Mechanistic Study of SmI2/H2O and SmI2/Amine/H2O-Promoted Chemoselective Reduction of Aromatic Amides (Primary, Secondary, Tertiary) to Alcohols via Aminoketyl Radicals

Article abstract of DOI:10.1021/acs.joc.7b00372

Samarium(II) iodide-water and samarium(II) iodide-water-amine complexes have been recognized as valuable reagents for the selective generation of aminoketyl radicals from amides and derivatives. The resulting aminoketyl radicals can undergo reduction or reductive cyclization pathways, providing a powerful method for (i) direct synthesis of alcohols from amides by the challenging N-C bond scission and (ii) synthesis of nitrogen-containing heterocycles via polarity reversal of the amide bond. This report describes mechanistic investigation into samarium(II) iodide-water and samarium(II) iodide-water-amine-mediated generation of benzylic aminoketyl radicals from aromatic primary, secondary, and tertiary amides (benzamides). The mechanistic experiments suggest that the rate and selectivity of the reduction is closely dependent on the water concentration and the type of amide undergoing the reduction. The data also suggest that benzylic aminoketyl radicals generated in the reduction of benzamides are significantly more dependent on the electronic effects of α-substitution than the corresponding aminoketyl radicals generated by single-electron transfer to unactivated aliphatic amides; however, little variation in terms of steric influence of N-substituents is observed. These observations will have implications for the design of reductive processes involving Sm(II)-mediated reduction of amides and reductive umpolung cyclizations via aminoketyl radicals as a key step.

Full text of DOI:10.1021/acs.joc.7b00372

Article
pubs.acs.org/joc
Mechanistic Study of SmI /H O and SmI /Amine/H O‑Promoted
2
2
2
2
Chemoselective Reduction of Aromatic Amides (Primary, Secondary,
Tertiary) to Alcohols via Aminoketyl Radicals
Syed R. Huq, Shicheng Shi, Ray Diao, and Michal Szostak*
Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United States
*
S Supporting Information
ABSTRACT: Samarium(II) iodide−water and samarium(II)
iodide−water−amine complexes have been recognized as
valuable reagents for the selective generation of aminoketyl
radicals from amides and derivatives. The resulting aminoketyl
radicals can undergo reduction or reductive cyclization
pathways, providing a powerful method for (i) direct synthesis
of alcohols from amides by the challenging N−C bond scission
and (ii) synthesis of nitrogen-containing heterocycles via polarity reversal of the amide bond. This report describes mechanistic
investigation into samarium(II) iodide−water and samarium(II) iodide−water−amine-mediated generation of benzylic
aminoketyl radicals from aromatic primary, secondary, and tertiary amides (benzamides). The mechanistic experiments suggest
that the rate and selectivity of the reduction is closely dependent on the water concentration and the type of amide undergoing
the reduction. The data also suggest that benzylic aminoketyl radicals generated in the reduction of benzamides are significantly
more dependent on the electronic effects of α-substitution than the corresponding aminoketyl radicals generated by single-
electron transfer to unactivated aliphatic amides; however, little variation in terms of steric influence of N-substituents is
observed. These observations will have implications for the design of reductive processes involving Sm(II)-mediated reduction of
amides and reductive umpolung cyclizations via aminoketyl radicals as a key step.
INTRODUCTION
In 2014, the first general process for the reduction of all types
of aliphatic amides (primary, secondary, and tertiary) to
alcohols with high C−N bond cleavage selectivity using
■
The reduction of amides is among the most important and
valuable processes in organic synthesis because of the versatility
of the resultant amine and alcohol reduction products in
15
SmI −amine−water reagent was reported (Figure 2A). The
2
1
success of this reaction relies on the high reduction potential of
industrial and academic settings. Typically, amide reduction
the SmI −amine−water reagent (E = −2.8 V vs SCE) that
2
1/2
proceeds via C−O bond cleavage in the tetrahedral
intermediate, resulting in the amine reduction products, and
many reagents and conditions for this transformation have been
permits direct electron transfer to unactivated aliphatic amides.
In the same year, mechanistic investigation of the reduction of
2
,3
aliphatic amides to alcohols using SmI −amine−water was
2
reported. In contrast, the analogous amide reduction to
16
reported (Figure 2B). These reactions exploit the synergistic
alcohols by selective C−N bond scission remains severely
underdeveloped (Figure 1A).
4
,5
effect of water and amines on increasing the reducing power of
17
Sm(II)-based reagents as elegantly demonstrated in several
Recently, samarium(II) iodide−water and samarium(II)
1
8
6
,7
breakthrough studies by Hilmersson and co-workers;
iodide−water−amine complexes have emerged as valuable
however, the corollary of using highly powerful reductants
involves the low stability of the formed aminoketyl radical
intermediates. In contrast, the use of a milder (E = −1.3 V vs
reagents for the selective generation of aminoketyl radicals from
8
amides and derivatives. The resulting aminoketyl radicals can
9
10
1
/2
undergo reduction or reductive cyclization pathways,
19
20,21
SCE) and much more selective SmI −water system
for
2
providing a powerful method for (i) direct synthesis of alcohols
from amides by the challenging N−C bond scission which is
often not easily available by other methods and (ii) synthesis of
nitrogen-containing heterocycles via polarity reversal of the
amide bond to enable nucleophilic reactivity of the typically
the reduction of amides has received comparatively less
attention. Limited studies on the reduction of primary aromatic
amides have been reported by Kamochi and Kudo (Figure
22,23
20a
2
C);
however, the role of water ligand and selectivity of
1
1,12
the amide reduction has not been investigated. Moreover, the
reduction side products have often been observed in the course
of umpolung reductive cyclization processes of amide
derivatives using SmI −H O, such as cyclic imides introduced
electrophilic amides (Figure 1B).
Coordination of the
13
14
azaphilic Lewis acid Sm to nitrogen at the carbinolamine
stage provides a driving force for the collapse of the
carbinolamine intermediate with high N−C bond scission
selectivity (Figure 1C). Note that Sm(III) might be able to act
as a specific Lewis acid, leading to changes in the reaction
selectivity.
2
2
Received: February 17, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.7b00372
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Article
particularly significant when considering (1) the fundamental
importance of the synthesis of alcohols from common, bench-
1
−3
stable amide precursors
where selected recent examples of
SmI -mediated reduction of carboxylic acid derivatives and
2
heterocycles demonstrate the utility of this reagent in complex
6
,19
synthesis; (2) the potential to engage the formed aminoketyl
radicals in reductive umpolung cyclization events to rapidly
6
−8
build up molecular complexity,
a process that, for example,
has been elegantly demonstrated by Procter and co-workers in
25
complex cyclization cascades of amide derivatives; and (3) the
potential to exploit these more easily reducible substrates in
other processes involving ketyl-type radicals, including photo-
27,28
redox catalysis.
Note that the use of aliphatic carboxylic
acid derivatives is currently beyond the scope of photoredox
mechanisms.
Herein, we present a systematic mechanistic investigation
into SmI −water and SmI −water−amine-mediated generation
2
2
of benzylic aminoketyl radicals from aromatic primary,
secondary, and tertiary amides (benzamides). The mechanistic
experiments suggest that the rate and selectivity of the
reduction is closely dependent on the water concentration
and the type of amide undergoing the reduction. The data also
suggest that benzylic aminoketyl radicals generated in the
reduction of benzamides are significantly more dependent on
the electronic effects of α-substitution than the corresponding
aminoketyl radicals generated by single-electron transfer to
unactivated aliphatic amides; however, little variation in terms
of steric factors of N-substituents is observed. A significant
difference in the reduction selectivity between the SmI −H O
Figure 1. Reaction pathways in the reduction of amides and derivatives
via (a) closed-shell and (b, c) open-shell mechanisms.
2
2
and SmI −H O−amine reagents in the reduction of secondary
2
2
and tertiary benzamides has been identified. Selectivity studies
demonstrate the relative reactivity order of carboxylic acid
derivations with Sm(II)-based reagents. Overall, these obser-
vations will have important implications for the design and
optimization of new reductive processes involving Sm(II)-
mediated reduction of amides to alcohols and reductive
umpolung cyclizations via aminoketyl radicals as a key step.
RESULTS AND DISCUSSION
■
SmI −H O: Effect of Water Stoichiometry. To gain
2
2
preliminary insight into the role of water as an activating ligand
21,20a,23
for Sm(II) in the reduction of aromatic amides,
of studies were conducted (Tables 1−3). 4-Methoxybenzamide
1), N-butyl-4-methoxybenzamide (3), and N,N-diethyl-4-
a series
(
methoxybenzamide (4) were selected as model substrates in
the reduction of primary, secondary, and tertiary aromatic
amides. No reaction was observed in the absence of water for
Figure 2. Previous studies (a−c) and this study (d) on the reduction
all three amides for prolonged reaction times (18 h, Tables
of amides to alcohols using Sm(II)-based reagents.
17
1
1
−3, entry 1). Next, we carefully monitored the reduction of
, 3, and 4 with increasing concentration of water and
24
by our laboratory and barbituric acids as recently elegantly
demonstrated by Procter and co-workers in several cascade
quenching the reactions with air after 5 min reaction time
(Tables 1−3, entries 2−7). Remarkably, upon addition of water
2
5
processes.
