Iridium-Catalyzed α-Methylation of α-Aryl Esters Using Methanol as the C1 Source

Article abstract of DOI:10.1021/acs.orglett.9b01025

IrCl(cod)₂]/dppe-catalyzed α-methylation of aryl esters using methanol as the C1 source was developed. This methylation process is useful in several fields including organic chemistry, biochemistry, and medicinal chemistry. Readily available methanol as methylation reagent was successfully adapted. The reaction processed high atom economy and efficient. By applying the reaction system, the synthesis method of naproxen was provided.

Full text of DOI:10.1021/acs.orglett.9b01025

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Iridium-Catalyzed α‑Methylation of α‑Aryl Esters Using Methanol as
the C1 Source
Yuya Tsukamoto, Satoshi Itoh, Masaki Kobayashi, and Yasushi Obora*
Department of Chemistry and Materials Engineering, Faculty of Chemistry, Materials and Bioengineering, Kansai University, Suita,
Osaka 564-8680, Japan
S
* Supporting Information
ABSTRACT: IrCl(cod)2]/dppe-catalyzed α-methylation of aryl esters using methanol as the C1 source was developed. This
methylation process is useful in several fields including organic chemistry, biochemistry, and medicinal chemistry. Readily
available methanol as methylation reagent was successfully adapted. The reaction processed high atom economy and efficient.
By applying the reaction system, the synthesis method of naproxen was provided.
arbon−carbon bond formation reactions via alkylation
using methanol is challenging to overcome the drawbacks of
the existing methylation process especially in the field of bio-
and medicinal chemistry.
In this paper, we report ester methylation catalyzed by a
[IrCl(cod)]2/dppe system using methanol as the methylating
reagent. The conventional method uses indomethane as the
methylation reagent.20 However, indomethane is a toxic
reagent and produces halogen-based waste. The reaction
developed in this work is atom-economical and environ-
mentally friendly.
We selected methyl phenylacetate (1a) as a model substrate
and examined its reaction with methanol under various
reaction conditions (Table 1). Substrate 1a (1 mmol) and
methanol (2, 3 mL) were reacted in the presence of
[IrCl(cod)]2 (0.05 mmol) as a catalyst, dppe (0.07 mmol)
as a ligand, and t-BuOK (0.35 mmol) as a base at 150 °C for
48 h, giving the desired product 3a in 88% gas-chromatography
(GC) yield and 79% isolated yield (entry 1). Ring methylation
was not observed under these conditions.
Other Ir complex catalysts gave moderate to high yields
(entries 2−4). In addition, although the yield decreased
slightly, using a Rh complex as a catalyst instead of an Ir
complex was also feasible (entry 5). In this reaction, the
phosphine ligand plays an important role to raise catalytic
activity (entry 6). Monophosphine or biphosphine allowed α-
methylation of aryl esters (entries 7−10). Furthermore,
aggregation was observed after the reaction in which dppe
was not added. Next, the base was investigated. A strong base
such as t-BuOK or KOH was suitable for the reaction (entries
1 and 11, respectively), whereas a weak base such as K2CO3 or
C
can transform simple substrates into valuable materials.1
Methylation reactions are important alkylation reactions that
are used in several fields such as organic chemistry,2
biochemistry,3 and medicinal chemistry.4 In particular,
regarding development of drugs,5 it is known that installation
of methyl groups can dramatically improve IC50 values.6 For
example, methylation increased the potency of inhibitors of
P38 mitogen-activated protein kinase by 208 times compared
with that before methylation.7 In addition, methylation was
useful to increase selectivity and improve half-life.8 Thus,
methylation is important to change the physical properties of
drugs; indeed, methyl groups in pharmaceuticals are known to
induce the “magic methyl effect”.9
Recently, methylation reactions using readily available and
renewable methanol with a transition-metal catalyst have been
extensively investigated for various substrates.10 Donohoe and
co-workers, Andersson and co-workers, and our group have
reported the α-methylation of ketones in the presence of a
rhodium- or iridium-based catalyst.11 Beller and colleagues
investigated the β-methylation of aryl alcohol in the presence
