Ruthenium-NHC Catalyzed α-Alkylation of Methylene Ketones Provides Branched Products through Borrowing Hydrogen Strategy

Article abstract of DOI:10.1021/acscatal.6b01351

The α-alkylation of a broad range of methylene ketones was achieved using a ruthenium(II)-NHC catalyst under borrowing hydrogen conditions. Primary alcohols served as alkylating agents and could be used in a one-to-one stoichiometry with respect to the ketone. The selectivity of the process for methyl over branched ketones enabled a one-pot double alkylation protocol utilizing two different alcohols with a single catalyst. Moreover, this methodology could be applied directly to the one-step synthesis of donepezil, the best-selling drug for the treatment of Alzheimer's disease.

Full text of DOI:10.1021/acscatal.6b01351

Subscriber access provided by University of Sussex Library
Letter
Ruthenium-NHC Catalyzed #-Alkylation of Methylene Ketones
Provides Branched Products through Borrowing Hydrogen Strategy
Christoph Schlepphorst, Biplab Maji, and Frank Glorius
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b01351 • Publication Date (Web): 27 May 2016
Downloaded from http://pubs.acs.org on May 29, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
ACS Catalysis is published by the American Chemical Society. 1155 Sixteenth Street
N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 6
ACS Catalysis
1
2
3
4
5
6
7
8
9
Ruthenium-NHC Catalyzed α-Alkylation of Methylene Ketones
Provides Branched Products through Borrowing Hydrogen Strategy
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Christoph Schlepphorst, Biplab Maji and Frank Glorius*
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstrasse 40, 48149 Münster,
Germany
KEYWORDS borrowing hydrogen, ruthenium, N-heterocyclic carbenes, homogenous catalysis, alkylation
ABSTRACT: The α-alkylation of a broad range of methylene ketones was achieved using a ruthenium(II)-NHC catalyst
under borrowing hydrogen conditions. Primary alcohols served as alkylating agents and could be used in a one-to-one
stoichiometry with respect to the ketone. The selectivity of the process for methyl over branched ketones enabled a one-
pot double alkylation protocol utilizing two different alcohols with a single catalyst. Moreover, this methodology could
directly be applied in the one-step synthesis of donepezil, the best-selling drug for the treatment of Alzheimer’s disease.
The use of the borrowing hydrogen (BH) strategy for the
alkylation of ketone enolates has emerged as a powerful
and green alternative for the construction of C-C bonds.1
The main advantage is the use of readily available and
easy to handle alcohols as alkylating agents. Furthermore,
salt waste is reduced as water is formed as the sole by-
product. A typical BH process involves the transfer of
hydrogen from the alcohol to a suitable transition metal
catalyst to form the corresponding aldehyde in situ, which
then forms a C-C bond with a nucleophilic enolate.
Finally, addition of the ‘borrowed’ hydrogen to the olefin
intermediate delivers the product.
hindered ortho-substituted phenyl and cyclopropyl
ketones. However, large excess of alcohol (5–10
a
equivalents) was required (Eq. 3).5 Similarly, the Zhang
group showed that a catalytic ruthenium-bisphosphine
system could achieve the α-alkylation of methylene
ketones when pyridyl methanols were employed as
alkylating agents (Eq. 4).6
Scheme 1. Strategies for the formation of α-branched
products with primary alcohols via borrowing
hydrogen (BH) methodology
The monoalkylation of methyl-ketones is well-
established,2 however, the use of α-substituted ketones to
form α-branched alkylation products is less developed
and almost exclusively relies on the use of methanol as
the alkylating agent (Scheme 1, Eq. 1),3,4 presumably due
to steric reasons as well as to the high reactivity of in situ
generated formaldehyde.
Donohoe and co-workers advanced this field of
chemistry by employing an iridium catalyst with a bulky
monodentate phosphine ligand, which interrupts the
catalytic BH cycle before hydrogenation of the enone.
Subsequent addition of a pronucleophile allowed for
conjugate addition to the enone to occur and thus gave
rise to various branched products (Eq. 2).3c Very recently,
they also reported an Ir-catalyzed α-alkylation of
ACS Paragon Plus Environment

ACS Catalysis
Table 1. Optimization of the reaction conditions.[a]
Page 2 of 6
1
2
3
4
5
6
7
8
9
No.
