Vicinal, Double C-H Functionalization of Alcohols via an Imidate Radical-Polar Crossover Cascade

Article abstract of DOI:10.1021/jacs.0c01318

A double functionalization of vicinal sp³ C-H bonds has been developed, wherein a β amine and γiodide are incorporated onto an aliphatic alcohol in a single operation. This approach is enabled by an imidate radical chaperone, which selectively affords a transient β alkene that is amino-iodinated in situ. Overall, the radical-polar-crossover cascade entails the following key steps: (i) β C-H iodination via 1,5-hydrogen atom transfer (HAT), (ii) desaturation via I₂ complexation, and (iii) vicinal amino-iodination of an in situ generated allyl imidate. The synthetic utility of this double C-H functionalization is illustrated by conversion of aliphatic alcohols to a diverse collection of α,β,γsubstituted products bearing heteroatoms on three adjacent carbons. The radical-polar crossover mechanism is supported by various experimental probes, including isotopic labeling, intermediate validation, and kinetic studies.

Full text of DOI:10.1021/jacs.0c01318

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Vicinal, Double C−H Functionalization of Alcohols via an Imidate
Radical-Polar Crossover Cascade
Allen F. Prusinowski, Raymond K. Twumasi, Ethan A. Wappes, and David A. Nagib*
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ABSTRACT: A double functionalization of vicinal sp3 C−H bonds has
been developed, wherein a β amine and γ iodide are incorporated onto an
aliphatic alcohol in a single operation. This approach is enabled by an
imidate radical chaperone, which selectively affords a transient β alkene
that is amino-iodinated in situ. Overall, the radical-polar-crossover cascade
entails the following key steps: (i) β C−H iodination via 1,5-hydrogen
atom transfer (HAT), (ii) desaturation via I2 complexation, and (iii)
vicinal amino-iodination of an in situ generated allyl imidate. The synthetic utility of this double C−H functionalization is illustrated
by conversion of aliphatic alcohols to a diverse collection of α,β,γ substituted products bearing heteroatoms on three adjacent
carbons. The radical-polar crossover mechanism is supported by various experimental probes, including isotopic labeling,
intermediate validation, and kinetic studies.
an iodo-oxazoline, which may then be readily converted to a
family of α,β,γ substituted amino alcohols.
INTRODUCTION
■
In nature, form and function are often intertwined. Likewise,
increased molecular complexity may increase utilityaffording,
for instance, more potent and selective medicines.1 Illustrating
this link between value and complexity, Figure 1a includes a
series of molecules, each containing a propanol backbone with
varying heteroatom substitution. Compared to 1-propanol (<
$0.1/mL), its N-containing analogs [serinol ($40/mL), 2,3-
diaminopropan-1-ol ($1000/mL), 2-aziridinemethanol (>
$10 000/mL)] are costlier and more challenging to synthesize.2
Yet, the latter, N-rich analogs are more likely to be found in
medicines,3 and thus methods for synthesizing such densely
oxidized scaffolds remain valuable.1 Typically, vicinal amino
alcohols may be synthesized by alkene difunctionalization of
allylic alcohols (Figure 1b).4 As a complementary route to access
products with α,β,γ heteroatom substitution, we sought to
directly employ aliphatic alcohols, without preinstallation of a
reactive alkenevia double C−H oxidation.
Building on our recent work in the area of directed C−H
functionalization by 1,5-hydrogen atom transfer (HAT),9,10 we
were cognizant of the unique ability of imidate radicals to
selectively convert alcohols to their β amines11,12 or β halides.13
As shown in Figure 2, this radical chaperone strategy entails
temporary conversion of an alcohol A to an imidate by coupling
with a nitrile.