of a ruthenium catalyst,12 and Cai et al.13 reported iridium-
catalyzed methylation of indoles and pyrroles. The catalyst
used for methylation needs to display high activity, so typically
heterogeneous,14 supported,15 or nanoparticle catalysts16 are
used in methylation reactions. These reactions involve C−C
bond formation via hydrogen transfer in one pot. Nevertheless,
the methylation of esters has rarely been reported because of
their low reactivity and the presence of side reactions such as
transesterification. The only example is the α-methylation of
esters with methanol under microwave irradiation in the
presence of [RuCp*Cl2]2 catalyst.17 There have also been few
reports of alkylation of esters using a highly reactive alcohol18
rather than methanol.19 Therefore, the α-methylation of esters
Received: March 22, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01025
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Reaction of Methyl Phenylacetate (1a) with
Methanol
Table 2. Iridium-Catalyzed α-Methylation of Various α-Aryl
Esters with Methanol
a
a
b
entry
catalyst
ligand
dppe
base
yield (%)
c
1
2
3
4
5
6
[IrCl(cod)]2
[Ir(OMe)(cod)]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[RhCl(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
KOH
K2CO3
Cs2CO3
t-BuOK
t-BuOK
t-BuOK
88 [79 ]
dppe
none
dppe
dppe
none
PPh3
dppm
dppb
Xantphos
dppe
dppe
dppe
dppe
dppe
dppe
82
53
36
71
4
60
69
62
28
64
56
58
36
49
32
d
7
8
9
10
11
12
13
e
14
f
15
g
16
a
Reaction conditions: 1a (1 mmol), 2a (3.0 mL), Ir catalyst (0.05
mmol), ligand (0.07 mmol), and base (0.35 mmol) were stirred at
b
c
150 °C for 48 h under Ar. GC yields based on 1a. Isolated yield.
d
e
f
PPh3 (0.14 mmol) was used. t-BuOK (1.0 mmol) was used. t-
BuOK (0.2 mmol) was used. At 120 °C.
g
a
Reaction conditions: 1 (1.0 mmol), 2 (3 mL), [IrCl(cod)]2 (0.05
mmol), dppe (0.07 mmol), and t-BuOK (0.35 mmol) were stirred at
150 °C for 48 h under Ar. t-BuOK (0.70 mmol) was used. Total
yield (3m + 3m′)
b
c
Cs2CO3 gave moderate yields (entries 12 and 13, respectively).
Increasing and decreasing the amount of base resulted in lower
yield (entries 14−15). The control of the amount of base was
crucial to achieve the high yield of the product. Therefore, the
basicity and amount of base present are important for
promoting the reaction. Our investigation indicated that a
high reaction temperature was also necessary (entry 16). The
reaction required high reaction temperature, long reaction, and
the use of excess methanol.
Based on the development of Ir-catalyzed α-methylation
using methanol, we also attempted to synthesize naproxen,
which is a nonsteroidal anti-inflammatory drug (Scheme 1).
Conventionally, naproxen is synthesized via methyl 6-
methoxynaphthalene-2-acetate (4) using iodomethane as a
methylating agent.21 Here, we reacted substrate 4 with
methanol using the [IrCl(cod)]2/dppe catalytic system. The
desired methyl ester (5) was obtained in 75% yield.
Compound 5 was then hydrolyzed to give naproxen.
Subsequently, α-methylation of various aryl esters (1) with
methanol under the optimized conditions was attempted
(Table 2). In this reaction, aryl esters with a phenyl ring
bearing electron-donating methyl (1b−1d) and methoxy
groups (1e) and electron-withdrawing chloro (1f) and
trifluoromethyl (1g) groups smoothly gave the corresponding
methylated products in good yield (3b−3g). In addition, a
methyl group was introduced at ortho-, meta-, and para-
positions on the phenyl ring (3b−3d). Naphthalene
compounds (1h and 1i) and heterocyclic compounds (1j
and 1k) gave corresponding products (3h−3k); however, an
alicyclic compound aryl ester did not give the corresponding
product (3l). It is generally reported that aliphatic compounds
possess lower CH acidity and stability than aromatic
compounds. We assumed that the low acidity and stability of
the alicyclic compound aryl ester were the reasons for its lack
of reaction. Next, diaryl esters were used as substrates in the
methylation reaction. An excess amount of base selectively
gave the dimethylated product (3m). Using this catalytic
system, α-methylation of phenylacetonitrile was realized in
high yield (3n). Reaction of methyl 3-phenylpropanoate with
methanol was carried out and gave a trace amount of the
methylation product under these conditions.
