Secondary amides as hydrogen atom transfer promoters for reactions of samarium diiodide

Article abstract of DOI:10.1021/acs.orglett.6b03664

Two secondary amides (N-methylacetamide and 2-pyrrolidinone) were used as additives with SmI₂ in THF to estimate the extent of N-H bond weakening upon coordination. Mechanistic and synthetic studies demonstrate significant bond-weakening, providing a reagent system capable of reducing a range of substrates through formal hydrogen atom transfer.

Full text of DOI:10.1021/acs.orglett.6b03664

Letter
pubs.acs.org/OrgLett
Secondary Amides as Hydrogen Atom Transfer Promoters for
Reactions of Samarium Diiodide
Tesia V. Chciuk, Anna M. Li, Andres Vazquez-Lopez, William R. Anderson, Jr.,
and Robert A. Flowers, II*
Department of Chemistry, Lehigh University, 6 East Packer Avenue, Bethlehem, Pennsylvania 18015, United States
*
S Supporting Information
ABSTRACT: Two secondary amides (N-methylacetamide
and 2-pyrrolidinone) were used as additives with SmI in
2
THF to estimate the extent of N−H bond weakening upon
coordination. Mechanistic and synthetic studies demonstrate
significant bond-weakening, providing a reagent system capable of reducing a range of substrates through formal hydrogen atom
transfer.
he use of additives in reactions of samarium diiodide (SmI2)
Although water as a proton donor is the promoter of choice for
many functional group reductions, we reasoned that a high
affinity ligand for Sm(II) containing a strong X−H bond that is
weakened upon coordination to the low-valent metal may
produce an alternative approach for reductions and reductive
coupling reactions. In considering potential choices, we were
drawn to the work of Knowles and Gansauer who have
demonstrated significant weakening of the N−H bonds of
T
in THF and other solvents has a profound impact on the
1
reactivity of the reagent. Additives are generally divided into
three subclasses: (1) Lewis bases, (2) inorganic salts, and (3)
proton donors. Among Lewis bases, HMPA is the most useful
and accelerates reactions by producing a more powerful Sm(II)
single electron transfer reductant while oftentimes enhancing the
stereochemical outcome of reactions and impacting post electron
11,12
2
secondary amides bound to low-valent titanocenes.
Knowles
transfer steps. Inorganic additives are typically utilized in two
has shown that coordination of a secondary amide to
ways. They can be employed to provide a source of ligands that
(
III)
Cp* Ti Cl led to a 33 kcal/mol weakening of the N−H
2
displace iodide from SmI (LiBr, LiCl, etc.) to produce a different
2
11
3
bond. Gansauer and co-workers demonstrated that a low-
Sm(II) reductant in situ. They can also be used to promote
valent titanocene containing a pendant amide on one of the Cp
ligands led to a reversible coordination of the amide carbonyl that
reactions of low-valent transition metals. For example, the
addition of Ni(II) salts to SmI2 generates Ni(0) that is
12
weakened the N−H bond by 39 cal/mol. With this precedent
4
responsible for the cross-coupling of substrates. Proton donors
established, we posited that coordination of a secondary amide to
the highly reducing Sm(II) should lead to substantial bond-
weakening as demonstrated in Scheme 1 below.
are typically represented by alcohols, glycols, and water. In early
synthetic work, alcohols and water were used with SmI solely as
2
proton donors. It was later discovered that some donors
coordinate to Sm(II), while others do not, and that coordination
Scheme 1. Bond-Weakening upon Coordination to Sm(II)
has a significant impact on the reactivity of the SmI −proton
2
5
donor complex.
Among proton donors, water is unique since its addition to
SmI in THF enables the reduction and reductive coupling of
2
functional groups well outside of the reducing power of SmI2
6
alone. The elegant work of Procter has exploited this unusual
reactivity of the SmI −water complex for the reduction of
2
lactones and related functional groups to enable bond-forming
7
,8
reactions of great synthetic importance. Given the unusual
reactivity of the Sm(II)−water complex, we became interested in
the origin of the unique reactivity and recently proposed that
substrate reductions proceed through proton-coupled electron-
If bond-weakening occurs as proposed above producing a
reagent that reduces substrates through hydrogen atom transfer
(HAT), it may be possible to develop alternative approaches for
substrates resistant to reduction through SET. Because amides
are relatively hard ligands, they may further enhance the
9
transfer (PCET). Additionally, we established that proton
donors that strongly interact with Sm(II) through chelation
promote reduction through a PCET process, demonstrating the
potential of other Sm(II)-proton donor combinations to reduce
substrates typically recalcitrant to reduction through single
Received: December 8, 2016
10
electron transfer (SET).
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03664
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Organic Letters
Letter
a
reactivity of Sm(II) by stabilizing the +3 oxidation state of Sm in
a manner analogous to that proposed for HMPA.
Table 1. Impact of Additive on Arene Reduction
13
entry
substrate
additive (equiv)
NMA (5)
yield (%)
The suppositions described above suggest that two
preconditions should be met for an amide to act as an effective
HAT agent in concert with Sm(II): (1) the amide should have a
high affinity for Sm(II) and (2) the reductant formed upon
coordination of the amide to Sm(II) should oxidize more readily,
producing a stronger reductant upon coordination. To test the
assertions above, we chose two secondary amides to study, N-
methylacetamide (NMA) and 2-pyrrolidinone (2-P). These
amides were chosen since they are readily available from
commercial sources and highly soluble in THF. The UV−vis
b
1
2
3
4
5
6
7
8
9
anthracene
99
b
anthracene
2-P (5)
94
b
trans-stilbene
trans-stilbene
phenanthrene
phenanthrene
phenanthrene
phenanthrene
phenanthrene
NMA (15)
2-P (10)
NMA (20)
2-P (20)
2-P (20)
NMP (20)
90
b
90
NR
c
26
d
39
NR
NMP (20) TFE (20)
NR
a
b
c
spectrum of SmI was examined with increasing amounts of
Conditions: 2.5 equiv of SmI
2
, rt, overnight. Isolated yield.
conversion of starting material by H NMR. 3 equiv of SmI .
%
2
1
d
NMA and 2-P. Unfortunately, the addition of NMA led to
2
gradual precipitation, but addition of 2-P provided a soluble
complex. Figure 1 contains UV−vis spectra of SmI and the
2
reduce anthracene (entries 1 and 2). Both amide promoters also
fully reduce trans-stilbene in concert with SmI (entries 3 and 4).
2
Interestingly, addition of up to 20 equiv of NMA to SmI lead to
2
only recovered starting material, whereas the same amount of 2-P
provides some reduction of phenanthrene (entries 5 and 6).
Increasing the concentration of SmI leads to further conversion
2
(
entry 7).
The reactions described above demonstrate that 2-P facilitates
the reduction of phenanthrene, but does not provide a basis for
the effect of the promoter. Since CV and spectroscopic studies
show that coordination of 2-P to SmI enhances the ease of metal
2
oxidation, it is possible that the effect of the additive is a
consequence of the reagent combination providing a more
powerful reductant. To investigate further the basis of the effect,
N-methyl-2-pyrrolidinone (NMP) was employed as an additive.
The addition of NMP to SmI is known to produce a more
powerful reductant, but the reagent lacks an N−H necessary
for proton transfer. Addition of 20 equiv of NMP to a solution of
2
16
Figure 1. UV−vis spectrum of 2.5 mM SmI in THF (blue ◆)
2
containing 8 equiv of 2-P (red ×) and 15 equiv of 2-P (green +).
SmI and phenanthrene led to the complete recovery of starting
material (Table 1, entry 8) after 24 h of reaction. Next we
2
impact of addition of 2-P. The data are fully consistent with
coordination of 2-P to Sm(II) in THF. Next, the influence of
employed NMP in concert with trifluoroethanol, a non-
17
amide addition to the redox potential of SmI was examined
coordinating proton donor. No reduction of phenanthrene
was observed after an extended time (Table 1, entry 9). In
addition, when N-deuterated 2-P was employed in the reduction
of trans-stilbene, deuterium incorporation in the product was
observed (see Supporting Information). The experiments
described above are consistent with our hypothesis that
secondary amides coordinated to Sm(II) can act as HAT
promoters.
2
using cyclic voltammetry (CV). The CV data demonstrates that
the addition of 10 equiv of 2-P to SmI shifts the redox potential
2
by −0.3 V, producing a more powerful reductant (see Supporting
Information). To further assess the impact of 2-P concentration
on the reducing power of SmI , we employed 1-bromododecane
2
as a substrate. This substrate was chosen since it is resistant to
reduction by SmI alone, does not coordinate to the metal, and is
2
15
reduced through a rate-limiting dissociative electron transfer.
To assess the degree of N−H bond-weakening upon amide
As a consequence, it provides a useful measure of the impact of
additive concentration on the reactivity of Sm(II) in the absence
of competing mechanistic pathways. Complete conversion to
dodecane was obtained with at least 13 equiv of the additive in
coordination to SmI , the bond dissociation free energies
2
(BDFEs) in THF for the N−H bond of 2-P and the initial
radical formed upon HAT to trans-stilbene and phenanthrene
were calculated using density functional calculations employing
18
relation to [SmI ]. Lower concentration of the reductant led to
standard methods. Subtraction of the N−H BDFE from the
arene radical provides an estimate of bond-weakening as
demonstrated in Scheme 2 for the reduction of phenenathrene
2
incomplete conversion (see Supporting Information). Taken
together, the UV−vis, CV, and substrate reduction experiments
demonstrate that 2-P coordinates to Sm(II) while simulta-
neously providing a more powerful reductant.
With data in hand supporting the hypothesis that amides can
potentially be used as hydrogen atom donors in reductions, we
next examined the reduction of a series of arenes. Both NMA and
by the combination of SmI and 2-P. Using this approach, the
2
bond-weakening required for reduction of trans-stilbene is 63.1
kcal/mol, while the limit of N−H bond-weakening for reduction
of phenanthrene is 70.8 kcal/mol. The range of N−H bond-
weakening of 63−71 kcal/mol is greater than that displayed for
1
1,12
2
-P were employed as additives in the reduction of anthracene,
amide-Ti(III) complexes
but consistent with O−H weak-
9,10
trans-stilbene, and phenanthrene (Table 1). Previous work by
ening in Sm(II)−water and glycol complexes.
Procter established that the addition of water to SmI promoted
With this data in hand, we employed both HAT promoters for
the reduction of a range of carbonyl compounds (Table 2).
Both NMA and 2-P promote pinacol coupling of the two
aldehydes examined. This could be a consequence of a sequential
2
the reduction of anthracene and partial reduction of stilbene, but
14
phenanthrene was found to be unreactive. In the present case,
only 5 equiv of NMA or 2-P (based on [SmI ]) are required to
2
B
DOI: 10.1021/acs.orglett.6b03664
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Estimate of Degree of N−H Bond Weakening upon
Coordination of 2-Pyrrolidinone to Sm(II) in THF
amide can be used to carry out a reductive coupling successfully
5a
providing comparable yields to SmI −water.
2
Overall, these studies demonstrate that secondary amides can
be employed as additives to promote formal HAT to substrates
when coordinated to SmI . The critical feature for successful
2
implementation of this approach is the high affinity of the
carbonyl oxygen for Sm(II) for bond-weakening of the N−H
bond. While it is premature to state unequivocally that strong
coordination leading to bond-weakening is a general phenom-
enon, we posit that water, glycols, amides, and related additives
capable of coordinating to Sm(II) can be considered HAT
9
,10
promoters in the cases that we have examined to date.
Table 2. Reduction of Substrates by SmI and NMA or 2-P
Furthermore, there is substantial literature evidence demonstrat-
ing that interaction of ligands with low-valent metals can also lead
significant weakening of N−H and C−H bonds proximal to the
site of coordination, suggesting that this approach can be used
for the activation of other strong bonds, providing potential
alternative avenues to reduction and bond-forming reactions. We
are currently examining this supposition in the study of other
Sm(II)-functional group interactions, and the results of this work
will be presented in due course.
2
yield
substrate
benzaldehyde
additive
product
hydrobenzoin
(%)
19
a
d
NMA
90
a
d
2
-P
81
a
b
c
d
heptanal
NMA
7,8-tetra decanediol
2-octanol
73
a
d
2
-P
77
e
2
5
-octanone
NMA
63
b
d
2
-P
72
f
-decanolide
NMA
1,5-decanediol
52
c
d
ASSOCIATED CONTENT
Supporting Information
2
-P
85
■
c
f
S
*
methyl anisate
NMA
4-methoxy benzyl
alcohol
73
c
d
2
-P
99
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b03664.
c
d
2
,4-dimethoxy-1-
nitrobenzene
NMA
2,4-dimethoxy aniline
91
c
d
2
-P
93
Experimental procedures and spectral and computational
data (PDF)
a
Conditions. 2.5 equiv of SmI , 5 equiv of additive (based on [SmI ]).
2
2
2
b
c
.5 equiv of SmI , 10 equiv of additive (based on [SmI ]). 6 equiv of
2 2
d e
SmI , 10 equiv of additive (based on [SmI ]). Isolated yield. GC
2
2
f
1
AUTHOR INFORMATION
Corresponding Author
yield. % conversion of starting material by H NMR.
■
*
E-mail: rof2@lehigh.edu.
9
a
electron−proton transfer or possibly reduced steric constraints
ORCID
that promote homocoupling after formal HAT. For the eaction
of 2-octanone with SmI , 2-P led to reduced product exclusively,
Robert A. Flowers II: 0000-0003-2295-1336
Notes
2
whereas NMA provided the reduced product with the pinacol
product (see Supporting Information). In the reduction of 5-
decanolide, 2-P provided a very good yield of 1,5-decanediol,
whereas the use of NMA provided only about 50% conversion.
Conversely, both additives were equally effective for the
reduction of methyl anisate and 2,4-dimethoxy-1-nitrobenzene.
It is important to note that the substrates in Table 2 can be
reduced with SmI containing water, but there are some minor
differences in reaction outcomes. For instance, reduction of
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Drs. Lawrence Courtney, Gregory Ferguson, and
Rebecca Miller in the Department of Chemistry at Lehigh
University for insightful discussions. T.V.C. thanks the Depart-
ment of Chemistry at Lehigh University for a graduate research
fellowship. R.A.F. is grateful to the National Science Foundation
1
2
9a
heptanal by SmI −water provides 1-heptanol, whereas the use
of NMA or 2-P leads to pinacol coupling.
2
(
CHE 1565741) for support of this work.
In addition to the substrates contained in Table 2, we also
examined a ketone alkene cyclization using 2-but-3-enyl-
cyclohexan-1-one (1). The use of 20 equiv of 2-P provided
complete conversion to the reduced product (2) and cyclized
product (3) as shown in Scheme 3. The use of lower amounts of
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(
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