Subjecting this imidate radical precursor to AcOI (prepared in
situ from NaI and PhI(OAc)2) then affords a transient N-iodo-
imidate B, whose weak N−I bond is readily homolyzed with
visible light. The resulting N-centered radical C is then well-
suited to undergo regioselective 1,5-HAT to afford β C-centered
radical D. Upon recombination with the caged iodine radical,
the key intermediate, β iodo imidate E, is formed. In our
previous studies, a polar solvent (e.g., MeCN) facilitates in situ
cyclization to yield oxazoline F, which can be hydrolyzed by
acidic workup to afford β amino alcohol G.11a−c In nonpolar
solvents (e.g., PhMe), 4-aryl oxazolines are further oxidized to
heretoaromatic azoles.11d Alternatively, β iodo imidate E may
undergo a second, iterative 1,5-HAT to selectively abstract the
remaining β C−H bond, which is weaker by ∼2 kcal/mol due to
C-X polarization, to afford β di-iodide H. Upon aminolysis,
geminal β di-iodide I is obtainedcomplementing Pd-catalyzed
To access products with three contiguous oxidized carbons,
we proposed a radical-polar cascade strategy may address this
challenge. Yet, whereas radical-polar crossover mechanisms5 are
typically initiated by radical addition to alkenes,6 we were
interested in pursuing a reversed strategy, entailing H•
abstraction to first generate an alkene and then harness its
polar reactivity. We were inspired by the pioneering studies of
Barluenga et al.7 converting alkane solvents to iodo-acetates
under highly oxidizing conditions via O-radicals, as well as an
N3I-mediated iodo-lactamization by Yu et al.8 To extend this
approach to enable selective C−H difunctionalization of
synthetically useful alcohols, we envisioned a radical chaperone
strategy, wherein an alcohol is converted to an imidate N-radical,
may allow in situ alkene generation via desaturation (Figure 1c).
Amino-halogenation of this transient intermediate would afford
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increasing polarity might enable I-oxidation−facilitating an
alternate radical-polar crossover mechanism.
In this third mechanistic possibility, iodine-centered oxidation
of β iodo imidate E may afford β hypervalent iodane J. This alkyl
λ3-iodane is a hypernucleofuge, which is a 106 times faster
leaving group than triflate.15 For this reason, we anticipated its
rapid β elimination would afford allyl imidate K. The
regioselectivity of this eliminationaway from the imidate
was expected based on imidate polarization. Again this reactivity
would complement Pd-catalyzed mechanisms, including 1,5-
HAT pathways recently developed by Gevorgyan and co-
workers to access enols, enamines, and terminal alkenes via
desaturation.16 Finally, we hoped allyl imidate K would directly
undergo AcOI-mediated halo-cyclization in a radical-polar
crossover cascade to afford γ iodo oxazoline L. We expected
that this intermediate could also be hydrolyzed to β amino
alcoholswith an additional γ iodo functional handle to enable
further nucleophilic substitution. With this added versatility, a
family of α,β,γ substituted amino alcohols would be rapidly
accessible from aliphatic alcohols by a desaturation-mediated
cascade.
RESULTS AND DISCUSSION
■
To test our radical-polar crossover cascade hypothesis, we
subjected imidate 1, whose tertiary β iodide intermediate we
expected to be prone to oxidative elimination, to excess AcOI (in
situ combination of NaI and PhI(OAc)2) in MeCN with visible
light irradiation (26W compact fluorescent light) (Figure 3). We
were pleased to find the cascade was indeed feasible, affording
iodo oxazoline 2 (43% yield) along with des-iodo oxazoline 3
(18% yield). Moreover, substituting a less polar solvent
(CH2Cl2) slows cyclization and affords more 2 (63% yield),
along with β iodide 4 (18% yield) and oxazoline 3 (12% yield).
Extending this trend, nonpolar PhCF3 solvent arrests cyclization
and exclusively affords β iodide 4 (60% yield). Alternatively, a
more polar 3:1 HFIP:CH2Cl2 solvent mixture yields oxazoline 3
(83% yield) selectively. Building on these observations, we
Figure 1. Radical-polar crossover enables synthetically valuable, double
C−H functionalization.
