Catalytic selective deuteration of halo(hetero)arenes

Article abstract of DOI:10.1039/c6ob00193a

Deuterium labeled aromatic and heteroaromatic compounds are synthesized in good to excellent yields with >98% deuterium purity via palladium catalyzed deuterodehalogenation reaction using commercially available and inexpensive reagents. Selective deuteration of bromoaniline is also demonstrated without H/D exchange in an amino N-H group.

Full text of DOI:10.1039/c6ob00193a

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DOI: 10.1039/C6OB00193A
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Catalytic Selective Deuteration of Halo(hetero)arenes
Manojkumar Jannia and S. Peruncheralathana*
Deuterium labeled aromatic and heteroaromatic compounds are synthesized in good to excellent yields with >98%
deuterium purity via palladium catalyzed deuterodehalogenation reaction using commercially available and inexpensive
reagents. Selective deuteration of bromoaniline is also demonstrated without H/D exchange in amino N—H group.
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
analogs (CC-122) in in vitro and in vivo efficacy models (Chart
Introduction
1).4 These findings open up
a new window to improve
therapeutic properties of other racemic drugs.4 Hence, the
deuterated drugs are increasingly in high demand in
pharmaceutical industries.2e Therefore, deuteration of organic
compounds especially drugs have a great potential to generate
new drugs with high therapeutic values.
Deuterated compounds are effectively utilized in studying
reaction mechanism (Kinetic Isotopic Effects), catalysts
pathways, for elucidation of biosynthetic pathways, as
analytical standards, and for altering selectivity in total
synthesis.1 Further, these compounds are realized as potential
drug candidates because of their unique ability of altering the
therapeutic profile and metabolic fate of the drug thereby
retaining its biochemical potency and selectivity.2 For example
deuterated analogues of tetrabenazine (SD-809) and lisofylline
(CTP-499) are in clinical trials for treatment of chorea associated
Deuteration of aromatic compounds by traditional methods
such as H/D exchange processes and metal-halogen exchange
process suffer from selectivity, strong basic conditions and less
functional group tolerances.5 Hence, several alternative
methods were developed to overcome those drawbacks.6 For
example: (i) immobilized triazene precursors were used for
selective D-incorporation into arenes;7 (ii) aromatic acids were
transformed into deutero aromatic compounds via copper and
silver mediated decarboxylative deuteration procedures;8 (iii)
,-dideutero alcohols were synthesized from carboxylic acids
by using SmI2 and D2O as deuterium source9 and (iv) palladium
catalyzed ortho-deuteration of arenes bearing weakly
coordinated directing groups was also developed.10 Despite
excellent selectivities and high D-incorporation, each of these
individual protocols has its own limitations owing to multi-step
synthesis of starting materials, use of large excess deuterated
solvents, excess of metal salts, higher catalyst loading & less
heterocyclic substrates. Therefore, developing a simple and
catalytic method for synthesis of deuterated compounds is
always needed.
with Huntingdon’s
disease and diabetic nephropat h y
respectively (Chart 1).3 Very recently, DeWitt al found that
differentiation of anti-inflammatory and antitumorige ni c
properties of deuterium stabilized enantiomers of thalidomide
The cross-coupling between aryl halides and aliphatic
alcohols represents a direct approach to synthesize alkyl aryl
ethers.11 During this process, a reduced arene (Ar−H) is usually
formed as by-product particularly primary and secondary
alcohols are used as nucleophiles. To suppress undesired
reduced product, Buchwald, Beller and other groups
individually developed new protocols by changing phosphin e
ligands and palladium precatalysts.11,12 However, few groups
cleverly demonstrated usefulness of this process for
dehalogenation of arenes especially polychlorinated aromatic
Chart 1. Selected Deuterated Drugs in Clinical Trials
aSchool of Chemical Sciences, National Institute of Science Education and Research
(NISER), Bhimpur-Padanpur (PO), Jatni (via), Khurda – 752050, Odisha, India. Fax:
+91-674-2494004; Tel: +91-674-2494173; E-mail: peru@niser.ac.in
†Electronic Supplementary Information (ESI) available: [Copies of 1H &13
C NMR
Spectra]. See DOI: 10.1039/x0xx00000x
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compounds.13-15 Further, deuterated alcohols are used to precursors such as PdCl2(MeCN)2, PdCl2(PPh3)2 and Pd2(dba)3
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establish mechanistic pathway of hydrodehalogenati o n were screened and found to be less beneDfiOciIa: 1l0.w10h3e9n/Cc6oOmBp00a1r9e3dA
reaction by Helquist,14 Nolan15c and recently Mclndoe.16 To our with Pd(OAc)2. However, in case of bases, K3PO4 gave better
surprise, high demand in deuterated organic compounds, no yield as compared with KOH, Et3N, K2CO3 and Cs2CO3.