Scheme 1. Synthesis of Naproxen
B
DOI: 10.1021/acs.orglett.9b01025
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
The time course of the reaction was then investigated
(Figure 1). As the reaction time was extended, the yield of
reaction, we used an excess amount of methanol (>70 equiv),
and the hydrogenation from methanol prevailed to the reaction
with water. However, the possibility of the hydrolysis by water
can not be ruled out.
Based on these experiments, a plausible reaction mechanism
was proposed, as shown in Scheme 3. First, the Ir catalyst
Scheme 3. Proposed Reaction Mechanism for Iridium-
Catalyzed α-Methylation of Aryl Esters
Figure 1. Time course of iridium-catalyzed α-methylation of aryl
esters using methanol
methylated product 3a increased and the conversion of methyl
phenylacetate gently rose (see the Supporting Information for
details). In addition, the formation of unsaturated ester 3aa
was also confirmed, although its yield remained low regardless
of the reaction time. These results suggested that the formation
of 3aa was low during the course of the reaction.
abstracts a hydrogen from methanol, which simultaneously
generates Ir−H and the formaldehyde intermediate. Sub-
sequently, the α-hydrogen of the carbonyl group is abstracted
by the base, and an unsaturated ester is produced via an aldol-
type condensation. Finally, the unsaturated bond allows
hydrogenation by Ir−H to proceed, giving the α-methyl
product.
In conclusion, we developed an iridium-catalyzed α-
methylation of aryl esters using methanol as the methylating
agent. Several aryl esters were successfully obtained by this
approach. This system was applied to the fragment synthesis of
naproxen.
In addition, we investigated potential reaction intermediates
(Scheme 2). First, we confirmed that unsaturated aryl ester 3aa
Scheme 2. Intermediates Considered in Iridium-Catalyzed
α-Methylation of Aryl Esters
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01025.
Experimental procedures and compound characteriza-
tion data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: obora@kansai-u.ac.jp.
ORCID
Yasushi Obora: 0000-0003-3702-9969
Notes
was produced using paraformaldehyde instead of methanol
with no catalyst (Scheme 2a). Next, the unsaturated aryl ester
3aa that was observed in the time-course experiment was
reacted in the presence of the Ir catalyst to give α-methyl aryl
ester 3a in 91% (83% in the presence of t-BuOK) (Scheme
2b). Moreover, a deuterium labeling reaction using methanol-
d4 was attempted. This reaction gave the deuterated product
9a in 45% yield (Scheme 2c). These results indicated that
formaldehyde and unsaturated ester 3aa were produced as
reaction intermediates and methanol acted as a hydrogen
source through oxidation and reduction reactions. In this
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
High-resolution mass spectra were performed at Global
Facility Center, Hokkaido University.
■
REFERENCES
■
(1) (a) Corma, A.; Navas, J.; Sabater, M. J. Advances in One-Pot
Synthesis through Borrowing Hydrogen Catalysis. Chem. Rev. 2018,
118, 1410−1459. (b) Nandakumar, A.; Midya, S. P.; Landge, V. G.;
Balaraman, E. Transition-Metal-Catalyzed Hydrogen-Transfer Annu-
C
DOI: 10.1021/acs.orglett.9b01025
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
lations: Access to Heterocyclic Scaffolds. Angew. Chem., Int. Ed. 2015,
54, 11022−11034. (c) Huang, F.; Liu, Z.; Yu, Z. C-Alkylation of
Ketones and Related Compounds by Alcohols: Transition-Metal-
Catalyzed Dehydrogenation. Angew. Chem., Int. Ed. 2016, 55, 862−
875. (d) Chelucci, G. Ruthenium and osmium complexes in C-C
bond-forming reactions by borrowing hydrogen catalysis. Coord.
