Cross β-alkylation of primary alcohols catalysed by DMF-stabilized iridium nanoparticles

Article abstract of DOI:10.1039/d1ob00045d

A simple method for the cross β-alkylation of linear alcohols with benzyl alcohols in the presence of DMF-stabilized iridium nanoparticles was developed. The nanoparticles were prepared in one-step and thoroughly characterized. Furthermore, the optimum reaction conditions have a wide substrate scope and excellent product selectivity.

Full text of DOI:10.1039/d1ob00045d

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
COMMUNICATION
Cross β-alkylation of primary alcohols catalysed by
DMF-stabilized iridium nanoparticles†
Masaki Kobayashi,a Hiroki Yamaguchi,a Takeyuki Suzuki b and Yasushi Obora
Cite this: Org. Biomol. Chem., 2021,
19, 1950
a
*
Received 9th January 2021,
Accepted 8th February 2021
DOI: 10.1039/d1ob00045d
rsc.li/obc
A simple method for the cross β-alkylation of linear alcohols with three reports on the cross benzylation reaction between 2-ary-
benzyl alcohols in the presence of DMF-stabilized iridium nano- lethanol and benzyl alcohol via the borrowing hydrogen reac-
particles was developed. The nanoparticles were prepared in one- tion are available (Scheme 1a). Ramón et al.11 first investigated
step and thoroughly characterized. Furthermore, the optimum benzylation using a recyclable iridium-impregnated oxide on
reaction conditions have a wide substrate scope and excellent magnetite as a catalyst, while Johnson et al.12 and Renaud
product selectivity.
et al.13 performed the reaction using ruthenium and iron com-
plexes as catalysts, respectively. However, the β-benzylation of a
linear alcohol starting material and the use of colloidal cata-
lysts have not been reported.
Alcohols are some of the most important organic compounds
in industry and research chemistry,1 and the β-alkylation of
alcohols is an important class of carbon–carbon-bond-forming
reactions.2 Conventionally, β-alkylated alcohols are prepared
by a multi-step process involving the oxidation of alcohols,
alkylation of the generated aldehydes or ketones with a
halogen reagent in the presence of a strong base, and finally
reduction under harsh conditions. Moreover, this approach
generates halogenated waste.3
The borrowing hydrogen approach is a powerful strategy for
the formation of carbon–carbon bonds.4 Recently, transition-
metal-catalyzed C-alkylation with alcohols as the alkyl source
via the borrowing hydrogen approach has been extensively
investigated using various nucleophiles, such as alcohols,5
ketones,6 amines,7 esters,8 and nitriles.9 The advantages of
this system are the use of readily available alcohols and its
environmental benignity, as water is the sole by-product.
Furthermore, another carbon–carbon-bond-forming reaction,
the Guerbet reaction, leads to the dimerization of primary
alcohols via β-alkylation.10 Our group has reported the
iridium-complex-catalyzed conversion of ethanol to butanol10b
and linear alcohol dimerization.10a,c However, cross
β-alkylation coupling reactions between primary alcohols have
been scarcely reported. To the best of our knowledge, only
aDepartment of Chemistry and Materials Engineering, Faculty of Chemistry,
Materials and Bioengineering, Kansai University, Suita, Osaka 564-8680, Japan.
E-mail: obora@ kansai-u.ac.jp; Fax: +81-6-6339-4026; Tel: +81-6-6368-0876
bComprehensive Analysis Center, The Institute of Scientific and Industrial Research
(ISIR), Osaka University, 8-1 Mihogaoka, Ibaraki, Osaka 567-0057, Japan
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1ob00045d
Scheme 1 β-Alkylation of primary alcohols with benzyl alcohol via the
borrowing hydrogen reaction: (a) cross alkylation of 2-arylethanol with
benzyl alcohol, (b) cross alkylation of linear alcohols with benzyl alcohol
(this work).
