Controlled Reduction of Carboxamides to Alcohols or Amines by Zinc Hydrides

Article abstract of DOI:10.1002/anie.201900233

New protocols for controlled reduction of carboxamides to either alcohols or amines were established using a combination of sodium hydride (NaH) and zinc halides (ZnX₂). Use of a different halide on ZnX₂ dictates the selectivity, wherein the NaH-ZnI₂ system delivers alcohols and NaH-ZnCl₂ gives amines. Extensive mechanistic studies by experimental and theoretical approaches imply that polymeric zinc hydride (ZnH₂)_∞ is responsible for alcohol formation, whereas dimeric zinc chloride hydride (H?Zn?Cl)₂ is the key species for the production of amines.

Full text of DOI:10.1002/anie.201900233

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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International Edition
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Accepted Article
Title: Controlled Reduction of Carboxamides to Alcohols or Amines by
Zinc Hydrides
Authors: Derek Yiren Ong, Zhihao Yen, Asami Yoshii, Julia Revillo
Imbernon, Ryo Takita, and Shunsuke Chiba
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201900233
Angew. Chem. 10.1002/ange.201900233
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10.1002/anie.201900233
Angewandte Chemie International Edition
COMMUNICATION
Controlled Reduction of Carboxamides to Alcohols or Amines by
Zinc Hydrides
Derek Yiren Ong,a Zhihao Yen,a Asami Yoshii,a Julia Revillo Imbernon,a Ryo Takita*b and Shunsuke
Chiba*a
Abstract: New protocols for controlled reduction of carboxamides to
alcohols or amines were established using combination of sodium
hydride (NaH) and zinc halides (ZnX2). Use of the different halide on
ZnX2 dictates the selectivity, where the NaH-ZnI2 system delivers
alcohols and that with ZnCl2 gives amines. Extensive mechanistic
studies by experimental and theoretical approaches imply that
polymeric zinc hydride (ZnH2)∞ is responsible for alcohol formation,
whereas dimeric zinc chloride hydride (H-Zn-Cl)2 is the key species
for production of amines.
the NaH-ZnX2 system (Scheme 1B). The halide ions on the ZnX2
play a critical role on the selectivity: use of ZnI2 offers selective
synthesis of alcohols, whereas ZnCl2 allows for the formation of
amines. The discovery, optimization, scope and limitation as well
as the detailed mechanistic investigation are described.
A. Reduction of carboxamides
O
aldehydes
R
H
aqueous
quench
Carboxamides have enriched chemical reactivity, and thus
have been utilized as adaptive materials in a series of synthetic
transformations for production of fine chemicals in various
fields.[1] Among them, reduction of carboxamides, commonly
mediated by metal hydrides, is one of the most frequently used
processes, that potentially delivers three possible products;
aldehydes, alcohols, and amines (Scheme 1A).[2,3] Aldehydes
are synthesized when tetrahedral anionic carbinol amine
intermediates I, formed via the first hydride transfer, are kept
intact prior to the aqueous quench. On the other hand, alcohols
or amines could be formed when the tetrahedral intermediates I
fragment through C-N or C-O bond scission, respectively, and
the resulting aldehydes or imine/iminium intermediates are
reduced by the second hydride. At present, the state-of-the-art
approaches for reduction of amides to alcohols are catalytic
hydrogenation by well-defined pincer complexes based on Ru,
Fe, and Mn under a highly pressurized H2 atmosphere,[4]
whereas those for production of amines are facilitated by
hydrosilylation[5] with various metals[6] or organoboranes[7] as
catalysts or through electrophilic activation of amides with triflic
anhydride.[8,9] Methodologies leveraging means of single-
electron-reduction have recently been emerged, enabling
controlled reduction of amides.[10] Nonetheless, implementation
of the amide reduction with precise and predictable control of the
C-N/C-O cleavage for the formation of alcohol/amine still
remains a challenge, that requires the sophisticated design of
the reaction settings. Herein, we report concise protocols for