Our ongoing interest in umpolung cyclizations by aminoketyl
(50−1600 equiv, 8.3−267 with respect to SmI ) excellent
2
conversions were observed in the reduction of primary amide 1
irrespective of the amount of water used (>85%, Table 1,
entries 2−7). The reduction of secondary amide 3 and tertiary
amide 4 showed a nonlinear dependence on water concen-
24
radicals using Sm(II)-based reagents and reactions of amides
26
proceeding by selective N−C bond scission prompted us to
undertake a thorough mechanistic investigation of the
reduction of aromatic amides to alcohols using SmI −H O
23a
tration (Tables 2 and 3, entries 2−7, and Figure 3). At low
concentrations of water, the rate was found to increase linearly
with slope for both 3 and 4 (50−200 equiv), reaching a
maximum at 100−200 equiv (3) and 200 equiv (4). Next, at
higher concentrations of water (400−1600 equiv), the rate
decreased dramatically, which may be indicative of substrate
2
2
and SmI −amine−H O reagents. While the use of SmI −
2
2
2
amine−H O reagents for the reduction of aliphatic amides has
2
15,16
been well studied,
the possibility of an analogous electron
transfer to common amide substrates that favor reductive transfer
events by their electronic properties remains unexplored. This gap is
B
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Table 1. Reduction of Primary Aromatic Amides to Alcohols
Using SmI −H O: Effect of Water Stoichiometry
2
2
b
b
SmI2
H O
conv
selectivity
(%)
H O/
2
2
a
entry
(equiv)
(equiv)
time
18 h
(%)
SmI2
1
2
3
4
5
6
7
6
6
6
6
6
6
6
0
50
<2
85
0
5 min
5 min
5 min
5 min
5 min
5 min
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
8.3
100
200
400
800
1600
>98
>98
>98
>98
>98
16.7
33.3
66.7
133.3
266.7
a
b
1
Quenched with air after the indicated time. Determined by H
NMR and/or GC−MS of crude reaction mixtures and comparison
c
with authentic samples. Selectivity refers to alcohol/amine ratio.
Conversion = (100 − SM).
Figure 3. Plot of reduction of aromatic amides 1, 3, and 4 using SmI2/
H O as a function of concentration of water.
2
Table 2. Reduction of Secondary Aromatic Amides to
Alcohols Using SmI −H O: Effect of Water Stoichiometry
can lead to lower conversions. The addition of water resulted in
a remarkable rate enhancement for all three amides examined
reaching full (1, > 95%) and appreciable conversion (3, 35−
2
2
3
7%; 4, 71%) after only 5 min reaction time.
A plot of N−C/C−O cleavage selectivity vs water
stoichiometry for amides 1, 3, and 4 is shown in Figure 4. In
b
c
SmI2
H O
conv
selectivity
(%)
H O/
2
2
a
entry
(equiv)
(equiv)
time
18 h
(%)
SmI2
1
2
3
4
5
6
7
6
6
6
6
6
6
6
0
50
<2
21
37
35
23
16
15
0
5 min
5 min
5 min
5 min
5 min
5 min
>98:2
95:5
8.3
100
200
400
800
1600
16.7
33.3
66.7
133.3
88:12
87:13
84:16
82:18
266.7
a
b
1
Quenched with air after the indicated time. Determined by H
NMR and/or GC−MS of crude reaction mixtures and comparison
c
with authentic samples. Selectivity refers to alcohol/amine ratio.
Conversion = (100 − SM).
Table 3. Reduction of Tertiary Aromatic Amides to Alcohols
Using SmI −H O: Effect of Water Stoichiometry
2
2
Figure 4. Plot of selectivity (alcohol/amine) in the reduction of
aromatic amides 1, 3, and 4 using SmI /H O as a function of
concentration of water.
b
c
SmI2
H O
conv
selectivity
(%)
H O/
2
2
a
2
2
entry
(equiv)
(equiv)
time
18 h
(%)
SmI2
1
2
3
4
5
6
7
6
6
6
6
6
6
6
0
50
<2
15
57
71
62
38
19
0
5 min
5 min
5 min
5 min
5 min
5 min
87:13
73:27
71:29
67:33
72:28
75:25
8.3
the reduction of primary amide 1, full N−C cleavage selectivity
for was observed (1, > 95:5) irrespective of ligand
stoichiometry (Figure 4). Interestingly, the reactions of
secondary amide 3 and tertiary amide 4 showed strong
dependence on the reduction selectivity vs concentration of
water (Figure 4); however, in all examples, high N−C scission
selectivity was observed (3, >80:20; 4, >65:35). These results
indicate that (1) water acts as a key additive to facilitate
reduction of primary, secondary, and tertiary benzamides using
100
200
400
800
1600
16.7
33.3
66.7
133.3
266.7
a
b
1
Quenched with air after the indicated time. Determined by H
NMR and/or GC−MS of crude reaction mixtures and comparison
with authentic samples. Selectivity refers to alcohol/amine ratio.
c
Conversion = (100 − SM).
SmI (vide infra); (2) the rate of the reduction of primary
2
benzamides is much faster than that of secondary and tertiary
benzamides; and (3) chemoselective reduction of model
primary, secondary, and tertiary amides by N−C scission is
23a
dissociation from the inner coordination sphere of Sm(II). It
should be noted that contaminants in water or traces of oxygen
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Table 4. Effect of Other Ligands on the Reduction of Tertiary Aromatic Amides to Alcohols Using SmI2
a
b
b
b
entry
ligand
MeOH
SmI (equiv)
ligand (equiv)
time
conv (%)
yield (%)
selectivity
2
1
2
3
4
5
6
6
6
6
4/1 v/v
36
3 h
3 h
3 h
3 h
<2
<2
<2
<2
<5
60
81
t-BuOH
(HOCH2)2
36
12
37:63
62:38
85:15
MeOH/Et N
72/72
>98
>98
3
c
H O/Et N
6
72/72
5 min
2
3
a
b
1
Quenched with air after the indicated time. Determined by H NMR analysis of crude reaction mixtures and comparison with authentic samples.
c
Conversion = (100 − SM). Yield refers to the yield of alcohol. Selectivity refers to alcohol/amine ratio. Other minor decomposition products were
also detected. v/v = by volume. Note that control reactions using more easily reducible primary aromatic amide 1 with MeOH (4/1 v/vol) and t-
BuOH (36 equiv) as ligands resulted in 19% and 16% conversion to the alcohol product, respectively.
a
Table 5. Effect of Reaction Conditions on the Reduction of Tertiary Aromatic Amides to Alcohols Using SmI −H O−R N
2
2
3
b
b
b
entry
R3N
SmI (equiv)
H O (equiv)
2
R3N (equiv)
conv (%)
yield (%)
selectivity
2
1
2
3
4
5
6
7
8
9
Et N
6
6
200
200
72
36
144
72
72
36
36
72
18
18
72
72
72
72
71
>98
>98
>98
>98
67
50
75
81
91
82
59
78
70
87
79
80
74
80
80
68
74
81
71:29
89:11
90:10
95:5
3
Et N
3
72
72
36
144
72
72
18
72
36
36
18
72
72
72
72
36
Et N
3
6
Et N
3
6
Et N
3
6
91:9
Et N
3
3
93:7
Et N
3
12
6
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
89:11
81:19
92:8
Et N
3
Et N
3
6
10
11
12
13
14
15
16
17
Et N
3
6
87:13
87:13
83:17
85:15
85:15
87:13
82:18
89:12
Et N
3
6
Et N
3
6
NMM
6
n-Bu N
6
3
pyrrolidine
n-BuNH2
TMEDA
6
6
6
72
a
b
1
Quenched with air after 5 min reaction time. Determined by H NMR analysis of crude reaction mixtures and comparison with authentic samples.
Conversion = (100 − SM). Yield refers to the yield of alcohol. Selectivity refers to alcohol/amine ratio. For studies on the effect of amines on the
selectivity of SmI −H O−R N reagents, see ref 18. NMM = N-methylmorpholine. TMEDA = N,N,N,N-tetramethylethylenediamine.
2
2
3
feasible. The effect of water concentration on the reduction of
activating Sm(II) for the reduction of aromatic amides;
23a
esters using SmI −H O has been studied. While in some
however, the addition of amines can significantly increase the
2
2
18,19,15,16
cases similar dependence was observed, it should be noted that
the maximum reduction rate is different for various functional
groups under synthetically relevant reaction conditions.
reduction rate, in agreement with previous studies.
SmI −H O−R N: Effect of Reaction Conditions. Since
2
2
3
our studies on the effect of water stoichiometry indicated that
(1) the reduction of secondary and tertiary aromatic amides is
slower than that of primary amides and (2) N−C scission
selectivity in the reduction of secondary and tertiary amides is
lower than in the case of primary amides, we next investigated
in detail the effect of reaction conditions on the reduction of
amides to alcohols withthe SmI −H O−R N system using
SmI −ROH: Effect of Other Ligands. To gain additional
2
insight into the electron transfer steps, we evaluated the
reduction of tertiary amide 4 using various Sm(II)−ROH
20b,23a
systems (Table 4).
Interestingly, the use of alcohols that
form complexes with SmI such as MeOH (entry 1) and
2
23
ethylene glycol (entry 3) as well as noncoordinating alcohols
2
2
3
23
such as t-BuOH (entry 2) resulted in no (entries 1−2) or
negligible (entry 3) reduction of 4. Moreover, control reactions
conducted with the more easily reducible primary amide 1
using MeOH and t-BuOH (not shown) resulted in 19% and
tertiary amide 4 as our model substrate. The results are
presented in Table 5. It is well-established that tricomponent
Sm(II)−H O−R N reagents lead to significant rate enhance-
2
3
ment in reductions due to base-assisted deprotonation of water,
18,19,15,16
1
6% conversion to the alcohol, respectively. By contrast, the use
which facilitates the electron-transfer step.