β C−H iodination by Yu et al., which forms distal di-iodides.14
We have found the key to this divergent reactivity rests in the
judicious choice of solvents. For example, while MeCN yields
cyclization to oxazoline F, a MeCN:CH2Cl2 mixture affords
iterative HAT (to β di-iodide I). We anticipate this less polar
solvent mixture allows a second N-oxidation to outcompete
cyclization. Furthering this hypothesis, we envisioned a solvent
that increases NaI (and thus AcOI) concentration without
t
tested BuOH, a moderately polar, protic solvent, and were
delighted to observe selective vicinal C−H difunctionalization to
2 (92% yield). Notably, the proposed intermediate alkene 5 was
Figure 2. Several single and double C−H functionalization mechanisms enabled by an imidate radical chaperone strategy.
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intermediate, showcasing the unique utility of this radical-
mediated strategy to doubly modify small rings. A variety of
functional groups are tolerated under these reaction conditions,
including ethers, amides, esters, and nitriles, affording spiro-
fused bis-heterocycles (10−13, 19). In addition to primary
alcohols, this cascade is also amenable to secondary alcohols,
which selectively undergo radical-polar crossover reactivity to
afford spirocyclic oxazolines (14, 15) rather than distal, iterative
HAT products.13 Additionally, γ acyclic alcohols afford γ iodo
oxazolines as well. In this case, both symmetric (di-Me, di-nBu)
or asymmetric (Me, nBu) substituents are toleratedwith the
latter affording 8:1 to 20:1 regioselectivity for the more
substituted γ iodide (16−19).
We have shown the cyclization of intermediate β iodo
imidates is challenging in the absence of benzylic activation, and
thus, more nucleophilic benzimidates (vs trichloroimidates) are
necessary to afford amination in these cases.11a Therefore, to test
the limits of this new radical-polar crossover, we investigated
such amination-prone imidates. Unexpectedly, a wide range of
benzimidates (accessed by addition of alcohols to benzonitriles)
are amenable to this cascade. For example, electronically diverse,
para-aryl substituents, ranging from −CH3 to −CF3 afford iodo
oxazolines (20−24) with excellent efficiency and diastereose-
lectivity (>70% yield, > 20:1 dr). Additionally, meta- and bis-
halide substitution are tolerated, as well as oxidatively sensitive
naphthalenes (25−28). Lastly, and perhaps, most surprisingly,
alkyl nitrile-derived imidates also efficiently afford spirocyclic
oxazolines (29, 30) despite increased nucleophilicity of these
imidates, which may otherwise cyclize to afford monoamination.
To further probe the functional group tolerance of this
radical-polar cascade, a robustness screen was performed.18 In
this investigation of 1 to 2, we observed medicinally relevant
five- and six-membered N-containing heterocycles (e.g.,
imidazole, pyridine) are well-tolerated. Interestingly, we
observed a slight decrease in diastereoselectivity in the presence
of these bases. We attribute this effect to I2-base complexation,19
which effectively decreases the concentration of I2 and rate of the
resulting polar amino-iodination pathway (see Supporting
Information, SI, for more details). Next, we were pleased to
find alkyl chlorides, which are prone to displacement by I−
(generated upon alkyl-iodide elimination), are also tolerated.
Additionally, alcohols, aldehydes, and amides are preserved,
despite the possibility of their consumption under these
oxidative conditions (see SI for an extended table of functional
group tolerance investigations).
Figure 3. Development of vicinal, double C−H functionalization.