controlled reduction of carboxamides to alcohols or amines by
O
[M]
H
O
C-N
R” scission
R”
[M]-H
O
[M]-H
R
N
R
OH
R
N
R’
R
H
alcohols
R’
amides
I
tetrahedral
intermediate
R”
N
C-O
scission
R
R’
R”
H
[M]-H
N
R’
amines
R
B. Controlled reduction of amides to alcohols or amines (this work)
O
NaH-ZnI2
NaH-ZnCl2
R
NMe2
R
OH
R
NMe2
Scheme 1. Reduction of carboxamides
We have recently uncovered a concise protocol to activate
NaH in the presence of dissolving iodides such as NaI/LiI in
tetrahydrofuran
unprecedented
hydrodecyanation
(THF)
reductive
of
and
the
composite
performs
transformations
benzyl
such
as
α-quaternary
cyanides,[11]
hydrodehalogenation of haloarenes,[12,13] and controlled
reduction of N,N-dimethylcarboxamides to aldehydes.[11,14] In
these reactions, it is assumed that activated NaH could be
generated through counter ion metathesis between polymeric
inactive NaH with dissolving NaI/LiI.[15] Stimulated by these
findings, our attention is directed to use of NaH for generation of
new metal hydrides of interest through the counter ion
metathesis with the corresponding metal halides and exploration
of their reactivity.
[a]
[b]
D. Y. Ong, Z. Yen, A. Yoshii, J. Revillo Imbernon, Prof. S. Chiba
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University, Singapore 637371 (Singapore)
E-mail: shunsuke@ntu.edu.sg
There have been reported a number of examples on
synthesis and characterization of molecular zinc hydrides in
either dimeric bridged hydride form or monomeric mono-hydride
form with proper chelating ligands, while their reactivity has been
examined only for reduction of simple and reactive carbonyl
compounds.[16-18] Ashby previously reported formation of
polymeric (ZnH2)∞ by mixing NaH and ZnI2 in THF for 24 h,[19]
Prof. R. Takita
Graduate School of Pharmaceutical Sciences, The University of
Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
E-mail: takita@mol.f.u-tokyo.ac.jp
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201900233
Angewandte Chemie International Edition
COMMUNICATION
whereas its detailed reactivity for the hydride reduction has thus
far not been examined. Considering that the counter ion
metathesis between NaH and ZnX2 (X = I, Br, Cl) includes a
double hydride-halide exchange, we assume that their reaction
kinetics will become different depending on the halide ion, thus
resulting in formation of different zinc hydride complexes having
unique chemical reactivity. Based on these backgrounds, we
first examined the reaction of amide 1a with NaH (3 equiv) and
ZnI2 (1.5 equiv) in THF (Table 1, entry 1). We found that the
reaction at 40 °C afforded alcohol 2a in 76% yield as the major
product with 22% yield of amine 3a. Interestingly, decreasing of
the amount of ZnI2 to 1 equiv could accelerate the process and
improved the yield of alcohol 2a to 88% (entry 2). Moreover,
addition of 1 equiv of NaI could suppress the formation of amine
completely to form alcohol 2a as a sole product in 95% yield
(entry 3). In the sharp contrast, it was found that the reaction
with ZnBr2 or ZnCl2 (1.5 equiv) in the presence of NaH (3 equiv)
delivered amine 3a as the major product (entries 4 and 5).
Furthermore, increase of the amounts of NaH and ZnCl2 to 5
equiv and 2.5 equiv, respectively, renders the process more
selective and efficient (entry 6). The reaction at 60 °C completed
the process within 30 min, giving amine 3a in 90% yield (entry 7).
It should be noted that both protocols could be implemented in
40 mmol scale, emphasizing the scalable nature of the present
protocols (Table 1, entries 3 and 7).
quaternary amides 1ab-1af could be reduced smoothly and
selectively to the corresponding alcohols 2 or amines 3. We
also observed that the reduction of amides 1ag-1al having
enolizable α-protons proceeds well in general to afford the
corresponding alcohols or amines in good yields except for
conversion of cyclopropanecarboxamide 1ak and α-secondary
amide 1al into the corresponding alcohols 2ak and 2al,
respectively, that is concomitant with formation of a significant
amount of the corresponding amines 3.