This effect
18
of tricomponent-amine-based Sm(II) systems resulted in high
conversion of 4 to the alcohol (entries 4−5). Overall, these
results demonstrate that water acts as a unique proton donor in
is evident from comparing the reduction of 4 using SmI −H O
2
2
(6−200 equiv, 5 min, 71% conversion) (entry 1) with the
reduction under identical conditions with the addition of amine
D
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Table 6. Effect of Amide N-Substituents on the Reduction of Aromatic Amides to Alcohols Using SmI −H O and
2
2
SmI −H O−Et N
2
2
3
a
b
Conditions A: SmI (6 equiv), THF, H O (200 equiv), 30 min, 23 °C. Conditions B: SmI (6 equiv), Et N (72 equiv), H O (72 equiv), 5 min, 23
2
2
2
3
2
1
°C. Ar = 4-MeO-C H . Quenched with air after the indicated time. Yields determined by H NMR analysis of crude reaction mixtures and
6 4
comparison with authentic samples. Yields refer to the yield of alcohol. Selectivity refers to alcohol/amine ratio. Note that incomplete conversions
were observed with SmI −H O reagent under these conditions. For a discussion of SmI −H O decay, see ref 23a.
2
2
2
2
(
SmI −H O−Et N, 6−200−72 equiv, 5 min, > 98% con-
reducing SmI /amine/H O reagents lead to lower selectivity
2 2
due to decomposition (entries 15 and 16). Overall, these results
2
2
3
version) (entry 2). Interestingly, the addition of amine also
leads to higher N−C bond scission selectivity in the reduction
demonstrate the beneficial effect of SmI −H O−amine system
2
2
(
71:29 vs 89:11) (entry 1 vs entry 2). Careful evaluation of the
on the reduction of tertiary benzamides to alcohols.
reagent stoichiometry (entries 3−12) revealed that optimum
Effect of Amide N-Substitution. We next performed
experiments to gain insight into the role of amide N-
substitution on the reduction efficiency and N−C/C−O
cleavage selectivity using SmI −H O (conditions A: 6−200
results in terms of conversion, product purity, and N−C
scission selectivity are obtained using 1:12:12 or 1:6:6 SmI /
2
H O/amine ratio (entries 3 and 4). Note that a stoichiometric
2
2
2
amount of SmI is required for the reduction (entry 6) and that
equiv, 30 min) and SmI −H O−Et N (conditions B: 6−72−72
2
2
2
3
the reaction selectivity does not significantly change at the
lower conversion (entry 6). Additionally, 1:6:12 reagent
stoichiometry gives good selectivity (entry 9). The effect of
other amine ligands on the reduction selectivity was also
investigated (Table 5, entries 13−17). Importantly, high
reduction selectivity of 4 to the alcohol is observed with
tertiary (entries 13−14), secondary (entry 15), primary (entry
equiv, 5 min) reagents (Table 6). N-Amide substitution is well-
known to impact the amide reduction selectivity by impeding
ligand coordination and changing the collapse pathway at the
3
,4
carbinolamine intermediate stage. Notably, we determined
that while both SmI −H O and SmI −H O−Et N reagents can
2
2
2
2
3
be used for the reduction of primary benzamide 1 with similar
efficiency and selectivity (entries 1 and 2), the use of SmI −
2
18d
1
6), and bidentate (entry 17) amine ligands. Note that more
H O−Et N provided generally better results than SmI −H O
2
3
2
2
E
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in the reduction of secondary (entries 3−12) and tertiary
SmI −H O: Hammett Studies. We next sought to gain
2
2
(
entries 13−24) amides. Moreover, a significant substituent
insight into the electronic stabilization of the aminoketyl radical
intermediate in the reduction of primary, secondary and tertiary
aromatic amides using SmI −H O (Figures 5-7). Hammett
effect on the reduction selectivity has been observed.
Specifically, the reduction of unhindered secondary amides
such as NHMe (entries 3 and 4) proceeds with good efficiency
with both reagent systems; however, a drop of N−C cleavage
selectivity using SmI −H O with increasing steric demand of
2
2
2
2
the substituent should be noted (entries 3−8). This effect is
also accompanied by much lower conversions with increasing
N-steric demand of the substituents. By contrast, the use of
SmI −H O−Et N permits high levels of N−C cleavage
2
2
3
selectivity and high reaction rates irrespective of steric demand
of the N-substituent (entries 3−8). Moreover, electronically
biased substituents which are often problematic in the
3g,4f
reduction of amides to alcohols,
such as N-allyl and N-
phenyl, do not interfere with the reduction selectivity using
SmI −H O−Et N (entries 9−12). Interestingly, in the
2
2
3
reduction of simple tertiary amides, such as N,N-dimethyl
and N,N-diethyl (entries 13−16), both systems perform with
good efficiency and selectivity; however, the SmI −H O−Et N
2
2
3
reagent outperforms SmI −H O in the reduction of cyclic
2
2
(
entries 17−22) and sterically hindered (entries 23−24)
amides.
Overall, these studies establish the ease of reduction of
aromatic amides to alcohols using SmI −H O and SmI −
2
2
2
H O−Et N reagents. Given the well established reversibility of
the first electron-transfer events in reductions of carbonyl
derivatives with Sm(II), these results strongly suggest that
amide N-substitution can be employed to tune the stability of
aminoketyl radicals from the reduction of aromatic secondary
and tertiary amides using SmI −H O. Importantly, in several
2
3
23a
2
2
Figure 5. Plot of log k vs σ for the reduction of benzamides with
SmI −H O. [Amide] = 0.025 M. [SmI ] = 0.050 M. [H O] = 1.25 M.
examples (entries 9, 13), a promising selectivity for the
synthetically useful switch of the reaction pathway for the C−O
scission has been observed, providing an entry point for future
studies.
2
2
2
2
T = 23 °C.
Divergent Reduction of Weinreb Amides. Weinreb
29
amides are excellent substrates for the reduction (Scheme 1).
Scheme 1. Divergent Reactivity of Aromatic Weinreb
Amides Using SmI −H O and SmI −Et N−H O: (a)
2
2
2
3
2
Deoxygenation; (b) Reduction to Alcohol
Interestingly, the presence of oxygen atom is not required for
Sm(II) coordination. In contrast, divergent selective deoxyge-
nation using SmI −H O (3−100 equiv) to give the secondary
2
2
benzamide (Scheme 1A) and selective reduction to the alcohol
using SmI −H O−Et N (8−72−72) (Scheme 1B) is observed.
2
2
3
The latter reaction proceeds via stepwise deoxygenation/
19
secondary amide reduction. Thus, aromatic Weinreb amides
follow the same reduction pathway as aliphatic amides using
Figure 6. Plot of log k vs σ for the reduction of N-butylbenzamides
with SmI −H O. [Amide] = 0.025 M. [SmI ] = 0.050 M. [H O] =
1
5
SmI reagents. Note that selective N−O cleavage with SmI
2
2
2
2
2
2
19
has been exploited in complex synthesis.
1.25 M. T = 23 °C.
F
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The Journal of Organic Chemistry
Article
Figure 7. Plot of log k vs σ for the reduction of N,N-
diethylbenzamides with SmI −H O. [Amide] = 0.025 M. [SmI ] =
Figure 8. Plot of log k vs σ for the reduction of benzamides with
SmI −Et N−H O. [Amide] = 0.025 M. [SmI ] = 0.050 M. [Et N] =
2
2
2
2
3
2
2
3
0
.050 M. [H O] = 1.25 M. T = 23 °C.
0.60 M. [H O] = 0.60 M. T = 23 °C.
2
2
correlations studies 0−32 were conducted for various para-
3
substituted benzamides (Figure 5), N-butylbenzamides (Figure
6), and N,N-diethylbenzamides (Figure 7) as representative
primary, secondary, and tertiary amides. Relative reaction rates
were obtained by intermolecular competition experiments using
concentrations of starting materials. Intercept was considered in
the analysis of the Hammett equation. Hammett correlation
2
studies showed large positive ρ values of +3.90 (R = 0.97),
2
2
+
4.37 (R = 0.95), and +3.70 (R = 0.97) for the reduction of
primary, secondary, and tertiary amides, respectively, which can
be compared with ρ values of +0.52, +0.13, and +0.60 for the
reduction of analogous (i.e., NH , NH-n-Bu, NEt ) para-
2
2
substituted 2-phenylacetamides using SmI −H O−Et N. Note
2
2
3
that the reduction of aliphatic amides using SmI −H O is not
2
2
feasible (vide infra). The very large positive ρ values suggest
that (1) an anionic intermediate is formed in the transition
state of the reduction of all three types of amides and (2) the
formed radical anion intermediate is stabilized to a much larger
extent than the related intermediate formed in the Sm(II)-
16
mediated reduction of aliphatic amides. This may have
significant implications for the design of reductive cyclization
processes of aromatic amides via stable benzylic aminoketyl
12,8
radical intermediates.
SmI −H O−Et N: Hammett Studies. The extent of
2
2
3
electronic stabilization of the aminoketyl radical in the
reduction of representative primary, secondary, and tertiary
Figure 9. Plot of log k vs σ for the reduction of N-butylbenzamides
with SmI −Et N−H O. [Amide] = 0.025 M. [SmI ] = 0.050 M.
aromatic amides using the SmI −H O−Et N reagent was also
2
2
3
2
3
2
2
30−32
evaluated (Figures 8−10).
for para-substituted benzamides (Figure 8), N-butylbenzamides
Figure 9), and N,N-diethylbenzamides (Figure 10) using
SmI −H O−Et N showed large positive ρ values of +1.56 (R
0.97), +3.49 (R = 0.97), and +2.97 (R = 0.97) for the
Hammett correlation studies
[
Et N] = 0.60 M. [H O] = 0.60 M. T = 23 °C.