attempts has been made to use this process for a general Interestingly, we obtained quantitative yield of 2a when the
synthetic protocol to access deuterated aromatic compou n ds catalyst loading was reduced from 5 mol% to 1 mol% and
from aryl halides.17 Herein we report a first catalytic method for reaction was completed within 16 hours.
selective deuteration of aryl and heteroaryl halides by using 1
mol% of Pd(OAc)2 and 2 mol% of Ad2PnBu and CD3OD as
deuterium source affording deuterated arenes and
heteroarenes good to excellent yields with >98% deuteriu m
incorporation.
The optimized conditions in our hand, we examined a series
of polyaromatic bromides for deuteration reaction. These
bromides
were effectively deuterated
furnishing
the
corresponding deutero polyaromatic compounds 2a-d in
excellent yields (Table 2, 2a-d). Next, we performed the
deuteration of the aryl halides having electron withdrawi n g
group
at para-position.
Thus,
4-cyano
and 4-nitro
Results and Discussion
bromobenzenes gave the corresponding deuterated 4-nitro and
4-cyanobenzenes only in moderated yields (Table 2, 2e-f). On
the other hand, benzoyl substituted phenyl chloride was
smoothly converted to 4-deuterobenzophenone (2g) in
excellent yield. Whereas the alkoxy substituted bromide 1h
gave only 66% of deuterated compound 2h. However, ortho
substituted bromide 1i afforded the corresponding product 2i
in excellent yield (90%). Similarly, the deuteration of sterically
hindered substrate 1-bromo-2,4,6-tritbutylbenzene gave the
corresponding deuterated product 2j in 85% yield. Interestingl y,
6,6’-dibromo-MOM-protected R-BINOL 1k was transforme d
into the corresponding deuterated product 2k in 90% of yield
Recently, we reported the first general and efficient method for
trideuteromethoxylation of aryl/heteroaryl halides with CD3OD
using a commercially available tBuXPhos ligand.18 During this
study, we observed that few ligands gave a mixture of deutero
and trideuteromethoxy aromatic compounds. To accomplish an
exclusive deuterated product, we started the optimizatio n
studies with a set of commercially available ligands L1-L7 for
deuteration of aryl halides (Table 1). Thus, the reaction of 2-
bromonaphthalene (1a) with CD3OD was investigated as a
model system in the presence of 5 mol% Pd(OAc)2 and 5-10
mol% ligands L1-L6 (Table 1). In most of the cases, the reaction (Table 2).
was completed within 12 hours, however yield of the product
Table 2. Catalytic Deuteration of Aryl Halides[a]
2a was ranging from 45 to 72%. Gratifyingly, an experimen t
performed in the presence of cataCXium®A (L7) ligand provided
an improved yield of 94%. On the other hand, with PEPPSI, a
carbene based ligand, gave a lower yield as compared to ligand
L7.19 For further fine tuning of this process, other palladium
Table 1. Ligand Screening for Deuteration of 2-Bromonaphthalenea-e
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Table 3. Catalytic Deuteration of Heteroaryl Bromides[a]
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DOI: 10.1039/C6OB00193A
Scheme 2. Deuteration of 4-Bromopyrazole 3g with CD3OH & CH3OD
As shown in Scheme 1, we propose a mechanism which
involves a palladium catalytic cycle. The first-step is the
Pd(OAc)2 in the presence of strong σ-donating ligand L7,
accelerating the oxidative addition of the catalyst A to form B.
