Triiodide-Mediated δ-Amination of Secondary C?H Bonds

Article abstract of DOI:10.1002/anie.201604704

The C_δ?H amination of unactivated, secondary C?H bonds to form a broad range of functionalized pyrrolidines has been developed by a triiodide (I₃^?)-mediated strategy. By in situ 1) oxidation of sodium iodide and 2) sequestration of the transiently generated iodine (I₂) as I₃^?, this approach precludes undesired I₂-mediated decomposition which can otherwise limit synthetic utility to only weak C(sp³)?H bonds. The mechanism of this triiodide-mediated cyclization of unbiased, secondary C(sp³)?H bonds, by either thermal or photolytic initiation, is supported by NMR and UV/Vis data, as well as intercepted intermediates.

Full text of DOI:10.1002/anie.201604704

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International Edition: DOI: 10.1002/anie.201604704
German Edition: DOI: 10.1002/ange.201604704
Radical Chemistry
À
Triiodide-Mediated d-Amination of Secondary C H Bonds
Ethan A. Wappes, Stacy C. Fosu, Trevor C. Chopko, and David A. Nagib*
À
Abstract: The Cd H amination of unactivated, secondary
À
C H bonds to form a broad range of functionalized pyrroli-
dines has been developed by a triiodide (I3À)-mediated strategy.
By in situ 1) oxidation of sodium iodide and 2) sequestration of
the transiently generated iodine (I2) as I3À, this approach
precludes undesired I2-mediated decomposition which can
3
À
otherwise limit synthetic utility to only weak C(sp ) H bonds.
The mechanism of this triiodide-mediated cyclization of
unbiased, secondary C(sp ) H bonds, by either thermal or
photolytic initiation, is supported by NMR and UV/Vis data, as
well as intercepted intermediates.
3
À
À
I
n the synthetically enabling realm of C H functionaliza-
3
tion,[1] selective amination of unactivated C(sp ) H bonds is
of primary interest because of the privileged nature of amines
in medicines and materials.[2,3] Some creative solutions for this
key synthetic challenge employ metallated amides and
À
nitrenes.[4,5] Radical-mediated strategies also enable C H
À
amination, albeit with differing selectivities.[6] For example,
nitrogen-centered radicals facilitate facile and selective
hydrogen-atom transfer (HAT) leading to complementary
[2,6,7]
À
C H amination approaches.
Although the selectivity of
single-electron-mediated strategies can be robust, the typi-
cally harsh means for generating these radicals have limited
their synthetic utility —until recently.[8] In this vein, we sought
to expand the scope and synthetic applicability of one of the
most powerful transformations in this class by introducing
a mild and general strategy for generating and harnessing the
reactivity of nitrogen-centered radicals.
Figure 1. Development of Hofmann–Lçffler–Freytag (HLF) reaction
and our proposed triiodide strategy to significantly broaden scope and
utility. TFA=trifluoroacetic acid, Ts=4-toluenesulfonyl.
The Hofmann–Lçffler–Freytag (HLF) reaction[9] converts
acyclic amines into pyrrolidines by transposition of an
N-haloamine to a d-haloamine by selective 1,5-HAT (Fig-
ure 1a). Despite the harsh reaction conditions required to
promote the classic HLF reaction[10] (through homolysis of
a preformed haloamine in refluxing acid), this radical-
PhI(OAc)2. Additionally, use of an electron-deficient nitro-
gen substituent replaces the need for strongly acidic con-
ditions by promoting 1,5-HAT by a polarized aminyl radical
À
intermediate. This modification enables C H functionaliza-
tion[12] of previously inaccessible, acid-sensitive molecules
(e.g. carbohydrates).[13] However, this transformation remains
À
À
mediated Cd H amination has enabled landmark syntheses
generally limited to weak or activated C H bonds (e.g.
(e.g. nicotine, gelsemicine).[2]
tertiary, benzylic, a-heteroatom).[14]
A major milestone in the development of HLF chemistry
is a discovery by Suꢀrez and co-workers, and it precludes the
need for haloamine pre-formation (Figure 1b).[11] In this
improved approach, generation of the N-centered radical is
facilitated by direct oxidation of an amine with Hg(OAc)2 or
A major obstacle to functionalization of less biased
À
substrates (e.g. secondary, nonbenzylic C H bonds) derives
from the requisite co-oxidant employed in this reaction.