Table 1: Optimization of reaction conditions.[a]
NaH
ZnX2
O
additive
NMe2
+
Ar
NMe2
Ar
OH
THF
conditions
2a
3a
1a
(Ar = 2-naphthyl)
yield [%][b]
NaH
(equiv)
ZnX2
(equiv)
additive
(equiv)
Temp
[°C]
t
[h]
Run
2a
76
3a
22
ZnI2
(1.5)
1
2
3
4
5
6
7
3
3
3
3
3
5
5
–
–
40
40
40
40
40
40
60
1.5
3
ZnI2
(1)
88
11
0
With the optimized reaction conditions (Table 1, entry 3 for
formation of alcohols 2; entry 7 for formation of amines 3), we
next investigated the scope and limitations of this controlled
reduction of carboxamides 1 (Scheme 2). For reduction of
aromatic amides (1b-1t), the process was not influenced by the
presence of a sterically demanding aromatic ring (for 1c-1e) and
tolerated substitution of different electronic nature such as
electro-donating groups (for 1f-1n) and electron-withdrawing
groups including halogen atoms that are often susceptible to the
common hydride reduction conditions (for 1o-1t) (Scheme 2A).
Amides based on electron-rich 5-membered heteroaromatic
rings such as indole 1u, pyrrole 1v, benzofuran 1w,
benzothiophene 1x and thiophene 1y as well as electron-
deficient 6-membered ring ones including quinoline 1z and
pyridine 1aa were also compatible (Scheme 2B). We found that
the current protocols are amenable to reduce a series of
ZnI2
(1)
NaI
(1)
95
(97)[c]
7
ZnBr2
(1.5)
–
–
–
–
7
18
8
53
62
88
ZnCl2
(1.5)
6
ZnCl2
(2.5)
2.5
0.5
6
ZnCl2
(2.5)
90
(89)[c]
4
[a] The reactions were conducted using 0.5 mmol of 1a in THF (2.5 mL). [b] 1H
NMR yields. [c] Isolated yields in the reactions of 40 mmol scale. NMR =
nuclear magnetic resonance.
aliphatic amides (Scheme 2C).
Sterically congested α-
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10.1002/anie.201900233
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COMMUNICATION
NaH (3 equiv)
ZnI2 (1 equiv)
NaI (1 equiv)
NaH (5 equiv)
ZnCl2 (2.5 equiv)
O
R
NMe2
R
OH
R
NMe2
THF, 60 °C
THF, 40 °C
2
3
1
A. Aromatic amides
O
alcohols amines
alcohols amines
alcohols amines
alcohols amines
O
O
O
O
2
3
2
3
2
3
2
3
NMe2
NMe2
O
O
NMe2
1k
NMe2
1b
R
3k 83%
2k 87%
R
2b 89% 3b 81%
2c 98% 3c 80%
Ph
1o (R = F)
2o 76% 3o 86%
2p 87% 3p 70%
2q 87% 3q 70%
2r 95% 3r 58%
1f (R = OMe)
1g (R = OBn)
1h (R = OTIPS)
2f 95%
3f 75%
2g 97% 3g 78%
2h 89% 3h 86%
1p (R = Cl)
1q (R = Br)
1r (R = CF3)
O
MeO
BnO
NMe2
1l
NMe2
2l 82% 3l 82%
OMe O
Cl
O
O
1c
MeO
NMe2
NMe2
NMe2
2s 86%
3s 63%
1i
2i 66% 3i 62%
R
O
O
1m
2m 88% 3m 82%
1s
O
NMe2
Cl
O
O
NMe2
NMe2
2d 89% 3d 74%
NMe2
1d (R = Me)
1e (R = Bn)
