Trideuteriomethoxylation of aryl and heteroaryl halides

Article abstract of DOI:10.1002/ejoc.201200753

Direct access to trideuteriomethoxylated aromatic and heteroaromatic compounds has been developed. Various aryl and heteroaryl halides underwent d₃-methoxylation under mild reaction conditions by using a catalyst system composed of the commercially available monodentate phosphane ligand tBuXPhos and Pd(OAc)₂. Inexpensive CD₃OD served as an efficient trideuteriomethoxylating agent. The simple and straightforward synthesis of labeled methyl (hetero)aryl ethers via palladium-catalyzed C-O cross-coupling reaction of (hetero)aryl halides with CD₃OD was developed. The tBuXPhos ligand is used for the first time in ether synthesis. Copyright

Full text of DOI:10.1002/ejoc.201200753

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201200753
Trideuteriomethoxylation of Aryl and Heteroaryl Halides
Pragyanditi Dash,[a] Manojkumar Janni,[a] and S. Peruncheralathan*[a]
Dedicated to Professor T. K. Chandrashekar[‡]
Keywords: Palladium / Cross-coupling / Ethers / Deuterium / Homogeneous catalysis
Direct access to trideuteriomethoxylated aromatic and het-
eroaromatic compounds has been developed. Various aryl
and heteroaryl halides underwent d3-methoxylation under
mild reaction conditions by using a catalyst system composed
of the commercially available monodentate phosphane li-
gand tBuXPhos and Pd(OAc)2. Inexpensive CD3OD served
as an efficient trideuteriomethoxylating agent.
Introduction
Selective incorporation of deuterium in place of hydro-
gen is a powerful tool in medicinal chemistry.[1] Although
they have received less attention, deuterium-containing
drugs have the unique ability of altering the therapeutic
profile and metabolic fate of the drug thereby retaining its
biochemical potency and selectivity.[2] These drugs are in-
creasingly in high demand in pharmaceutical industries[3]
and are essential for clinical studies. For example, deuter-
ated analogues[4] of paroxetine (CTP-347; antidepressant
drug), [D9]- and [D22]etacrynic acid n-hexylamides (diuretic
drug), venlafaxine (SD-254; serotonin-norepinephrine re-
uptake inhibitor), and Atazanavit (CTP-518; HIV protease
inhibitor) have entered in clinical trials, and the results are
promising.[1a,5] Especially, [D3]methoxy incorporated aryl
compounds are very important motifs in various drugs such
as venlafaxine (SD-254), [D6]-ψ-DOM, [D3]Glyburide
([D3]methoxy), 2-(2-Boc-aminoethoxy)[D3]anisole, and
[D3]Urapidil ([D3]methoxy) shown in Figure 1.[6] Therefore,
synthesis of deuterium-labeled compounds has a great po-
tential to generate new drugs.
Figure 1. Selected C–OCD3 bond containing structural motifs.
functional group tolerance.[8] Therefore, transition-metal-
catalyzed cross-coupling methodologies[9] have become an
efficient and versatile tool for the synthesis of alkyl (hetero)-
aryl ethers. Especially, Pd-catalyzed C–O cross-coupling re-
actions are well developed with phenol and primary, sec-
ondary, and tertiary alcohols under comparably mild condi-
tions.[10] During the last decade, Buchwald,[11] Hartwig,[12]
Singer,[13] and Beller[14] have designed a series of phosphane
ligands that facilitate the Pd-catalyzed C–O cross-coupling
of various (hetero)aryl halides with different types of
alcohols. Each of these individual protocols has its own
limitations including the cumbersome synthesis of ligands,
low selectivity of alcohols, low substrate scope, and un-
wanted formation of reduced arenes. In addition, simple
methanol or its deuterated analogue was very difficult to
couple with (hetero)aryl halides because of competing β-
hydride elimination.