This step is most commonly believed to be the rate determini n g
step. The displacement of the halide (C) by using base (K3PO4),
β-D-elimination of
D and reductive elimination of E to
regenerate the Pd(0) species (A). To validate the proposed
cycle, we performed two separate experiments with CD3OH and
CH3OD respectively (Scheme 2). The first experiment gave
exclusively deuterated product 4g whereas the second
experiment did not give a trace amount of 4g, instead formed
4g' (Scheme 2). These experiments clearly support that the D/H
transfer occurs from the CD3/CH3. However, mechanistic
investigation of deuterodehalogenation of aryl iodide in
presence of CH3OD gave mixture of products which was
proposed by McIndoe et al. Interestingly our methodol o gy
provides a highly selective product depending upon methanol
We next turned our attention towards to the synthesis of
deuterated heterocycles by applying our established synthetic
methodology. Thus, 3- and 5-bromoquinolines were smoothly
converted into the corresponding deuterated quinolines in
good to very good yields (Table 3, 4a-b). This process could also
be successfully applied to 4-bromoisoquinoline yielding 78% of
4c. Further, other heteroaryl bromides like 5-bromo- N-
methylindole and 4-bromo-N-methylcarbazole proved to be
suitable substrates for this process to deliver deuterated
products in 68% & 81% yields respectively (Table 3, 4d-e).
20
(CD3OH vs CH3OD).16,
To see if this methodology is reasonable, we performed an
experiment with Boc protected 4-bromoaniline. We obtained
exclusively 4-deuteroaniline 2l without exchange of acidic
proton (Scheme 3). Hence, we believe that there is no H/D
exchange during reaction and deuterium incorporation occurs
from reductive elimination process.
Interestingly,
bromosubstituted
pyrazoles
3f-h
were
transformed into the corresponding deuterated products 4f-h
in very good to excellent yield (Table 3).
Scheme 3. Selective Deuteration of 4-Bromoaniline 1l with CD3OH
Conclusions
In conclusion, we have described the first general catalytic
method for deuteration of aryl and heteroaryl halides with 1
mol% of Pd(OAc)2/2 mol% of Ad2PnBu. The present protocol is
simple and straight forward providing a variety of deuteriu m
Scheme 1. Mechanism of Deuteration of Aryl and Heteroaryl Halides
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labeled aryl/heteroaryl compounds in good to excellent yields yield and conversion of the reactions were calculated from GC
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DOI: 10.1039/C6OB00193A
using hexadecane as internal standard.
with 98% deuterium purities from readily available reagents .
The potential application of the protocol was also
General Procedure for the Palladium-Catalyzed Deuteration of
Aryl Halides and Heteroaryl Halides with CD3OD
demonstrated by the bromoaniline without H/D exchange in
amino N—H group. Further studies directed towards
understanding the mechanism of this reaction and extendin g
the application of selective incorporation of D moiety in the
existing drugs are underway.
An oven-dried
8 mL reaction vial was charged with
Pd(OAc)2(1-5 mol-%), ligand L7(2-10 mol-%) and K3PO4 (0.75
mmol), respective aryl/heteroaryl halide (0.5 mmol) in CD3OD
(0.25 mL) and toluene (2.0 mL) was stirred at 80 °C for 7-19 h.
The reaction mixture was stirred at 80 °C and was monitored by
TLC or GC/MS analysis. After the starting material had been
completely consumed, the reaction mixture was then cooled to
room temperature and was purified by flash chromatography.
Acknowledgements
This work was supported by the Department of Atomic Energy,
Government of India.
2-Deuteronaphthalene (2a)21: Reaction time: 16 h. Yield: 99%,
as a white colour solid. Melting point: 64 – 66 oC. Rf: 0.40 in
petroleum ether. 1H NMR (400 MHz, CDCl3) δ = 7.89 – 7.87 (m,
4H), 7.52 – 7.49 (m, 3H). 13C NMR (100 MHz, CDCl3) δ = 133.6,
128.0, 127.9, 125.95, 125.8, 125.7 (t, J = 24 Hz). MS (EI, 70eV):
m/z (%) = 129 (100).
