C9H6DN requires 130.0641.
15. Molina de la Torre, J. A.; Espinet, P.; Albeniz, A. C. Organometallics 2013, 32,
5428–5434.
16. Boyle, R. C.; Mague, J. T.; Fink, M. J. J. Am. Chem. Soc. 2003, 125, 3228–3229.
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