NHC
Temperature
Base
Solvent
Ratio[b] of starting material (1a) :
product (3a) : reduced byproducts
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
4
5
5
5
5
5
5
5
5
5
5
-
80 °C
LDA
THF/n-hexane
57:10:33
0:41:59
2
80 °C
LDA
THF/n-hexane
3
4[c]
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
LDA
THF/n-hexane
0:47:53
27:35:38
33:60:7
33:61:6
LDA
THF/n-hexane
5
LDA
t-AmylOH/n-hexane
t-AmylOH/n-hexane
t-AmylOH/n-hexane
t-AmylOH/n-hexane
t-AmylOH/n-hexane
t-AmylOH/n-hexane
t-AmylOH/n-hexane
t-AmylOH/n-hexane
t-AmylOH/n-hexane
6
LiOt-Bu
LiOH
KOt-Bu
Cs2CO3
LiOt-Bu
LiOt-Bu
LiOt-Bu
-
7
100:0:0
78:5:17
8
9
93:7:0
2:96:2 (91%)[e]
10[d]
11[d],[f]
12[d],[g]
13
24:71:5
22:10:68
100:0:0
5
[a] General reaction conditions: [Ru(cod)(2-methylallyl)2] (4 µmol), KOt-Bu (8.4 µmol) and NHC·HX (8 µmol) were stirred at
70 °C in n-hexane (0.4 mL) for 16 h, after which the mixture was added to a solution of 1a (0.2 mmol) and base (0.2 mmol) in
t-AmylOH (0.5 mL). To this reaction mixture was then added BnOH (2a, 0.2 mmol) and the reaction was heated to the indicated
temperature for 24 h. [b] Determined by GC-MS analysis of the crude reaction mixture. [c] 2.0 equivalents of benzyl alcohol were
used. [d] 2.0 equivalents of base were used. [e] Isolated yield in parentheses. [f] The ruthenium complex was not pre-stirred prior
to the reaction. [g] Neither ruthenium source nor NHC precursor were added.
We previously reported a ruthenium(II)-N-heterocyclic
carbene (NHC) catalyst system which proved to be highly
reactive in the dehydrogenative activation of methanol to
achieve N-formylation of amines7 as well as in arene
hydrogenations.8 We envisioned that this reactive catalyst
system could also promote the α-alkylation of enolates via
a BH mechanism. Herein, we report on the Ru(NHC)2
catalyzed α-alkylations of diversely functionalized
methylene ketones with a variety of primary alcohols as
alkylating agents. Notably, the alkylating agent could be
used in a one-to-one stoichiometry with respect to the
ketone. To showcase the synthetic potential of this
method, donepezil, the best-selling drug for the
treatment of Alzheimer’s disease, was synthesized in one
step.
a number of reduced byproducts were observed, and
>50% of unreacted starting material 1a remained (Entry
1). During our studies in the field of arene hydrogenation,
the SINpEt NHC precursor (5•HBF4) showed unique
reactivity when combined with
a
ruthenium(II)
precursor.8 Indeed, employing this catalytic system9
enhanced our transformation and provided a promising
product distribution. Ketone 1a was completely consumed
and a significant amount of the desired product 3a could
be observed along with the reduced byproducts (Entry 2).
Increasing the temperature to 100 °C caused a slight
increase in the selectivity for 3a (Entry 3), while
increasing the amount of alcohol to two equivalents
proved detrimental for the reaction (Entry 4). Changing
the solvent system to t-AmOH/n-hexane led to a slight
decrease in reactivity, but enhanced the selectivity for the
formation of 3a (Entry 5). Among other bases, LiOt-Bu
gave slightly better results, whereas LiOH, KOt-Bu and
Cs2CO3 are inefficient (Entry 6-9). Finally, increasing the
amount of base to two equivalents resulted in the
selective formation of 3a and the desired product could
be isolated in 91% yield (Entry 10). The product could also
be detected when the ruthenium catalyst was not pre-
As an initial test reaction, the coupling of
dihydrochalcone 1a with benzyl alcohol (2a, 1.05 equiv.)