Experimental
All reactions were performed by using standard vial technique
with rubber septum. All solids were weighed in air. CD3OD,
CD3OH and CH3OD used as received (without adding any drying
agent) from Acros. Toluene, Cs2CO3, K3PO4, KOH, K2CO3 and Et3N
were purchased from Aldrich, Acros, Merck or Alfa-Aesar and
used as received. Pd(PPh3)4, Pd(CH3CN)2Cl 2 and Pd(OAc)2 were
purchased from Aldrich. Aryl and heteroaryl bromides and
chlorides were purchased from Aldrich, Acros, Afla-Aesar and
Spectrochem. Tri-(o-tolyl)-phosphine, tri-(2-furyl)-phosphi n e,
1,1'-bis(diphenylphosphino)ferrocene,
butyl phosphine, [1,3-bis(2,6-diisopropylphenyl)imidazol- 2-
ylidene](3-chloropyridyl)palladium(II) dichloride (PEPPSI-iPr), 2′-
(dicyclohexylphosphino)-acetophenone ethylene ketal,
ethylene bis-(diphenylphosphine), triphenylphosphine were
purchased from Aldrich. All other reagents were purchased
from common suppliers and used without further purification.
Flash chromatography was performed using Merck Silica gel
(230-400 mesh). Fractions were monitored by thin-layer
chromatography on precoated silica gel 60 F254 plates (Merck
& co.) and were visualized by UV. NMR data were recorded on
Bruker ARX 400 spectrometers. 13C and 1H NMR spectra were
recorded in CDCl3 and were referenced accrording to signals of
deutero solvent. Gas chromatography analysis was performe d
on ThermoFisher ITQ 900 instrument with a FID detector and
HP-5 capillary column (polydimethylsiloxane with 5% phenyl
groups, 30 m, 0.32 mm i.d., 0.25 μm film thickness) using helium
as carrier gas. Gas chromatography-Mass analysis was carried
out on Thermo Fisher ITQ 900 instrument (EI) and TG-SQC
capillary column using helium carrier gas. ESI and APCI HR-MS
measurements were performed on Bruker micro TOF-Q-II mass-
spectrometer.
1-Deuteronaphthalene (2b)21: Reaction time: 16 h. Yield: 98%,
as a colourless solid. Melting point: 71 – 73 oC. Rf: 0.50 in
hexane. 1H-NMR (400 MHz, CDCl3): δ = 7.85 – 7.88 (m, 3H), 7.48
– 7.52 (m, 4H). 13C-NMR (100 MHz, CDCl3): δ = 133.6, 133.5,
128.0, 127.9, 127.7 (t, J = 23 Hz), 125.9, 125.8. MS (EI, 70eV):
m/z (%) = 129 (100).
di-(1-adamantyl )- n-
9-Deuteroanthracene (2c)22: Reaction time: 16 h. Yield: 99%, as
a white colour solid. Melting point: 198 – 201 oC. Rf: 0.32 in
petroleum ether. 1H NMR (400 MHz, CDCl3) δ = 8.44 (s, 1H), 8.03
– 8.01 (m, 4H), 7.49 – 7.47 (m, 4H). 13C NMR (100 MHz, CDCl3) δ
= 131.8, 131.7, 128.3, 128.2, 126.3, 126.00 (t, J = 24 Hz), 125.5
(2C). HR-MS (APCI): Calcd. for C14H9D (M+H): 180.0918, found:
180.0928.
9-Deuterophenanthrene (2d)23: Reaction time: 16 h. Yield: 94%,
o
as a white colour solid. Melting point: 88 – 90 C. Rf: 0.30 in
petroleum ether. IR (KBr): ν (cm-1) = 3050, 2925, 2368, 1638,
1428, 1006, 771, 754. 1H NMR (400 MHz, CDCl3) δ = 8.72 (d, J =
8.2 Hz, 2H), 7.92 (dd, J = 7.8, 1.4 Hz, 2H), 7.76 (s, 1H), 7.70 – 7.60
(m, 4H). 13C NMR (100 MHz, CDCl3) δ = 132.2, 132.1, 130.4,
128.71, 128.66, 126.9, 126.74 (t, J = 24 Hz), 126.70, 122.8. HR-
MS (APCI): Calcd. for C14H9D (M+H): 180.0918, found: 180.0926.
4-Deuterobenzonitrile (2e) 8a: Reaction time: 10.5 h. Yield: 58%,
as a colourless oily liquid. Rf: 0.36 in 10% diethyl ether in
Petroleum ether. 1H NMR (400 MHz, CDCl3) δ = 7.66 – 7.64 (m,
2H), 7.49 (d, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ = 132.6
(t, J = 25 Hz), 132.2, 129.1, 118.9, 112.5. MS (EI, 70eV): m/z (%)
= 104 (100), 77 (20).