1950 | Org. Biomol. Chem., 2021, 19, 1950–1954
This journal is © The Royal Society of Chemistry 2021

View Article Online
Organic & Biomolecular Chemistry
Communication
Transition-metal nanoparticles (M-NPs) are highly active at Ir-NPs (0.1 mol%) and KOtBu (0.5 mmol) as the base at 150 °C
low catalyst loadings owing to their large surface areas com- for 24 h under Ar, giving the main product 3a with 4a as the
pared with those of the corresponding bulk metals.14 homoalkylation by-product in 92% total yield and 98 : 2 selecti-
Typically, the synthesis of M-NPs requires a reductant and a vity (entry 1). The use of IrCl3·nH2O as the catalyst resulted in
protectant. However, our group has reported a simple method low yields (entries 2 and 3). Other iridium complexes known to
for the synthesis of DMF-stabilized M-NPs and their use in be good catalysts for hydrogen autotransfer reactions gave the
catalytic reactions.15 In this methodology, DMF is used as a desired products in moderate yields (entries 4–6).
reductant, protectant, and solvent.16 Among the different Furthermore, we investigated whether the reaction proceeds
M-NPs, Ir-NPs show high catalytic activity for β-dimethylation without a catalyst or a base (entries 7 and 8), confirming that
of secondary alcohols with methanol via the borrowing hydro- both are essential for this reaction to proceed. Other weak and
gen system.15e However, this system does not allow catalyst re- strong bases (K2CO3, Cs2CO3, and KOH) gave the desired
cycling. Herein, we report the DMF-method solution synthesis product in lower yields than that achieved using KOtBu
of Ir-NPs, their structural characterization, and their use as a (entries 9–11). The base (0.5 mmol) is sufficient enough for
catalyst in the cross β-alkylation of primary alcohols with the reaction under these conditions. When 1 mmol of benzyl
benzyl alcohol.
alcohol instead of 5 mmol was used, the total yield was
The oxidation state of the Ir-NPs was measured using X-ray similar, but the selectivity was poor (entry 12). The reaction
photoelectron spectroscopy (XPS). The main peaks of Ir-NPs at temperature was demonstrated to be an important factor
60.7 eV of 4f7/2 and 63.8 eV of 4f5/2 were comparable to those (entry 13), and when the slightly polar solvent toluene was
17
of Ir(0) (60.9 eV of 4f7/2 and 63.9 eV of 4f5/2
)
(Fig. S1, S2 and used, the main product was obtained in moderate yield (entry
Table S1†).
14). Furthermore, the cross β-alkylation reaction proceeded
We investigated the Ir-NP-catalyzed cross β-alkylation of with very low catalyst loading, with the desired product being
1-decanol (1a) with benzyl alcohol (2a) as model substrates obtained in 36% yield when 0.001 mol% of Ir-NPs was used as
under different conditions (Table 1). The reaction of 1a the catalyst (entry 15). The reaction proceeded smoothly both
(1 mmol) with 2a (5 mmol) was performed in the presence of in the presence of a small amount of water (entry 16) and
under an air atmosphere (entry 17).
We also explored the substrate scope of the reaction
(Table 2). The o-, m-, and p-methylated benzyl alcohols gave
Table 1 Ir-NP-catalyzed β-alkylation of 1-decanol (1a) with benzyl
alcohol (2a)a
the corresponding desired products in good yields (3b–d). The
methoxy- and tert-butyl-substituted benzyl alcohol derivatives
3e and 3f were obtained in 65% and 74% yields, respectively.
Electron-withdrawing groups (Cl and CF3) led to the formation
of the corresponding alcohols in poor yields (3g and 3h).
Cyclopropanemethanol (2i) and 2-naphthalenemethanol (2j)
as alkyl reagents reacted smoothly. Interestingly, heterocyclic
compounds were obtained in good yields (3k and 3l), and ali-
phatic alcohols with different alkyl chain lengths reacted suc-
cessfully under the optimized conditions (3m–p).
Furthermore, a methoxy-terminated linear alcohol gave the
corresponding alkyl product 3q in 64% yield. However, a
branched alcohol exhibited low reactivity in this reaction (3r).