3j 89%
2j 92%
1j
3e 67%
2e 98%
NMe2
Fe
2n 69%[b]
3n 86%
1n
MeO
2t 90%
1t
3t 77%
Br
B. Heteroaromatic amides
alcohols amines
alcohols amines
alcohols amines
alcohols amines
O
NMe2
2
3
2
3
2
3
2
3
O
O
O
1y 2y 74% 3y 75%
3z 56%
Me
2z 93%
2u 89% 3u 78%
3w 80%
1z
1u
1w 2w 76%
O
S
N
Me
S
NMe2
Me
NMe2
NMe2
N
Ph
O
O
1v 2v 75% 3v 78%
3x 88%
2x 82%
O
1x
1aa
3aa 55%
N
Bn
2aa 84%
Ph
N
NMe2
NMe2
NMe2
C. Aliphatic amides
alcohols amines
alcohols amines
alcohols amines
alcohols amines
Me
2
3
2
3
2
3
2
3
O
O
O
Ph
3
NMe2
N
3ab 77%
1ab 2ab 97%
NMe2
NMe2
1aj[d]
O
O
1ae 2ae 90% 3ae 72%
NMe2
1ag
2ag 92% 3ag 68%
2aj 91% 3aj 84%
Bn
Me
O
3
NMe2
O
Ph
3ac 77%
3ad 68%
O
1ac 2ac 86%
1ah 2ah 76% 3ah 81%
NMe2
NMe2
2ak 56%[e]
2al 44%[f]
3ak 76%
1ak
O
NMe2
O
H
O
1af 2af 88% 3af 68%[c]
Ph
3
NMe2
1ad
Ph
O
H
2ad 92%
NMe2
2ai 74% 3ai 77%
1ai
3al 79%
4
NMe2
O
1al
Scheme 2. Substrate scope. [a] The reactions were conducted using 0.5 mmol of amides 1. Isolated yields of alcohols 2 and amines 3 are given. [b] The reaction
was conducted using 5 equiv of NaH, 2 equiv of ZnI2 and 2 equiv of NaI. [c] The reaction was conducted using 7 equiv of NaH and 3.5 equiv of ZnCl2. [d] 1aj
>98%ee; 2aj >97%ee; 3aj >98% ee measured by the Mosher method (see the SI). [e] Amine 3ak was formed in 35% yield. [f] Amine 3al was formed in 31% yield.
Ph = phenyl; Bn = benzyl; TIPS = triisopropylsilyl.
It is noteworthy that the reactions of α-enantioenriched
amides 1am and 1am’ derived from the Myers chiral auxiliary[20]
under the NaH-ZnI2 system delivered alcohols (S)- and (R)-2am
with complete retention of the α-chirality (Scheme 3).
NaH (5 equiv)
ZnI2 (2 equiv)
NaI (2 equiv)
O
Ph
OH
Ph
Ph
Ph
Ph
N
OH
THF, 40 °C
(S)-2am
83%, 99%ee
1am 99% de
To identify the active zinc hydride species, we designed
several experiments as shown in Scheme 4. By following the
2 h
NaH (5 equiv)
ZnI2 (2 equiv)
NaI (2 equiv)
Ashby’s protocol,[19] zinc hydride polymer (ZnH2)∞
4 was
O
N
Ph
OH
prepared and its infrared (IR) spectroscopy analysis showed one
strong absorption band at 1443 cm–1 (Scheme 4A). Amide 1a
was then added to the mixture of the resulting (ZnH2)∞ 4, that
provided alcohol 2a in 92% yield. Interestingly, when a 3:1:1
mixture of NaH, ZnI2, and NaI was stirred at 24 °C for 3 h,
formation of (ZnH2)∞ 4 could be observed by the IR spectroscopy,
while no other zinc hydride species was found from the mixture
OH
1am’ 99% de
THF, 40 °C
(R)-2am
2 h
87%, 99%ee
Scheme 3. Reduction of enantioenriched amides.