3 2
(
2
with SmI −H O−Et N the 4-Cl substrate undergoes dearoma-
2
2
3
2
2
3
2
2
=
tization. These results demonstrate (1) greater electronic
stabilization of the aminoketyl radical intermediate in the
reduction of primary, secondary, and tertiary amides,
respectively. Note that in the reduction of primary amides
16
reduction of aromatic vs aliphatic amides (ρ values of +0.52,
G
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The Journal of Organic Chemistry
Article
reagent system. The lower stabilization of the aminoketyl
radical from primary amides under the SmI −H O−Et N
2
2
3
conditions suggests that an additional charge is present in the
transition state of the reaction (e.g., N−H deprotonation may
be taking place prior to the rate-determining step of the
reaction).
SmI −H O: Taft Studies. To gain further insight into the
2
2
steric stabilization the aminoketyl radical intermediate in the
reduction of aromatic amides, Taft correlation studies using
33
SmI −H O were carried out (Figure 11). Taft correlation was
2
2
Figure 10. Plot of log k vs σ for the reduction of N,N-
diethylbenzamides with SmI −Et N−H O. [Amide] = 0.025 M.
2
3
2
[
SmI ] = 0.050 M. [Et N] = 0.60 M. [H O] = 0.60 M. T = 23 °C.
2 3 2
+
0.13 and +0.60) using the same SmI −H O−Et N system
2
2
3
(
note that both sets of experiments were conducted under the
same experimental conditions) as a result of radical generation
at the benzylic position; (2) comparable, albeit slightly lower,
stabilization of the radical from secondary and tertiary amides
using SmI −H O−Et N than SmI −H O (ρ values of +4.37
2
2
3
2
2
and +3.70); and (3) much lower stabilization of the radical
intermediate from primary amides using SmI −H O−Et N
2
2
3
Figure 11. Plot of log k vs E for the reduction of N-mono and N,N-
S
than SmI −H O (ρ value of +3.90). Table 7 summarizes the
2
2
disubstituted benzamides with SmI −H O. [Amide] = 0.025 M.
2
2
electronic and steric effect (see section below) observed in the
reduction of aromatic amides using SmI −H O and SmI −
[SmI ] = 0.050 M. [H O] = 1.25 M. T = 23 °C.
2 2
2
2
2
H O−Et N reagents. While Hammett correlations for an aryl
2
3
directly connected to the reactive center should show more
conjugation than for aliphatic amides, this study gives insight
into the extent of the conjugation and the effect of the reagent
system (SmI −H O and SmI −H O−Et N). In addition, note
obtained by plotting log(k ) vs E in a series of N-mono- and
obs S
N,N-disubstituted benzamides and showed positive slopes of
2
2
+0.73 (R = 0.93) and +2.78 (R = 0.99) for the reduction of
secondary and tertiary amides, respectively. These values can be
compared with a positive slope of +0.92 and +3.25 determined
for the reduction of N-mono- and N,N-disubstituted 3-
2
2
2
2
3
that Hammett correlations using SmI −H O for the reduction
2
2
of aliphatic amides are not possible due to low reactivity of the
Table 7. Summary of Hammett and Taft Studies in the Reduction of Aromatic Amides to Alcohols Using SmI −H O and SmI −
2
2
2
a,b
Et N−H O
3
2
c
entry
amide (NR′R″)
SmI −H O (Hammett ρ)
SmI −Et N−H O (Hammett ρ)
SmI −Et N−H O (Hammett ρ)
2
2
2
3
2
2
3
2
1
2
3
NH (1° amide)
NHn-Bu (2° amide)
3.90
4.37
3.70
1.56
3.49
2.97
0.52
0.13
0.59
2
NEt (3° amide)
2
d
entry
amide (NR′R″)
SmI −H O (Taft E )
SmI −Et N−H O (Taft E )
SmI −Et N−H O (Taft E )
2
2
S
2
3
2
0.52
3.16
S
2
3
2
S
1
2
(2° amides)
(3° amides)
0.73
2.78
0.92
3.25
a
b
For comparison, data for the reduction of aliphatic amides using SmI −Et N−H O are shown. Conditions: [amide] = 0.025 M. [SmI ] = 0.050 M.
2
3
2
2
c
[
Et N] = 0.60 M. [H O] = 0.60 M. T = 23 °C. Data from the reduction of 2-phenylacetamides with SmI −Et N−H O. [Amide] = 0.025 M. [SmI ]
3
2
2
3
2
2
d
=
0.050 M. [Et N] = 0.60 M. [H O] = 0.60 M. T = 23 °C. See ref 16 for additional details. Data from the reduction of 3-phenylpropanamides
3 2
SmI −Et N−H O. [Amide] = 0.025 M. [SmI ] = 0.050 M. [Et N] = 0.60 M. [H O] = 0.60 M. T = 23 °C. See ref 16. for additional details.
2
3
2
2
3
2
H
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The Journal of Organic Chemistry
Article
phenylpropanamides using SmI −H O−Et N as determined
Kinetic Isotope Effect Studies. Kinetic isotope effect
studies in the reduction of aromatic amides using SmI −H O
2
2
3
previously. Thus, these findings indicate that (1) steric factors
play a significant role in the reduction of aromatic amides using
2
2
(Scheme 2A) and SmI −H O−Et N (Scheme 2B) were
2
2
3
34
SmI −H O; (2) the slower reaction rate with increasing steric
2
2
conducted by intermolecular competition. Studies on KIE
24d,23a
hindrance results from inhibition of the coordination of Sm(II)
in Sm(II)-mediated reactions have been published.
to the amide carbonyl group; and (3) the steric effect in the
reduction of aromatic amides using SmI −H O is similar to that
2
2
Scheme 2. Kinetic Isotope Effect Studies in the Reduction of
Aromatic Amides to Alcohols: (a) SmI −H O; (b) SmI −
16
in the reduction of aliphatic amides using SmI −H O−Et N,
2
2
3
2
2
2
which is in sharp contrast to the electronic effects observed in
these reactions.
Et N−H O
3
2
SmI −H O−Et N: Taft Studies. To compare the effect of
2
2
3
33
steric stabilization of aminoketyl radical intermediate, Taft
correlation studies were conducted in the reduction of aromatic
amides using the SmI −H O−Et N reagent (Figure 12). The
2
2
3
Selectivity Studies. Amides are the least reactive carboxylic
35
acid derivatives due to Nlp → π*CO conjugation. As a
consequence, direct reduction of amides in the presence of
other carboxylic acid functional groups remains a significant
1
−5
challenge.
Selectivity studies in the reduction of aromatic amides using
SmI −H O (Scheme 3A) and SmI −H O−Et N (Scheme 3B)
2
2
2
2
3
demonstrate that selective reduction of primary amides in the
presence of an aromatic ester group may be possible; in
contrast, selective aromatic ester reduction in the presence of
secondary and tertiary aromatic amides is observed. Previous
studies established that esters are reduced at a similar rate as
16,9
d
carboxylic acids using Sm(II)-based reagents.
The high
Scheme 3. Selectivity Studies in the Reduction of Aromatic
Amides to Alcohols vs Reduction of Esters: (a) SmI −H O;
2
2
(
b) SmI −Et N−H O
2
3
2
Figure 12. Plot of log k vs E for the reduction of N-mono and N,N-
S
disubstituted benzamides with SmI −Et N−H O. [Amide] = 0.025 M.
2
3
2
[
SmI ] = 0.050 M. [Et N] = 0.60 M. [H O] = 0.60 M. T = 23 °C.
2 3 2
Taft correlation study obtained by plotting log(k ) vs E in the
obs
S
same series of N-mono- and N,N-disubstituted benzamides
2
2
showed positive slopes of +0.52 (R = 0.96) and +3.16 (R =
.95) for the reduction of secondary and tertiary amides,
0
respectively. These results suggest that (1) the reduction of
tertiary benzamides using SmI −H O−Et N is subject to
2
2
3
similar steric effects as the reduction of aliphatic amides using
the same reagent system (slope of +3.25) and (2) the reduction
of secondary benzamides using SmI −H O−Et N is less
2
2
3
sensitive to the steric effect of N-substituents than the reduction
of aliphatic secondary amides using SmI −H O−Et N (slope of
2
2
3
+
+
0.92) and secondary benzamides using SmI −H O (slope of
2
2
0.73). Overall, these findings suggest that Sm coordination to
the amide bond using SmI −H O−Et N is similar to using
2
2
3
1
3,14
SmI −H O.
2
2
Table 7 summarizes steric effects observed in the reduction
of aromatic amides using SmI −H O and SmI −H O−Et N.
2
2
2
2
3
I
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The Journal of Organic Chemistry
Article
selectivity for the reduction of primary amides is synthetically
As discussed above, primary benzamides undergo rapid
significant because efficient reduction of these substrates to
reduction with SmI −H O and SmI −H O−amine systems
2
2
2
2
4
5
alcohols using metal hydrides or catalytic hydrogenation is
currently unknown. Thus, the reduction of aromatic amides
follows the same trends of reactivity as the reduction of
aliphatic carboxylic acid derivatives using Sm(II) reagent
with excellent N−C/C−O scission selectivity. Steric effects of
N-substituents contribute to the reactivity of secondary and
tertiary benzamides. In general, SmI −H O−amine gives higher
2
2
reduction selectivity than SmI −H O; however, the reactivity of
2
2
1
6
systems.
simple unhindered secondary and tertiary amides is similar
using both Sm(II) reagent systems.
Full selectivity for the reduction of aromatic amides in the
presence of aliphatic amides using SmI −H O is observed
The study also provides extensive insights into the stability of
benzylic aminoketyl radicals generated in the reduction of
aromatic amides. Our data demonstrate that these radicals are
significantly more stable than the corresponding aminoketyl
radicals generated by single-electron transfer to unactivated
aliphatic amides. However, little difference in terms of steric
effect of the substituents on the stability of aminoketyl radicals
from aromatic and aliphatic amides has been found. The
present reaction allowed us to compare the electronic and steric
effects involving aminoketyl radicals between SmI −H O and
2
2
1
9,20a
(Scheme 4A).