Procedure for the Optimization of Palladium-Catal yze d
Deuteration of 2-Bromonaphthalene with CD3OD
4-Deuteronitrobenzene (2f) 24: Reaction time: 18 h. Yield: 64%,
as a brown colour oily liquid. Rf: 0.32 in 5% ethyl acetate in
petroleum ether. IR (as film in CCl4): ν (cm-1) = 2921, 2360, 1657,
1310, 1276, 938. 1H NMR (400 MHz, CDCl3) δ = 8.24 – 8.21 (m,
2H), 7.55 (dd, J = 7.6, 0.8 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ =
148.3, 134.4 (t, J = 25 Hz), 129.3, 123.6.
An oven-dried
8 mL reaction vial was charged with
Pd(OAc)2(5 mol-%), ligand (10 mol%), base (1.5 equiv), 2-
Bromonaphthalene (0.5 mmol), hexadecane (50 mg) and
toluene (1.0 mL). The reaction mixture was stirred at 80 °C for
12 h. The reaction was monitored by TLC or GC/MS analysis. The
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4-Deuterobenzophenone (2g)25: Reaction time: 10.5 h. Yield: 150.3, 148.2, 136.2, 129.6, 129.4, 128.4, 127.9, 126.7, 120.9 (t,
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96%, as a pale yellow oily liquid. Rf: 0.35 in 10% diethyl ether in J = 25 Hz). HR-MS (ESI): Calcd. for C9H6DDONI: 1(0M.1+0H39):/C61O31B.000711934A,
petroleum ether. IR (as film in CCl4): ν (cm-1) = 3060, 2920, 2423,
2264, 1659, 1651, 1599, 1513, 1472, 1447, 1408, 1311, 1277,
1175, 1149, 1108, 1076, 1026. 1H NMR (400 MHz, CDCl3) δ =
7.82 – 7.80 (m, 4H), 7.61 – 7.57 (m, 1H), 7.50 – 7.46 (m, 4H). 13C
NMR (100 MHz, CDCl3) δ = 196.8, 137.7, 132.5, 132.2 (t, J = 25
Hz), 130.2, 128.4, 128.3. HR-MS (APCI): Calcd. for C13H9DO
(M+H): 184.0867, found: 184.0870.
found: 131.0716.
5-Deuteroquinoline (4b)28: Reaction time: 8 h. Yield: 80%, as a
colourless liquid. Rf: 0.24 in 10% ethyl acetate in hexane. 1H
NMR (400 MHz, CDCl3) δ = 8.89 (dd, J = 4.2, 1.8 Hz, 1H), 8.14 –
8.09 (m, 2H), 7.70 (dd, J = 8.4, 7.2 Hz, 1H), 7.52 (dd, J = 6.8, 0.8
Hz, 1H), 7.37 (dd, J = 8.2, 4.0 Hz, 1H). 13C NMR (100 MHz, CDCl3)
δ = 150.4, 148.2, 136.2, 129.6, 129.4, 128.3, 127.5 (t, J = 25 Hz),
4-Benzyloxy-1-deuterobenzene (2h): Reaction time: 8 h. Yield: 126.5, 121.1. HR-MS (ESI): Calcd. for C9H6DN (M+H): 131.0714,
o
found: 131.0725.
66%, as a white colour solid. Melting point: 36 – 38 C. Rf: 0.29
in hexane. IR (KBr): ν (cm-1) = 3035, 2907, 2867, 2373, 1590,
1467, 1377, 1293, 1245, 1170, 1107, 1022. 1H NMR (400 MHz,
CDCl3): δ = 7.48 – 7.46 (m, 2H), 7.44 – 7.40 (m, 2H), 7.37 – 7.33
(m, 3H), 7.03 – 7.00 (m, 2H), 5.09 (s, 2H). 13C NMR (100 MHz,
CDCl3): δ = 158.9, 137.2, 129.5, 128.7, 128.1, 127.6, 120.8 (t, J =
24 Hz), 114.9, 70.0. MS (EI, 70eV): m/z (%) = 185 (25), 91(100).
HR-MS (APCI): Calcd. for C13H11DO (M+): 185.0954, found:
185.0915.