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10.1002/anie.201900233
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(Scheme 4B).[21] Lower frequency shift of the band was
observed when NaD[22] was used as a deuteride source. These
reactions of benzamide with ZnH2 dimer as the model of (ZnH2)∞
4[25] or zinc hydride chloride dimer 5 were thus carried out at the
ωB97XD/SDD&6-31+G* (scrf = smd, THF) level of theory. In the
cases of both complexes, by taking advantage of the flexible
conformation change in dimeric structures, the efficient amide
reduction lead to the formation of stable tetrahedral
intermediates (i.e. INT1’ complexes). Thus, the selectivity for
benzyl alcohol or amine formation should be determined
kinetically by the energy barriers of the subsequent C–O/C–N
bond scission processes. With the ZnH2 dimer (Scheme 5A),
both oxygen and nitrogen atoms can coordinate to two zinc
centers in INT1’ZnH2/C-N, and the C–N bond scission efficiently
proceeds with the activation barrier of +16.0 kcal/mol. In contrast,
the C–O scission process begins from the stable INT1’ZnH2/C-O, in
which two zinc centers of dimeric species activates the oxygen
atom. The C–O bond is cleaved, concomitant with the
degradation of dimeric structure and formation of Zn-O-Zn
species in INT2ZnH2/C-O, which requires a rather high energy (∆G‡
+35.5 kcal/mol). The further reductions into benzyl alcohol/amine
were found to proceed readily with the generated zinc hydride in
INT2 complexes (see the SI), while other hydride species may
also be possibly involved. Scheme 5B depicts the reaction
pathways promoted by the zinc hydride chloride dimer. With the
aid of Lewis acidic monomeric ZnCl2(thf) generated in the
formation of tetrahedral intermediate, the C–O bond cleavage is
kinetically feasible via TS2ZnHCl/C-O (∆G‡ +21.3 kcal/mol) to afford
the iminium intermediate INT2ZnHCl/C-O. On the other hand, the
C–N bond scission starts from the stable complex INT1’ZnHCl/C-N
having the O,N-chelation to one zinc center, and requires a
higher activation energy (∆G‡ +26.3 kcal/mol). Thus, these
calculated results clearly explain that the amide reduction by
both NaH-ZnI2 and NaH-ZnCl2 system proceeds smoothly and
selectively. In particular, given that 1) the flexible conformation
change is profitable for the first amide reduction, 2) the dimeric
ZnH2 species efficiently activates the tetrahedral intermediate for
the C–N scission process, and 3) the formation of Lewis acidic
ZnCl2 facilitates the dissociation of Zn-O-Zn species, the
structural and electronical requirements on each active species
are responsible for the controlled reduction process.
experimental observation suggested that (ZnH2)∞
4
is
responsible for the alcohol formation. On the other hand,
treatment of a 2:1 mixture of NaH and ZnCl2 within 10 min in
THF afforded
a distinct zinc hydride species having an
absorption at 1648 cm–1 in the IR spectrum and a broad peak at
δ 3.71 in the 1H NMR spectrum (Scheme 4C). We detected
mass of zinc hydride chloride dimer with two THF molecules by
the cold-spray time-of-flight (TOF) mass. Based on the reported
data[23] as well as the theoretical prediction, we characterized
this zinc hydride chloride dimer as chloride bridged terminal
hydride 5,[24] which should be the reactive species for the
formation of amines. We found that the second hydride-chloride
exchange from 5 to (ZnH2)∞ 4 would be much slower. This could
be ascertained by the incubation study of the NaH-ZnCl2 system
for the reduction of 1a (Scheme 4D). While the direct treatment
of 1a with NaH and ZnCl2 gave alcohol 2a in less than 4% yield
with 90% yield of amine 3a (Table 1, entry 7), treatment of 1a
after incubation of the mixture of NaH and ZnCl2 for 5 h
significantly increased the amount of alcohol 2a to 54% yield
with 44% yield of amine 3a. Incubation for 12 h completely
switched the selectivity toward formation of alcohol 2a.