Full selectivity (>50:1) in the reduction of
Scheme 4. Selectivity Studies in the Reduction of Amides to
Alcohols: Aromatic vs Aliphatic Amides
2
2
SmI −H O−amine reagents for the first time. Selectivity
2
2
studies were used to determine the relative reactivity order of
carboxylic acid derivatives with Sm(II)-based reagents. These
similarities and differences between the reagent systems will
have important implications for the design and optimization of
new reductive processes involving the SmI −H O and SmI −
2
2
2
H O−amine-mediated reduction of amides to alcohols and
secondary and tertiary aromatic amides in the presence of the
2
reductive umpolung cyclizations via aminoketyl radicals as a key
step. Studies aimed at this direction are underway in our
laboratories, and these results will be reported shortly.
corresponding aliphatic amides using SmI −H OEt N is
2
2
3
observed, while primary amides give modest selectivity (4:1)
1
6
(
not shown). Moreover, other aliphatic carboxylic acid
derivatives are not reduced by the SmI −H O reagent,
2
2
1
9,20a
providing synthetically valuable selectivity.
Although
EXPERIMENTAL SECTION
■
aliphatic amides are reduced to alcohols using SmI −H O−
2
2
General Methods. All products and staring materials used in this
16
Et N (Scheme 4B), reduction of aromatic amides in the
15,16
3
study are commercially available or have been previously reported.
The products were identified using 1H NMR, GC, and GC−MS
presence of aliphatic amides using SmI −H O−Et N is readily
2
2
3
1
6
accomplished.
analysis and comparison with authentic samples. The reaction progress
1
Relative Reactivity Order. On the basis of our work, the
relative reactivity order of aromatic carboxylic acid derivatives
to alcohols using Sm(II)-based reagents can be summarized as
shown in Figure 13. Noteworthy features include (1) facile
was quantified by H NMR and/or GC−MS analysis using internal
standards after workup unless stated otherwise. Characterization data
for all alcohol products have been previously reported. All experiments
were performed using standard Schlenk techniques under argon
atmosphere. All solvents were purchased at the highest commercial
grade and used as received or after purification by passing through
activated alumina columns or distillation from sodium/benzophenone
under nitrogen. All solvents were deoxygenated by freeze−pump−
thawing or sparging with argon prior to use. Samarium(II) iodide was
2
3a
prepared as described previously. Samarium metal was purchased as
40 mesh and stored at room temperature in a closed container on a
−
bench prior to use. 1,2-Diiodoethane was stored at 4 °C and used after
purification as described previously. All other chemicals were
purchased at the highest commercial grade and used as received.
Reaction glassware was oven-dried at 140 °C for at least 24 h or flame-
dried prior to use, allowed to cool under vacuum and purged with
Figure 13. Relative reactivity order in reduction of main functional
groups using SmI -based reagents.
2
24a
argon (three cycles). Other general methods have been published.
Procedure A. Effect of Water Concentration. An oven-dried
vial containing a stir bar was placed under a positive pressure of argon
and subjected to three evacuation/backfilling cycles under high
vacuum. A previously published procedure was followed. Samarium-
(II) iodide (THF solution, 0.10 M, 6 equiv) was added followed by
reduction of primary benzamides, most likely driven by Sm
35
coordination to the amidic nitrogen, and (2) the ability to
tune the relative rate of reduction by N-substitution in
secondary and tertiary benzamides.
23a
H O (50−1600 equiv) with vigorous stirring, which resulted in the
2
CONCLUSIONS
In conclusion, this paper describes extensive insights into the
mechanism of the SmI −H O and SmI −H O−amine-
mediated reduction of aromatic benzamides (primary, secon-
dary and tertiary) to alcohols via selective N−C bond amide
cleavage. The mechanistic experiments showed that the rate
and selectivity of the reduction depends on the water
concentration and the type of amide undergoing the reduction.
formation of a characteristic burgundy-red color of the SmI (H O)
2
2
n
■
complex (n > 5 with respect to SmI ). A solution of substrate (stock
2
solution in THF, 0.20 M, 0.10 mmol) was added, and the reaction
mixture was vigorously stirred under argon for 5 min. The excess of
Sm(II) was oxidized by bubbling air through the reaction mixture until
decolorization to white had occurred. The reaction mixture was diluted
with CH Cl (30 mL) and NaOH (1 N, 30 mL). The aqueous layer
2
2
2
2
2
2
was extracted with CH Cl (3 × 30 mL), and the organic layers were
2
2
combined, dried over Na SO , filtered, and concentrated. The sample
2
4
J
DOI: 10.1021/acs.joc.7b00372
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The Journal of Organic Chemistry
Article
1
was analyzed by H NMR (CDCl , 500 MHz) and GC−MS to obtain
equiv, stock solution in THF) was added and the reaction mixture was
stirred at room temperature for 5 min. The excess of Sm(II) was
oxidized by bubbling air through the reaction mixture. Workup and
analysis were performed as described for procedure A.
3
conversion and yield using internal standard (CH NO or 1,3,5-
trimethoxybenzene) and comparison with authentic samples.
3
2
Procedure B. Effect of Other Ligands. An oven-dried vial
containing a stir bar was placed under a positive pressure of argon and
subjected to three evacuation/backfilling cycles under high vacuum.
Samarium(II) iodide (THF solution, 0.10 M) was added followed by
amine (if applicable) and alcohol with vigorous stirring, which resulted
Characterization Data. Characterization data for amide and
1
5,16
1
13
alcohol products have been previously reported.
H and C NMR
data for the amide and alcohol products used in the current study are
presented below for characterization purposes. All amines were
2
0
36
in the color change characteristic to a given Sm(II) complex.
A
assigned by comparison with literature data: phenylmethanamine, N-
9
c
37
solution of substrate (stock solution in THF) was added, and the
reaction mixture was vigorously stirred under argon for a given time.
The excess of Sm(II) was oxidized by bubbling air through the
reaction mixture until decolorization to white or yellow had occurred.
Workup and analysis were performed as described for procedure A.
Procedure C. Effect of N-Substituents. An oven-dried vial
containing a stir bar was placed under a positive pressure of argon, and
subjected to three evacuation/backfilling cycles under high vacuum.
Samarium(II) iodide (THF solution, 0.60 mmol, 6.0 equiv, 0.10 M)
was added followed by H O with vigorous stirring, which resulted in
the formation of a characteristic burgundy-red color of the
SmI (H O) complex (n > 5 with respect to SmI ). A solution of
substrate (0.10 mmol, 1.0 equiv, stock solution in THF) was added
and the reaction mixture was stirred at room temperature for 30 min.
The excess of Sm(II) was oxidized by bubbling air through the
reaction mixture. Workup and analysis was performed as described for
procedure A. For runs using SmI −Et N−H O complex, samarium(II)
iodide (THF solution, 0.60 mmol, 6.0 equiv, 0.10 M) was added
followed by Et N and H O with vigorous stirring, which resulted in the
formation of a characteristic dark brown color of the SmI −Et N−
H O complex. A solution of substrate (0.10 mmol, 1.0 equiv, stock
solution in THF) was added, and the reaction mixture was stirred at
room temperature for 5 min. The excess of Sm(II) was oxidized by
bubbling air through the reaction mixture. Workup and analysis were
performed as described for procedure A.
Procedure D. Relative Reactivity Studies. An oven-dried vial
containing a stir bar was placed under a positive pressure of argon and
subjected to three evacuation/backfilling cycles under high vacuum.
Samarium(II) iodide (THF solution, 0.20 mmol, 2.0 equiv, 0.10 M)
was added followed by H O (50 equiv) with vigorous stirring, which
resulted in the formation of a characteristic burgundy-red color of the
SmI (H O) complex (n > 5 with respect to SmI ). A preformed
solution of two substrates (each 0.10 mmol, 1.0 equiv, stock solution
in THF) was added, and the reaction mixture was stirred until
decolorization to white had occurred. Workup and analysis was
performed as described for procedure A. For runs using SmI −Et N−
H O complex, samarium(II) iodide (THF solution, 0.20 mmol, 2.0
equiv, 0.10 M) was added followed by Et N (24 equiv) and H O (24
benzylbutan-1-amine, N-benzyl-N-ethylethanamine, N-methyl-1-
3
8
39
phenylmethanamine, N-benzyl-2-methylpropan-2-amine, N-benzy-
4
0
41
laniline, N-benzylprop-2-en-1-amine, N,N-dimethyl-1-phenylme-
thanamine, 1-benzylpyrrolidine, 1-benzylpiperidine, 4-benzylmor-
pholine, and N-benzyl-N-isopropylpropan-2-amine. All other
4
2
9c
3s
9
c
43
alcohols were assigned by comparison with literature data: phenyl-
44
45
methanol, (4-(trifluoromethyl)phenyl)methanol, (4-fluorophenyl)-
45
46
methanol, (4-chlorophenyl)methanol1.
4
-Methoxybenzamide (Table 1): H NMR (300 MHz, CDCl ) δ
3
2
3
.88 (s, 3 H), 5.93 (br, 2 H), 6.96 (d, J = 8.7 Hz, 2 H), 7.81 (d, J = 8.7
13
Hz, 2 H); C NMR (75 MHz, CDCl ) δ 55.5, 113.8, 125.4, 129.3,
3
2
2
n
2
1
62.7, 168.9.