4-Deuteroisoquinoline (4c)29: Reaction time: 17 h. Yield: 78%,
as a brown colour oily liquid. Rf: 0.28 in 20% ethyl acetate in
petroleum ether. IR (as film in CCl4): ν (cm-1) = 2926, 2345, 2372,
1626, 1583, 1493, 1381, 1260, 1230, 1162, 941. 1H NMR (400
MHz, CDCl3) δ = 9.24 (s, 1H), 8.51 (s, 1H), 7.96 (d, J = 8.2 Hz, 1H),
7.81 (dd, J = 8.2, 0.8 Hz, 1H), 7.70 – 7.66 (m, 1H), 7.61 – 7.57 (m,
1H). 13C NMR (100 MHz, CDCl3) δ = 152.5, 142.9, 135.8, 130.5,
128.7, 127.7, 127.4, 126.5, 120.3 (t, J = 25 Hz). HR-MS (APCI):
Calcd. for C9H6DN (M+H): 131.0714, found: 131.0732.
6-Benzyloxy-3,4-dimethoxy-1-deuterobenzene (2i): Reaction
time: 8 h. Yield: 90%, as a pale yellow colour solid. Melting
point: 67 – 70 C. Rf: 0.33 in 20% ethyl acetate in hexane. IR
5-Deutero-N-methylindole (4d): Reaction time: 7 h. Yield: 68%,
as a colourless oily liquid. Rf: 0.32 in 5% ethyl acetate in
petroleum ether. IR (as film in CCl4): ν (cm-1) = 3100, 3046, 2943,
2816, 2264, 1870, 1610, 1513, 1471, 1442, 1422, 1382, 1333,
1288, 1243, 1194, 1148, 1107, 1079, 1018. 1H NMR (400 MHz,
CDCl3) δ = 7.69 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.0 Hz,
1H), 7.09 – 7.08 (m, 1H), 6.55 – 6.54 (m, 1H), 3.82 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ = 136.8, 128.9, 128.6, 121.5, 120.9,
119.1 (t, J = 24 Hz), 109.3, 100.9, 32.9. HR-MS (APCI): Calcd. for
C9H8DN (M+H): 133.0871, found: 133.0887.
o
(KBr): ν (cm-1) = 2997, 2961, 2937, 2835, 1595, 1508, 1402,
1376, 1340, 1229, 1159, 1080.1H NMR (400 MHz, CDCl3) δ = 7.34
– 7.28 (m, 2H), 7.02 – 6.96 (m, 4H), 6.88 (s, 1H), 5.00 (s, 2H), 3.90
(s, 3H), 3.89 (s, 3H). 13C NMR (100 MHz, CDCl3) δ = 158.8, 149.2,
148.9, 129.5, 129.47, 120.9, 120.0 (t, J = 25 Hz), 114.9, 111.0
(2C), 69.9, 55.96, 55.90. HR-MS (ESI): Calcd. for C15H15DO3 (M+):
245.1157, found: 245.1166.
2,4,6-Tri-t-butyldeuterobenzene (2j)26: Reaction tme: 18 h.
Yield: 85%, as a colourless solid. Melting point: 55 – 58 oC. Rf:
0.71 in n-Pentane. 1H NMR (400 MHz, CDCl3) δ = 7.26 (s, 2H),
1.34 (s, 27H). 13C NMR (100 MHz, CDCl3) δ = 150.1, 150.0, 119.6,
35.1, 31.7. MS (EI, 70eV): m/z (%) = 247 (25), 232 (100), 204
(20), 176 (5), 57 (15).
3-Deutero-9-methyl-9H-carbazole (4e): Reaction time: 16 h.
o
Yield: 81%, as a white colour solid. Melting point: 80 – 83 C. Rf:
0.41 in 3% ethyl acetate in hexane. IR (KBr): ν (cm-1) = 3049,
2888, 2823, 2352, 2320, 2267, 1623, 1596, 1476, 1457, 1423,
1350, 1331, 1285, 1246, 1142. 1H NMR (400 MHz, CDCl3) δ =
6,6'-Dibromo-2,2' -bis
(methoxymethoxy)-1,1' -binaphthale ne 8.15 – 8.13 (m, 2H), 7.54 – 7.50 (m, 2H), 7.43 (d, J = 8.0 Hz, 2H),
(2k): Reaction time: 19 h. Yield: 94%, as a white colour solid. 7.30 – 7.28 (m, 1H), 3.86 (s, 3H). 13C NMR (100 MHz, CDCl3) δ =
Melting point: 93 – 96 oC. Rf: 0.27 in 20% diethyl ether in 141.1, 125.8, 125.7, 122.9, 120.4, 120.3, 118.9, 118.7 (t, J = 24
petroleum ether. IR (KBr): ν (cm-1) = 3055, 3026, 2998, 2952, Hz), 108.5, 29.1. HR-MS (ESI): Calcd. for C13H10DN (M)+:
182.0949, found: 182.0923.