A. Preparation of (ZnH2)∞ by Ashby’s protocol
O
NaH
(5 equiv)
Ar
NMe2
1a
(ZnH2)∞
4
IR: 1443 cm–1
+
ZnI2
(2.5 equiv)
Ar
OH
THF
24 °C, 24 h
40 °C, 3 h
2a 92%
(Ar = 2-naphthyl)
B. Formation of (ZnH2)∞ from the NaH-ZnI2-NaI system
NaH
NaD
(3 equiv)
(3 equiv)
+
+
ZnI2
(1 equiv)
ZnI2
(1 equiv)
(ZnH2)∞
4
(ZnD2)∞ 4-d
THF
24 °C, 1 h
IR: 1443 cm–1
(for Zn-H)
THF
24 °C, 3 h
IR: 1048 cm–1
(for Zn-D)
+
NaI
+
NaI
(1 equiv)
(1 equiv)
C. Formation of (H-Zn-Cl)2 from the NaH-ZnCl2 system
H
NaH
(2 equiv)
O
Cl
The present protocols offer concise and cost-economical
Zn
Zn
(ZnH2)∞
alternatives
for controlled
reduction
of bench-stable
Cl
O
+
H
slow
4
THF
24 °C
10 min
carboxamides into alcohols and amines. Further studies on the
chemical reactivity of these zinc hydrides are under investigation.
ZnCl2
(1 equiv)
5
for Zn-H
found theoretical*
IR (cm–1
1H NMR (δ)
)
1648
3.71
1711
3.84
*at M06-2X/cc-pVTZ
scrf=(smd, THF)
D. Incubation of the NaH-ZnCl2 system
Acknowledgements
O
NaH
(5 equiv)
Ar
NMe2
1a
This work was supported by funding from Nanyang
Technological University (NTU) (for S.C.), the Singapore
Ministry of Education (Academic Research Fund Tier 1:
RG10/17 for S.C.), and Takeda Science Foundation (for R.T.).
Computations were performed using Research Center for
Computational Science at Okazaki, Japan. We thank Prof.
Subodh G. Mhaisalkar (School of Materials Science and
Engineering, NTU) and Prof. Han Sen Soo (School of Physical
and Mathematical Sciences, NTU) for the assistance in powder
X-ray diffraction (XRD) experiments.
+
OH
Ar
NMe2
+
Ar
THF
24 °C
time
60 °C, 3 h
ZnCl2
(2.5 equiv)
2a
3a
time
0 h
5 h
<4%
54%
96%
90%
44%
<1%
12 h
Scheme 4. Characterization of the active zinc hydride species.
To gain the insights into the detailed reaction pathway and
selectivity, density functional theory (DFT) calculations for model
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10.1002/anie.201900233
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COMMUNICATION
A. Reaction pathways of benzamide reduction promoted by ZnH2 dimeric species
H
C-N
scission
pathway
H
1.57
1.56
H
1.57
H
1.57
H
1.58
‡
1.61
H
1.90
H
thf
H
Zn
thf
1.61
Zn
1.58
Zn
1.58
2.60
1.82
thf
Zn
2.44
∆G‡ +16.0
Zn
1.88
2.30
2.18
1.92
H
Zn
H
H
1.61
1.76
O
O
H
1.61
thf
2.19
O
O
1.12
2.49
1.68
O
H
2.41
1.23
1.23
H
1.10
1.10
1.25
1.37
Zn
1.36
1.34
1.55
1.10 H
H
H
1.47
Zn
Zn
Me
Me
H
1.88
1.58
Zn 1.55
1.57
N
H
Me N1.86
N
2.14
Me