was conducted using 2 mol% of Ru-catalyst and one
equivalent of lithium diisopropylamide (LDA) at 80 °C
(Table 1). In a mixture of THF/n-hexane, using Ru/ICy as
catalyst, only trace amounts of the desired product 3a
could be observed. However, presumably due to the high
potency of the Ru/ICy catalyst in transfer hydrogenation,
ACS Paragon Plus Environment

Page 3 of 6
ACS Catalysis
[a] General reaction conditions: See Table 1, Entry 7. Yields
formed prior to the reaction, but the ruthenium and NHC
1
2
3
4
5
6
7
8
of the isolated products are given. [b] 1.00 g (7.45 mmol) of 1c
was used. [c] Reaction run for 36 h.
precursors were used directly (Entry 11). A control
experiment without any ruthenium catalyst revealed that
3a could only be formed in trace amounts (Entry 12),
similar to the observations made by the group of Xu and
co-workers.2j Without any base no reaction could be
observed at all (Entry 13).
Next, we further explored the scope of the primary
alcohol (Scheme 3). In general, a wide variety of primary
alcohols 2a-j with different electronic and steric
properties could be employed under the reaction
conditions to deliver the α-branched products in good to
excellent yields with a minimal excess of substrate. The
bromo substituent on 4-bromo benzyl alcohol 1c was well
tolerated in the reaction providing 3bc, 3ec, and 3hc in
good to excellent yields. The cyclopropyl ketone 1e
required a prolonged reaction time (48 h) to achieve good
conversions with either 1c or furfuryl alcohol 1d giving the
corresponding products 3ec and 3ed. When aliphatic
alcohols 2e-j were employed, the use of 3 equivalents of
base was needed to increase the conversion, presumably
in order to sustain high enolate concentrations
throughout the reaction. Nonetheless, after treatment
with purely aliphatic long chain alcohols n-hexanol (2g)
and tetrahydrogeraniol (2h), the tetralone derivative 1k
could be converted into the corresponding branched
products 3kg and 3kh in excellent yields (94% and 99%
yield respectively). Similarly the α-branched product 3gi
was obtained in 68% yield from 2-methyl cyclohexanone
(1g). We also applied this process to the direct synthesis
of donepezil (3ij), which is currently the best-selling drug
for treatment of Alzheimer’s disease.10 Although
donepezil was isolated in a moderate 40% yield, this
represents the shortest synthetic route to this important
molecule, requiring only one step from commercially
available starting materials.11
We then set out to investigate the reaction scope. A
range of α-substituted ketones were benzylated under
these conditions in good to excellent yields (Scheme 2).
Neither the ketone substituent nor the α-substituent
affected the outcome of the reaction. Abundant and
readily available unsubstituted phenyl ketones were
smoothly converted to the corresponding branched
products bearing either small groups such as methyl (3ca)
or more sterically demanding benzyl (3aa) or phenyl
(3ba) groups. When propiophenone (1c) was reacted with
benzyl alcohol on gram-scale, the corresponding product
was isolated in 94% yield, highlighting the practicability
of this protocol. Notably, despite the use of a lithium
base, the chloro substituent in 1d was tolerated in the
reaction, giving the α-branched product 3da in 80% yield.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
A
cyclopropyl ketone 1e was converted to the
corresponding branched product 3ea in 61% yield with
increased reaction time of 36 h. Cyclohexyl (1g) or
tetralone substrates (1h-i) bearing
a cyclic carbon
skeleton were successfully benzylated in excellent yields.
Interestingly, when cholestanone 1j was subjected to the
reaction conditions, 67% of one single regio- and
stereoisomeric product was isolated which was assigned
to be 3ja by 2D NMR studies. Only a trace amount of
another product could be detected (see the supporting
information for details). We attribute the observed
regioselectivity to steric reasons.
To further investigate the functional group tolerance of
this reaction, we conducted a robustness screen as
previously reported by the Glorius group (see the
supporting information).12 We found that aryl halides
(chlorides, bromides, iodides), cyanides and heterocycles
(imidazole, pyridine, pyrrole, benzofuran, thiophene) are
tolerated. However, reducible functional groups such as
nitro, esters, amides and alkynes deteriorate the reaction
outcome.
Scheme 2. α-Alkylation of various methylene ketones
1 with benzyl alcohol 2a[a]
Scheme 3. α-Alkylation of various ketones 1 with
primary alcohols 2b-j[a]
ACS Paragon Plus Environment

ACS Catalysis
Scheme
Page 4 of 6
of
4.