Conditions: 0.2 mmol imidate, I2 or NaI (3 equiv), PhI(OAc)2 (3
equiv), tBuOH [0.3 M], and 3 min stir before visible light irradiation for
1 h. Yields and dr determined by 1H NMR vs internal standard.
not recovered from any of these experiments, and tBuOH affords
<5% of side-products 3 or 4. It is worth highlighting the strong
solvent effect observed, wherein three divergent transformations
are controlled by solvent choice. For example, imidate 1 can be
tuned to selectively afford: β C−H iodination (4) in PhCF3, β
C−H amination (3) in HFIP:CH2Cl2, or vicinal C−H β-amino-
γ-iodination (2) in tBuOH.
t
In further probing our hypothesis that BuOH is optimal
because it best solubilizes AcOI precursors and increases oxidant
concentration, we switched the iodine reagent from NaI to I2.
Although we previously found I2 to work well in some cases,11c
its photolytic initiation often affords significant side-product
formation and poor desired reactivity.10a Thus, we were
t
pleasantly surprised to find that in BuOH, I2 forms iodo
oxazoline 2 efficiently (84% yield) and with high diastereose-
lectivity (19:1 dr). As reaction controls, we probed the effects of
added base (2,6-lutidine) and immediate irradiation (without a
3 min prestir to ensure I2 solubility before irradiation). Both
changes resulted in significantly lower diastereoselectivity with
similar efficiency. Lastly, as expected, absence of PhI(OAc)2 (to
generate AcOI), I2 (to facilitate iodide elimination), or light (to
initiate N−I homolysis) affords no reactivity.
MECHANISTIC INVESTIGATIONS
■
A detailed description of our proposed mechanism is shown in
Figure 5a. First, in situ generation of AcOI occurs by
combination of PhI(OAc)2 and I2 via a ligand exchange
mechanism.20 Next, an alcohol-derived imidate I undergoes
N-iodination by displacement of AcOI, which is electrophilic at
iodine.21 The resulting N-iodo imidate II contains a weak N−I
bond that is homolyzed under visible light irradiation. The
electrophilic, N-centered radical III may then undergo a
thermodynamically and kinetically driven 1,5-HAT to generate
nucleophilic, C-centered radical IV. Upon radical recombina-
tion with I•, β alkyl iodide V is formedterminating the radical
component of the radical-polar crossover mechanism. To
promote polar elimination, Lewis acidic complexation of I2 to
iodide V would form the alkyl triiodide nucleofuge VI.22
SYNTHETIC SCOPE
■
Having developed a regio- and diastereo- selective vicinal,
double C−H amino-iodination of alcohols via an imidate-
radical-polar crossover mechanism, we sought to investigate the
generality and utility of this cascade reaction (Figure 4). To this
end, we found a range of cyclic alcohols are efficiently amino-
iodinated to afford spirocyclic oxazolines fused to 4−8
membered carbocycles (2, 6−9). Notably, even cyclobutane
(a common motif in medicines and natural products)17 is
amino-iodinated (9), likely through a strained cyclobutene
Upon net elimination of HI and I2, a resulting allyl imidate VII
is generated and amino-iodinated under these oxidative
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Figure 4. Synthetic utility of vicinal C−H amino-iodination of alcohols. Conditions: 0.2 mmol imidate, I2 (3 equiv), PhI(OAc)2 (3 equiv), tBuOH [0.3
M], and 3 min stir before visible light irradiation. aNaI (3 equiv). bI2 (2 equiv). cPhI(OAc)2 (5 equiv). d NMR yield. ePhI(OAc)2 (4 equiv). Isolated
yields indicated, along with diastereoselectivity (dr) or regioselectivity (rr), as determined by NMR of the crude reaction mixture.
conditions. This halo-cyclization may occur by either a polar,
iodonium (VIII) or radical, π-addition (5-exo-trig cyclization of
IX) mechanism. The high diastereoselectivity observed for
trans-iodo-oxazoline X suggests that a polar mechanism is
operativeentailing intramolecular cyclization of iodonium
VIII by the tethered imidate. Nucleophile-induced prepolariza-
tion via this pathway may also account for the observed
stereoselectivity.23
D
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Figure 5. Vicinal C−H amino-iodination via imidate radical chaperone desaturation−addition cascade: (a) Proposed mechanism. (b) Mechanistic
probes for various key steps. (c) KIE and rate studies.
