Exhaustive Reduction of Esters Enabled by Nickel Catalysis

Article abstract of DOI:10.1021/jacs.0c02405

We report a one-step procedure to directly reduce unactivated aryl esters into their corresponding tolyl derivatives. This is achieved by an organosilane-mediated ester hydrosilylation reaction and subsequent Ni/NHC-catalyzed hydrogenolysis. The resulting conditions provide a direct and efficient alternative to multi-step procedures for this transformation that often require the use of hazardous metal hydrides. Applications in the synthesis of -CD₃-containing products, derivatization of bioactive molecules, and chemoselective reduction in the presence of other C-O bonds are demonstrated.

Full text of DOI:10.1021/jacs.0c02405

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Exhaustive Reduction of Esters Enabled by Nickel Catalysis
Adam Cook, Sekar Prakash, Yan-long Zheng, and Stephen G. Newman
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c02405 • Publication Date (Web): 22 Apr 2020
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Journal of the American Chemical Society
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Exhaustive Reduction of Esters Enabled by Nickel Catalysis
Adam Cook,‡ Sekar Prakash,‡ Yan-Long Zheng, Stephen G. Newman*
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Centre for Catalysis Research and Innovation, Department of Chemistry and Biomolecular Sciences, University of
Ottawa, 10 Marie Curie, Ottawa, Ontario K1N 6N5, Canada
ABSTRACT: We report a one-step procedure to directly reduce unactivated aryl esters into their corresponding tolyl-
derivatives. This is achieved by an organosilane-mediated ester hydrosilylation reaction and subsequent Ni/NHC catalyzed
hydrogenolysis. The resulting conditions provide a direct and efficient alternative to multi-step procedures for this
transformation that often require use of hazardous metal hydrides. Applications in the synthesis of –CD3 containing products,
derivatization of bioactive molecules, and chemoselective reduction in the presence of other C–O bonds is demonstrated.
The reduction of carboxylic acids, as well as their
derivatives such as esters and amides, is of fundamental
importance in organic synthesis.1 This is most commonly
achieved by the action of aggressive metal hydride reducing
agents, enabling the formation of the corresponding alcohol
product.2 Exhaustive reduction – that is, reduction all the
way to the methyl oxidation state – is less readily achieved.
Reasons why one may seek to perform this reaction include
the profound effects of methyl groups on bioactivity, 3a-b the
ability to exploit the electronic effects of an ester group
prior to reduction,3c or its ability to create deuterium-
labelled tolyl derivatives.3d-e In rare cases, single step
transformation of an ester into a methyl group can be
realized,4 for example by the use of excess lithium aluminum
hydride in refluxing ethereal solvent (Scheme 1a).5 More
often, this transformation is carried out by a three-step
sequence via initial reduction to the alcohol, functional
group interconversion to an alkyl halide, and further
reduction to the methyl product (Scheme 1b).6
Alternatively, catalytic hydrogenolysis can be used to
reduce an alcohol to the methyl oxidation state (Scheme
1c).7
2a),9 the Rueping lab on the reduction of phenyl esters to
arenes (Scheme 2b),10 and the Garg lab on transforming
amides to amines (Scheme 2c),11 among others,12 served as
inspiration that silane reagents could act as mild hydride
donors in Ni-catalyzed reactions. With this precedent in
mind, we initiated a study on the reaction of silanes with
methyl esters in the presence of Ni. To our surprise, when
using 1,1,3,3-tetramethyldisiloxane (TMDSO)13 as
a
reducing agent in the presence of Ni(cod)2, 1,3-
dicyclohexylimidazolium tetrafluoroborate salt (ICy·HBF4),
and potassium tert-butoxide,
Scheme 2. Ni-catalyzed reductions mediated by
organosilane reducing agents.
a) Ni-catalyzed aryl ether to arene reduction (Martin, 2010)
[Ni] catalyst
TMDSO
H
O
R
R
PhMe, 110 °C
b) Ni-catalyzed phenyl ester to arene reduction (Rueping, 2016)
O
[Ni] catalyst
H
Scheme 1. Contemporary methods to achieve the ester-to-
methyl transformation
PHMS
OPh
R
R
PhMe, 170 °C
LiAl 4 (excess), reflux, 12-24
h
A
H
c) Ni-catalyzed amide to amine reduction (Garg, 2017)
halogenation
H
LiAl
H
4
LiAl
4
H
Ar-C 2X
Ar-CO2Me
H
Ar-C
3
H
Ar-C 2OH
[Ni] catalyst
O
B
H
H
PhSiH3
H
catalyst,
C
2
R'
R'
R
N
R
N
Our group and others have recently demonstrated that Ni
catalysts are capable of the catalytic activation of methyl
esters, presumably initiated by oxidative addition into the
C(acyl)–O bond.8 In the course of these studies, we
hypothesized that useful catalytic reductions of these esters
may be achievable using a similar strategy. Related work
from the Martin lab for reducing anisoles to arenes (Scheme
PhMe, 115 °C
R''
R''
d) Ni-catalyzed exhaustive reduction of esters (this work)
O
H
H
[Ni] catalyst
TMDSO
OMe
H
R
R
PhMe, 110 °C
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the major product was the corresponding tolyl derivative
benzofuran (35), and dibenzofuran (36). Derivatization of
commercial pharmaceuticals bifendatatum and probenecid
successfully formed reduction products 37 and 38,
respectively. Reduction of a
1
2
3
4
(Scheme 2d). Given the absence of general, functional group
tolerant methods to achieve this transformation in a single
step, we further explored this reaction and report the
results herein.