One-pot
double
alkylation
1
2
acetophenone derivatives by sequential addition of
primary alcohols
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To probe the unusually high reactivity of this
ruthenium(II)-NHC system in alkylating various
methylene
ketones
under
borrowing
hydrogen
conditions, the key aldol condensation reaction between
dihydrochalcone 1a and benzaldehyde was carried out
under transition metal free conditions, our Ru-NHC
catalyzed conditions as well as conditions based on
established Fe2g (Knölker’s complex), Ir3c and Rh3a
catalysts in BH reactions (Scheme 5).
[a] General reaction conditions: See Table 1, Entry 7. Yields of
isolated products are given. [b] 3 equivalents of LiOt-Bu were
used. [c] Reaction run for 48 h.
Scheme 5. Control experiments
To exploit the potential of this method to deliver
branched products, we conducted a one-pot double
alkylation process. This protocol could allow for rapid
access to highly branched carbon skeletons from very
simple and readily available starting materials (α-methyl
ketones and primary alcohols) with a single catalyst.
Acetophenones were chosen as ketone substrates that
[a] Determined by GC-MS analysis of the crude reaction
mixture.
were alkylated by different primary alcohols in
successive manner (Scheme 4).
a
The catalyst-free reaction shows a ratio of 1:1.9 between
1a and 6 after one hour with 6 as the sole product. While
Ir, Rh and Fe-based catalysts gave similar results
compared to the uncatalyzed reaction, the Ru-NHC
catalyst significantly improved the conversion, giving a
ratio of 1:11.5 between 1a and 6. This result indicates that
the ruthenium-complex is not only catalyzing the
borrowing hydrogen steps (dehydrogenation of the
primary alcohol and hydrogenation of the aldol
condensation product), but is also involved in the crucial
C–C bond forming condensation reaction.
Crucial to the success of this transformation is the
selective monoalkylation in the first step. After subjecting
1m to the standard reaction conditions with exactly one
equivalent of benzyl alcohol, we were pleased to detect
only the mono-benzylated product 3ma by means of
GC-MS analysis after three hours. Although a second
alkylation with the same alcohol is, in principle, possible
with this catalytic system, the higher reactivity of the α-
unsubstituted enolate of 1m compared to the substituted
enolate of 3ma is presumably the reason for the observed
product selectivity. A second addition of catalyst and
base, together with the alcohol 2c, led to the formation of
hetero- bis-alkylated compound 3mac which could be
isolated in 63% yield, proving the concept of one-pot
double alkylation with a single catalyst. Several other
ketones and alcohols could be coupled via this method,
although we found that aliphatic alcohols work less
efficient in this process.13
In summary, we have developed a ruthenium(II)-NHC
catalyzed practical and scalable α-alkylation of methylene
ketones with primary alcohols under borrowing hydrogen
conditions to give rise to a variety of branched ketones. In
general, good to excellent yields of the α-branched
products were obtained either without or with only a
minimal excess of the alcohol substrate. This protocol
significantly broadens the scope of borrowing hydrogen
catalysis in alkylation reactions, enabling the access to the
blockbuster drug donepezil in a single synthetic step.
Furthermore, we were able to exploit the inherent
ACS Paragon Plus Environment

Page 5 of 6
ACS Catalysis
(j) Liang, Y.-F.; Zhou, X.-F.; Tang, S.-Y.; Huang, Y.-B.; Fenga, Y.-
S.; Xu, H.-J. RSC Advances, 2013, 3, 7739-7742.
(3) For examples using methanol, see: (a) Chan, L. K. M.;
reactivity of methyl vs. methylene ketones to accomplish
the double alkylation of methyl ketones in a one-pot
procedure with a single catalyst.
1
2
Poole, D. L.; Shen, D.; Healy, M. P.; Donohoe, T. J. Angew. Chem.
Int. Ed. 2014, 53, 761-765; (b) Li, Y.; Li, H.; Junge, H.; Beller, M.
Chem. Commun. 2014, 50, 14991-14994; (c) Shen, D.; Poole, D. L.;
Shotton, C. C.; Kornahrens, A. F.; Healy, M. P.; Donohoe, T. J.
Angew. Chem. Int. Ed. 2015, 54, 1642-1645; (d) Quan, X.;
Kerdphon, S.; Andersson, P. G. Chem. Eur. J. 2015, 21, 3576-3579.