To better understand this radical-polar crossover mechanism,
we conducted a series of experiments probing the elementary
steps of this cascade. First, two of the key proposed
intermediates, β alkyl iodide 4 and β alkene 5 (representing V
and VII, respectively), were independently synthesized and
subjected to the reaction (Figure 5b). Both of these imidates
afford iodo oxazoline 2 (up to 98%)validating their likely
intermediacy in the cascade mechanism. As further support,
We then interrogated the mechanism of β alkyl iodide
eliminationan important question, given its similarity to the
stable γ iodo product. Since a variety of relevant additives (e.g.,
NaOAc, HOAc; see SI for a full list) do not promote elimination
of intermediate 4 (or V), we hypothesized the iodide may be first
oxidized to a λ3-iodane, which is an elimination-prone
hypernucleofuge.15 Upon subjecting 4 to each reaction
component (individually or as combinations), the oxidation/
elimination/cyclization sequence to form iodo oxazoline 2 was
only observed in the presence of AcOI (98% yield with I2,
PhI(OAc)2; 36% yield with I2, NaOAc). Interestingly, use of
1
iodide 4 was observed by H NMR during the course of the
reaction (alkene 5 is also observed when the reaction is
performed in toluene; see SI for details).
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PhI(OAc)2 alone does not oxidize the alkyl iodide, unlike what
has been observed in other systems.24 Another notable
observation is that I2 alone provides full consumption of 4,
albeit without formation of 2. Further discussion of the nature of
this β iodide-selective oxidation/elimination is provided in
subsequent sections.
beyond its synthetic limitation of tertiary (3°) β C−H bonds.
This goal is further complicated by the observation that
secondary (2°) γ iodide products are stable, while tertiary β
iodide intermediates are not. Our rationale for this observed
selectivity is that Lewis acidic I2 may reversibly bind to alkyl
halides, especially in nonpolar solvents (Figure 6).22 Notably,
As our next line of enquiry, we focused on the proposed β
alkene 5 and its ability to afford iodo oxazoline 2 via either a
radical or polar pathway. Interestingly, when CH2Cl2 is used as
t
solvent (vs BuOH), only 5:1 dr is observed (vs 20:1 dr in
tBuOH). Suspecting the lower stereoselectivity might be a result
of a radical pathway (via IX), we added TEMPO to the CH2Cl2
reaction and observed a recovery of high stereoselectivity (20:1
dr). On the basis of these data, we reasoned that the
t
stereoselective BuOH conditions suggest a polar mechanism
for the amino-iodination of alkene 5 (via trans intramolecular
imidate addition to iodonium VIII).
Next, we sought to probe if alternate mechanisms, such as β
fragmentation or nondirected functionalization, are operative
(Figure 5b). In the first case, the C−H amination side-product
(oxazoline 3) could afford amino-iodinated product (iodo
oxazoline 2) by β fragmentation of a γ C-radical (inset). While
there is no obvious driving force for γ selective C−H abstraction
(or regeneration of an N-centered radical via this pathway), a
related mechanism was identified by Yu and co-workers in their
iodo-lactamization.8 Nevertheless, when resubjected to reaction
conditions, oxazoline 3 remains intact and does not afford iodo
oxazoline 2. Similarly, we sought to investigate if a nondirected
pathway, as described by Barluenga et al.,7 is operative. Noting
that AcOI (I2, PhI(OAc)2) in tBuOH may form tBuO-I, whose
homolysis would generate a reactive HAT reagent (tBuO•),25 we
replaced the imidate directing group with a similarly polar ester.
In this case, subjecting acetate 31 to reaction conditions does
not form β iodide 32 or any other relevant products. This
observation supports our hypothesis that the regioselective
cascade is mediated by imidate radical 1,5-HAT rather than
nondirected HAT (by tBuO•; see inset).