2901, 2846, 2824, 1620, 1586, 1499, 1463, 1347, 1298, 1241,
1196, 1147, 1094, 1075, 1039, 1026. 1H NMR (400 MHz, CDCl3)
δ = 7.96 (d, J = 8.8 Hz, 2H), 7.88 (s, 2H), 7.59 (d, J = 8.8 Hz, 2H),
7.24 (d, J = 8.8 Hz, 2H), 7.18 (dd, J = 8.4, 0.4 Hz, 2H), 5.09 (d, J=
6.8 Hz, 2H), 4.99 (dd, J = 6.8, 0.4 Hz, 2H), 3.158 (s, 3H), 3.156 (s,
3H). 13C NMR (100 MHz, CDCl3) δ = 152.8, 134.2, 130.0, 129.5,
127.9, 126.3, 125.7, 123.9 (t, J = 23 Hz) 121.4, 117.4, 95.3, 55.9.
HR-MS (ESI): Calcd. for C24H20D2O4 (M+): 376.1638, found:
376.1640.
4-Deutero-1,3,5-triphenyl-1H-pyrazole (4f): Reaction time:
10.5 h. Yield: 92%, as a white colour solid. Melting point: 132 –
o
136 C. Rf: 0.38 in 10% diethyl ether in Petroleum ether. IR (KBr):
ν (cm-1) = 3061, 2352, 2332, 1596, 1498, 1479, 1455, 1366,
1358, 1311, 1178, 1159, 1001. 1H NMR (400 MHz, CDCl3) δ =
7.96 – 7.93 (m, 2H), 7.47 – 7.43 (m, 2H), 7.41– 7.28 (m, 11H). 13C
NMR (100 MHz, CDCl3) δ = 152.0, 144.5, 140.2, 133.1, 130.7,
129.0, 128.9, 128.8, 128.6, 128.4, 128.1, 127.6, 125.9, 125.4,
3-Deuteroquinoline (4a)27: Reaction time: 7 h. Yield: 70%, as a 105.1 (t, J = 25 Hz). HR-MS (ESI): Calcd. for C21H15DN2 (M+H):
298.1449, found: 298.1440.
brown colour oily liquid. Rf: 0.26 in 20% diethyl ether in
petroleum ether. 1H NMR (400 MHz, CDCl3) δ = 8.91 (s, 1H), 8.15
(s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.74 –
7.69 (m, 1H), 7.56 – 7.52 (m, 1H). 13C NMR (100 MHz, CDCl3) δ =
4-Deutero-3,5-dimethyl-1-phenyl-1H-pyrazole (4g): Reaction
time: 8 h. Yield: 85%, as a pale yellow liquid. Rf: 0.35 in 10% ethyl
acetate in hexane. IR (as film in CCl4): ν (cm-1) = 3067, 2926,
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Journal Name
2362, 1598, 1542, 1504, 1458, 1415, 1381, 1364, 1140, 1072, 7.28 (d, J = 8.4 Hz, 2H), 1.52 (s, 9H). HR-MS (ESVI)i:ewCAratilccled.Onflioner
+
1047, 1024, 911. 1H NMR (400 MHz, CDCl3) δ = 7.45 – 7.40 (m,
4H), 7.36 – 7.30 (m, 1H), 2.30 (s, 3H), 2.29 (s, 3H). 13C NMR (100
MHz, CDCl3) δ = 148.9, 139.9, 139.3, 129.0, 127.3, 124.8, 106.7
(t, J = 26 Hz), 13.5, 12.4. HR-MS (APCI): Calcd. for C11H11DN2
(M+H): 174.1136, found: 174.1132.
DOI: 10.1039/C6OB00193A
C11H14DNO2 (M) : 194.1160, found: 194.1134.
