Iron-Catalyzed Borrowing Hydrogen β- C(sp3)-Methylation of Alcohols

Article abstract of DOI:10.1021/acscatal.9b02461

Herein we report the iron-catalyzed β-C(sp³)-methylation of primary alcohols using methanol as a C1 building block. This borrowing hydrogen approach employs a well-defined bench-stable (cyclopentadienone)iron(0) carbonyl complex as precatalyst (5 mol %) and enables a diverse selection of substituted 2-arylethanols to undergo β-C(sp³)-methylation in good isolated yields (24 examples, 65% average yield).

Full text of DOI:10.1021/acscatal.9b02461

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Letter
pubs.acs.org/acscatalysis
Cite This: ACS Catal. 2019, 9, 8575−8580
Iron-Catalyzed Borrowing Hydrogen β‑C(sp3)‑Methylation of
Alcohols
Kurt Polidano,† Jonathan M. J. Williams,‡ and Louis C. Morrill*,†
†Cardiff Catalysis Institute, School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff, CF10 3AT, U.K.
‡Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, U.K.
S
* Supporting Information
ABSTRACT: Herein we report the iron-catalyzed β-C(sp3)-methyl-
ation of primary alcohols using methanol as a C1 building block. This
borrowing hydrogen approach employs a well-defined bench-stable
(cyclopentadienone)iron(0) carbonyl complex as precatalyst (5 mol %)
and enables a diverse selection of substituted 2-arylethanols to undergo
β-C(sp3)-methylation in good isolated yields (24 examples, 65%
average yield).
KEYWORDS: borrowing hydrogen, iron catalysis, methylation, methanol, homogeneous catalysis
Scheme 1. C(sp3)-Me Motif and BH C(sp3)-Methylation
he incorporation of methyl groups can have a significant
impact upon the pharmacological properties of a
T
molecule.1 Inspection of Njarđarson’s poster entitled “Top
200 Brand Name Drugs by Prescription in 2016” reveals that a
significant proportion contain the C(sp3)−Me motif (Scheme
1A).2 As such, the development of new synthetic methods for
the direct methylation of C(sp3)−H bonds is an important area
of scientific endeavor.3 Methanol is an attractive reagent for
methylation processes.4 It is an abundant, biodegradable liquid
that is less hazardous relative to commonly employed
methylation reagents such as diazomethane, dimethyl sulfate,
and iodomethane.5
The borrowing hydrogen (BH) approach combines a
transfer hydrogenation process with a concurrent reaction on
the in situ generated reactive intermediate.6 Employing
methanol in BH alkylation represents a challenging process,
which is partly due to the increased energy of dehydrogenation
of methanol to form the required transient reactive form-
aldehyde intermediate in relation to benzyl and longer chain n-
alkyl alcohols (ΔH (MeOH) = +84 kJ mol−1, cf. ΔH (EtOH)
= +68 kJ mol−1).7 Nevertheless, the BH approach has been
utilized for the α-C(sp3)-methylation of ketones using
methanol as the alkylating agent, employing both precious
and earth-abundant metal catalysts (Scheme 1B).8 The use of
methanol in the catalytic upgrading of ethanol and propanol to
iso-butanol has been reported at very high temperatures
(typically ≥180 °C).9 However, the general β-C(sp3)-
methylation of functionalized alcohols using methanol remains
underdeveloped.10 In 2014, Beller and co-workers reported a
homogeneous catalytic system for this challenging process,
which required a combination of two distinct ruthenium
complexes, namely, Ru-MACHO and Shvo’s complex, in
addition to pressure release from the reaction vessel to obtain
satisfactory conversion across a modest range of 2-
arylethanols.10a,b Subsequently, others have described the use
Received: June 12, 2019
Revised: July 30, 2019
© XXXX American Chemical Society
8575
DOI: 10.1021/acscatal.9b02461
ACS Catal. 2019, 9, 8575−8580