In general, alkyl (hetero)aryl ethers are synthesized
through the classical method of O-alkylation by using
strong alkylating agents (MeI, Me2SO4) that are often car-
cinogenic.[7] Further, traditional Williamson ether synthesis
carried out at higher temperatures (300 °C) leads to low
[a] School of Chemical Sciences,
National Institute of Science Education and Research,
Institute of Physics Campus, Bhubaneswar 751001, Odisha,
India
Fax: +91-674-2304070
E-mail: peru@niser.ac.in
Recently, an alternative method for the selective incorpo-
ration of the D3CO group into arenes was reported[15] by
Jung and Bräse using immobilized triazenes as precursors
via deuterio-dediazoniation procedures in the presence of
[D4]methanol and [D1]TFA (Scheme 1). However, this
Homepage: http://www.niser.ac.in/~peru/
[‡] For his contribution to core-modified expanded porphyrin
chemistry
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200753.
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P. Dash, M. Janni, S. Peruncheralathan
SHORT COMMUNICATION
method requires a multistep synthesis of the starting mate- the Supporting Information); however, bulky monodentate
rials, scaling-up of the reaction, and also requires the use ligand L5 turned out to be the best for this model reaction.
of an excess amount of deuterated methanol. Very recently, These results once again emphasized the importance of
Beller et al. also synthesized[16] a few deuterated anisoles bulky diaryl phosphane ligands for cross-coupling reactions
via the Pd-catalyzed C–O cross-coupling reaction of acti- of aryl halides with alcohols.
vated aryl halides with deuterated methanol by using a non-
commercial adamantyl-based phosphane ligand.[17] How-
Table 1. Screening of ligands for trideuteriomethoxylation.[a]
ever, commercially available ligands are more attractive
than the synthesis of new ligands for this process. Overall,
no general methodology is available for the simple cross-
coupling reaction of (hetero)aryl halides with CD3OD in
the presence of air-stable, readily available ligands. Herein,
we report the Pd-catalyzed cross-coupling of (hetero)aryl
halides with inexpensive CD3OD by using the commercially
available tBuXPhos ligand[18] to afford the corresponding
[D3]methoxylated compounds in up to 90% yield.
Scheme 1. Synthetic approaches for the preparation of deuterated
methyl aryl ethers.
[a] Reaction conditions: 1-bromonaphthalene (0.5 mmol), CD3OD
(0.5 mL), Pd(OAc)2 (5 mol-%), L1–L6 (10 mol-%), Cs2CO3
(1.5 mmol), toluene (0.5 mL), 80 °C, 8 h. Conversions are given in
Results and Discussion
parentheses. GC yields are given. [b] Without any co-solvent.
Over the last 10 years, commercially available Buchwald
diaryl phosphane ligands have drawn interest in the devel-
To our delight, the use of tBuXPhos gave rise to an 85%
opment of palladium-catalyzed cross-coupling reactions yield of desired 1-[D3]methoxynaphthalene as a benchmark
thereby meeting both academic and industrial needs.[19] reaction. For further fine-tuning of this process, other palla-
Therefore, we decided to investigate bulky ligands for the dium precursors such as PdCl2(MeCN)2, PdCl2(PPh3)2, and
Pd-catalyzed C–O cross-coupling reaction of aryl halides Pd2(dba)3 were screened and found to be less beneficial
with CD3OD – a difficult coupling partner. Initially, the when compared with Pd(OAc)2.[20] The coupling process
reaction of 1-bromonaphthalene (1a) with CD3OD was in- was further optimized by varying bases such as KOH, Et3N,
vestigated as a model system in the presence of 5 mol-% K2CO3, and Cs2CO3, and the best results were obtained by
Pd(OAc)2 and ligands L1–L6 (Table 1). In the absence of using Cs2CO3.[20] Interestingly, we observed that preacti-
ligands L1–L6 only the well-known side product dehaloge- vation of Pd(OAc)2 (3 mol-%) and L5 (6 mol-%) in toluene
nated naphthalene 3a was observed. However, the use of at 80 °C followed by subsequent addition of 1-bromonaph-
the bulky mono-trippyPhos (L1) ligand under similar con- thalene in CD3OD gave an improved yield (90%, GC yield).