N-Butyl-4-methoxybenzamide (Table 2): H NMR (300 MHz,
CDCl ) δ 0.86 (t, J = 7.5 Hz, 3 H), 1.24−1.37 (m, 2 H), 1.46−1.57
1
3
(m, 2 H), 3.34 (q, J = 6.0 Hz, 2 H), 3.76 (s, 3 H), 6.81 (d, J = 8.7 Hz, 2
13
H), 6.94 (t, J = 4.5 Hz, 1 H), 7.74 (t, J = 9.0 Hz, 2 H); C NMR (75
2
3
2
MHz, CDCl ) δ 13.8, 20.2, 31.8, 39.8, 55.3, 113.5, 127.1, 128.8, 161.9,
3
1
67.3.
N,N-Diethyl-4-methoxybenzamide (Table 3): H NMR (300
3
2
1
2
3
MHz, CDCl ) δ 1.09−1.26 (m, 6 H), 3.13−3.62 (m, 4 H), 3.82 (s, 3
3
2
13
H), 6.90 (d, J = 8.4 Hz, 2 H), 7.35 (d, J = 8.7 Hz, 2 H); C NMR (75
MHz, CDCl ) δ 13.6, 39.6, 43.0, 55.3, 113.7, 128.2, 129.5, 160.3,
3
1
71.2.
4-Methoxyphenyl)methanol (Table 1): H NMR (300 MHz,
CDCl ) δ 1.57 (br, 1 H), 3.74 (s, 3 H), 4.54 (s, 2 H), 6.82 (d, J = 8.7
1
(
3
13
Hz, 2 H), 7.22 (d, J = 8.7 Hz, 2 H); C NMR (75 MHz, CDCl ) δ
3
5
5.3, 65.1, 114.0, 128.7, 133.2, 159.3.
-Methoxy-N-methylbenzamide (Table 6, entry 3): H NMR
500 MHz, CDCl ) δ 3.02 (d, J = 4.5 Hz, 3 H), 3.87 (s, 3 H), 6.10 (br,
1
4
(
1
3
2
13
H), 6.94 (d, J = 8.5 Hz, 2 H), 7.75 (d, J = 8.5 Hz, 2 H); C NMR
(
125 MHz, CDCl ) δ 26.8, 55.4, 113.7, 127.0, 128.6, 162.1, 167.7.
3
2
2
n
2
N-tert-Butyl-4-methoxybenzamide (Table 6, entry 7): 1H
NMR (500 MHz, CDCl ) δ 1.48 (s, 9 H), 3.85 (s, 3 H), 5.89 (br, 1
3
1
3
H), 6.91 (d, J = 9.0 Hz, 2 H), 7.70 (d, J = 8.5 Hz, 2 H); C NMR
125 MHz, CDCl ) δ 28.9, 51.5, 55.4, 113.6, 128.3, 128.4, 161.9,
(
3
2
3
1
66.4.
-Methoxy-N-phenylbenzamide (Table 6, entry 9): H NMR
500 MHz, CDCl ) δ 3.90 (s, 3 H), 7.00 (d, J = 8.5 Hz, 2 H), 7.16 (t, J
2
1
4
3
2
(
equiv) with vigorous stirring, which resulted in the formation of a
characteristic dark brown color of the SmI −Et N−H O complex. A
preformed solution of two substrates (each 0.10 mmol, 1.0 equiv, stock
solution in THF) was added and the reaction mixture was stirred until
decolorization to white had occurred. Workup and analysis was
performed as described for procedure A.
Procedure E. Determination of Kinetic Isotope Effect. An
oven-dried vial containing a stir bar was placed under a positive
pressure of argon and subjected to three evacuation/backfilling cycles
under high vacuum. Samarium(II) iodide (THF solution, 0.60 mmol,
3
=
7.5 Hz, 1 H), 7.39 (t, J = 7.5 Hz, 2 H), 7.65 (d, J = 7.5 Hz, 2 H),
2
3
2
13
7.76 (br, 1 H), 7.87 (d, J = 8.5 Hz, 2 H); C NMR (125 MHz,
CDCl
) δ 55.5, 114.0, 120.1, 124.4, 127.2, 128.9, 129.1, 138.1, 162.5,
3
165.2.
1
N-Allyl-4-methoxybenzamide (Table 6, entry 11): H NMR
(500 MHz, CDCl ) δ 3.86 (s, 3 H), 4.09 (t, J = 5.5 Hz, 2 H), 5.17−
3
5.21 (m, 2 H), 5.91−5.99 (m, 1 H), 6.24 (br, 1 H), 6.93 (d, J = 8.5 Hz,
2 H), 7.77 (d, J = 8.5 Hz, 2 H); 13C NMR (125 MHz, CDCl
) δ 42.4,
3
55.4, 113.7, 116.5, 126.7, 128.7, 134.4, 162.2, 166.8.
4-Methoxy-N,N-dimethylbenzamide (Table 6, entry 13): H
1
6
.0 equiv, 0.10 M) was added followed by an equimolar mixture of
D O and H O with vigorous stirring, which resulted in the formation
NMR (500 MHz, CDCl ) δ 3.04 (s, 6 H), 3.82 (s, 3 H), 6.89 (d, J =
8.5 Hz, 2 H), 7.39 (d, J = 8.5 Hz, 2 H); C NMR (125 MHz, CDCl3)
2
2
3
13
of a characteristic burgundy-red color of the SmI (H O) complex (n
2
2
n
>
5 with respect to SmI ). A solution of substrate (0.10 mmol, 1.0
δ 35.5, 39.8, 55.3, 113.5, 128.4, 129.1, 160.6, 171.5
2
equiv, stock solution in THF) was added, and the reaction mixture was
stirred at room temperature for 30 min. The excess of Sm(II) was
oxidized by bubbling air through the reaction mixture. Workup and
analysis were performed as described for procedure A. For runs using
SmI −Et N−H O complex, samarium(II) iodide (THF solution, 0.60
(4-Methoxyphenyl)(pyrrolidin-1-yl)methanone (Table 6,
1
entry 17): H NMR (500 MHz, CDCl ) δ 1.84−1.89 (m, 2 H),
3
1.92−1.97 (m, 2 H), 3.48 (t, J = 5.5 Hz, 2 H), 3.63 (t, J = 6.5 Hz, 2 H),
1
3
3.83 (s, 3 H), 6.89 (d, J = 7.5 Hz, 2 H), 7.51 (d, J = 7.5 Hz, 2 H);
C
2
3
2
NMR (125 MHz, CDCl ) δ 24.5, 26.5, 46.3, 49.8, 55.3, 113.4, 129.2,
3
mmol, 6.0 equiv, 0.10 M) was added followed by Et N and an
129.5, 160.8, 169.4.
3
equimolar mixture of D O and H O with vigorous stirring, which
resulted in the formation of a characteristic dark brown color of the
(4-Methoxyphenyl)(piperidin-1-yl)methanone (Table 6,
2
2
1
entry 19): H NMR (500 MHz, CDCl ) δ 1.48−1.72 (m, 6 H),
3
SmI −Et N−H O complex. A solution of substrate (0.10 mmol, 1.0
3.31−3.76 (m, 4 H), 3.83 (s, 3 H), 6.91 (d, J = 8.0 Hz, 2 H), 7.37 (d, J
2
3
2
K
DOI: 10.1021/acs.joc.7b00372
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
=
8.5 Hz, 2 H); 13C NMR (125 MHz, CDCl ) δ 24.7, 26.1, 43.4, 48.9,
Brookhart, M. J. Am. Chem. Soc. 2012, 134, 11304. (m) Park, S.;
Brookhart, M. J. Am. Chem. Soc. 2012, 134, 640. (n) Hanada, S.;
Tsutsumi, E.; Motoyama, Y.; Nagashima, H. J. Am. Chem. Soc. 2009,
131, 15032. (o) Motoyama, Y.; Mitsui, K.; Ishida, T.; Nagashima, H. J.
Am. Chem. Soc. 2005, 127, 13150. (p) Sunada, Y.; Kawakami, H.;
Imaoka, T.; Motoyama, Y.; Nagashima, H. Angew. Chem., Int. Ed. 2009,
3
55.3, 113.6, 128.6, 128.9, 160.5, 170.3.
(
4-Methoxyphenyl)(morpholino)methanone (Table 6, entry
1
2
1): H NMR (500 MHz, CDCl ) δ 3.51−3.78 (m, 8 H), 3.84 (s, 3
3
13
H), 6.92 (d, J = 8.5 Hz, 2 H), 7.39 (d, J = 8.5 Hz, 2 H); C NMR (125
MHz, CDCl ) δ 43.1, 48.0. 55.4, 66.9, 113.8, 127.4, 129.2, 160.9,
3
1
70.4.
4
8, 9511. (q) White, J. M.; Tunoori, A. R.; Georg, G. I. J. Am. Chem.
N,N-Diisopropyl-4-methoxybenzamide (Table 6, entry 23):
Soc. 2000, 122, 11995. (r) Spletstoser, J. T.; White, J. M.; Tunoori, A.
R.; Georg, G. I. J. Am. Chem. Soc. 2007, 129, 3408. (s) Tinnis, F.;
Volkov, A.; Slagbrand, T.; Adolfsson, H. Angew. Chem., Int. Ed. 2016,
1
H NMR (500 MHz, CDCl ) δ 1.04−1.67 (m, 12 H), 3.46−3.92 (m, 2
3
H), 3.83 (s, 3 H), 6.90 (d, J = 7.5 Hz, 2 H), 7.29 (d, J = 7.5 Hz, 2
13
H); C NMR (125 MHz, CDCl ) δ 20.8, 47.1, 49.1, 55.3, 113.7, 127.5,
3
5
(
(
5, 4562.