ACS Catalysis
Letter
of iridium nanoclusters10c,d and Pt/C10e as heterogeneous
catalysts. Importantly, there are no reports to date that employ
a homogeneous or heterogeneous catalyst system based on an
earth-abundant first-row transition metal for this process. As
part of our ongoing interest in the development of
homogeneous hydrogen transfer methods,11 herein we report
the use of a well-defined bench-stable (cyclopentadienone)-
iron(0) carbonyl complex (5 mol %)12 for the operationally
simple and efficient catalytic β-C(sp3)-methylation of various
primary alcohols using methanol as the alkylating agent
(Scheme 1C).
contains a more electron-rich cyclopentadienone framework,
was uniquely effective for the desired transformation, with the
use of alternative iron precatalysts 4−8 resulting in no
observable formation of methylated alcohol 3 (entry 5).17
Employing K2CO3 as base or reducing the quantity of NaOH
to 20 mol % resulted in lower conversion to 3 (entries 6 and
7). Furthermore, altering the reaction concentration (entries 8
and 9), reaction temperature (entries 10 and 11), reducing
reaction time (entry 12), or reducing the catalyst loading
(entry 13), all lowered the efficiency of the β-C(sp3)-
methylation of 1. Employing ethanol as solvent using otherwise
standard reaction conditions resulted in 80% recovered 1 with
no conversion to any identifiable products. However, when
benzyl alcohol was employed as solvent, 38% conversion to the
β-C(sp3)-benzylated product was observed.
To commence our studies, we selected the β-C(sp3)-
methylation of 2-phenylethanol 1 as a model system (Table
1). After extensive optimization,13 it was found that a BH
Table 1. Optimization of Iron-Catalyzed β-C(sp3)-
With optimized reaction conditions in hand (Table 1, entry
1), the full scope of the iron-catalyzed BH β-C(sp3)-
methylation of alcohols was explored (Scheme 2).18 Gratify-
ingly, a diverse selection of substituted 2-arylethanols under-
went efficient β-C(sp3)-methylation, giving the corresponding
methylated products in good to excellent isolated yields
(products 3 and 9−30). Within the aryl unit, 4-Me, 3-Me, and
2-Me substitution was tolerated in addition to extended
aromatic systems (2-Np and 1-Np). However, the attenuated
yields obtained for products 11 and 22 (40% and 23%,
respectively) indicated that the increased steric encumbrance
provided by aryl substitution at the 2-position hindered β-
C(sp3)-methylation. Electron-donating aryl substituents (4-
OMe, 4-OPh and 4-OBn) were tolerated in addition to an
acetal-protected catechol motif (products 15-18). Interest-
ingly, when 2-(4-aminophenyl)ethan-1-ol was subjected to the
optimized reaction conditions, both β-C(sp3)-methylation and
N-methylation occurred,19 providing 19 in 52% isolated yield.
Substrates containing electron-withdrawing (4-CF3 and 3,5-
(CF3)2) aromatic substituents performed particularly well,
giving products 20 and 21 in 80% and 88% isolated yields,
respectively. The high yields obtained using these substrates
may be attributed toward the increased acidity of the in situ
generated aldehyde intermediates. Halogen incorporation
within the substrate was accommodated, with 2-(4-
bromophenyl)ethan-1-ol successfully employed to provide an
additional functional handle within product 23 for subsequent
elaboration via established cross-coupling methods. Further-
more, a variety of 2-heteroarylethanols underwent β-C(sp3)-
methylation, including alcohols containing pyridyl, furan,
thiophene, and unprotected indole motifs (products 26-30).
The β-C(sp3)-methylation procedure performs well upon
scale-up, with the formation of 3 successfully carried out on
a 10 mmol scale in 76% isolated yield (1.02 g of product).
Lengthening the carbon chain proved challenging, with 3-
phenylpropan-1-ol being converted to product 31 in only 9%
NMR yield. The requirement of a β-aryl group for high
conversion was attributed toward the increased acidity of the
corresponding in situ-generated aldehyde intermediate.
Despite examining a range of alternative reaction conditions
4-OH, 4-NO2, 4-I, and 4-vinyl aryl substitution were not
tolerated, producing a complex mixture of unidentified
products in each case (Scheme 2B). 2-Phenoxyethan-1-ol
and decan-1-ol were unreactive, with starting materials
returned.
a
Methylation
b
entry
variation from “standard” conditions
none
no [Fe] precatalyst
no NaOH
no Me3NO
[Fe] precatalysts 4−8 (5 mol %) instead of 2
K2CO3 (2 equiv.) instead of NaOH
NaOH (20 mol %)
[1] = 0.25 M
[1] = 1 M
yield (%)
1
2
3
4
5
6
7
8
85 (75)
<2
<2
81
<2
75
54
57
69
64
9
10
11
12
120 °C
140 °C
6 h
79
70
62
c
13
[Fe] precatalyst 2 (2 mol %)
a
Reactions performed using 1 (0.5 mmol) and reagent grade MeOH.
b
[1] = 0.5 M. As determined by 1H NMR analysis of the crude
reaction mixture with 1,3,5-trimethylbenzene as the internal standard.
c
Isolated yield given in parentheses. Me3NO (4 mol %).
system composed of (cyclopentadienone)iron(0) carbonyl
complex 2 (5 mol %),14 Me3NO (10 mol %), and NaOH (2
equiv.) in MeOH ([1] = 0.5 M) at 130 °C for 24 h, enabled
the efficient β-C(sp3)-methylation of 1, giving 3 in 85% NMR
yield and 75% isolated yield (entry 1). No alkylation occurred
in the absence of iron precatalyst 2 or NaOH (entries 2 and 3).
A small decrease in conversion is observed in the absence of
Me3NO (entry 4),15 which indicated that NaOH can also
activate the precatalyst (Hieber’s method).16 Interestingly,
from the iron complexes employed in this study, it was found
that (cyclopentadienone)iron carbonyl precatalyst 2, which
Next, we explored the β-C(sp3)-methylation of secondary
alcohols. Guided by our success with 2-arylethanol substrates,
the previously optimized reaction conditions (Table 1, entry 1)
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Letter
§
Scheme 2. Scope of Iron-Catalyzed β-C(sp3)-Methylation
§
Reactions performed using 0.5 mmol of alcohol starting material and synthesis grade MeOH. All yields are isolated yields after chromatographic
a
b
purification. Ten mmol of alcohol starting material. As determined by 1H NMR analysis of the crude reaction mixture with 1,3,5-
trimethylbenzene as the internal standard.
were employed using 1-phenylethan-1-ol as substrate, giving an
encouraging 11% conversion to dimethylated product 32.
Unfortunately, despite reoptimization efforts, this figure
could not be increased, although isolated yields of 28% and
38% were obtained for products 33 and 34, respectively, which
contain electron-withdrawing aryl substitution. The same trend
was observed for β-C(sp3)-monomethylation using 1-arylpro-
pan-1-ol substrates. Pleasingly, 30% isolated yield was obtained
for product 35, whereas double β-C(sp3)-methylation of 2,3-
dihydro-1H-inden-2-ol produced 36 in 42% isolated yield as a
71:29 mixture of separable diastereoisomers. For the majority
of secondary alcohols examined, 1H NMR analysis of the crude
reaction mixtures revealed the presence of α-C(sp3)-methy-
lated ketones. This observation was particularly evident in the
formation of α-C(sp3)-methylated cyclic ketones 37 and 38 in
62% and 53% isolated yields, respectively. As such, the lower
conversions observed for secondary alcohols is likely due to the
inability of the iron−hydrogen complex species to efficiently
reduce the ketone functionality.
The proposed mechanism begins with CO decoordination
of [Fe] precatalyst 2 by Me3NO to form the active iron
complex (Scheme 3).15 However, based upon our observation
that catalysis can proceed in the absence of Me3NO (Table 1,
entry 4), precatalyst activation may also proceed via addition of
hydroxide to a CO ligand followed by loss of CO2 (Hieber’s
method) and subsequent loss of H2 upon reaction with
methanol.16 The active iron complex can then abstract
hydrogen from 2-phenylethanol 1 and methanol to form the
required transient 2-phenylacetaldehyde 39 and formaldehyde
intermediates. A subsequent Aldol reaction generates β-
hydroxy aldehyde 40 that undergoes base-catalyzed dehy-
dration to form enal 41, which may exist in equilibrium with
methyl ether 42. Finally, global reduction of enal 41 by the
iron−hydrogen complex gives β-C(sp3)-methylated product 3
with regeneration of the active iron complex. To obtain
supporting evidence for the proposed reaction mechanism, the
validity of several plausible reaction intermediates was probed
(Scheme 4A). Diol 43, allylic alcohol 44, and methyl ether 45
could be formed via hydrogenation of 40, 41, and 42,
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ACS Catalysis
Letter
alcohols using methanol as a C1 building block via the
borrowing hydrogen approach. This is the first report that
employs a catalyst system based on an earth-abundant first-row
transition metal for this process. A diverse selection of
substituted 2-arylethanols underwent β-C(sp3)-methylation in
good to excellent isolated yields (24 examples, 65% average
yield). Some encouraging preliminary results were also
obtained for the β-C(sp3)-methylation of secondary alcohols,
which will be the subject of further investigation from our
laboratory.
Scheme 3. Proposed Reaction Mechanism
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.9b02461.
■
S
Optimization data, experimental procedures, character-
ization of new compounds, and spectral data (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: MorrillLC@cardiff.ac.uk.
Scheme 4. Mechanistic Experiments
■
ORCID
Louis C. Morrill: 0000-0002-6453-7531
Notes
The authors declare no competing financial interest.
Information about the data that underpins the results
presented in this article, including how to access them, can
be found in the Cardiff University data catalogue at http://doi.
org/10.17035/d.2019.0082983146.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the School of Chemistry, Cardiff
University for generous support, the EPSRC-funded Bath/
Bristol/Cardiff Catalysis Centre for Doctoral Training (K.P.,
EP/L016443/1) and the EPSRC UK National Mass
Spectrometry Facility at Swansea University.
a
1
As determined by H NMR analysis of the crude reaction mixture
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