Table 1. Optimization of ester reduction reactiona
5
The Ni-catalyzed exhaustive reduction of methyl esters to
the corresponding tolyl derivative was optimized using N-
Me indole 1. Heating the substrate at 110 °C in toluene in
the presence of Ni(cod)2 (10 mol%), ICy·HBF4 (20 mol%),
TMDSO (2 equiv), and KOtBu (1 equiv) afforded methyl-
bearing indole 2 in 84% yield (Table 1, entry 1). Running
the reaction in the absence of either KOtBu or siloxane
resulted in no conversion (entry 2). However, removing just
the Ni(cod)2 led to complete consumption of 1, with the
corresponding benzyl alcohol as the only major identifiable
product after working the reaction up with TBAF (entry 3).
Using this alcohol as a starting material in the presence of
the Ni catalyst resulted in efficient formation of 2,
suggesting that the reaction proceeds through a non-
catalyzed reduction to a silylated alcohol14 followed by
catalytic reduction of this species to form the alkane (entry
4). Further experiments on benzyl-alcohol derived species
confirm this (Table S8, Supporting Information).
Alternative ligands (entry 5, 6), bases (entry 7, 8) and
organosilane reducing agents (entry 9, 10) were all less
efficient. Despite being highly reducing conditions, Ni(II)
precatalysts such as NiCl2 (entry 11) or NiBr2·glyme (entry
12) gave poor yields. The addition of 0.2 equiv Mn gave a
moderate improvement to 35% (entry 13), while 1
equivalent of Mn gave 78% yield (entry 14), providing a
viable alternative set of conditions that can be performed
without the use of a glovebox. Applying these conditions in
the absence of TMDSO resulted in no formation of 2 (entry
15), indicating that TMDSO is ultimately responsible for the
substrate reduction. Notably, the reaction was found to be
similarly efficient when starting from the corresponding
tBu, Bn or Ph ester (entry 16).
standard conditions
6
7
8
9
Ni(cod)2 (10 mol%)
ICy·HBF4 (20 mol%)
+
Si
Si
MeO
KOtBu (1 equiv)
H
O
H
N
H3C
N
O
Me
PhMe, 10 h, 110 °C
TMDSO
(2 equiv)
Me
2
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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34
35
36
37
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Entry Deviation from standard reaction conditions
% Yield
84
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
None
No base or no siloxane
No nickel
0b
Alcohol as starting material instead of ester
IPr·HCl instead of ICy·HBF4
Xantphos instead of ICy·HBF4
KOH instead of KOtBu
73
70
35
12
51
42
20
4
KOEt instead of KOtBu
Et3SiH (4.0 equiv)
(EtO)3SiH (4.0 equiv)
NiCl2 instead of Ni(cod)2
NiBr2·glyme instead of Ni(cod)2
NiBr2·glyme + Mn (0.2 equiv)
NiBr2·glyme + Mn (1.0 equiv)
NiBr2·glyme + Mn (1.0 equiv), no TMDSO
-tBu, -Bn, or -Ph ester instead of -Me ester
7
35
78
0
73-77
aReactions ran on a 0.20 mmol scale. Yields determined by NMR
using 1,3,5-trimethoxybenzene as internal standard. b Alcohol
(1-methyl-1H-indol-6-yl)methanol observed as major product
after work-up with TBAF.
lactone proceeded smoothly to form alcohol-bearing tolyl-
derivative 39 upon quenching with TBAF. Certain functional
groups such as alkynes and organofluorines were found to
decompose under our conditions. By using KF as the
stoichiometric base, fluoro (40), triflurotolyl (41), nitro (42),
alkyne (43), and furan-bearing (44) substrates, as well an ,-
unsaturated ester (45) were into scope. Substrates bearing
aliphatic rather than aryl esters were halted at the alcohol
oxidation state. Starting materials containing free N–H
bonds and electrophilic functionalities prone to side
reactions were not tolerated (Scheme S3, Supporting
Information). Glovebox-free conditions using NiBr2·glyme
were also studied with a range of substrates – these
conditions were observed to give synthetically viable yields,
albeit with slightly lower efficiency than when using
Ni(cod)2. Lastly, a gram scale reaction was performed in a
50 mL heavy-walled pressure tube, providing 7 in 71%
yield. Gratifyingly, we were able to obtain 7 in similar yields
at the gram scale while reducing the catalyst loading to 3%
Ni/ 6% ICy·HBF4.
With optimized conditions, we turned our attention
towards the reaction scope (Scheme 3). Electron-neutral
and rich methyl arenes 3-7 were formed from their
corresponding esters in 73–86% yield. Subjecting a styrene-
bearing methyl ester to the conditions led to partial
reduction of the olefin; however, slightly milder conditions
enabled 8 to be selectivity formed in 74% yield. Slightly
milder conditions also allowed recovery of stilbene 9 in
similar yields. In contrast with prior work on Ni-catalyzed
hydrogenolysis of anisoles and related compounds,9a,12c-f no
C(aryl)–O cleavage was observed when using ethereal or
phenol-containing substrates (10–15). Further, carboxylic-
acid bearing esters (16) could also be tolerated, provided
that an extra equivalent of base is used. In many classical
heterocycle-forming reactions, ester-containing starting
materials like malonates or propiolates are used to facilitate
cyclizations, thus making the ester-containing products
more accessible than the corresponding methyl analogs.