4) (a) Brown, H. C.; Kim, S. C. Synthesis 1977, 1977, 635.
b) Hutchins, R. O.; Learn, K.; El-Telbany, F.; Stercho, Y. P. J. Org.
131.4, 159.9, 171.0.
N,4-Dimethoxy-N-methylbenzamide (Scheme 1): 1H NMR
(
(
500 MHz, CDCl ) δ 3.37 (s, 3 H), 3.57 (s, 3 H), 3.86 (s, 3 H), 6.91
d, J = 8.5 Hz, 2 H), 7.74 (d, J = 8.5 Hz, 2 H); C NMR (125 MHz,
3
Chem. 1984, 49, 2438. (c) Fisher, G. B.; Fuller, J. C.; Harrison, J.;
Alvarez, S. G.; Burkhardt, E. R.; Goralski, C. T.; Singaram, B. J. Org.
Chem. 1994, 59, 6378. (d) Pasumansky, L.; Goralski, C. T.; Singaram,
B. Org. Process Res. Dev. 2006, 10, 959. (e) Myers, A. G.; Yang, B. H.;
Kopecky, D. J. Tetrahedron Lett. 1996, 37, 3623. (f) Myers, A. G.;
Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.; Gleason, J. L. J.
Am. Chem. Soc. 1997, 119, 6496. (g) Krackl, S.; Someya, C. I.;
Enthaler, S. Chem. - Eur. J. 2012, 18, 15267.
(5) For recent progress using catalytic hydrogenation under high
pressure, see: (a) Balaraman, E.; Gnanaprakasam, B.; Shimon, L. J. W.;
Milstein, D. J. Am. Chem. Soc. 2010, 132, 16756. (b) Ito, M.; Koo, L.
W.; Himizu, A.; Kobayashi, C.; Sakaguchi, A.; Ikariya, T. Angew. Chem.,
Int. Ed. 2009, 48, 1324. (c) Ito, M.; Ootsuka, T.; Watari, R.; Shiibashi,
A.; Himizu, A.; Ikariya, T. J. Am. Chem. Soc. 2011, 133, 4240. (d) John,
J. M.; Bergens, S. H. Angew. Chem., Int. Ed. 2011, 50, 10377.
13
CDCl ) δ 33.9, 55.3, 60.9, 113.2, 126.0, 130.5, 161.5, 169.4.
3
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b00372.
1H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*
E-mail: michal.szostak@rutgers.edu.
ORCID
(e) Cabrero-Antonino, J. R.; Alberico, E.; Drexler, H. J.; Baumann, W.;
Michal Szostak: 0000-0002-9650-9690
Notes
The authors declare no competing financial interest.
Junge, K.; Junge, H.; Beller, M. ACS Catal. 2016, 6, 47. (f) Kita, Y.;
Higuchi, T.; Mashima, K. Chem. Commun. 2014, 50, 11211. (g) Garg,
J. A.; Chakraborty, S.; Ben-David, Y.; Milstein, D. Chem. Commun.
2
016, 52, 5285. (h) Rezayee, N. M.; Samblanet, D. C.; Sanford, M. S.
ACS Catal. 2016, 6, 6377. (i) Schneck, F.; Assmann, M.; Balmer, M.;
Harms, K.; Langer, R. Organometallics 2016, 35, 1931.
ACKNOWLEDGMENTS
■
Financial support was provided by Rutgers University. S.H.
thanks Rutgers University for an FASN Dean’s Undergraduate
Summer Research Fellowship and the Chemistry Department
(
6) Recent reviews on SmI : (a) Szostak, M.; Fazakerley, N. J.;
2
Parmar, D.; Procter, D. J. Chem. Rev. 2014, 114, 5959. (b) Just-
Baringo, X.; Procter, D. J. Acc. Chem. Res. 2015, 48, 1263.
(
Rutgers University) for a Summer Undergraduate Fellowship.
(7) Reviews on metal-mediated radical reactions: (a) Szostak, M.;
The Bruker 500 MHz spectrometer used in this study was
supported by an NSF-MRI grant (CHE-1229030).
Procter, D. J. Angew. Chem., Int. Ed. 2012, 51, 9238. (b) Gansau
Bluhm, H. Chem. Rev. 2000, 100, 2771. (c) Cuerva, J. M.; Justicia, J.;
Oller-Lopez, J. L.; Oltra, J. E. Top. Curr. Chem. 2006, 264, 63.
d) Justicia, J.; Alvarez de Cienfuegos, L.; Campan
Jakoby, V.; Gansauer, A.; Cuerva, J. M. Chem. Soc. Rev. 2011, 40, 3525.
e) Streuff, J. Synthesis 2013, 45, 281. (f) Murphy, J. J. Org. Chem.
̈
er, A.;
́
̀
(
̃
a, A. G.; Miguel, D.;
REFERENCES
■
̈
(
1) (a) Trost, B. M.; Fleming, I. Comprehensive Organic Synthesis;
(
Pergamon Press, 1991. (b) Hudlicky, M. Reductions in Organic
Chemistry; Ellis Horwood: Chichester, 1984. (c) Seyden-Penne, J.
Reductions by Alumino and Borohydrides in Organic Synthesis; Wiley:
New York, 1997. (d) Andersson, P. G.; Munslow, I. J. Modern
Reduction Methods; Wiley-VCH: Weinheim, 2008. (e) Addis, D.; Das,
S.; Junge, K.; Beller, M. Angew. Chem., Int. Ed. 2011, 50, 6004.
2
014, 79, 3731. (g) Meciarova, M.; Tisovsky, P.; Sebesta, R. New J.
Chem. 2016, 40, 4855.
8) Reviews: (a) Turecek, F.; Julian, R. R. Chem. Rev. 2013, 113,
(
̈
6
691. (b) Zhurov, K. O.; Fornelli, L.; Wodrich, M. D.; Laskay, U. A.;
Tsybin, Y. O. Chem. Soc. Rev. 2013, 42, 5014. (c) Renaud, P.; Giraud,
L. Synthesis 1996, 1996, 913. (d) Aurrecoechea, J. M.; Suero, R.
ARKIVOC 2004, 10.
(
2) (a) Ricci, A. Modern Amination Methods; Wiley, 2000. (b) Carey,
J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol. Chem.
006, 4, 2337.
3) Selected examples of chemoselective amide reductions: (a) Das,
S.; Addis, D.; Zhou, S.; Junge, K.; Beller, M. J. Am. Chem. Soc. 2010,
32, 1770. (b) Das, S.; Wendt, B.; Moller, K.; Junge, K.; Beller, M.
(
9) Selected examples of recent SmI -mediated reductions: (a) Duffy,
2
2
L. A.; Matsubara, H.; Procter, D. J. J. Am. Chem. Soc. 2008, 130, 1136.
b) Guazzelli, G.; De Grazia, S.; Collins, K. D.; Matsubara, H.; Spain,
M.; Procter, D. J. J. Am. Chem. Soc. 2009, 131, 7214. (c) Thurow, S.;
Lenardao, E.; Just-Baringo, X.; Procter, D. J. Org. Lett. 2017, 19, 50.
(
(
1
̈
Angew. Chem., Int. Ed. 2012, 51, 1662. (c) Das, S.; Join, B.; Junge, K.;
Beller, M. Chem. Commun. 2012, 48, 2683. (d) Das, S.; Addis, D.;
Junge, K.; Beller, M. Chem. - Eur. J. 2011, 17, 12186. (e) Zhou, S.;
Junge, K.; Addis, D.; Das, S.; Beller, M. Angew. Chem., Int. Ed. 2009,
(
10) Selected examples of recent SmI -mediated cyclizations:
2
(
a) Helm, M. D.; Da Silva, M.; Sucunza, D.; Findley, T. J. K.;
Procter, D. J. Angew. Chem., Int. Ed. 2009, 48, 9315. (b) Helm, M. D.;
Da Silva, M.; Sucunza, D.; Helliwell, M.; Procter, D. J. Tetrahedron
4
8, 9507. (f) Das, S.; Zhou, S.; Addis, D.; Junge, K.; Enthaler, S.;
2
009, 65, 10816. (c) Fazakerley, N. J.; Helm, M. D.; Procter, D. J.
Beller, M. Top. Catal. 2010, 53, 979. (g) Barbe, G.; Charette, A. B. J.
Am. Chem. Soc. 2008, 130, 18. (h) Pelletier, G.; Bechara, W. S.;
Charette, A. B. J. Am. Chem. Soc. 2010, 132, 12817. (i) Bechara, W. S.;
Pelletier, G.; Charette, A. B. Nat. Chem. 2012, 4, 228. (j) Reeves, J. T.;
Tan, Z.; Marsini, M. A.; Han, Z. S.; Xu, Y.; Reeves, D. C.; Lee, H.; Lu,
B. Z.; Senanayake, C. H. Adv. Synth. Catal. 2013, 355, 47. (k) Stein,
M.; Breit, B. Angew. Chem., Int. Ed. 2013, 52, 2231. (l) Cheng, C.;
Chem. - Eur. J. 2013, 19, 6718. (d) Cha, J. Y.; Yeoman, J. T. S.;
Reisman, S. E. J. Am. Chem. Soc. 2011, 133, 14964. (e) Yeoman, J. T.
S.; Mak, V. W.; Reisman, S. E. J. Am. Chem. Soc. 2013, 135, 11764.
(f) Yeoman, J. T. S.; Cha, J. Y.; Mak, V. W.; Reisman, S. E. Tetrahedron
2014, 70, 4070. (g) Li, Z.; Nakashige, M.; Chain, W. J. J. Am. Chem.
Soc. 2011, 133, 6553. (h) Breitler, S.; Carreira, E. M. Angew. Chem., Int.