Specifically, iodine (I2), and in situ generated acetyl hypoio-
dite (AcOI),[15] are prone to photoinitiated homolysis which
[16]
À
leads to undesired oxidations of weaker C H bonds. To
avoid these byproducts, HLF substrates are often designed
[*] E. A. Wappes, S. C. Fosu, T. C. Chopko, Prof. Dr. D. A. Nagib
Department of Chemistry and Biochemistry
The Ohio State University
À
with limited functionality and weak Cd H bonds to favor 1,5-
HAT. Thus, the necessity of I2 severely limits the scope and
À
utility of such N-centered radical C H functionalizations.
Columbus, OH 43210 (USA)
E-mail: nagib.1@osu.edu
Homepage: http://www.chemistry.osu.edu/faculty/nagib
Recent attempts to overcome this limitation have focused
on decreasing the reaction concentration of I2, and thus
AcOI.[17] Martꢁnez and MuÇiz have reported the first system
which employs iodine as a catalyst, through the use of
a tailored oxidant which facilitates efficient turnover of the
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201604704.
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active iodine species (Figure 1b).[18] This innovative approach
enables the use of sensitive functionality, such as alkenes and
observed that thermal initiation (508C, without added light)
proved superior to visible-light irradiation in some cases (see
the Supporting Information).
À
anisoles. Nonetheless, the protocol still requires weak C H
bonds or the incorporation of entropic bias. Another strategy
to avoid unproductive I2-mediated oxidations has been
developed by Herrera and co-workers.[19] Through iterative
oxidant addition, reaction efficiency could be improved for
Having successfully developed
a
protocol for the
À
d-amination of unbiased, secondary C H bonds, we applied
this triiodide strategy to the cyclization of a wide range of
amines bearing medicinally relevant functionalities. As illus-
À
À
a range of primary C H bond functionalizations, also allow-
ing in situ subsequent oxidation to lactams.
trated in Table 2, the d-functionalization of secondary C H
bonds is efficient and synthetically tractable by this triiodide
In our strategy, we hypothesized that a solution to the I2
problem entails slow, in situ I2 generation from innocuous
iodide (IÀ) salts (Figure 1c). This approach allows 1) attenu-
ated formation of transiently reactive AcOI, and 2) decreased
generation of byproducts by in situ sequestration of I2 as
strategy. Notably, selective functionalization of unactivated,
3
À
secondary C(sp ) H bonds in the presence of weaker
3
À
C(sp ) H bonds is accomplished under these reaction con-
ditions [e.g. benzylic (6–8), a-oxy (5, 10), a-CF3 (13), and
a-carbonyl (11, 12, 15, 16): 65–75% yields]. We observed
À
triiodide (I3 ). We were inspired by the classical “iodine
clock” experiment, where I2 is formed by combination of
iodide salts and an oxidant.[20] In the presence of excess IÀ, the
in situ generated I2 forms I3À, because of a Lewis acid/base
interaction between IÀ and I2. This equilibrium is well
elucidated[21] and has been harnessed in battery technologies
À
Table 2: Scope and generality of the triiodide-mediated Cd H amination.
which employ an IÀ/I3 electron shuttle.[22] Ultimately, we
À
hypothesized that triiodide formation should minimize the
concentration of I2 in solution, thus allowing selective
À
amination of unactivated C H bonds within functionalized
substrates.
To this end, we explored the cyclization of N-tosyl (Ts)
3
À
heptyl amide, which contains unbiased, secondary C(sp ) H
bonds at the d position (Table 1). As expected, I2-mediated
conditions provide low yields of desired pyrrolidine (entry 1),
leading instead to several, inseparable decomposition prod-
ucts. Next, we sought to test our hypothesis that IÀ sequestra-
À
tion of I2 as I3 prevents undesired byproduct pathways.
Indeed, increasing NaI in the I2-based conditions improved
reaction efficiency (entries 3–5). We then sought to decrease
initial I2 concentration by relying on direct in situ oxidation of
NaI. Again, increasing IÀ (even in the absence of initial I2)
provides the cleanest and most efficient functionalization of
3
À
this unbiased, secondary C(sp ) H bond (entry 9). We also
À
Table 1: Discovery of a triiodide-mediated Cd H amination.
Entry[a]
I2 (equiv)
NaI (equiv)
Yield [%][b]
1
2
3
4
5
6
7
8
9
2
4
2
2
2
–
–
–
–
–
–
1
2
4
1
2
4
4
33
32
58
65
71
37
68
Reaction conditions: 0.2 mmol amide, NaI (4 equiv), PhI(OAc)2
(4 equiv), 0.1m MeCN, visible light, 2–48 h, 23 W compact fluorescent
light (CFL) or ambient light in fume hood at 508C. Yields are those of
isolated products. Products 4–8, 13–16 are obtained by thermal
initiation, all others are photolytically initiated. Diastereomeric ratio (d.r.)
indicated within parentheses. Ms=methanesulfonyl, Ns=nitrobenze-
nesulfonyl, SES=2-trimethylsilylethanesulfonyl, TBS=tert-butyldime-
thylsilyl. X-ray structure of 16 is shown. Thermal ellipsoids are shown at
50% probability.[30]
73
79 (74)[c]
[a] Reaction conditions: 0.2 mmol amide, PhI(OAc)2 (4 equiv), 0.1m
MeCN, visible light, 4 h, 23 W compact fluorescent light (CFL). [b] Yields
determined by H NMR spectroscopy using an internal standard.
[c] Yield of isolated product after a 9 h reaction time.
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À
exclusive Cd H amination in all cases, in lieu of competitive
each case, only the pyrrolidine is obtained, thus further
supporting the 1,5-HAT transition-state model.
decomposition, or regioisomeric products.[23] Also, while the
À
weak a-oxy C H bonds of ethanolamine efficiently generate
This method is predicated on the mechanistic hypothesis
that in situ I2 generation in the presence of excess IÀ favors I3
À
the oxazolidine 14, cyclization of the amino acid analogue Ts-
3
norleucine, is selective at a secondary C(sp ) H bond over the
formation[21] and limits undesired I2-based reactivity (Fig-
ure 1c). Our mechanistic hypothesis for the improved,
triiodide-mediated process is supported by the observation
of clean conversion of unactivated amines into pyrrolidines.
Notably, 1H NMR spectral data of this reaction shows
significantly less impurities than the I2-mediated reaction,
thus suggesting a minimization of over-oxidation typically
associated with I2 and AcOI homolysis. As shown in Figure 2,
the I2-initiated reaction (red) results in multiple, inseparable
À
weaker
À
a-oxy C H bonds (12). As expected in rapid, radical-
mediated transformations, the diastereoselectivity of this
amination is modest (1:1 to 2:1), although it is improved
with nearby electron-deficient substituents [CO2Me (12) and
CF3 (13)]. The major diastereomer obtained in all cases
(except 11) has been assigned as the cis isomer by NMR
spectroscopy and confirmed by X-ray analysis of the b-keto
pyrrolidine 16 (see the Supporting Information).
byproducts, while the IÀ/I3 -mediated conditions (blue)
À
À
This C H amination reaction exhibits a wide tolerance for
affords clean conversion into the desired product 1 (green).
These cleaner reaction profiles lead to increased pyrrolidine
formation and simplified isolation.
biologically relevant functionality, including ethers, esters,
ketones, arenes, and organofluorines (5–16). To further probe
its synthetic utility, we investigated varying amine protecting
groups. Although radical initiation and subsequent cyclization
was limited for some protecting groups (e.g. Boc, Ac, TFA),
all investigated sulfonamides underwent d-amination, despite
varied electronics of the aminyl radical in each case (17–22).
Importantly, each of these sulfonamide pyrrolidine products
is deprotected by an orthogonal method, including the
synthetically valuable SES group, which is removed by
fluoride-induced desilylation.[24]
Figure 2. 1H NMR spectra of the pyrrolidine product 1 (a; green)
Interestingly, this method exhibits unique, exclusive
d-selectivity, even in the presence of weaker C(sp ) H
bonds. Unlike other protocols, which typically require tertiary
À
compared to crude reaction mixtures mediated by either I3 (b; blue)
3
À
or I2 (c; red).
À
or benzylic C H bonds, this method appears to disfavor ring
closure at unactivated tertiary C H bonds. To further probe
Central to our hypothesis, I3À formation plays a key role in
attenuating I2-mediated decomposition. To confirm the
presence of triiodide, we obtained UV/Vis spectroscopic
data for the reactions depicted in Table 1. As illustrated in
Figure 3, a strong absorbance at l = 360 nm is observed,
À
this seemingly divergent selectivity, we subjected a pair of
menthol-derived amides to our I3À-mediated conditions
À
(Scheme 1). In the first competition experiment, Cd
H
À
amination is selective at the secondary over tertiary C H
bonds (23 to 24 only). This atypical selectivity is notable given
the additional observation that exocyclic ring formation is
completely preferred over transannular cyclization (25 to 26
only), as observed in a second competition experiment. In
which is consistent with the presence of triiodide.[20] This I3
À
signal is absent in I2-based conditions, but it is present and
amplified with increasing quantities of NaI, including that of
our reaction (4 equiv).
In the course of developing this triiodide-based protocol,
we hypothesized that other salts might also be oxidized in situ
to form the active oxidant. Interestingly, counterions apart
from Na+ (e.g. Li+, K+, Bu4N+) are uniformly inferior in
promoting this transformation (see the Supporting Informa-
tion). We propose this result is due to the beneficial role of the
Figure 3. UV/Vis spectra of reaction mixtures confirm the presence of
Scheme 1. Atypical selectivities observed in this triiodide reaction.
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
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basic NaOAc, which is formed in the reaction and may
Acknowledgments
promote the final cyclization of the d-iodo amide. While
addition of exogenous bases provides varying levels of
product formation, none are superior to the standard reaction
conditions.
Interestingly, the use of sodium halide salts (NaX), in
place of NaI, enabled isolation and characterization of two
proposed intermediates (Scheme 2). For example, NaCl leads
We gratefully acknowledge The Ohio State University (OSU)
and the American Chemical Society Petroleum Research
Fund for support of this research. We are also grateful for
fellowship support to E.A.W. (OSU) and S.C.F (National
Institutes of Health Chemistry-Biology Interface Training
Program NIH GM08512). We also wish to thank Dr. Judith
Gallucci (OSU) for assistance with X-ray crystallographic
characterization.
À
to exclusive formation of the haloamine (N Cl) intermediate
À
Keywords: amination · C H functionalization ·
radical chemistry · hydrogen atom transfer · triiodide
À
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À
À
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À1
À1 [27]
À
À
(BDE: C I = 50.0 kcalmol ; N I = 38.0 kcalmol ).
A
radical-mediated mechanism is further supported by the
decreased yields observed in the presence of typical traps,
including TEMPO and galvinoxyl radicals or molecular
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À
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3
À
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À
[16] AcOI homolysis-derived radicals can oxidize a-aminyl C H
bonds. This byproduct-forming oxidation is competitive with 1,5-
HAT for unactivated C H bonds, which limits reaction scope to
activated C H bonds.
À
À
[17] For an alternate strategy, see: C. Zhu, Y. Liang, X. Hong, H. Sun,
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Revised: June 2, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Radical Chemistry
E. A. Wappes, S. C. Fosu, T. C. Chopko,
D. A. Nagib*
&&&& — &&&&
Triiodide-Mediated d-Amination of
À
Secondary C H Bonds
I2 as I3À, this approach precludes unde-
sired I2-mediated decomposition. The
mechanism is discussed and supported
by NMR and UV/Vis data, as well as
intercepted intermediates.
À
Just add salt: The Cd H amination of
3
À
unactivated, secondary C(sp ) H bonds
to form a broad range of functionalized
pyrrolidines has been developed. By in
situ oxidation of sodium iodide and
sequestration of the transiently generated
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!