Chem. Rev. 2017, 331, 1−36. (e) Aitchison, H.; Wingad, R. L.; Wass,
D. F. Homogeneous Ethanol to Butanol Catalysis - Guerbet Renewed.
ACS Catal. 2016, 6, 7125−7132. (f) Hamid, M. H. S. A.; Slatford, P.
A.; Williams, J. M. J. Borrowing Hydrogen in the Activation of
Alcohols. Adv. Synth. Catal. 2007, 349, 1555−1575.
(2) (a) Natte, K.; Neumann, H.; Beller, M.; Jagadeesh, R. V.
Transition-Metal-Catalyzed Utilization of Methanol as a C1 Source in
Organic Synthesis. Angew. Chem., Int. Ed. 2017, 56, 6384−6394.
(b) Yan, G.; Borah, A. J.; Wang, L.; Yang, M. Recent Advances in
Transition Metal-Catalyzed Methylation Reactions. Adv. Synth. Catal.
2015, 357, 1333−1350. (c) Chen, Y. Recent Advances in
Methylation: A Guide for Selecting Methylation Reagents. Chem. -
Eur. J. 2019, 25, 3405−3439. (d) Dai, Q.; Jiang, Y.; Yu, J.; Cheng, J.
Peroxide: A Novel Methylating Reagent. Synthesis 2016, 48, 329−339.
(e) Guo, S.; Wang, Q.; Jiang, Y.; Yu, J.-T. tert-Butyl peroxybenzoate-
Promoted α-Methylation of 1,3-Dicarbonyl Compounds. J. Org.
Chem. 2014, 79, 11285−11289.
J. Discovery of [(2R,5R)-5-{[(5-Fluoropyridin-2-yl)oxy]methyl}-2-
methylpiperidin-1-yl][5-methyl-2-(pyrimidin-2-yl)phenyl]methanone
(MK-6096): A Dual Orexin Receptor Antagonist with Potent Sleep-
Promoting Properties. ChemMedChem 2012, 7, 415−424.
(7) Angell, R.; Aston, N. M.; Bamborough, P.; Buckton, J. B.;
Cockerill, S.; deBoeck, S. J.; Edwards, C. D.; Holmes, D. S.; Jones, K.
L.; Laine, D. I.; Patel, S.; Smee, P. A.; Smith, K. J.; Somers, D. O.;
Walker, A. L. Biphenyl amide p38 kinase inhibitors 3: Improvement of
cellular and in vivo activity. Bioorg. Med. Chem. Lett. 2008, 18, 4428−
4432.
(8) (a) Li, L.; Beaulieu, C.; Carriere, M.-C.; Denis, D.; Greig, G.;
Guay, D.; O’Neill, G.; Zamboni, R.; Wang, Z. Potent and highly
selective DP1 antagonists with 2,3,4,9-tetrahydro-1H-carbazole as
pharmacophore. Bioorg. Med. Chem. Lett. 2010, 20, 7462−7465.
(b) Leonetti, F.; Capaldi, C.; Pisani, L.; Nicolotti, O.; Muncipinto, G.;
Stefanachi, A.; Cellamare, S.; Caccia, C.; Carotti, A. Solid-Phase
Synthesis and Insights into Structure-Activity Relationships of
Safinamide Analogues as Potent and Selective Inhibitors of Type B
Monoamine Oxidase. J. Med. Chem. 2007, 50, 4909−4916.
(c) Gomtsyan, A.; Bayburt, E. K.; Keddy, R.; Turner, S. C.;
Jinkerson, T. K.; Didomenico, S.; Perner, R. J.; Koenig, J. R.; Drizin,
I.; McDonald, H. A.; Surowy, C. S.; Honore, P.; Mikusa, J.; Marsh, K.
C.; Wetter, J. M.; Faltynek, C. R.; Lee, C.-H. α-Methylation at
benzylic fragment of N-aryl-N’-benzyl ureas provides TRPV1
antagonists with better pharmacokinetic properties and higher efficacy
in inflammatory pain model. Bioorg. Med. Chem. Lett. 2007, 17, 3894−
3899. (d) Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.;
Collins, P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.; Malecha, J. W.;
Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.; Yu, S. S.; Anderson, G.
D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.; Koboldt, C. M.;
Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.; Isakson,
P. C. Synthesis and Biological Evaluation of the 1,5-Diarylpyrazole
Class of Cyclooxygenase-2 Inhibitors: Identification of 4-[5-(4-
Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-
benzenesulfonamide (SC-58635, Celecoxib). J. Med. Chem. 1997, 40,
1347−1365.
(3) (a) Luo, M. Chemical and Biochemical Perspectives of Protein
Lysine Methylation. Chem. Rev. 2018, 118, 6656−6705. (b) Cheng,
X.; Blumenthal, R. M. Coordinated Chromatin Control: Structural
and Functional Linkage of DNA and Histone Methylation.
Biochemistry 2010, 49, 2999−3008. (c) Erdmann, A.; Halby, L.;
Fahy, J.; Arimondo, P. B. Targeting DNA Methylation with Small
Molecules: What’s Next? J. Med. Chem. 2015, 58, 2569−2583.
(d) Cock-Rada, A.; Weitzman, J. B. The methylation landscape of
tumour metastasis. Biol. Cell 2013, 105, 73−90. (e) Choy, J. S.; Wei,
S.; Lee, J. Y.; Tan, S.; Chu, S.; Lee, T.-H. DNA Methylation Increases
Nucleosome Compaction and Rigidity. J. Am. Chem. Soc. 2010, 132,
1782−1783. (f) Lachner, M.; O’Carroll, D.; Rea, S.; Mechtler, K.;
Jenuwein, T. Methylation of histone H3 lysine 9 creates a binding site
for HP1 proteins. Nature 2001, 410, 116−120.
̈
(9) Schonherr, H.; Cernak, T. Profound Methyl Effects in Drug
(4) (a) Barreiro, E. J.; Ku
̈
mmerle, A. E.; Fraga, C. A. M. The
Discovery and a Call for New C-H Methylation Reactions. Angew.
Chem., Int. Ed. 2013, 52, 12256−12267.
Methylation Effect in Medicinal Chemistry. Chem. Rev. 2011, 111,
5215−5246. (b) Caro-Diaz, E. J. E.; Urbano, M.; Buzard, D. J.; Jones,
R. M. C-H activation reactions as useful tools for medicinal chemists.
Bioorg. Med. Chem. Lett. 2016, 26, 5378−5383.
(10) (a) Irrgang, T.; Kempe, R. 3d-Metal Catalyzed N- and C-
Alkylation Reactions via Borrowing Hydrogen or Hydrogen
Autotransfer. Chem. Rev. 2019, 119, 2524−2549. (b) Obora, Y. C-
Alkylation by Hydrogen Autotransfer Reactions. Top. Curr. Chem.
2016, 374, 11. (c) Obora, Y. Recent Advances in α-Alkylation
Reactions using Alcohols with Hydrogen Borrowing Methodologies.
ACS Catal. 2014, 4, 3972−3981. (d) Chakrabarti, K.; Maji, M.; Panja,
D.; Paul, B.; Shee, S.; Das, G. K.; Kundu, S. Utilization of MeOH as a
C1 Building Block in Tandem Three-Component Coupling Reaction.
Org. Lett. 2017, 19, 4750−4753. (e) Li, F.; Lu, L.; Liu, P. Acceptorless
Dehydrogenative Coupling of o-Aminobenzamides with the Activa-
tion of Methanol as a C1 Source for the Construction of
Quinazolinones. Org. Lett. 2016, 18, 2580−2583.
(5) (a) Sun, S.; Fu, J. Methyl-containing pharmaceuticals:
Methylation in drug design. Bioorg. Med. Chem. Lett. 2018, 28,
3283−3289. (b) Cernak, T.; Dykstra, K. D.; Tyagarajan, S.; Vachal,
P.; Krska, S. W. The medicinal chemist’s toolbox for late stage
functionalization of drug-like molecules. Chem. Soc. Rev. 2016, 45,
546−576. (c) Leung, C. S.; Leung, S. S. F.; Tirado-Rives, J.;
Jorgensen, W. L. Methyl Effects on Protein-Ligand Binding. J. Med.
Chem. 2012, 55, 4489−4500. (d) Chatterjee, J.; Gilon, C.; Hoffman,
A.; Kessler, H. N-Methylation of Peptides: A New Perspective in
Medicinal Chemistry. Acc. Chem. Res. 2008, 41, 1331−1342.
(6) (a) Kuntz, K. W.; Campbell, J. E.; Keilhack, H.; Pollock, R. M.;
Knutson, S. K.; Porter-Scott, M.; Richon, V. M.; Sneeringer, C. J.;
Wigle, T. J.; Allain, C. J.; Majer, C. R.; Moyer, M. P.; Copeland, R. A.;
Chesworth, R. The Importance of Being Me: Magic Methyls,
Methyltransferase Inhibitors, and the Discovery of Tazemetostat. J.
Med. Chem. 2016, 59, 1556−1564. (b) O’Reilly, M. C.; Scott, S. A.;
Brown, K. A.; Oguin, T. H., III; Thomas, P. G.; Daniels, J. S.;
Morrison, R.; Brown, H. A.; Lindsley, C. W. Development of Dual
PLD1/2 and PLD2 Selective Inhibitors from a Common 1,3,8-
Triazaspiro[4.5]decane Core: Discovery of ML298 and ML299 That
Decrease Invasive Migration in U87-MG Glioblastoma Cells. J. Med.
Chem. 2013, 56, 2695−2699. (c) Coleman, P. J.; Schreier, J. D.; Cox,
C. D.; Breslin, M. J.; Whitman, D. B.; Bogusky, M. J.; McGaughey, G.
B.; Bednar, R. A.; Lemaire, W.; Doran, S. M.; Fox, S. V.; Garson, S. L.;
Gotter, A. L.; Harrell, C. M.; Reiss, D. R.; Cabalu, T. D.; Cui, D.;
Prueksaritanont, T.; Stevens, J.; Tannenbaum, P. L.; Ball, R. G.;
Stellabott, J.; Young, S. D.; Hartman, G. D.; Winrow, C. J.; Renger, J.
(11) (a) Chan, L. K. M.; Poole, D. L.; Shen, D.; Healy, M. P.;
Donohoe, T. J. Rhodium-Catalyzed Ketone Methylation Using
Methanol Under Mild Conditions: Formation of α-Branched
Products. Angew. Chem., Int. Ed. 2014, 53, 761−765. (b) Shen, D.;
Poole, D. L.; Shotton, C. C.; Kornahrens, A. F.; Healy, M. P.;
Donohoe, T. J. Hydrogen-Borrowing and Interrupted-Hydrogen-
Borrowing Reactions of Ketones and Methanol Catalyzed by Iridium.
Angew. Chem., Int. Ed. 2015, 54, 1642−1645. (c) Ogawa, S.; Obora, Y.
Iridium-catalyzed selective α-methylation of ketones with methanol.
Chem. Commun. 2014, 50, 2491−2493. (d) Quan, X.; Kerdphon, S.;
Andersson, P. G. C-C Coupling of Ketones with Methanol Catalyzed
by a N-Heterocyclic Carbene-Phosphine Iridium Complex. Chem. -
Eur. J. 2015, 21, 3576−3579.
(12) (a) Li, Y.; Li, H.; Junge, H.; Beller, M. Selective ruthenium-
catalyzed methylation of 2-arylethanols using methanol as C1
feedstock. Chem. Commun. 2014, 50, 14991−14994. (b) Oikawa,
K.; Itoh, S.; Yano, H.; Kawasaki, H.; Obora, Y. Preparation and use of
D
DOI: 10.1021/acs.orglett.9b01025
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
DMF-stabilized iridium nanoclusters as methylation catalysts using
methanol as the C1 source. Chem. Commun. 2017, 53, 1080−1083.
(13) Chen, S.-J.; Lu, G.-P.; Cai, C. Iridium-catalyzed methylation of
indoles and pyrroles using methanol as feedstock. RSC Adv. 2015, 5,
70329−70332.
(14) Siddiki, S. M. A. H.; Touchy, A. S.; Jamil, M. A. R.; Toyao, T.;
Shimizu, K. C-Methylation of Alcohols, Ketones, and Indoles with
Methanol Using Heterogeneous Platinum Catalysts. ACS Catal. 2018,
8, 3091−3103.
(15) Jiang, L.; Guo, F.; Shi, Z.; Li, Y.; Hou, Z. Syndiotactic
Poly(aminostyrene)-Supported Palladium Catalyst for Ketone Meth-
ylation with Methanol. ChemCatChem 2017, 9, 3827−3832.
(16) Reddy, C. B.; Bharti, R.; Kumar, S.; Das, P. Supported
Palladium Nanoparticle Catalyzed α-Alkylation of Ketones Using
Alcohols as Alkylating Agents. ACS Sustainable Chem. Eng. 2017, 5,
9683−9691.
(17) Dang, T. T.; Seayad, A. M. A Convenient Ruthenium-Catalysed
α-Methylation of Carbonyl Compounds using Methanol. Adv. Synth.
Catal. 2016, 358, 3373−3380.
(18) (a) Iuchi, Y.; Obora, Y.; Ishii, Y. Iridium-Catalyzed α-Alkylation
of Acetates with Primary Alcohols and Diols. J. Am. Chem. Soc. 2010,
132, 2536−2537. (b) Guo, L.; Ma, X.; Fang, H.; Jia, X.; Huang, Z. A
General and Mild Catalytic α-Alkylation of Unactivated Esters Using
Alcohols. Angew. Chem., Int. Ed. 2015, 54, 4023−4027. (c) Deibl, N.;
Kempe, R. General and Mild Cobalt-Catalyzed C-Alkylation of
Unactivated Amides and Esters with Alcohols. J. Am. Chem. Soc. 2016,
138, 10786−10789.
(19) (a) Qian, M.; Liauw, M. A.; Emig, G. Formaldehyde synthesis
from methanol over silver catalysts. Appl. Catal., A 2003, 238, 211−
222. (b) Lin, W.-H.; Chang, H.-F. A study of ethanol dehydrogen-
ation reaction in a palladium membrane reactor. Catal. Today 2004,
97, 181−188.
(20) (a) Shono, T.; Kashimura, S.; Nogusa, H. A Novel
Electrogenerated Base. Alkylation of Methyl Arylacetates at the α-
Methylene Group. J. Org. Chem. 1984, 49, 2043−2045. (b) Natarajan,
A.; Ng, D.; Yang, Z.; Garcia-Garibay, M. A. Parallel Syntheses of (+)-
and (−)-α-Cuparenone by Radical Combination in Crystalline Solids.
Angew. Chem., Int. Ed. 2007, 46, 6485−6487. (c) Puthiyapurayil, P.;
Poojary, B.; Chikkanna, C.; Buridipad, S. K. Synthesis, spectral
characterization and biological evaluation of a novel series of 6-
arylsubstituted-3-[2-(4-substitutedphenyl)propan-2-yl]-7H-[1,2,4]-
triazolo[3,4,-b][1,3,4]thiadiazines. Eur. J. Med. Chem. 2012, 57, 407−
416. (d) Matsumura, Y.; Kakizaki, Y.; Tateno, H.; Kashiwagi, T.;
Yamaji, Y.; Atobe, M. Continuous in situ electrogenaration of a 2-
pyrrolidone anion in a microreactor: application to highly efficient
monoalkylation of methyl phenylacetate. RSC Adv. 2015, 5, 96851−
96854.
(21) Harrison, I. T.; Lewis, B.; Nelson, P.; Rooks, W.; Roszkowski,
A.; Tomolonis, A.; Fried, J. H. Nonsteroidal Antiinflammatory Agents.
I. 6-Substituted 2-Naphthylacetic Acids. J. Med. Chem. 1970, 13, 203−
205.
E
DOI: 10.1021/acs.orglett.9b01025
Org. Lett. XXXX, XXX, XXX−XXX