Figure 6. Selective oxidation of tertiary over secondary alkyl iodide.
this complexation is substrate-controlled, with highly sub-
stituted alkyl iodides binding more strongly than less substituted
variants (binding constants, K: tertiary, 1.3 ≫ secondary, 0.4).
Thus, we propose that preferential formation of the tertiary
−
triiodide allows selective dissociation to I3 and a 3° cation
enabling elimination and subsequent cyclization. On the basis of
our experimental data, it appears this equilibrium-dependent
heterolysis is driven in the forward direction by AcOI-mediated
Finally, we investigated the role of HAT in the double C−H
functionalization by measuring relative reaction rates of
individual steps, while also considering the effects of heavy
atom labels on these rates (Figure 5c). In the overall reaction, a
negligible, primary kinetic isotope effect (KIE) was determined
by measuring parallel rates of reactivity of 1 vs β deutero 1 (kH/
kD = 1.2). Interestingly, when rates of formation of intermediate
4 are measured (vs cascade product 1), a slightly larger primary
KIE is observed (kH/kD = 2.3). Together, these data suggest that
while HAT is rate-determining for intermediate C−H
iodination, it is not the rate-determining step of the overall
amino-iodination cascade. Similarly, comparison of the relative
rates of the overall reaction (double C−H amino-iodination; k1
−
oxidation of I3 . This mechanistic pathway provides an
explanation for the observed selectivity for oxidation of tertiary
β iodide intermediate, but not 2° γ iodide product. Nevertheless,
this proposal suggests an inherent synthetic limitation that we
wished to address.
To overcome this β methylene challenge, we designed a suite
of strategies to access amino-iodination of 2 °C−H bonds
even in cases where oxidation of, or I2 complexation to, a 2° β
iodide intermediate is disfavored (Figure 7). First, incorporating
electron-withdrawing groups (e.g., ketone, ester) at the γ
position sufficiently enhances acidity of the γ proton and
facilitates β iodide eliminationaffording cascade products
with four consecutively oxidized carbons (33−36). A second
strategy entails use of a γ halide leaving group to promote
iodonium formation from the vicinal dihalide intermediate (37,
38). A third approach employs the β-silicon effectenhancing
the leaving group ability of a β iodide by incorporating a γ silyl
group (39−40). Finally, if no additional functionality is desired,
then simply incorporating a 3 °C−H bond at the γ (vs β)
position also facilitates the cascade (41, 42). In this case, since
1,5-HAT is favored over 1,6-HAT,11c we anticipate that the sec-
isopentyl β iodide is sufficiently strained to behave more like the
tertiary β iodides (undergoing I2 complexation and subsequent
I3− oxidative elimination).
= 1.0) to stepwise formation of β iodide 4 (mono C−H
rel
iodination; k2 rel = 2.1) and its subsequent conversion to product
(elimination/cyclization; k3 rel = 1.3) illustrates the bottleneck in
this cascade. Specifically, radical-mediated C−H iodination was
found to be 1.6-times faster than subsequent conversion to the
iodo-oxazoline, which supports our earlier observation that
HAT precedes the rate-limiting step.
STRATEGY FOR SECONDARY β C−H BONDS
Building on this mechanistic understanding that conversion of
the β alkyl iodide to product represents the slowest step(s) and
biggest challenge, we sought to expand the scope of this cascade
■
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Figure 7. Double C−H functionalization of imidates with β methylenes.
providing access to γ-iodo oxazolines. Similarly, while a γ ester-
substituted imidate previously yielded single β C−H amination
efficiently, β-amino-γ-iodide 36 is exclusively obtained by the
new strategy described herein. Finally, whereas an imidate
bearing a γ tertiary C−H solely afforded C−H amination before
(with >20:1 β regioselectivity), we now show alternate access to
a more densely functionalized, β-amino-γ-iodide (42) is also
possible.