L
DOI: 10.1021/acs.joc.7b00372
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Ed. 2013, 52, 11168. (i) Just-Baringo, X.; Clark, E.; Gutmann, M. J.;
Procter, D. J. Angew. Chem., Int. Ed. 2016, 55, 12499.
Chem. Soc. 1990, 112, 219. (c) Honda, T.; Ishikawa, F. Chem.
Commun. 1999, 1065.
(29) Balasubramaniam, S.; Aidhen, I. Synthesis 2008, 3707.
(
11) Classic review on carbonyl umpolung: Seebach, D. Angew.
Chem., Int. Ed. Engl. 1979, 18, 239.
12) (a) Renaud, P.; Sibi, M. Radicals in Organic Synthesis; Wiley-
(30) Hammett, L. P. J. Am. Chem. Soc. 1937, 59, 96. (b) Jaffe,
́
H. H.
(
Chem. Rev. 1953, 53, 191.
VCH, 2001. (b) Chatgilialoglu, C.; Studer, A. Encyclopedia of Radicals
in Chemistry, Biology and Materials; Wiley-Blackwell, 2012. (c) Curran,
D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical Reactions;
Wiley-VCH, 1996. (d) Hasegawa, E.; Curran, D. P. Tetrahedron Lett.
(31) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165.
(32) (a) Brown, H. C.; Okamoto, Y. J. Am. Chem. Soc. 1958, 80,
4979. (b) Chapman, N. B.; Shroter, J. Advances in Linear Free Energy
Relationships; Plenum Press, 1972.
1
993, 34, 1717. (e) Curran, D. P.; Fevig, T. L.; Jasperse, C. P.;
Totleben, J. Synlett 1992, 1992, 943.
13) (a) Tsuruta, H.; Yamaguchi, K.; Imamoto, T. Chem. Commun.
999, 1703. (b) Evans, W. J. Inorg. Chem. 2007, 46, 3435.
14) Laurence, C.; Gal, J. F. Lewis Basicity and Affinity Scales: Data
and Measurement; Wiley: Chichester, 2009.
15) Szostak, M.; Spain, M.; Eberhart, A. J.; Procter, D. J. J. Am.
Chem. Soc. 2014, 136, 2268.
16) Szostak, M.; Spain, M.; Eberhart, A. J.; Procter, D. J. J. Org.
Chem. 2014, 79, 11988.
17) Szostak, M.; Spain, M.; Procter, D. J. J. Org. Chem. 2014, 79,
522 and references cited therein.
18) (a) Dahlen, A.; Hilmersson, G. Tetrahedron Lett. 2002, 43, 7197.
b) Dahlen, A.; Hilmersson, G. Chem. - Eur. J. 2003, 9, 1123.
c) Dahlen, A.; Hilmersson, G. J. Am. Chem. Soc. 2005, 127, 8340.
d) Ankner, T.; Stalsmeden, A. S.; Hilmersson, G. Chem. Commun.
013, 49, 6867 and references cited therein. For a recent mechanistic
study, see: (e) Yitzhaki, O.; Hoz, S. Chem. - Eur. J. 2015, 21, 9242.
19) Review on chemoselective SmI reductions: Szostak, M.; Spain,
(33) For computational studies on the geometry of ketyl radicals, see:
(a) Wu, Y. D.; Houk, K. N. J. Am. Chem. Soc. 1992, 114, 1656.
(b) Kefalidis, C. E.; Perrin, L.; Maron, L. Eur. J. Inorg. Chem. 2013,
2013, 4042.
(34) Simmons, E. M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2012, 51,
3066 and references cited therein.
(35) Greenberg, A., Breneman, C. M., Liebman, J. F., Eds. The Amide
Linkage: Structural Significance in Chemistry, Biochemistry, and Materials
Science; Wiley: New York, 2000.
(36) Shao, Z.; Fu, S.; Wei, M.; Zhou, S.; Liu, Q. Angew. Chem., Int.
Ed. 2016, 55, 14653.
(
1
(
(
(
(
2
(
(
(
(
(
37) Molander, G. A.; Gormisky, P. E.; Sandrock, D. L. J. Org. Chem.
008, 73, 2052.
38) Cardullo, F.; Donati, D.; Fusillo, V.; Merlo, G.; Paio, A.; Salaris,
M.; Solinas, A.; Taddei, M. J. Comb. Chem. 2006, 8, 834.
39) Yagafarov, N. Z.; Usanov, D. L.; Moskovets, A. P.; Kagramanov,
N. D.; Maleev, V. I.; Chusov, D. ChemCatChem 2015, 7, 2590.
40) Elangovan, S.; Neumann, J.; Sortais, J.-B.; Junge, K.; Darcel, C.;
Beller, M. Nat. Commun. 2016, 7, 12641.
41) Kennemur, J. L.; Kortman, G. D.; Hull, K. L. J. Am. Chem. Soc.
016, 138, 11914.
42) Mukherjee, D.; Shirase, S.; Mashima, K.; Okuda, J. Angew.
Chem., Int. Ed. 2016, 55, 13326.
2
(
́
́
́
(
̊
2
(
(
2
(
2
(
M.; Procter, D. J. Chem. Soc. Rev. 2013, 42, 9155.
20) For reviews on additives to SmI , see: (a) Szostak, M.; Spain,
(
2
M.; Parmar, D.; Procter, D. J. Chem. Commun. 2012, 48, 330.
(
b) Dahlen
́
, A.; Hilmersson, G. Eur. J. Inorg. Chem. 2004, 2004, 3393.
(43) Hauser, A.; Bohlmann, R. Synlett 2016, 27, 1870.
(
c) Kagan, H. B.; Namy, J. L. In Lanthanides: Chemistry and Use in
(44) Ogata, O.; Nakayama, Y.; Nara, H.; Fujiwhara, M.; Kayaki, Y.
Organic Synthesis; Ed. Kobayashi, S.; Springer: 1999; p 155.
21) For a seminal study on the effect of water on SmI -mediated
Org. Lett. 2016, 18, 3894.
45) Wei, Y.; Liu, S. X.; Mueller-Bunz, H.; Albrecht, M. ACS Catal.
016, 6, 8192.
46) Tan, X.; Wang, Y.; Liu, Y.; Wang, F.; Shi, L.; Lee, K. H.; Lin, Z.;
Lv, H.; Zhang, X. Org. Lett. 2015, 17, 454.
(
2
(
2
(
reductions, see: Hasegawa, E.; Curran, D. P. J. Org. Chem. 1993, 58,
008.
5
(
(
22) Kamochi, Y.; Kudo, T. Chem. Lett. 1993, 22, 1495.
23) Selected mechanistic studies: (a) Szostak, M.; Spain, M.;
Procter, D. J. J. Am. Chem. Soc. 2014, 136, 8459 and references cited
therein. (b) See ref 16. (c) Chopade, P. R.; Prasad, E.; Flowers, R. A.,
II J. Am. Chem. Soc. 2004, 126, 44. (d) Prasad, E.; Flowers, R. A., II J.
Am. Chem. Soc. 2005, 127, 18093. (e) Tarnopolsky, A.; Hoz, S. J. Am.
Chem. Soc. 2007, 129, 3402. (f) Amiel-Levy, M.; Hoz, S. J. Am. Chem.
Soc. 2009, 131, 8280. (g) Upadhyay, S. K.; Hoz, S. J. Org. Chem. 2011,
76, 1355.
(
24) (a) Shi, S.; Szostak, M. Org. Lett. 2015, 17, 5144. (b) Shi, S.;
Lalancette, R.; Szostak, M. Synthesis 2016, 48, 1825. (c) Shi, S.;
Lalancette, R.; Szostak, R.; Szostak, M. Chem. - Eur. J. 2016, 22, 11949.
(
d) Shi, S.; Szostak, R.; Szostak, M. Org. Biomol. Chem. 2016, 14, 9151
and references cited therein.
25) (a) Huang, H. M.; Procter, D. J. J. Am. Chem. Soc. 2016, 138,
(
7
1
770. (b) Huang, H. M.; Procter, D. J. J. Am. Chem. Soc. 2017, 139,
661.
(
26) Meng, G.; Shi, S.; Szostak, M. Synlett 2016, 27, 2530.
(
27) Reviews: (a) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C.
Chem. Rev. 2013, 113, 5322. (b) Yoon, T. P.; Ischay, M. A.; Du, J. Nat.
Chem. 2010, 2, 527. (c) Narayanam, J. M. R.; Stephenson, C. R. J.
Chem. Soc. Rev. 2011, 40, 102. (d) Beatty, J. W.; Stephenson, C. R. J.
Acc. Chem. Res. 2015, 48, 1474. (e) Tucker, J. W.; Stephenson, C. R. J.
J. Org. Chem. 2012, 77, 1617. (f) Romero, N. A.; Nicewicz, D. A.
Chem. Rev. 2016, 116, 10075. (g) Nagib, D. A.; MacMillan, D. W. C.
Nature 2011, 480, 224. (h) Petronijevic, F. R.; Nappi, M.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2013, 135, 18323. (i) Fava, E.; Nakajima,
M.; Nguyen, A. L. P.; Rueping, M. J. Org. Chem. 2016, 81, 6959.
(
28) Selected examples of electron-transfer reactions to carboxylic
acid derivatives using Sm(II) and other reductants: (a) Hou, Z.; Fujita,
A.; Zhang, Y.; Miyano, T.; Yamazaki, H.; Wakatsuki, Y. J. Am. Chem.
Soc. 1998, 120, 754. (b) Evans, W. J.; Ulibarri, T.; Ziller, J. W. J. Am.
M
DOI: 10.1021/acs.joc.7b00372
J. Org. Chem. XXXX, XXX, XXX−XXX