1.53
N
N
H
Me
thf
Me
Me
Me
Me
Me
INT0ZnH2
(0.0)
INT1ZnH2
(–1.6)
INT1’ZnH2/C-N
(–4.5)
TS2ZnH2/C-N
(11.5)
INT2ZnH2/C-N
(13.1)
‡
thf
2.28
H
Zn1.66
1.58
H
1.79
H
H
1.54
H
thf
2.03
H
Zn
1.67
1.59
thf
1.64
2.45
Zn
O
2.49
1.65
O
‡
thf
1.71
2.22
1.81
1.54
H
O
Zn
1.79
1.56
1.28 1.66 H
H
Zn
1.94
1.64
Zn
H
∆G‡ +35.5
Zn 1.57
1.64
1.95
H
Zn
1.78
Me
1.99
N
1.38
2.03
1.40
1.45
H
H
O
Me
2.68
H
H
1.11
1.29
H
1.10
Me
Me
Me
1.08
N
N
C-O
scission
pathway
TS1ZnH2
(15.2)
1.29
N
Me
Me
Me
INT1’ZnH2/C-O
TS2ZnH2/C-O
INT2ZnH2/C-O
(–6.6)
(28.9)
(25.8)
B. Reaction pathways of benzamide reduction promoted by ZnHCl dimeric species
C-N
scission
pathway
H
Cl
H 1.56
1.54
2.20
Cl
2.26
thf
2.08
1.54
Cl
2.03
‡
2.20 Zn
thf
H
2.08
H
2.31
1.53
Cl
2.26
Zn
Zn
1.87
Cl
Zn
Cl
Cl
2.09
1.85
2.24
∆G‡ +26.3
Zn
1.97
Zn
1.86
2.23
1.54
Me
2.21
2.22
Cl
H
Zn
H
N
2.41
2.06
2.04
2.23
Zn
1.57
1.97
thf
N
Zn
2.15
Cl
Zn
2.15
O
O
O
1.40
Cl
Me
O
O
thf
Me
1.26
Me
2.06
Me
1.39
H
1.24
1.24
1.50
1.47
Me
Me
N
N
N
1.10
1.33
H
thf
H
H
Me
Me
1.12
Me
INT0ZnHCl
(0.0)
INT1ZnHCl
(11.1)
INT1’ZnHCl/C-N
TS2ZnHCl/C-N
(12.6)
INT2ZnHCl/C-N
(–13.7)
(11.5)
H
1.55
‡
Zn 2.24
2.45
H
1.95
2.41
Cl
thf
1.54
O
1.30
Cl
‡
Cl
2.31
Cl
2.24
Zn
2.32
2.12 Zn
1.39Me
Cl
1.79
∆G‡ +21.3
H
Zn 1.53
2.06
Zn
2.01
2.23
1.65
thf 2.13 Zn
1.88
Cl 2.31
2.14
1.87
N
thf
O
H
O1.79
H
1.54
Zn
1.89
O
Zn 2.29
1.52 Me
Cl
H
Me
1.44
Me
Me
1.09
1.44
2.94
Cl
1.29 N
Me
thf
C-O
scission
pathway
TS1ZnHCl
(16.5)
N
1.09
N
1.29
H
Me
H
1.10
Me
INT1’ZnHCl/C-O
TS2ZnHCl/C-O
(13.1)
INT2ZnHCl/C-O
(–8.2)
(11.0)
Scheme 5. DFT calculations for model reactions of benzamide with (ZnH2)2 or (ZnHCl)2 species. Energy changes and bond lengths at the ωB97XD/SDD&6-
31+G* (scrf = smd, THF) level of theory are shown in kcal/mol and Å, respectively.
ACS Catal. 2016, 6, 47. With Fe: d) N. M. Rezayee, D. C. Samblanet,
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Derek Yiren Ong,a Zhihao Yen,a Asami
Yoshii,a Julia Revillo Imbernon,a Ryo
Takita*b and Shunsuke Chiba*a
Page No. – Page No.
Controlled
Reduction
of
Carboxamides to Alcohols or Amines
by Zinc Hydrides
New protocols for controlled reduction of carboxamides to alcohols or amines were
established using combination of sodium hydride (NaH) and zinc halides (ZnX2).
Use of the different halide on ZnX2 dictates the selectivity, where the NaH-ZnI2
system delivers alcohols and that with ZnCl2 gives amines.
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