SINGLE VS DOUBLE C−H FUNCTIONALIZATIONS
To illustrate the utility of this new double C−H functionalization
strategy (Figure 8) for accessing divergent β,γ amino-iodination
■
DIVERSIFICATION OF VICINAL PRODUCTS
■
Having demonstrated the broad scope of this double C−H
functionalization, we next sought to showcase the synthetic
utility of these γ iodo-oxazolines (Figure 9). Notably, we
envisioned both the γ C−I bond and the oxazoline C−O bond
could be orthogonally diversified to access a range of densely
functionalized products. First, the γ iodide was displaced with a
variety of nucleophiles to access α,β,γ heteroatom substitution.
For example, phthalimide and azide afford γ amination (43, 44),
while phenoxide and acetates afford γ oxygenation, including
with biotin (45−47). Next, the oxazoline was hydrolyzed by
either HCl (aq) to access the free γ-iodo-β-amino alcohol (48)
or with TsOH to afford the N-protected variant (49).
Interestingly, in the absence of water, HCl causes a C−O to
C−Cl displacement to afford α-chloro-β-amino-γ-iodide (50).
Alternatively TMS-Br mediates C−O to C−Br conversion to
afford another nonsymmetric dihalide: α-bromo-β-amino-γ-
iodide (51).
Finally, multisite reactivity of γ iodo-oxazoline was observed
in the presence of some nucleophiles. For example, EtSH
displaces the C−I to form a thioether while also incorporating
another thioether onto the oxazoline through chloride displace-
ment/reduction of the −CCl3 group (52).26 However, the
“hard” nucleophile, cyanide, selectively adds to the imidate
carbon, allowing subsequent N-anion attack of the adjacent C−I
to form bicyclic aziridine 53. Finally, through a one-pot
protocol, the oxazoline is converted to β hydroxy aziridine 54
by acidic hydrolysis, base-mediated ring closure, and then Ts-
protection.
Figure 8. Single vs double C−H functionalizations.
reactivity (versus our previous studies on single β C−H
amination),11 we compared the fate of several alcohols under
either reaction condition (Figure 9). In each case, selective
formation of complementary product classes was observed. For
example, imidates containing β methines exclusively afforded
oxazolines previously, whereas we have now illustrated two
examples (17, 18) of a radical-polar crossover mechanism
To illustrate the value of this radical chaperone-mediated
strategy for the rapid diversification of alcohols, we also
developed a streamlined, one-pot protocol for the sequence,
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Figure 9. Postsynthetic diversification of iodo-oxazolines by C−I, C−O, and multisite functionalization.
including: (i) chaperone addition, (ii) vicinal C−H amino-
iodination, and (iii) chaperone removal (Figure 10). In the case
(see Figure 10), initial combination of all reagents (alcohol,
nitrile, and oxidants) appeared to be an insurmountable
challenge. In this case, an alcohol must couple the nitrile
without first reacting with the potent oxidants. Yet, given the
68% recovery of octanol in our functional group tolerance
studies (see Figure 4), we posited that the desired competition
might be possible. To test this hypothesis, all reagents (alcohol,
nitrile, base, and oxidants) were combined at once and subjected
t
to visible light irradiation in BuOH (Figure 11). Remarkably,
Figure 10. One-pot protocol and structure validation. Conditions: (i)
Cl3CCN, DBU, DCM; (ii) I2, PhI(OAc)2, tBuOH; (iii) TsOH, MeOH,
H2O; and (iv) HCl (aq).
of cyclohexyl methanol, either the protected, or free, γ-iodo-β-
amino alcohol can be obtained, depending on whether TsOH or
HCl is used to facilitate the final hydrolysis (55 or 56,
respectively). In both cases, a single diastereomer is easily
isolated by column chromatography. Additionally, the free
amino alcohol 56 obtained by the latter protocol afforded single
crystals, enabling X-ray structure determination to confirm the
trans relationship between the iodide and amine.