2-Phenylethanol, the model substrate used in a previous study,
was found to be applicable to this catalyst system (3s). Under
the optimized reaction conditions, γ-phenyl and -cyclohexyl
propanol reacted with benzyl alcohol to give the desired pro-
ducts in good yields (3t and 3u). We also investigated the sub-
strate scope using 1,6-hexanediol (1v). As a result, the dibenzyl
product was obtained in 20% yield.
The recyclability of the DMF-stabilized Ir-NPs in this system
was also investigated. After performing the reaction with
1-butanol 1m and benzyl alcohol 2a, the base was removed by
a cotton filter from the reaction mixture. Next, substrates 1m,
2a, the desired product 3m, and solvent were removed by
vacuum distillation at 110 °C for 1 h under 0.3 mm Hg
(Scheme S1†) then reused. In the first and second cycles,
product 3m was obtained in 77% and 68% yields, respectively
(Fig. S3†). Thus, the Ir-NPs can be reused. A slight increase in
Total yieldb,c [%]
Entry
[Ir]
Base
Selectivity (3a : 4a)d
1
Ir-NPs
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
None
92 (98 : 2) [76]
25 (84 : 16)
35 (92 : 8)
86 (90 : 10)
62 (85 : 15)
63 (87 : 13)
Trace
2
IrCl3·nH2O
IrCl3·nH2O
[Cp*IrCl2]2
[IrCl(cod)]2
[Ir(OMe)(cod)]2
None
Ir-NPs
Ir-NPs
Ir-NPs
Ir-NPs
Ir-NPs
Ir-NPs
Ir-NPs
Ir-NPs
Ir-NPs
Ir-NPs
3e
4
5
6
7
8
n.d.
Trace
9
K2CO3
Cs2CO3
KOH
10
11
12f
13g
14h
15i
16j
17k
33 (91 : 9)
57 (88 : 12)
93 (53 : 47)
49 (86 : 14)
76 (88 : 12)
45 (80 : 20)
88 (89 : 11)
>99 (89 : 11)
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
a Reaction conditions: 1a (1 mmol) was allowed to react with 2a
(5 mmol) in the presence of an Ir catalyst (0.1 mol%) and base
(0.5 mmol) in 1,4-dioxane (1 mL) at 150 °C for 24 h. b GC yield based
on 1a. c Numbers in square brackets show the isolated yields.
d Numbers in parentheses show the selectivity for 3a and 4a. e Ir cata-
lyst (5 mol%) was used. f 1a (1 mmol) and 2a (1 mmol) were used. g At
130 °C. h Toluene was used instead of 1,4-dioxane. i Ir-NPs
(0.001 mol%) for 48 h. j One drop (10.7 mg) of water was added under
standard conditions. k Under an air atmosphere.
This journal is © The Royal Society of Chemistry 2021
Org. Biomol. Chem., 2021, 19, 1950–1954 | 1951

View Article Online
Communication
Organic & Biomolecular Chemistry
Table 2 Ir-NP-catalyzed β-alkylationa
Isolated yieldb (%)
Fig. 1 (a) ADF-STEM image (scale bar = 20 nm) of the Ir-NPs before the
reaction; (b) particle-size distribution of the Ir-NPs before the reaction;
(c) ADF-STEM image (scale bar = 20 nm) of the Ir-NPs after the reaction;
(d) particle size distribution of the Ir-NPs after the reaction.
using benzyl alcohol-d7. A deuterated product was obtained in
74% yield. These results indicate that 1-decanal and benz-
aldehyde are the reaction intermediates in this system and
that the benzyl alcohol acts as the hydrogen source
(Scheme S3†). Based on these results, we propose the catalytic
cycle shown in Scheme 2. Briefly, the transformation begins
with the dehydrogenation of alcohols to aldehydes with the
generation of an Ir-NP-hydride. Then, the aldehydes react
through a base-catalyzed aldol-type condensation to produce
an α,β-unsaturated aldehyde and water. Subsequently, the
double bond and aldehyde group are hydrogenated by the Ir-
NP-hydride.
a Condition: the same as entry 1, Table 1. b Yields of the isolated
product after purification. c 1a (10 mmol) reacted with 2a (50 mmol) in
the presence of Ir-NPs (0.05 mol%) and base (5 mmol) in 1,4-dioxane
(5 mL) at 150 °C for 48 h. d KOH was used instead of KOtBu at 48 h.
e Reaction time, 48 h. f KOtBu (1 mmol) was used.
the size of the nanoparticles resulted in a decrease in the yield
of 3m during the recycling steps.