Notes and references
1
a) E. V. Anslyn and D. A. Dougherty, in Modern Physical
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1-(4-Deuterophenyl)-3,5-dimethyl-1H-pyrazole (4h): Reaction
time: 10.5 h. Yield: 91%, as a pale yellow liquid. Rf: 0.40 in 10%
ethyl acetate in petroleum ether. IR (as film in CCl4): ν (cm-1) =
2924, 2367, 1595, 1556, 1500, 1415, 1382, 1366, 1133, 1104,
1025, 977. 1H NMR (400 MHz, CDCl3) δ = 7.46 – 7.41 (m, 4H),
6.00 (s, 1H), 2.30 (s, 3H), 2.30 (s, 3H). 13C NMR (100 MHz, CDCl3)
δ = 149.0, 139.9, 139.5, 128.9, 127.0 (t, J = 25 Hz), 124.9, 107.0,
13.6, 12.5. HR-MS (APCI): Calcd. for C11H11DN2 (M+H): 174.1136,
found: 174.1154.
2
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Procedure for the Palladium-Catalyzed Deuteration of 4-
Bromopyrazole/4-Bromoaniline derivatives with CD3OH or
CH3OD
An oven-dried 8 mL reaction vial was charged with Pd(OAc)2 (5
mol-%), L7 (10 mol-%) and K3PO4/KOt Bu (1.5 equiv), bromo
derivative (0.5 mmol) in CD3OH/CH3OD (0.5 mL) in toluene (0.5
mL). The reaction mixture was stirred at 80 °C for 3-12 h. The
reaction mixture was monitored by TLC or GC/MS analysis. After
the starting material had been completely consumed, the
reaction mixture was then cooled to room temperature and was
purified by flash chromatography.
3
4
A. Katsnelson, Nature Med., 2013, 19, 656.
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4-Deutero-3,5-dimethyl-1-phenyl-1H-pyrazole (4g): Reaction
time: 12 h. Yield: 98%, as a pale yellow liquid. Rf: 0.35 in 10%
ethyl acetate in hexane. IR (as film in CCl4): ν (cm-1) = 3067, 2926,
2362, 1598, 1542, 1504, 1458, 1415, 1381, 1364, 1140, 1072,
1047, 1024, 911. 1H NMR (400 MHz, CDCl3) δ = 7.45 – 7.40 (m,
4H), 7.36 – 7.30 (m, 1H), 2.30 (s, 3H), 2.29 (s, 3H). 13C NMR (100
MHz, CDCl3) δ = 148.9, 139.9, 139.3, 129.0, 127.3, 124.8, 106.7
(t, J = 26 Hz), 13.5, 12.4. HR-MS (APCI): Calcd. for C11H11DN2
(M+H): 174.1136, found: 174.1132.
6
Recent examples: a) E. Khaskin and D. Milstein, ACS Catal.,
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3,5-Dimethyl-1-phenyl-1H-pyrazole (4g')30: Reaction time: 3-12
h. Yield: 98%, as a pale yellow liquid. Rf: 0.30 in 10% ethyl
acetate in hexane. 1H NMR (400 MHz, CDCl3) δ = 7.45 – 7.41 (m,
4H), 7.36 – 7.31 (m, 1H), 5.99 (s, 1H), 2.30 (s, 6H). 13C NMR (100
MHz, CDCl3) δ = 148.99, 139.97, 139.46, 129.05, 127.30, 124.82,
106.98, 13.56, 12.42. HR-MS (ESI): Calcd. for C11H12N2(M+ H):
173.1073, found: 173.1085.
7
8
S. Vanderheiden, B. Bulat, T. Zevaco, N. Jung and S. Bräse,
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9
o
84%, as a white colour solid. Melting point: 124 – 126 C. Rf: 0.40
in 10% ethyl acetate in hexane. IR (KBr): ν (cm-1) = 3305, 2984,
2372, 1689, 1522, 1407, 1312, 1297, 1243, 1155, 1060. 1H NMR
(400 MHz, CDCl3) δ = 7.36 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.4 Hz,
2H), 6.51 (s, 1H), 1.52 (s, 9H). 13C NMR (100 MHz, CDCl3) δ =
152.9, 138.5, 128.9, 122.9(t, J = 25 Hz), 118.7, 80.6, 28.5. 1H
NMR (400 MHz, CDCl3) (D2O shake) δ = 7.35 (d, J = 8.4 Hz, 2H),
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e) S. Gowrisankar, H. Neumann and M. Beller, ChemCatChe m,
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