Figure 11. Challenge of single-step strategy: competitive oxidation.
this one-step procedure affords 20% amino-iodinated product 2
directly from alcohol. To further improve this protocol, we
investigated the rate of intermediate formation. In the absence of
oxidants, we observed imidate synthesis is slow in tBuOH (only
15% 1 after 15 min). Moreover, a parallel reaction including
oxidants yields 0% 1 after 60 minalbeit with full alcohol
consumption, suggesting that competitive oxidation of the
alcohol (to aldehydes, acids, and so forth) is operative.
With the hopes of outcompeting oxidative degradation of the
alcohol by desired imidate formation, we conducted a survey of
the competitive rates of these processes in various solvents.
Interestingly, we found nonpolar solvents, such as PhCF3,
ONE-STEP STRATEGY
■
With a one-pot protocol in hand to convert alcohols to their β-
amino-γ-iodo analogs, we questioned if this strategy may be
further streamlined into a single step. Although we showed in
situ conversion of an alcohol to its imidate and subsequent,
double C−H functionalization without purification is possible
H
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Article
facilitate more rapid imidate synthesis (vs oxidative degrada-
Experimental procedures and characterization for all new
compounds (PDF)
1H and 13C NMR spectral data (PDF)
tion). For example, in the absence of oxidants, 100% imidate 1 is
t
formed within 15 min (vs 15% in BuOH). Upon inclusion of
oxidants, 78% imidate 1 is still formed. Notably, this rapid
formation of imidate (vs oxidation) allows ensuing double C−H
functionalization to occur efficientlyyielding 75% product 2.
An explanation for this improved overall reactivity in PhCF3
(75% vs 20% in tBuOH) entails slower oxidation in the nonpolar
solvent (24 h needed vs 1 h, typically; see also Figure 3, entry 3)
coupled with accelerated imidate formation.
To probe the generality of this single-step strategy, a range of
alcohols was subjected to this streamlined protocol that
combines both imidate synthesis and the amino-iodination
cascade in a single operation (Figure 12). To our delight,
X-ray crystallographic data from the Cambridge Crys-
tallographic Data Centre (CCDC 1967638) (CIF)
AUTHOR INFORMATION
Corresponding Author
■
David A. Nagib − Department of Chemistry and Biochemistry,
The Ohio State University, Columbus, Ohio 43210, United
States; orcid.org/0000-0002-2275-6381; Email: nagib.1@
osu.edu
Authors
Allen F. Prusinowski − Department of Chemistry and
Biochemistry, The Ohio State University, Columbus, Ohio
43210, United States
Raymond K. Twumasi − Department of Chemistry and
Biochemistry, The Ohio State University, Columbus, Ohio
43210, United States
Ethan A. Wappes − Department of Chemistry and Biochemistry,
The Ohio State University, Columbus, Ohio 43210, United
States
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c01318
Notes
Figure 12. Direct, double C−H functionalization of alcohols in one
step.
The authors declare no competing financial interest.
combining all reagents in PhCF3 and irradiating with visible light
for 24 h directly yields β-amino-γ-iodo heterocycles from several
alcohols. For example, both cyclic and acyclic alcohols with
varied branching, ring size, and substituents are amino-iodinated
efficiently (55−59, 58−75% yields by NMR). Subsequent
hydrolysis with TsOH affords the free γ-iodo-β-amino alcohol in
each case (51−70% isolated yields).
ACKNOWLEDGMENTS
■
We thank the National Institutes of Health (R35 GM119812),
National Science Foundation (CAREER 1654656), and Sloan
Foundation for financial support. R.K.T. is supported by an NSF
graduate fellowship. Structural data were collected by Dr
Nicholas Settineri at the UC Berkeley X-ray Crystallography
Facility (supported by NIH S10-RR027172).
CONCLUSIONS
■
REFERENCES
■
In summary, we have developed a radical-mediated cascade that
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c01318.
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