With this in mind, we were excited to see that many
heterocycles were tolerated, including pyridines (17–20),
morpholines (21, 22), piperidines (23, 24), indoles (25-
29), carbazoles (30–32), an indazole (33), quinoline (34),
Given the importance of deuterated molecules in the study
of reaction mechanisms, pharmaceuticals, and as tools for
understanding metabolic pathways,15 we next explored the
potential of our exhaustive reduction to synthetically
introduce –CD3 groups. While the development of methods
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Journal of the American Chemical Society
to perform this transformation is of contemporary
interest,16 this is commonly achieved by using LiAlD4 or
LiEt3BD as a reducing agent in the three-step procedure
described in
1
2
3
4
5
6
7
8
Scheme 3. Scope of substrates tolerated in the methyl ester reduction
Ni(cod)2 (10 mol%)
ICy·HBF4 (20 mol%)
O
H
C
Si
Si
3
+
KOtBu (1 equiv)
Ar
H
H
O
Ar
O
PhMe, 110 °C, 10 h
methyl ester
organosilane
methyl arene
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
H
C
3
C
H
3
H
C
H
C
H
C
3
3
3
N
H
C
3
a
b
c
a
5:
6:
76%
73%
4:
7:
8:
74%
3:
76% (70%)
73% (77%)
86% (73%)
H
C
3
H
O
O
C
H
C
3
3
OH
H
O
C
O
H
C
3
3
Ph
O
H
PhO
C
O
O
3
c
a
9:
10:
11:
12:
13:
14:
71%
69%
71%
N
63%
72% (64)
N
66%
N
H
C
H
C
3
3
tBu
HO
C
3
H
C
H
C
H
C
3
H
3
3
N
N
tBu
O
HOOC
16:
N
N
81%d (67)a
82%
73%
78%
d
19:
57%
15:
17:
18:
20:
78%
H
C
3
3
H
4
C
H
3
C
N
H
H
3
C
C
H
3
3C
3
2
N
N
N
O
N
N
6
O
O
O
a
a
21:
23:
24:
27:
28:
73%
72%
68%
3-CH3: 53%
2-CH3: 41%
22:
25:
77% (71)
6-CH3: 79% (76)
4-CH3: 70%
26:
H
3C
t-Bu
H
C
H
3C
O
3
H
C
3
H
C
3
N
N
N
N
N
N
N
H
3C
Me
Bn
30:
Me
29:
31:
32:
33:
34:
67%
72%
65%
68%
59%
63%
O
H
C
O
O
3
O
O
S
H
C
3
O
H
3
C
via
O
O
N
H
C
3
O
C
O
H
3C
O
O
H
C
OH
3
O
O
c
39:
c
74%
Bifendatatum derivative
35:
63%
Probenecid derivative
36:
81%
e
38:
36%
37:
76%
H
H
H
C
3
C
C
3
3
H
C
3
H
3
H
C
3
O
O
F
F3C
O2N
f
f
f
f
f
f
45:
48%
40:
41:
42:
43:
44:
71%
74%
84%
79%
68%
General reaction conditions: ester (0.20 mmol), TMDSO (0.40 mmol), KOtBu (0.20 mmol), ICy·HBF4 (20 mol%), Ni(cod)2 (0.02
mmol) in toluene (0.8 mL), 110 °C for 10 h. [a] NiBr2·glyme (0.02 mmol) and Mn (0.20 mmol) used instead of Ni(cod)2; reactions
setup without use of a glovebox. [b] Yield obtained upon reacting 5.58 mmol (1 g) of starting material using 3 mol% Ni, 6 mol%
ICy·HBF4. [c] TMDSO (0.30 mmol), 90 °C for 6 h. [d] KOtBu (0.44 mmol) [e] TMDSO (0.80 mmol), KOtBu (0.40 mmol). [f] KF (0.20
mmol) and KOtBu (20 mol%) used instead of KOtBu (0.20 mmol).
3
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Scheme 1.6f-k For instance, Salvadori and co-workers used a
Scheme 4. Applications of exhaustive reduction of esters
1
2
3
4
5
6
7
8
three-step, three-day procedure to synthesize CD3-
containing 2,5-dimethoxy-d3-toluene (49) towards the
preparation of d3-δ-tocopherol.17 Reduction of the
corresponding ester to alcohol with LiAlD4, halogenation
with PBr3, and a second LiAlD4 reduction afforded product
in an overall yield of 69%. Using d2-TMDSO18 alongside
Ni(cod)2 gave incomplete deuterium incorporation. In
contrast, theuse of NiBr2·glyme/TMDSO/Mn in toluene-d8
While several Ni-catalyzed methods to cleave benzylic
C(sp3)–O bonds are known,19 established conditions for
reductions are selective for C(sp2)–O bonds. For instance,
catalytic reduction of phenols20 and siloxyarenes21 can
occur, leaving benzyl ethers and related species untouched.
The similarity between our conditions to reduce methyl
esters (including intermediate benzyl alcohol derivatives)
and those which Martin and co-workers used to reduce
anisole derivatives is particularly notable.9a These methods
differ primarily in the choice of ligand and the presence of
base. To directly probe the selectivity, esters 50-53 were
subjected to both sets of reaction conditions (Scheme 4b).
Using a Ni/ICy catalyst in the presence of KOtBu resulted in
chemoselective formation of the ester reduction products
54-57 in 54–82% yield. Using base-free conditions with a
Ni/PCy3 catalyst resulted in a complete switch, cleaving of
the ethereal bond while leaving the methyl ester untouched
in products 58–60. The Ni/PCy3 system has been proposed
to act via a Ni(I)– SiR3 active catalyst;9b the contrasting
chemoselectivity in our system suggests that both a
different active catalyst and different mechanistic pathway
are operative.
A
Catalytic deuteration
9
NiBr2·glyme (10 mol%)
ICy·HBF4 (20 mol%)
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
CO2Me
D
C
3
d
2-TMDSO
+
Ar
Mn (1 eq), KOtBu (1 equiv)
Ar
(2 equiv)
d8-PhMe, 110 °C, 10 h
D
C
3
O
D
D
3
C
C
3
D
C
3
N
Bu
O
49:
68%
>95% D
48:
>95% D
65%
46:
72%
>95% D
47:
68%
>95% D
ref 17
LiAlD4
CD2Br
LiAlD4
PBr3
CD2OH
CO2Me
Ar
Ar
Ar
B
Controlling selectivity for esters and ethers
To gain further mechanistic information, the method of
variable time normalization analysis was applied to the
reduction of methyl naphthoate 59 (Scheme 5).22 Positive
reaction orders were observed for all studied species – the
Ni catalyst, substrate, siloxane, and base. While the exact
nature of reducing agent is not clear, the rate dependency
on the base and literature precedent both support a
hypervalent OtBu-siloxane species being involved in the key
hydride transfer.23 Further mechanistic evidence was
obtained upon comparing the reduction of 59 to that of
napthalene-2-methanol, as we discovered that the ester-to-
methyl transformation kinetically mirrors the alcohol-to-
methyl transformation, while the initial ester-to-alcohol
transformation occurs rapidly (Scheme S10, Supporting
Information). Finally, a primary kinetic isotope effect of
2.24 was observed for the reduction of napthalene-2-
methanol. With this information, we tentatively propose
that a hypervalent siloxane rapidly reduces the ester into a
silylated alcohol. The resultant alcohol could react with a
Ni(0)24 catalyst by a reversible, endothermic oxidative
addition to form a benzylic Ni(II) intermediate.25 Reduction
of this species with an activated siloxane may turn over the
catalyst.26
Both conditions
Ni(cod)2 (10 mol%)
TMDSO (1-2 equiv)
Conditions A
ICy•HBF4 (20 mol%)
KOtBu (1 equiv)
Conditions B
PCy3 (20 mol%)
no base
PhMe (0.5 M), 110 °C, 12 h
CO2Me
CH3
CO2Me
+
N
N
N
H
OMe
OMe
54
76%
0%
58
0%
75%
50
Conditions A:
Conditions B:
CH3
+
CO2Me
CO2Me
MeO
H
MeO
55
88%
0%
59
0%
60%
51
Conditions A:
Conditions B:
CH3
CO2Me
CO2Me
H
+
OMe
OMe
52
56
Conditions A: 78%
Conditions B: 0%
59
0%
90%
OMe
OMe
OMe
CO2Me
CH3
In summary, we have developed a new method to convert
methyl esters into the corresponding tolyl derivative. In
contrast to established multi-step sequences for this
transformation, the reaction takes place under a single set
of conditions, comprised of a rapid, non-catalyzed siloxane-
mediated reduction to a silylated alcohol followed by
subsequent Ni-catalyzed reduction to the corresponding –
CH3 group. We believe this reaction will be particularly
useful in the synthesis of methyl-bearing heterocycles,
where the corresponding esters are more readily abundant,
as well as in reductive deuteration as a method to install –
CD3 groups. This transformation sharply contrasts previous
CO2Me
H
+
OMe
57
OMe
60
53
Conditions A: 73%
Conditions B: 0%
0%
78%
resulted in an efficient 73% yield with >95%D
incorporation (Scheme 4a). This procedure was found to be
general, enabling the synthesis of several –CD3-containing
molecules in good yield and high deuterium incorporation
(46-49). Experiments in non-deuterated toluene gave ~5-
10% reduced deuterium incorporation.
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Journal of the American Chemical Society
and Future Directions. Chem. Soc. Rev. 2015, 44, 3808–3833. (b)
reports of Ni-catalyzed reductions with siloxanes of, e.g.,
amides, ethers, and phenyl esters. The inclusion of a KOtBu
is proposed to be a key feature, which generates a more
aggressive siloxane reducing agent in situ.
Magano, J.; Dunetz, J. R. Large-Scale Carbonyl Reductions in the
Pharmaceutical Industry. Org. Process Res. Dev. 2012, 16, 1156–
1184. (c) Addis, D.; Das, S.; Junge, K.; Beller, M. Selective Reduction
of Carboxylic Acid Derivatives by Catalytic Hydrosilylation. Angew.
Chem. Int. Ed. 2011, 50, 6004–6011.
1
2
3
4
5
6
7
8
(2) (a) Berk, S. C.; Kreutzer, K. A.; Buchwald, S. L. A Catalytic Method
for the Reduction of Esters to Alcohols. J. Am. Chem. Soc. 1991, 113,
5093–5095. (b) Turek, D.; Trimm, D.; Cant, N. W. The Catalytic
Hydrogenolysis of Esters to Alcohols. Catal. Rev. - Sci. Eng. 1994,
36, 645–683. (c) Krishnamurthy, S.; Brown, H. C. Forty Years of
Hydride Reductions. Tetrahedron. 1979, 35, 567–607. (d) Zheng, J.,
Scheme 5. Apparent rate law determination by variable
time normalization kinetic analysis
9
Ni/ICy catalyst
TMDSO ; KOtBu
CH3
CO2Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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59
60
Darcel, C., Sortais, J. P.
Hydrosilylation of Carbonyl Derivatives. Catal. Sci. Technol. 2012,
3, 81–84.
A
Convenient Nickel-catalyzed
PhMe, 110 °C
59
4
0.25
0.2
(3) (a) Barreiro, E. J.; Kümmerle, A. E.; Fraga, C. A. M. The
Methylation Effect in Medicinal Chemistry. Chem. Rev. 2011, 111,
5215–5246. (b) Schönherr, H.; Cernak, T. Profound Methyl Effects
in Drug Discovery and a Call for New C–H Methylation Reactions.
Angew. Chem. Int. Ed. 2013, 52, 12256–12267. (c) Sambiagio, .;
Schoenbauer, D.; Blieck, R.; Dao-Huy, T.; Pototschnig, G.; Schaaf, P.;
Wiesinger, T.; Zia, M. F.; Wencel-Delord, J.; Besset, T.; Maes, B. U. W.;
Shnurch, M. A Comprehensive Overview of Directing Groups
Applied in Metal-catalyzed C-H Functionalization Chemistry. Chem.
Soc. Rev. 2018, 47, 6603–6743. (d) Pirali, T.; Serafini, M.; Cargnin,
S.; Genazzani, A.A. Applications of Deuterium in Medicinal
Chemistry. J. Med. Chem. 2019, 62, 5276–5297 (e) Liu, J. F.;
Harbeson, S. L.; Brummel, C. L.; Tung, R.; Silverman, R.; Doller, D.
Chapter Fourteen – A Decade of Deuteration in Medicinal
Chemistry. Annu. Rep. Med. Chem. 2017, 50, 519–542.
0.15

std. cond.
(M)
[TMDSO] = 0.50 M
[KOtBu] = 0.25 M
[59] = 0.25 M
[4]
[catalyst] = 0.025 M
0.1

[catalyst] = 0.05 M
[59] = 0.50 M
[TMDSO] = 1.0 M
[KOtBu] = 0.50 M
0.05
0



0
2
4
6
8
10
12
[59]1[catalyst]1[KOtBu]1[TMDSO]1
t


(4) (a) Yamamoto, Y.; Bajracharya, G. B.; Nogami, T.; Jin, T.;
Matsuda, K.; Gevorgyan, V. Reduction of Carbonyl Function to a
Methyl Group. Synthesis. 2004, 2, 308–311 (b) Yamamoto, Y.; Liu,
J.; Rubin, M.; Gevorgyan, V. A Direct Reduction of Aliphatic
Aldehyde, Acyl choride and Carboxylic Functions into a Methyl
Group. J. Org. Chem. 2001, 66, 1672–1675. (c) Okita, T.; Muto, K.;
Yamaguchi, J. Decarbonylative Methylation of Aromatic Esters by a
Nickel Catalyst. Org. Lett. 2018, 20, 3132−3135.
AUTHOR INFORMATION
Corresponding Author
*stephen.newman@uottawa.ca
Author Contributions
‡ These authors contributed equally.
(5) (a) Zhang, J.; Kohlbouni, S. T.; Borhan, B. Cu-Catalyzed Oxidation
of C2 and C3 Alkyl-Substituted Indole via Acyl Nitroso Reagents.
Org. Lett. 2019, 21, 14–17. (b) Zhang, Z.; Ji, C. L.; Yang, C.; Chen, J.;
Hong, X.; Xia, J. B. Nickel Catalyzed Kumada Coupling of boc-
Activated Aromatic Amines via Nondirected Selective Aryl C-N
bond Cleavage. Org. Lett. 2019, 21, 1226–1231. (c) Borger, C.;
Knolker, H. J. A General Approach to 1,6-Dioxygenated Carbazole
Alkaloids – First Total Synthesis of Clausine G, Clausine I and
Clausine Z. Synlett. 2008, 11, 1698–1702. (d) Conover, L.H.;
Tarbell, D.S. Hydrogenolysis of Certain Substituted Aromatic Acids
and Carbonyl Compounds by Lithium Aluminum Hydride. J. Am.
Chem. Soc. 1950, 72, 3586-3588.
Supporting Information
Information regarding experimental procedures, optimization
tables, troubleshooting, characterization of organic molecules,
mechanistic studies is available free of charge via the Internet
at http://pubs.acs.org.
ACKNOWLEDGMENT
Financial support for this work was provided by BASF, the
National Science and Engineering Research Council of Canada
(NSERC), and the Canada Research Chair program. Martin
McLaughlin, Mathias Schelwies, Stephan Zuend, and Roland
Götz (BASF) are thanked for helpful discussions. The Canadian
Foundation for Innovation (CFI) and the Ontario Ministry of
Research, Innovation, & Science are thanked for essential
infrastructure.
(6) (a) Fuchs, B.; Zizuashvili, J.; Abramson, S. Geometrically Biased
Homoconjugated Ketones. Synthetic Avenues to 1-acyl-2,4-
cyclohexadienes. J. Org. Chem. 1982, 47, 3474–3477. (b) Beckwith,
A.; Gerba, S. The Stereochemistry of Ring Closure of Some
Monosubstituted o-(but-3-enyl)phenyl Radicals. J. Aus. Chem.
1992, 45, 289–308. (c) Kanomata, N.; Sakaguchi, R.; Sekine, K.;
Yamashita, S.; Tanaka, H. Enantioselective Cyclopropanation
Reactions with Planar-Chiral Pyridinium Ylides: a Substituent
Effect and a Remote Steric Effect. Adv. Synth. & Cat. 2010, 352,
2966–2978. (d) Robaa, D.; Enzensperger, C.; Abulazm, S. E.; M.
Hefnawy, M.; I. El-Subbagh, H.; A. Wani, T.; Lehmann, J. Chiral
Indole [3,2-f][3]benzecine-type Dopamine Receptor Antagonists:
REFERENCES
(1) (a) Pritchard, J.; Filonenko, G. A.; van Putten, R.; Hensen, E. J.;
Pidko, E. A. Heterogeneous and Homogeneous Catalysis for the
Hydrogenation of Carboxylic Acid Derivatives: History, Advances
5
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 7
Synthesis and Activity of Racemic and Enantiopure Derivatives. J.
Med. Chem. 2011, 54, 7422–7426. (e) Crockett, M.; Urbanus, J. H.;
Konst, P. M.; De Koning, M. C. Preparation of Phenolics from
(9) (a) Alvarez-Bercedo, P.; Martin, R. Ni-Catalyzed Reduction of
Inert-C–O Bonds: A New Strategy for Using Aryl Ethers as Easily
Removable Directing Groups. J. Am. Chem. Soc. 2010, 132, 17352–
17353. (b) Cornella, J.; Gómez-Bengoa, E.; Martin, R. Combined
Experimental and Theoretical Study on the Reductive Cleavage of
Inert C–O Bonds with Silanes: Ruling out a Classical Ni(0)/Ni(II)
Catalytic Couple and Evidence for Ni(I) Intermediates. J. Am. Chem.
Soc. 2013, 135, 1997–2009.
1
2
3
4
5
6
7
8
Biomass.
Nederlandse
Organisatie
voor
Toegepast-
Natuurwetenschappeljik Onderzoek TNO, Neth. WO 2016114668.
21 July 2016. (f) Pollack, S.K.; Raine, B.C.; Hehre, W.J.
Determination of the Heats of Formation of the Isomeric Xylylenes
by Ion Cyclotron Double-Resonance Spectroscopy. J. Am. Chem. Soc.
1981, 103, 6308–6313. (g) Holland, H.L.; Brown, F.M.; Conn, M.
Side Chain Hydroxylation of Aromatic Compounds by Fungi.
Influence of the para Substituent on Kinetic Isotope Effects During
Benzylic Hydroxylation by Mortierella isabelline. J. Chem. Soc.
Perkin Trans. 2 1990, 10, 1651–1655. (h) Hanzlik, R. P.; Schaefer,
A. R.; Moon, J. B.; Judson, C. M. Primary and Secondary Kinetic
Deuterium Isotope Effects and Transition-state Structures for
Benzylic Chlorination and Bromination of Toluene. J. Am. Chem.
Soc. 1987, 109, 4926–4930. (i) Koshiyama, T.; Hirai, K.; Tomioka,
(10) Yue, H.; Guo, L.; Lee, S.-C.; Liu, X.; Rueping, M. Selective
Reductive Removal of Ester and Amide Groups from Arenes and
Heteroarenes through Nickel-Catalyzed C−O and C−N Bond
Activation. Angew. Chem. Int. Ed. 2017, 129, 4030–4034.
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
(11) Simmons, B. J.; Hoffmann, M.; Hwang, J.; Jackl, M. K.; Garg, N. K.
Nickel-Catalyzed Reduction of Secondary and Tertiary Amides.
Org. Lett. 2017, 19, 1910–1913.
H.
Generation,
Reactions,
and
Kinetics
of
Di(naphthyl)carbenes: Effects of the Methyl Group. The Journal of
Physical Chemistry A. 2002, 106, 10261–10274. (j) Hayama, T.;
Baldridge, K. K.; Wu, Y.-T.; Linden, A.; Siegel, J. S. Steric Isotope
Effects Gauged by the Bowl-Inversion Barrier in Selectively
Deuterated Pentaarylcorannulenes. J. Am. Chem. Soc. 2008, 130,
1583–1591. (k) Courchay, F. C.; Sworen, J. C.; Ghiviriga, I.; Abboud,
K. A.; Wagener, K. B. Understanding Structural Isomerization
During Ruthenium-Catalyzed Olefin Metathesis: A Deuterium
Labelling Study. Organometallics. 2006, 25, 6074–6086.
(12) (a) Ritleng, V.; Henrion, M.; Chetcuti, M. J. Nickel N-
Heterocyclic Carbene-Catalyzed C–Heteroatom Bond Formation,
Reduction, and Oxidation: Reactions and Mechanistic Aspects. ACS
Catal. 2016, 6, 890–906. (b) Dey, A.; Sasmal, S.; Seth, K.; Lahiri, G.
K.; Maiti, D. Nickel-Catalyzed Deamidative Step-Down Reduction of
Amides to Aromatic Hydrocarbons. ACS Catal. 2016, 7, 433–437.
(c) Tobisu, M.; Morioka, T.; Ohtsuki, A.; Chatani, N. Nickel-Catalyzed
Reductive Cleavage of Aryl Alkyl Ethers to Arenes in Absence of
External Reductant. Chem. Sci. 2015, 6, 3410–3414. (d) Sergeev, A.;
Webb, J.; Hartwig, J. F. A Heterogenous Nickel Catalyst for the
Hydrogenation of Ethers without Arene Hydrogenation. J. Am.
Chem. Soc. 2012, 134, 20226–20229. (e) Sergeev, A.; Hartwig, J. F.
Selective Nickel-Catalyzed Hydrogenolysis of Ethers. Science.
2011, 332, 439–443. (f) Tobisu, M.; Yamakawa, K.; Shimasaki, T.;
Chatani, N. Nickel-Catalyzed Reductive Cleavage of Aryl-Oxygen
Bonds in Alkoxy and Pivaloxyarenes using Hydrosilanes as a Mild
Reducing Agent. Chem. Comm. 2011, 47, 2946–2948. (g) Iosub,
A.V.; Moravcik, S.; Wallentin, C.-J.; Bergman, J. Nickel-Catalyzed
Selective Reduction of Carboxylic Acids to Aldehydes. Org. Lett.
2019, 21, 7804.
(7) (a) Barfield, M.; Collins, M. J.; Gready, J. E.; Sternhell, S.; Tansey,
C. W. Bond-order Dependence o Orthobenzylic Coupling Constants
Involving a Methyl Group. J. Am. Chem. Soc. 1989, 111, 4285–4290.
(b) Maj, A. M.; Suisse, I.; Hardouin, C.; Agbossou-Niedercorn, F.
Synthesis
of
New
Chiral
2-functionalized-1,2,3,4-
tetrahydroquinoline Derivatives via Asymmetric Hydrogenation of
Substituted Quinolines. Tetrahedron 2013, 69, 9322–9328. (c)
Sorella, G. L.; Sperni, L.; Canton, P.; Coletti, L.; Fabris, F.; Strukul, G.;
Scarso, A. Selective Hydrogenations and Dechlorinations in Water
Mediated by Anionic Surfactant-Stabilized Pd Nanoparticles. J. Org.
Chem. 2018, 83, 7438–7446. (d) Shiraishi, Y.; Fujiwara, K.; Sugano,
Y.; Ichikawa, S.; Hirai, T. N-Monoalkylation of Amines with Alcohols
by Tandem Photocatalytic and Catalytic Reactions on TiO2 Loaded
with Pd Nanoparticles. ACS Catal. 2013, 3, 312–320. (e) He, J.; Zhao,
C.; Lercher, J. A. Ni-Catalyzed Cleavage of Aryl Ethers in the
Aqueous Phase. J. Am. Chem. Soc. 2012, 134, 20768–20775. (f)
Covert, L. W.; Connor, R.; Adkins, H. Use of Nickel as a Catalyst for
Hydrogenation. J. Am. Chem. Soc. 1932, 54, 1651–1663. (g) Baltzly,
R.; Buck, J. S. Catalytic Debenzylation. The Effect of Substitution on
the Strength of the O-Benzyl and N-Benzyl Linkages. J. Am. Chem.
Soc. 1943, 65, 1984–1992.
(13) Pesti, J.; Larson, G. L. Tetramethyldisiloxane: A Practical
Organosilane Reducing Agent. Org. Process Res. Dev. 2016, 20,
1164–1181.
(14) The combination of base and organosilanes are known to
form species capable of reducing carbonyl groups. For examples,
see: (a) Kobayashi, Y.; Takahisa, E.; Nakano, M.; Watatani, K.
Reduction of Carbonyl Compounds by using Polymethylhydro-
Siloxane: Reactivity and Selectivity. Tetrahedron. 1997, 53, 1627–
1634 (b) Fernández-Salas, J. A.; Manzini, S.; Nolan, S. P. Facile and
Efficient KOH-Catalysed Reduction of Esters and Tertiary Amides.
Chem. Comm. 2013, 49, 9758–9760. (c) Hojo, M.; Murakami, C.;
Fujii, A.; Hosomi, A. New Reactivity of Methoxyhydridosilane in the
Catalytic Activation System. Tetrahedron Lett. 1999, 40, 911–914.
(d) Addis, D.; Zhou, S.; Das, S.; Junge, K.; Kosslick, H.; Harloff, J.;
Lund, H.; Schulz, A.; Beller, M. Hydrosilylation of Ketones: From
Metal-Organic Frameworks to Simple Base Catalysts. Chem. Asian J.
2010, 5, 2341–2345. (e) Hosomi, A.; Hayashida, H.; Kohra, S;
Tominaga, Y. Pentacoordinate Silicon Compounds in Synthesis:
Chemo- and Stereo-selective Reduction of Carbonyl Compounds
using Trialkoxy-substituted Silanes and Alkali Metal Alkoxides. J.
Chem. Soc. Chem. Commun. 1986, 18, 1411–1412.
(8) (a) Ben Halima, T.; Masson-Makdissi, J.; Newman, S. G. Nickel
Catalyzed Amide Bond Formation from Methyl Esters. Angew.
Chemie. Int. Ed. 2018, 57, 12925–12929. (b) Zheng, Y.-L.; Newman,
S. G. Methyl esters as cross-coupling electrophiles: Direct Synthesis
of Amide Bonds. ACS Catal. 2019, 9, 4426–4433. (c) Hie, L.; Fine
Nathel, N. F.; Hong, X.; Yang, Y.-F.; Houk, K. N.; Garg, N. K. Nickel-
Catalyzed Activation of Acyl C−O Bonds of Methyl Esters. Angew.
Chemie. Int. Ed. 2016, 55, 2810–2814. (d) Yue, H.; Zhu, C.; Rueping,
M. Catalytic Ester to Stannane Functional Group Interconversion
via Decarbonylative Cross-Coupling of Methyl Esters. Org. Lett.
2018, 20, 385–388. (e) Rosen, B. M.; Quasdorf, K. W.; Wilson, D.
A.; Zhang, N.; Resmerita, A. M.; Garg, N. K.; Percec, V. Nickel-
Catalyzed Cross-Couplings Involving Carbon–Oxygen Bonds. Chem.
Rev. 2011, 111, 1346–1416. (f) Walker, J. A., Jr; Vickerman, K. L.;
Humke, J. N.; Stanley, L. M. Ni-Catalyzed Alkene Carboacylation via
Amide C–N Bond Activation. J. Am. Chem. Soc. 2017, 139, 10228–
10231.
(15) (a) Mullard, A. Deuterated Drugs Draw Heavier Backing. Nat.
Rev. Drug Discov, 2016, 15, 219–221. (b) Pirali, T.; Serafini, M.;
Cargnin, S.; Genazzani, A. A. Applications of Deuterium in Medicinal
Chemistry. J. Med. Chem. 2019, 62, 5276–5297. (c) Tung, R. D.
6
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Journal of the American Chemical Society
Deuterium Medicinal Chemistry Comes of Age. Future Med. Chem.
2016, 8, 491–494.
(22) (a) Burés, J. Variable Time Normalization Analysis: General
Graphical Elucidation of Reaction Orders from Concentration
Profiles. Angew. Chem. Int. Ed. 2016, 55, 16084–16087. (b) Neilsen,
D.-T. C.; Burés, J. Visual Kinetic Analysis. Chem. Sci. 2019, 10, 348–
353.
1
2
3
4
5
6
7
8
(16) (a) Shen, Z.; Shang, S.; Geng, H.; Wang, J.; Zhang, X.; Zhou, A.;
Yao, C.; Chen, X.; Want, W. Trideuteromethylation Enabled by a
Sulfoxonium Metathesis Reaction. Org. Lett. 2019, 21, 448–452. (b)
He, Z.-T.; Li, H.; Haydl, A.; Whiteker, G.; Hartwig, J. F.
Trimethylphosphate as a Methylating Agent for Cross Coupling: A
Slow-Release Mechanism for the Methylation of Arylboronic
Esters. J. Am. Chem. Soc. 2018, 140, 17197–17202. (c) Han, X.;
Yuan, Y.; Shi, Z. Rhodium-Catalyzed Selective C−H
Trideuteromethylation of Indole at C7 Position Using Acetic ‑d6
Anhydride. J. Org. Chem. 2019, 84, 12764. (d) Hu, L.; Liu, X.; Liao, X.
Nickel-Catalyzed Methylation of Aryl Halides with Deuterated
Methyl Iodide. Angew. Chem. Int. Ed. 2016, 55, 9743–9747.
(23) (a) Larson, G. L.; Fry, J. L. Ionic and Organometallic-Catalyzed
Organosilane Reductions. Organic Reactions, Vol. 71; Denmark, S.
E., Ed.; Wiley and Sons, 2008. (b) Rendler, S.; Oestreich, M.
Hypervalent Silicon as a Reactive Site in Selective Bond-Forming
Processes. Synthesis. 2005, 11, 1727–1747. (c) Dieters, J. A.;
Holmes, R. R. Enhanced Reactivity of Pentacoordinated Silicon
Species. An ab Initio Approach. J. Am. Chem. Soc. 1990, 112, 7197–
7202. (d) Revunova, K.; Nikonov, G. I. Base-Catalyzed
Hydrosilylation of Ketones and Esters and Insight into the
Mechanism. Chem. Eur. J. 2013, 20, 839–845. (e) Drew, M. D.;
Lawrence, N. J.; Fontaine, D.; Sehkri, D.; Bowles, S. A.; Watson, W.
A Convenient Procedure for the Reduction of Esters, Carboxylic
Acids, Ketones and Aldehydes using Tetrabutylammonium
Fluoride and Polymethylhydrosiloxane. Synlett. 1997, 8, 989–911.
(f) Brook, M. A. Silicon in Organic, Organometallic, and Polymer
Chemistry; Interscience Publisher, Inc.: New York, 2000, Chap. 4,
97.
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
(17) Mazzini, F.; Alpi, E.; Salvadori, P.; Netscher, T. First Synthesis
of (8-2H3)-(all-rac)-δ-Tocopherol. Eur. J. Org. Chem. 2003, 15,
2840–2844.
(18) (a) Smart, K. A.; Mothes-Martin, E.; Annaka, T.; Grellier, M.;
Sabo-Etienne, S. Silane Deuteration Catalyzed by Ruthenium
Bis(dihydrogen) Complexes or Simple Metal Salts. Adv. Synth. Catal.
2014, 356, 759–764. (b) Zhou, R.; Li, J.; Cheo, H. W.; Chua, R.; Zhan,
G.; Hou, Z.; Wu, J. Visible-Light Mediated Deuteration of Silanes
with Deuterium Oxide. Chem. Sci. 2019, 10, 7340–7344.
(24) An anionic Ni(0) complex has been proposed in related base-
promoted catalytic C–O bond cleaving reactions. See: Xu, L.; Chung,
L. W.; Wu, Y.-D. Mechanism of Ni-NHC Catalyzed Hydrogenolysis of
Aryl Ethers: Roles of the Excess Base. ACS Catal. 2015, 6, 483-493
(19) (a) Guan, B.-T.; Xiang, S.-K.; Wang, B.-Q.; Sun, Z.-P.; Wang, Y.;
Zhao, K.-Q.; Shi, Z.-J. Direct Benzylic Alkylation via Ni-Catalyzed
Selective Benzylic sp3 C−O Activation. J. Am. Chem. Soc. 2008, 130,
3268–3269. (b) Cao, Z.-C.; Yu, D.-G.; Zhu, R.-Y.; Wei, J.-B.; Shi, Z.-J.
Direct cross-coupling of benzyl alcohols to construct
(25) For studies on related endothermic C–O bond oxidative
addition reactions with Ni(0), see ref 8c and ref 9b.
diarylmethanesviapalladium catalysis. Chem. Commun. 2015,(5216,)(a (26) For studies on the reduction of isolated Ni(II) complexes,
2683–2686. (c) Yu, D.-G.; Wang, X. ; Zhu, R.-Y.; Luo, S.; Zhang, X.-B.;
Wang, B.-Q.; Wang, L.; Shi, Z.-J. Direct
Arylation/Alkylation/Magnesiation of Benzyl Alcohols in the
Presence of Grignard Reagents via Ni-, Fe-, or Co-Catalyzed sp3 C–
O Bond Activation J. Am. Chem. Soc. 2012, 134, 14638.
see: (a) Saper, N. I.; Hartwig, J.F. Mechanistic Investigations of the
Hydrogenolysis of Diaryl Ethers Catalyzed by Nickel Complexes of
N-Heterocyclic Carbene Ligands. J. Am. Chem. Soc. 2017, 139,
17667-17676. (b) Kelley, P.; Lin, S.; Edouard, G.; Day, M.; Agapie,
T. Nickel-Mediated Hydrogenolysis of C-O Bonds of Aryl Ethers:
What Is the Source of the Hydrogen? J. Am. Chem. Soc. 2012, 134,
5480-5483.
(20) Ohgi, A.; Nakao, Y. Selective Hydrogenolysis of Arenols with
Hydrosilanes by Nickel Catalysis. Chem. Lett. 2016, 45, 45–47.
(21) Wiensch, E. M.; Todd, D. P.; Montgomery, J. Silyloxyarenes as
Versatile Coupling Substrates Enabled by Nickel-Catalyzed C−O
Bond Cleavage. ACS Catal. 2017, 7, 5568–5571.
[H] to alcohol
then FGI
then [H] to Me
multistep synthesis
harsh metal hydrides
poor chemoselectivity
common route
O
direct reduction
H
C
3
Ar
Ni catalyst
TMDSO/KOtBu
direct route
up to 88% yield
>40 examples
Ar
OMe
synthesis
Ar CD3
7
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