In conclusion, Ir-NPs catalyze the cross β-alkylation reaction
of linear alcohols with benzyl alcohols. This reaction exhibits
high product selectivity without the use of ligands and a broad
substrate scope. The catalyst shows high catalytic activity and
can be recycled two times.
Annular
dark-field
(ADF)
scanning
transmission
electron microscopy (STEM) and dynamic light scattering
(DLS) analyses were used, which was performed using 1m
(1 mmol) and 2a (5 mmol) in the presence of Ir-NPs
(0.1 mol%) and KOH (0.5 mmol) as the base at 150 °C for 48 h
under Ar. The results of the analyses show that, before the
reaction, the Ir-NPs are mostly 1–5 nm in size (Fig. 1a, b, and
S4a†). After the reaction, the Ir-NP sizes are mostly 10–12 nm
(Fig. 1c, d, and S4b†). The DLS analyses show that the size of
the nanoparticles slightly increased during the course of the
reaction (Fig. S4†).
To investigate the mechanism of the cross β-alkylation of
linear alcohols with benzyl alcohols catalyzed by Ir-NPs, we
carried out monitoring of the reaction intermediates and label-
ing studies. When 1-decanal was allowed to react with benz-
aldehyde under the optimal conditions determined above, the
reaction gave an α,β-unsaturated aldehyde in 22% yield
(Scheme S2†). We attempted a deuterium-labeling experiment Scheme 2 A plausible reaction mechanism.
1952 | Org. Biomol. Chem., 2021, 19, 1950–1954
This journal is © The Royal Society of Chemistry 2021

View Article Online
Organic & Biomolecular Chemistry
Communication
7 (a) C. M. Wong, R. T. McBurney, S. C. Binding,
M. B. Peterson, V. R. Gonçales, J. J. Gooding and
B. A. Messerle, Green Chem., 2017, 19, 3142; (b) S. Huang,
S. Wu, Q. Zhou, H. Cui, X. Hong, Y. Lin and X. Hou,
J. Organomet. Chem., 2018, 868, 14; (c) Y. Ai, P. Liu,
R. Liang, Y. Liu and F. Li, New J. Chem., 2019, 43, 10755.
8 (a) Y. Iuchi, Y. Obora and Y. Ishii, J. Am. Chem. Soc., 2010, 132,
2536; (b) L. Guo, X. Ma, H. Fang, X. Jia and Z. Huang, Angew.
Chem., Int. Ed., 2015, 54, 4023; (c) Y. Tsukamoto, S. Itoh,
M. Kobayashi and Y. Obora, Org. Lett., 2019, 21, 3299.
9 (a) M. Morita, Y. Obora and Y. Ishii, Chem. Commun., 2007,
27, 2850; (b) R. Grigg, C. Lofberg, S. Whitney, V. Sridharan,
A. Keep and A. Derrick, Tetrahedron, 2009, 65, 849;
(c) Y. Iuchi, M. Hyotanishi, B. E. Miller, K. Maeda, Y. Obora
and Y. Ishii, J. Org. Chem., 2010, 75, 1803; (d) T. Sawaguchi
and Y. Obora, Chem. Lett., 2011, 40, 1055;
(e) S. Thiyagarajan and C. Gunanathan, ACS Catal., 2017, 7,
5483.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported partly by JSPS KAKENHI Grant
Number 19K05573. We thank Mr Yosuke Murakami and Mr
Takeshi Ishibashi of the Comprehensive Analysis Center and
Ms. Nao Eguchi of the Center for Scientific Instrument
Renovation and Manufacturing Support, SANKEN (ISIR),
Osaka University, for TEM and ICP-AES analyses.
Notes and references
1 (a) J. Sheehan, A. Aden, K. Paustian, K. Killian, J. Brenner, 10 (a) T. Matsu-Ura, S. Sakaguchi, Y. Obora and Y. Ishii, J. Org.
M. Walsh and R. Nelson, J. Ind. Ecol., 2003, 7, 117;
(b) C. Jin, M. Yao, H. Liu, C. F. Lee and J. Ji, Renewable
Sustainable Energy Rev., 2011, 15, 4080.
Chem., 2006, 71, 8306; (b) K. Koda, T. Matsu-ura, Y. Obora
and Y. Ishii, Chem. Lett., 2009, 38, 838; (c) Y. Obora,
Y. Anno, R. Okamoto, T. Matsu-Ura and Y. Ishii, Angew.
Chem., Int. Ed., 2011, 50, 8618; (d) S. Fu, Z. Shao, Y. Wang
and Q. Liu, J. Am. Chem. Soc., 2017, 139, 11941;
(e) F. Storgårds, P. Mäki-Arvela, N. Kumar, J. Peltonen,
J. Salonen, M. Perula, K. Eränen, V. Russo, D. Y. Murzin
and H. Grénman, Top. Catal., 2018, 61, 1888;
(f) C. N. Neumann, S. J. Rozeveld, M. Yu, A. J. Rieth and
2 (a) R. Shrestha, S. C. M. Dorn and D. J. Weix, J. Am. Chem.
Soc., 2013, 135, 751; (b) M. Biermann, H. Gruß,
W. Hummel and H. Gröger, ChemCatChem, 2016, 8, 895;
(c) K. J. Pellow, R. L. Wingad and D. F. Wass, Catal. Sci.
Technol., 2017, 7, 5128; (d) T. W. Ng, G. Liao, K. K. Lau,
H. Pana and Y. Zhao, Angew. Chem., 2020, 59, 11384;
(e) X. Chen, W. Rao, T. Yang and M. J. Koh, Nat. Commun.,
2020, 11, 5857.
ˇ
M. Dinca, J. Am. Chem. Soc., 2019, 141, 17477.
11 R. Cano, M. Yus and D. J. Ramón, Chem. Commun., 2012,
48, 7628.
3 D. Caine, in Comprehensive Organic Synthesis, ed.
B. M. Trost and I. Fleming, Pergamon, Oxford, 1991, vol. 3, 12 S. Manojveer, S. Salahi, O. F. Wendt and M. T. Johnson,
p. 1. J. Org. Chem., 2018, 83, 10864.
4 (a) M. H. S. A. Hamid, P. A. Slatford and J. M. J. Williams, 13 L. Bettoni, S. Gaillard and J. Renaud, Org. Lett., 2019, 21,
Adv. Synth. Catal., 2007, 349, 1555; (b) G. Guillena, 8404.
D. J. Ramón and M. Yus, Angew. Chem., Int. Ed., 2007, 46, 14 (a) A. Roucoux, J. Schulz and H. Patin, Chem. Rev., 2002,
2358; (c) J. T. Kozlowski and R. J. Davis, ACS Catal., 2013, 3,
1588; (d) Y. Obora, ACS Catal., 2014, 4, 3972;
(e) D. Gabriëls, W. Y. Hernández, B. Sels, P. V. D. Voort and
A. Verberckmoes, Catal. Sci. Technol., 2015, 5, 3876;
(f) F. Huang, Z. Liu and Z. Yu, Angew. Chem., Int. Ed., 2016,
55, 862; (g) A. Corma, J. Navas and M. J. Sabater, Chem.
Rev., 2018, 118, 1410.
102, 3757; (b) J. Dupont and J. D. Scholten, Chem. Soc. Rev.,
2010, 39, 1780; (c) A. Kumar and V. Kumar, Chem. Rev.,
2014, 114, 7044; (d) I. Chakraborty and T. Pradeep, Chem.
Rev., 2017, 117, 8208; (e) T. S. Rodrigues, M. Zhao, T. Yang,
K. D. Gilroy, A. G. M. da Silva, P. H. C. Camargo and Y. Xia,
Chem. – Eur. J., 2018, 24, 16944; (f) L. Liu and A. Corma,
Chem. Rev., 2018, 118, 4981.
5 (a) K. Fujita, C. Asai, T. Yamaguchi, F. Hanasaka and 15 (a) M. Hyotanishi, Y. Isomura, H. Yamamoto, H. Kawasaki
R. Yamaguchi, Org. Lett., 2005, 7, 4017; (b) Y. Li, H. Li,
H. Junge and M. Beller, Chem. Commun., 2014, 50, 14991;
(c) Q. Liu, G. Xu, Z. Wang, X. Liu, X. Wang, L. Dong, X. Mu
and Y. Obora, Chem. Commun., 2011, 47, 5750;
(b) H. Yamamoto, H. Yano, H. Kouchi, Y. Obora,
R. Arakawa and H. Kawasaki, Nanoscale, 2012, 4, 4148;
(c) Y. Isomura, T. Narushima, H. Kawasaki, T. Yonezawa
and Y. Obora, Chem. Commun., 2012, 48, 3784; (d) H. Yano,
Y. Nakajima and Y. Obora, J. Organomet. Chem., 2013, 745,
258; (e) K. Oikawa, S. Itoh, H. Yano, H. Kawasaki and
Y. Obora, Chem. Commun., 2017, 53, 1080; (f) H. Oka,
K. Kitai, T. Suzuki and Y. Obora, RSC Adv., 2017, 7, 22869;
(g) R. Azuma, S. Nakamichi, J. Kimura, H. Yano,
H. Kawasaki, T. Suzuki, R. Kondo, Y. Kanda, K. Shimizu,
K. Kato and Y. Obora, ChemCatChem, 2018, 10, 2378;
and
H.
Liu,
ChemSusChem,
2017,
10,
4748;
(d) M. Kobayashi, S. Itoh, K. Yoshimura, Y. Tsukamoto and
Y. Obora, J. Org. Chem., 2020, 85, 11952.
6 (a) K. Taguchi, H. Nakagawa, T. Hirabayashi, S. Sakaguchi
and Y. Ishii, J. Am. Chem. Soc., 2004, 126, 72; (b) K. Maeda,
Y. Obora, S. Sakaguchi and Y. Ishii, Bull. Chem. Soc. Jpn.,
2008, 81, 689; (c) S. Ogawa and Y. Obora, Chem. Commun.,
2014, 50, 2491; (d) D. Wang, R. T. McBurney, I. Pernik and
B. A. Messerle, Dalton Trans., 2019, 48, 13989.
This journal is © The Royal Society of Chemistry 2021
Org. Biomol. Chem., 2021, 19, 1950–1954 | 1953

View Article Online
Communication
Organic & Biomolecular Chemistry
(h) K. Onishi, K. Oikawa, H. Yano, T. Suzuki and Y. Obora, 16 (a) M. M. Heravi, M. Ghavidel and L. Mohammadkhani,
RSC Adv., 2018, 8, 11324; (i) T. Nagata, T. Inoue, X. Lin,
S. Ishimoto, S. Nakamichi, H. Oka, R. Kondo, T. Suzuki
and Y. Obora, RSC Adv., 2019, 9, 17425; ( j) T. Nagata and
Y. Obora, ACS Omega, 2020, 5, 98; (k) J. Ishida,
RSC Adv., 2018, 8, 27832; (b) Y. Yang, J. Zhang, Y. Wei,
Q. Chen, Z. Cao, H. Li, J. Chen, J. Shi, Z. Xie and L. Zheng,
Nano Res., 2018, 11, 656; (c) M. Cui, C. Wang, D. Yang and
Q. Song, Microchim. Acta, 2018, 185, 1.
M. Nakatsuji, T. Nagata, H. Kawasaki, T. Suzuki and 17 M. Scohy, S. Abbou, V. Martin, B. Gilles, E. Sibert, L. Dubau
Y. Obora, ACS Omega, 2020, 5, 9598.
and F. Maillard, ACS Catal., 2019, 9, 9859.
1954 | Org. Biomol. Chem., 2021, 19, 1950–1954
This journal is © The Royal Society of Chemistry 2021