3
4
5
6
ASSOCIATED CONTENT
Supporting Information.
1
Experimental procedures, characterization data, and H and
13C NMR spectra.
7
8
9
This material is available free of charge via the Internet at
http://pubs.acs.org
(4)
For other examples, see: (a) Cho, C. S.; Kim, B. T.; Kim,
T.-J.; Shim, S. C. J. Org. Chem. 2001, 66, 9020-9022; (b) Taguchi,
K.; Nakagawa, H.; Hirabayashi, T.; Sakaguchi, S.; Ishii, Y. J. Am.
Chem. Soc. 2004, 126, 72-73; (c) Kwon, M. S.; Kim, N.; Seo, S. H.;
Park, I. S.; Cheedrala, R. K.; Park, J. Angew. Chem. Int. Ed. 2005,
44, 6913-6915; (d) Martínez, R.; Ramón, D. J.; Yus, M.
Tetrahedron 2006, 62, 8988-9001.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
AUTHOR INFORMATION
Corresponding Author
*E-mail for F.G.: glorius@uni-muenster.de.
(5)
Frost, J. R.; Cheong, C. B.; Akhtar, W. M.; Caputo, D. F.
Notes
J.; Stevenson, N. G.; Donohoe, T. J. J. Am. Chem. Soc. 2015, 137,
15664-15667.
(6)
M.; Jiang, H. Tetrahedron 2014, 70, 1193-1198.
(7)
1776-1779.
(8)
Glorius, F. Angew. Chem. Int. Ed. 2011, 50, 3803-3806; (b) Ortega,
N.; Urban, S.; Beiring, B.; Glorius, F. Angew. Chem. Int. Ed. 2012,
51, 1710-1713; (c) Zhao, D.; Beiring, B.; Glorius, F. Angew. Chem.
Int. Ed. 2013, 52, 8454-8458; (d) Ortega, N.; Tang, D.-T. D.;
Urban, S.; Zhao, D.; Glorius, F. Angew. Chem. Int. Ed. 2013, 52,
9500-9503; (e) Wysocki, J.; Ortega, N.; Glorius, F. Angew. Chem.
Int. Ed. 2014, 53, 8751-8755; (f) Wysocki, J.; Schlepphorst, C.;
Glorius, F. Synlett 2015, 26, 1557-1562.
The authors declare no competing financial interest.
Yan, F.-X.; Zhang, M.; Wang, X.-T.; Xie, F.; Chen, M.-
ACKNOWLEDGMENT
Ortega, N.; Richter, C.;Glorius, F. Org. Lett. 2013, 15,
We thank the Alexander von Humboldt Foundation (B.M.)
and the Deutsche Forschungsgemeinschaft (Leibniz Award)
for generous support. We also thank Dr. Klaus Ditrich/BASF
for the generous donation of chemicals and constant support
and Dr. Kathryn M. Chepiga for many helpful discussions.
For selected examples, see: (a) Urban, S.; Ortega, N.;
REFERENCES
(1)
For selected reviews, see: (a) Pan, S.; Shibata, T.; ACS
Catal. 2013, 3, 704-712; (b) Gunanathan, C.; Milstein, D.; Science
2013, 341, 1229712; (c) Ketcham, J. M.; Shin, I.; Montgomery, T. P.;
Krische, M. J. Angew. Chem. Int. Ed. 2014, 53, 9142-9150; (d)
Obora, Y. ACS Catal. 2014, 4, 3972-3981; (e) Huang, F.; Liu, Z.;
Yu, Z. Angew. Chem. Int. Ed. 2016, 55, 862-875; (f) Dobereiner, G.
E.; Crabtree, R. H.; Chem. Rev. 2010, 110, 681-703; pioneering
work by Grigg et al.: (g) Bibby, C. E.; Grigg, R.; Price, R. J. Chem.
Soc. Dalton Trans. 1977, 872-876; (h) Grigg, R.; Mitchell, T. R. B.;
Sutthivaiyakit, S. Tetrahedron Lett. 1979, 20, 1067-1068; (i) Grigg,
R.; Mitchell, T. R. B.; Sutthivaiyakit, S.; Tongpenyai, N. J. Chem.