ditions gave a negligible amount of desired 1-[D3]methoxy-
With the optimized conditions in our hand, we examined
naphthalene (2a) along with a considerable amount of re- a series of polyaromatic bromides. These bromides were ef-
duced product 3a (Table 1, entry 1). The results were even fectively coupled with CD3OD to furnish the corresponding
more disappointing with the commercially available ferro- [D3]methoxy polyaromatic compounds in excellent yields
cene-based dppf (L2) ligand. On the other hand, experi- (Table 2, 2a–d). Next, we performed the coupling of o-
ments performed in the presence of DavePhos (L3) pro- bromotoluene and the corresponding chloride with CD3OD
vided a better yield than that obtained with ligands L1 and and both of them were smoothly converted into the corre-
L2 but gave only 11% yield of 2a. On the basis of this re- sponding ether in moderate yield (65 and 60% respectively;
sult, we started screening the known bisnaphthyl ligand Table 2, 2e). Similarly, the sterically hindered substrate 1-
TrixiePhos (L4), which afforded expected product 2a in bromo-2-isopropylbenzene gave the corresponding ether in
75% yield. Unfortunately, the use of this ligand in the ab- 75% yield (Table 2, 2f). On the other hand, substrates pos-
sence of a co-solvent resulted in a decrease in the yield by sessing an electron-withdrawing group at either the meta or
45%. Gratifyingly, when the experiment was performed in para position (CN, OCF3, and COPh) were coupled suc-
the presence of the commercially available tBuXPhos (L5) cessfully with CD3OD to afford the products in moderate
ligand, the yield improved to 83%. To further improve the to very good yields (Table 2, 2h–k). Interestingly, 2,5-di-
yield, we examined different ligands (Table 1, L6; see also bromo-p-xylene was transformed into corresponding ether
2
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Trideuteriomethoxylation of Aryl and Heteroaryl Halides
product 2l in 72% yield. The reaction takes place via di- Table 3. Pd-catalyzed coupling reactions of heteroaryl halides with
deuterated methanol.[a]
[D3]methoxylation in [D4]methanol as described in the reac-
tion conditions.
Table 2. Pd-catalyzed coupling reactions of aryl halides with deu-
terated methanol.[a]
[a] Reaction conditions: 1-bromonaphthalene (0.5 mmol), CD3OD
(0.5 mL), Pd(OAc)2 (3 mol-%), L5 (6 mol-%), Cs2CO3 (1.5 mmol),
toluene (0.5 mL), 80 °C, 8 h. Isolated yields are given. Complete
consumption of starting material was monitored by TLC and GC–
MS.
parable to those of the [D3]methoxylated products. The
present protocol adds to the known catalytic systems devel-
oped by Buchwald[11] and Beller[14] for the synthesis of alkyl
[a] Reaction conditions: 1-bromonaphthalene (0.5 mmol), CD3OD
(hetero)aryl ethers, and hence, it has immense applications
(0.5 mL), Pd(OAc)2 (3 mol-%), L5 (6 mol-%), Cs2CO3 (1.5 mmol),
in organic synthesis.
toluene (0.5 mL), 80 °C, 8 h. Isolated yields are given. Complete
consumption of the starting material was monitored by TLC and
Table 4. Pd-catalyzed coupling reactions of (hetero)aryl halides
GC–MS. [b] Pd(OAc)2 (6 mol-%) and L5 (12 mol-%) were used.
with methanol.[a]
We next turned our attention towards the synthesis of
[D3]methoxylated heterocycles by applying our established
synthetic methodology. Unfortunately, this coupling reac-
tion was not explored in substrates such as activated and
non-activated quinoline, isoquinoline, pyrimidine, and in-
dole. Thus, 2-chloroquinoline was rapidly coupled with
CD3OD to afford 2-[D3]methoxyquinoline in very good
yield (82%; Table 3, 5a). In addition, non-activated sub-
strates like 3- and 5-bromoquinolines were smoothly con-
verted into the corresponding coupled products in excellent
yields (Table 3, 5b and 5c). This process could also be suc-
cessfully applied to the more challenging substrate 4-
bromoisoquinoline to give 5d in 87% yield. Further, other
heteroaryl halides like 2-chloro-3-cyanopyridine and 2-
bromopyrimidine proved to be suitable substrates for this
process and delivered the products in moderate yields
[a] Reaction conditions: 1-bromonaphthalene (0.5 mmol), CD3OD
(0.5 mL), Pd(OAc)2 (3 mol-%), L5 (6 mol-%), Cs2CO3 (1.5 mmol),
toluene (0.5 mL), 80 °C, 8 h. Isolated yields are given. Complete
(Table 3, 5e and 5f). Unfortunately, 5-bromo-N-tosylindole
gave only detosylated indole, and desired product 5g was
not detected in the reaction mixture.[21]
consumption of the starting material was monitored by TLC and
GC–MS. [b] GC yield.
To date, only one general synthetic methodology for the
cross-coupling of aryl halides with methanol has been re-
ported.[16,22] Therefore, our present methodology could also
be effective for the synthesis of methoxylated (hetero)aryl
compounds. As expected, activated and non-activated (het-
ero)aryl bromides and chlorides were also effectively cou-
Conclusions
In summary, we have demonstrated the first general and
pled with methanol to afford the corresponding meth- efficient method for the trideuteriomethoxylation of (het-
oxylated products in moderate to excellent yields (60–90%; ero)aryl halides with CD3OD by using the commercially
Table 4, 2Јa–e, 2Јk, 5Јb, and 5Јe), and the yields were com- available tBuXPhos ligand; the yields are moderate to excel-
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P. Dash, M. Janni, S. Peruncheralathan
SHORT COMMUNICATION
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Experimental Section
General Procedure for Trideuteriomethoxylation: An oven-dried, 8-
mL reaction vial was charged with Pd(OAc)2 (3 mol-%), ligand L5
(6 mol-%), Cs2CO3 (0.75 mmol), and toluene (0.5 mL), and the
mixture was stirred at 80 °C for 5 min. Then, it was cooled and the
aryl halide (0.5 mmol) in [D4]methanol (0.5 mL) was added. The
reaction mixture was stirred at 80 °C and was monitored by TLC
or GC–MS. After the starting material had been completely con-
sumed, the reaction mixture was cooled to room temperature and
purified by flash chromatography.
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Supporting Information (see footnote on the first page of this arti-
cle): Screening of the reaction conditions, general experimental pro-
cedures, characterization data, and NMR spectra of the isolated
products.
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Acknowledgments
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18, 2498–2502.
This work was supported by the National Institute of Science Edu-
cation and Research (NISER), Bhubaneswar. We are grateful to
School of Chemicals Sciences, NISER for providing infrastructure
facilities and analytical services.
[17] 5-(Di-1-adamantylphosphanyl)-1-(1,3,5-triphenyl-1H-pyrazol-4-
yl)-1H-pyrazole was modified from Singer’s Bippyphos ligand.
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[21] Detected by GC–MS.
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Received: June 5, 2012
Published Online: ᭿
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Trideuteriomethoxylation of Aryl and Heteroaryl Halides
C–O Cross Coupling
P. Dash, M. Janni,
S. Peruncheralathan* ........................ 1–5
Trideuteriomethoxylation of Aryl and Het-
eroaryl Halides
Keywords: Palladium / Cross-coupling /
Ethers / Deuterium / Homogeneous cataly-
sis
The simple and straightforward synthesis
of labeled methyl (hetero)aryl ethers via
palladium-catalyzed C–O cross-coupling
reaction of (hetero)aryl halides with
CD3OD was developed. The tBuXPhos li-
gand is used for the first time in ether syn-
thesis.
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