Soc. Chem. Commun. 1981, 611-612; (j) Grigg, R.; Mitchell, T. R. B.;
Sutthivaiyakit, S. Tetrahedron 1981, 37, 4313-4319; (k) Grigg, R.;
Mitchell, T. R. B.; Sutthivaiyakit, S.; Tongpenyai, N. Tetrahedron
Lett. 1981, 22, 4107-4110.
(9)
The enantiomerically pure amine (R)-(+)-1-(1-
naphthyl)ethylamine from which the NHC ligand is derived is
commercially available and cheaper than in its racemic form
(Supplier: Combi-Blocks Inc., (R)-(+)-1-(1-naphthyl)ethylamine:
35 $/25 g, racemic 1-(1-naphthyl)ethylamine: 160 $/25 g).
(10)
(a) Sugimoto, H.; Ogura, H.; Arai, Y.; Iimura, Y.;
Yamanishi, Y. Jpn. J. Pharmacol. 2002, 89, 7-20; (b)
http://meshmedicaldevicenewsdesk.com/aricept-23-an-unusual-
dose-means-more-dollars-for-drug-companies
(11)
For selected syntheses of donepezil, see: (a) Dubey, S.
K.; Kharbanda, M.; Dubey, S. K.; Mathela, C. S. Chem. Pharm.
Bull. 2010, 58, 1157-1160; (b) Sugimoto, H.; Iimura, Y.; Yamanishi,
Y.; Yamatsu, K. J. Med. Chem, 1995, 38, 4821-4829; (c) Stephen, L.
US-5606064 1997; (d) Elati, C. R.; Kolla, N.; Chalamala, S. R.;
Vankawala, P. J.; Sundaram, V.; Vurimidi, H.; Mathad, V. T.
Synth. Commun. 2006, 36, 169-174; (e) Reddy, K. K. V. S. R.;
Moses Babu, J.; Anil Kumar, P.; Chandrasekhar, E. R. R.; Mathad,
V. T. S.; Eswaraiah, M. S.; Reddy, K.; Vyas, K. J. Pharm. BioMed.
Anal. 2004, 35, 1047-1058.
(12)
Collins, K. D.; Rühling, A.; Glorius, F. Nat. Protoc. 2014, 9, 1348.
(13) Attempts to achieve double alkylation with alkanols
usually resulted in inseparable mixtures where the desired
products were detected via GC in yields 30-50%.
(2)
For recent examples, see: (a) Alonso, F.; Riente, P.; Yus,
M. Eur. J. Org. Chem. 2008, 29, 4908-4914, (b) Srimani, D.;
Balaraman, E.; Gnanaprakasam, B.; Ben-David, Y.; Milstein, D.
Adv. Synth. Catal. 2012, 354, 2403-2406; (c) Kuwahara, T.;
Fukuyama, T.; Ryu, I. Org. Lett. 2012, 14, 4703-4705; (d) Bhat, S.;
Scridharan, V. Chem. Commun. 2012, 48, 4701-4703; (e) Li, F.;
Ma, J.; Wang, N. J. Org. Chem. 2014, 79, 10447-10455; (f) Xu, G.;
Li, Q.; Feng, J.; Liu, Q.; Zhang, Z.; Wang, X.; Zhang, X.; Mu, X.
ChemSusChem 2014, 7, 105-109; (g) Chan, L. K. M.; Poole, D. L.;
Shen, D.; Healy, M. P.; Donohoe, T. J. Angew. Chem. Int. Ed.
2014, 53, 761-765; (h) Elangovan, S.; Sortais, J.-B.; Beller, M.;
Darcel, C. Angew. Chem. Int. Ed. 2015, 54, 14483-14486; transition
metal catalyst-free reactions: (i) Xu, Q.; Chen, J.; Tian, H.; Yuan,
X.; Li, S.; Zhou, C.; Liu, J. Angew. Chem. Int. Ed. 2014, 53, 225-229;
a) Collins, K. D.; Glorius, F.; Nat. Chem. 2013, 5, 597; b)
ACS Paragon Plus Environment

ACS Catalysis
Page 6 of 6
α-Branched ketones are accessible under borrowing hydrogen conditions by using a ruthenium(II)-NHC catalyst.
Primary alcohols serve as alkylating agents and can be used in a one-to-one ratio. A one-pot double alkylation with
a single catalyst but two different alcohols is also possible under these conditions, as is the one-step synthesis
donepezil, the best-selling Alzheimer’s disease drug.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment