Catalyst-Controlled C-H Functionalization of Adamantanes Using Selective H-Atom Transfer

Article abstract of DOI:10.1021/acscatal.9b01394

A method for the direct functionalization of diamondoids has been developed using photoredox and H atom transfer catalysis. This C-H alkylation reaction has excellent chemoselectivity for the strong 3° C-H bonds of adamantanes in polyfunctional molecules.

Full text of DOI:10.1021/acscatal.9b01394

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Article
Catalyst-Controlled C–H Functionalization of
Adamantanes using Selective H-Atom Transfer
Hai-Bin Yang, Abigail Feceu, and David BC Martin
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b01394 • Publication Date (Web): 13 May 2019
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Catalyst-Controlled C–H Functionalization of Adamantanes using
Selective H-Atom Transfer
Hai-Bin Yang,† Abigail Feceu and David B. C. Martin*
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Department of Chemistry, University of California Riverside, Riverside, California 92521, United States
Supporting Information Placeholder
to the unusually high C–H bond strengths.5 The rigid
caged structure of adamantane (1, Figure 1A) results in
ABSTRACT: A method for the direct functionalization
of diamondoids has been developed using photoredox
and H-atom transfer catalysis. This C–H alkylation
reaction has excellent chemoselectivity for the strong 3º
C–H bonds of adamantanes in polyfunctional molecules.
In substrate competition reactions, a reversal in
selectivity is observed for the new H-atom transfer
catalyst reported here when compared to five known
photochemical systems. Derivatization of a broad scope
of diamondoids and adamantane-containing drugs
highlights the versatility and functional group tolerance
of this C–H functionalization strategy.
KEYWORDS: photoredox catalysis, H-atom transfer, C-
H functionalization, drug derivatization, adamantane
The direct functionalization of aliphatic C–H bonds
is critical to the large-scale processing of hydrocarbon
feedstocks and its inherent chemical difficulty has
inspired the development of new methods that push the
frontiers of reactivity and selectivity in organic
synthesis. In particular, the selective functionalization of
one type of C–H bond in the presence of a variety of
Figure 1. Strong adamantane bonds lead to
functionalization challenges: previous methods unselective
compared to amine radical cation 5.
different C–H bonds represents
a
long-standing
challenge.1 Many successful strategies employ
a
an increased 3º C–H bond dissociation energy (BDE) of
99 kcal/mol, which exceeds the 2º C–H BDE of 96
kcal/mol and most other hydrocarbons.6 The unique
structure and chemical properties of diamondoids have
led to many applications in nanoscale frameworks,
optical materials and clinically approved drugs (e.g.
directing group to guide a metal catalyst to the desired
site of reactivity, while others rely on the innate
reactivity of weak C–H bonds such as those at tertiary,
benzylic or heteroatom-substituted positions (Figure
1A).2,3,4 New methods that bypass such activated
positions in favor of unactivated aliphatic C–H bonds
would significantly broaden the potential applications of
direct C–H functionalization.1 A difficulty for the
selective activation of strong alkane C–H bonds is the
high kinetic barrier associated with their cleavage.
Intermediates capable of activating these bonds often do
so at the expense of selectivity, limiting applications in
complex molecules due to poor functional group
compatibility.
memantine,
anti-dementia).7,8
Hydrogen
atom
abstraction methods that directly generate the adamantyl
radical include halogen and alkoxyl radicals, as well as
catalytic hydrogen atom transfer (HAT) species such as
diarylketone and decatungstate photocatalysts (Figure
1B).9 The high reactivity of these abstractors results in
variable, often low selectivity between different types of
C–H bonds, rendering them impractical for many
applications.10,11 We sought to overcome previous
limitations through the systematic study of adamantanes
to identify a catalyst system that can target strong C–H
bonds in the presence of weaker activated bonds. Recent
The diamondoids are a compelling substrate class for
the investigation of selective C–H functionalization due
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aReaction performed on 0.5 mmol scale with 2 x 40W blue
LED lamps. Conversion of 7 determined after 8h by H
NMR with internal standard. Yield of 8 determined by GC
with internal standard. Isolated yield in parentheses.
bConversion of 1 after 24h by GC with internal standard.
reports have highlighted the power of HAT to activate a
range of C–H bonds using photoredox catalysis.12,13,14,15
In particular, MacMillan and coworkers have combined
a quinuclidine-mediated HAT cycle with several C–C
bond forming processes.14 Herein, we report a new 3º
amine-based HAT catalyst system that leverages charge-
transfer character in the C–H functionalization step to
provide high chemoselectivity independent of significant
BDE differences (e.g. 4  6, Figure 1C).16 This dual
catalyst system provides a general platform for the direct
functionalization of diamondoids and an unprecedented
selectivity profile in polyfunctional substrates.
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limiting reagent, the reaction proceeds in 55% yield
when performed with limiting hydrocarbon (Entry 6),
giving 23% of dialkylated product 9 as the major side-
product. In addition, reducing the Ir-1 loading to 0.5
mol% maintains high conversion and good yield (73%,
Entry 7). In all cases, we observed complete selectivity
for the 3º (C1) position of adamantane and detected no
C2 products.11 Control reactions demonstrate that the
iridium catalyst, quinuclidine catalyst and light are all
necessary for this direct C–H alkylation process.19
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We began our studies by examining the reaction of
adamantane with phenyl vinyl sulfone (7, Table 1).17
Inspired by reports of C–H functionalization reactions
via heteroatom-stabilized radicals by MacMillan and
others, we examined the use of quinuclidines as HAT
catalysts due to the very strong N–H bond generated (≥
100 kcal/mol).14,15lmn,18,19 We identified optimal
conditions using the highly oxidizing photocatalyst
Ir(dF(CF3)ppy)2(d(CF3)bpy)PF6 (Ir-1) and newly
designed sulfonylated quinuclidinol Q-1 to provide
alkylated product 8 in 79% yield by GC (72% isolated
yield, Entry 1).20 The optimized sulfonate derivative Q-1
is more effective than the previously reported acetate Q-
2 or Q-3 (Entries 2 and 3) in terms of yield and reaction
rate. A synergistic effect between the two catalysts was
observed, as shown by the improved performance of Q-
3 when paired with Ir-2 (66%, Entry 5 vs 3 and 4).
While optimal yields are obtained with the alkene as
With optimal catalytic conditions in hand, we
investigated the scope of the alkylation reaction of
adamantane (Table 2). A number of alkenes with
different electron-withdrawing groups including
sulfones, nitriles, ketones and esters are effective
partners, giving a single regioisomer of product (8, 10–
14, 57–91% yield).21 Ethyl acrylate was successfully
employed in this chemistry using catalysts Ir-2/Q-3 to
facilitate the more challenging reduction step of the
catalytic cycle (see 52, Scheme 2).22 A dehydroalanine
derivative was an excellent substrate in this C–H
alkylation, delivering amino acid derivative 15 in 89%
yield.23 Olefins with two electron-withdrawing groups
were particularly effective, including 1,2-disubstituted
and trisubstituted variants (16–20, 82–94% yield).
Adjacent tertiary and quaternary centers are forged,
highlighting the power of radical chemistry to generate
highly congested centers.24
Table 1. Optimization studies of adamantane alkylationa
We also investigated the scope of adamantane
coupling partners. As shown in Table 2, a broad range of
substituents at the 1-position including alkyl, aryl, OH,
halides and nitriles were well tolerated, providing the
corresponding 3-alkylated products in 64–72% yield
(21–26). Selected examples using only 1.5 equivalents
of adamantane are shown in parentheses with a modest
decrease in yield. Electron-deficient 2-adamantanone
and 1-acetyladamantane could be alkylated in 60% and
75% yield, respectively. Direct comparison of sulfonate
catalyst Q-1 and acetoxy Q-2 again shows that the more
electron-deficient catalyst leads to a faster and higher-
yielding reaction with several electron-withdrawn
adamantanes (e.g. product 25: 42% (with Q1) vs 24%
(with Q2) at an early time point; see Table S13).19
Diamantane, the simplest higher order diamondoid, gave
the corresponding sulfone product 29 in 62% yield and
succinate product 30 in 65% yield as a 1.1–1.2:1 mixture
of regioisomers. This implies a moderate inherent
selectivity (~3:1) for the apical position.25 We also
investigated the alkylation of clinically approved drug
derivatives such as N-Boc-amantadine (31, 63% yield).
N-Boc-memantine was alkylated with good efficiency
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using it as the limiting reagent to give tetrasubstituted rich aryl and methoxy groups (33, 51% yield). The
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adamantane 32 in 74% yield. A precursor to the anti-
acne medication differin underwent alkylation at the 3º
position without significant interference of the electron-
success of this HAT strategy in medicinally relevant
substrates
Table 2. Scope of direct alkylation of substituted adamantanes and diamantanes with electron deficient alkenes.a
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aReaction performed on 0.5 mmol scale with 2 x 40W blue LED lamps, standard conditions, typically 8–48 h. All yields are
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isolated yields. Yield in parentheses with 1.5 equiv adamantane partner, determined by GC with internal standard. Reaction
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performed using Ir-2 and Q-3. Solvent is CH3CN. Reaction temperature approximately 38 ºC. Regioisomeric ratio (r.r.) was
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g
determined by H NMR of the purified product. Major isomer shown, minor site of reaction highlighted. 1 equiv N-Boc-
memantine, equiv 7.
2
demonstrates a level of versatility and predictability that
is necessary for late-stage functionalization applications.
in closely related substrates, favoring activation of the
weaker aldehyde and 3º C–H bonds.15c,g,k As a result,
these methods represent complementary strategies for
targeted C-H functionalization.
Next we investigated the selectivity of amine catalyst
Q-1 in polyfunctional substrates with multiple Csp3–H
bonds (Scheme 1). Boc-protected 34 derived from
antiviral drug rimantadine was monoalkylated in 68%
yield at the 3º position. We did not observe
functionalization at the α-amino methine position, which
is electronically activated but sterically hindered.14 An
adamantane ester substrate bearing an additional tertiary
site undergoes alkylation on the adamantane group (35,
70% yield, >20:1 r.r.). Aldehyde product 36 was formed
in 70% yield with only 3% ketone product resulting
from activation of the weak aldehyde C–H bond.
Notably, Glorius and coworkers described a carboxyl
radical HAT system that shows the opposite selectivity
To assess the limits of the observed selectivity, we
performed intermolecular competition experiments with
prototypical substrates for HAT methodologies
including alkanes, ethers, aldehydes, alcohols and
amides.4,14,15 In all cases, the reactivity of adamantane
was dominant and 46–80% of alkylation product 8 was
obtained. Other tertiary C–H bonds such as those in
norbornane and 2,2,4-trimethylpentane were virtually
unreactive.26 Only octanal, THF and isopropanol, having
very electronically activated C–H bonds, gave
significant amounts of product (14–27%), but
adamantane 8 was still the major product.27 We then
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performed a competition with polyfunctional natural
octanal.28 Similar trends were observed with THF
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products and observed high chemoselectivity. Menthol
was essentially unreactive, providing only 4% of the
corresponding product 45 along with 75% of
adamantane 8. Progesterone, limonin and sclareolide
(not shown) were also tested and no alkylation products
were identified using catalyst Q-1, instead affording
only adamantane product 8.19 The wide range of C–H
bond types that remain untouched in favor of
adamantanes is a remarkable demonstration of the
competitions (Table S12), highlighting the unique
selectivity profile of the 3º amine-based quinuclidine
catalysts and the complementarity of substrate
selectivity through proper catalyst selection.
In order to shed light on this new photoredox
catalyzed reaction, we performed a series of mechanistic
experiments. The alkylation reaction is inhibited by
radical scavengers BHT and TEMPO. Stern–Volmer
luminescence studies showed no quenching by
adamantane or phenyl vinyl sulfone, however HAT
catalyst Q-1
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Table 3. Comparison of catalyst systems for C–H bond
selectivitya
aReactions performed under standard conditions; see SI
b
for catalyst structures and light source information. 2-
Chloroanthraquinone.
c5,7,12,14-Pentacenetetrone.
d(Bu4N)4(W10O32). eNicewicz acridinium photocatalyst,
see SI.
resulted in a dramatic decrease in luminescence.19 This
is consistent with the redox potentials of these species;
the excited photocatalyst Ir-1* (E1/2red (*IrIII/IrII) = +1.68
V vs saturated calomel electron (SCE) in CH3CN)15a is
a sufficiently strong oxidant to generate the radical
red
cation from quinuclidine Q-1 (E1/2 = +1.41 V vs SCE
Scheme 1. Competition experiments demonstrating the
selective functionalization of adamantanes in the
presence of activated C–H bonds.
in CH3CN).19 Similarly, photocatalyst Ir-2 is well
matched with quinuclidine Q-3.29,18 The direct
oxidation of adamantane by the photocatalyst or
red
chemoselectivity that is unique to the quinuclidine
catalyst system reported here.
quinuclidine radical cation is not favorable (E1/2
=
+2.72 V vs SCE in CH3CN), rendering a direct
oxidation/deprotonation mechanism unlikely.10d,30 We
also performed deuterium labeling experiments to
investigate the HAT step (Figure 2). No incorporation of
deuterium into the starting material or adamantyl C–H
bonds of the product was observed, suggesting that HAT
is irreversible. Small kinetic isotope effect (KIE) values
obtained from an intramolecular competition experiment
with 1-D2 (kH/kD = 1.6)
To further demonstrate this, we compared the chemo-
selectivity of amine Q-1 for the strong C–H bonds of
adamantane
to
several
previously
reported
photocatalytic HAT systems (Table 3).9,12c,15 While
the amine-based catalyst system provided 4.5:1
selectivity for adamantane over octanal (Entry 1), all
other catalysts investigated were either poorly selective
(e.g. 1:2 for quinone photocatalysts) or favored
functionalization of the weaker C–H bond (Entries 2–
6).19 The decatungstate photocatalyst and carboxyl
radical gave moderate yields but a 1:5 ratio favoring
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ammonium 50 and adamantyl radical 2, which rapidly
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adds to the electron-deficient olefin 51 to generate α-
red
acyl radical 52.17 Reduction of radical 52 (E1/2 = –
0.66 V vs SCE in CH3CN)32 by iridium(II) intermediate
red
47 (E1/2 (IrIII/IrII) = –0.69 V for Ir-1 and –1.37 V for
Ir-2 vs SCE in CH3CN)29,15a and protonation by
quinuclidinium 50 (or water as a proton shuttle) provides
the final product 13 and closes both catalytic cycles.
The optimal selectivity of quinuclidine Q-1 for C1 of
adamantane over other “activated” substrates is
proposed to result from enhanced polar effects. HAT is
known to be highly influenced by polar effects and
radical cation 5 is the only species examined that is
positively charged, compared to neutral, oxygen-
centered radicals as H-atom abstractors in other
protocols.9,14,16 This suggests that the high reactivity
and selectivity of Q-1 can be attributed to increased
charge-transfer character in the HAT transition state TS-
1 that is further enhanced by the electron-withdrawing
substituent.16 Increased positive charge development on
adamantane is favorable due to the high stability of the
3º-adamantyl carbocation 53.6 Stabilization of this
transition state does not depend on significant
rehybridization of the sp3 carbons, which is unfavorable
in the rigid cage structure of the diamondoids compared
to competing substrates. Finally, while the electron-
withdrawing substituent (OBs) on quinuclidine does not
significantly change the reaction selectivity (Entries 1
and 7, Table 3), it generally increases the reaction rate
and product yield. This effect is attributed to an increase
in the driving force for HAT by strengthening the N–H
bond of ammonium 50.18
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Figure 2. Deuterium labeling experiment and kinetic
isotope effect experiments.
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In summary, we have reported a highly selective C–
H functionalization strategy for the direct alkylation of
adamantanes in the presence of weaker alkyl and α-
heteroatom C–H bonds. A synergistic effect between the
photocatalyst and electron-deficient quinuclidine HAT
catalyst was observed for the first time, providing an
unprecedented selectivity profile based on polar effects.
New quinuclidine catalyst Q-1 enables a broad substrate
scope with respect to alkenes, substituted adamantanes,
diamantane and derivatives of clinically approved
adamantyl amines. The demonstration of the
accelerating effect induced by electron-withdrawing
groups will benefit the design of stronger HAT catalysts
based on the quinuclidine scaffold. We anticipate that
this catalytic strategy will be amenable to other direct
C–H functionalization reactions of adamantanes and
higher order diamondoids and will greatly expand
synthetic access to these fascinating molecules.
Scheme 2. Proposed mechanism of dual catalytic
alkylation process and charge transfer model for
selectivity.
and intermolecular competition experiments in parallel
reactions (kH/kD = 1.3) indicate that the HAT process is
likely not the turnover-limiting step in the catalytic
cycle.31 These data are consistent with HAT as an
irreversible, exergonic process with an early transition
state, although other mechanistic possibilities cannot be
ruled out at this point.14a
ASSOCIATED CONTENT
Based on this evidence, the proposed mechanism
begins with excitation of the photocatalyst followed by
oxidation of quinuclidine Q-1 to yield the radical cation
5 (Scheme 2). Subsequent HAT gives the corresponding
Supporting Information.
The Supporting Information is available free of charge on the
ACS Publications website.
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Experimental procedures, characterization data, H and 13C NMR
X.; Zhao, H.; Li, G.; Su, W. Recent Advances in Directed C–H
Functionalizations Using Monodentate Nitrogen-Based Directing
Groups. Org. Chem. Front. 2014, 1, 843–895. (f) Hrdina, R. Directed
C–H Functionalization of the Adamantane Framework. Synthesis
2019, 51, 629–642.
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spectra of all new compounds (PDF)
AUTHOR INFORMATION
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Radical Substitution and Addition Reactions? Angew. Chem. Int. Ed.
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Alkane Transformations via Radicals and Radical Cations:ꢀ Insights
into the Activation Step from Experiment and Theory. Chem. Rev.
2002, 102, 1551–1593. (c) Chen, M. S.; White, M. C. Combined
Effects on Selectivity in Fe-Catalyzed Methylene Oxidation. Science
2010, 327, 566–571. (d) Newhouse, T.; Baran, P. S. If C-H Bonds
Could Talk: Selective C-H Bond Oxidation. Angew. Chem., Int. Ed.
2011, 50, 3362−3374.
†Current address: School of Chemical Engineering and
Light Industry, Guangdong University of Technology,
Guangzhou 510006, China
Corresponding Author
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* E-mail: dave.martin@ucr.edu
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ORCID
Abigail Feceu: 0000-0003-1316-9414
David B. C. Martin: 0000-0002-8084-8225
(4) Luo, Y. R., Comprehensive Handbook of Chemical Bond
Energies; CRC Press: Boca Raton, FL, 2007.
Notes
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G.; Carlson, R. M. K. Isolation and Structure of Higher Diamondoids,
Nanometer-Sized Diamond Molecules. Science 2003, 299, 96–99. (e)
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No competing financial interests have been declared.
ACKNOWLEDGMENT
This work was supported by generous start-up funds from
the University of California, Riverside. A.F. acknowledges
support from the UC Riverside Graduate Research
Mentorship Program. NMR instrumentation for this
research was supported by funding from the NSF (CHE-
1626673) and the U.S. Army (W911NF-16-1-0523). Mass
spectrometry instrumentation for this research was
supported by funding from the NSF (CHE-0541848). We
thank Prof. W. Hill Harman (UC Riverside) for helpful
discussions and assistance with electrochemical
measurements and Dr. Felix Grun (UC Irvine) for
assistance with mass spectrometry. D.B.C.M is a member
of the UC Riverside Center for Catalysis.
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be within 1 kcal/mol of each other. See ref 10d. The apical position is
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(27) All reactions were carried out with 3 equiv each of
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(19) See Supporting Information for details.
(20) (dF(CF3)ppy)2
= 2-(2,4-difluorophenyl)-5-trifluoromethyl-
pyridine, d(CF3)bpy = 5,5′-bis(trifluoromethyl)-2,2′-bipyridine. See:
Zhu, Q.; Gentry, E. C.; Knowles, R. R. Catalytic Carbocation
Generation Enabled by the Mesolytic Cleavage of Alkoxyamine
Radical Cations. Angew. Chem., Int. Ed. 2016, 55, 9969–9973.
(21)
A 6:1 ratio of C1/C2 selectivity was reported using
stoichiometric benzophenone and acrylonitrile as adamantane radical
trap; see ref. 9h. A 91:9 of C1/C2 selectivity was reported using tert-
butoxide radical and acrylophenone as adamantane radical trap; see
ref. 9p.
(22) The yield of ester 13 using Ir-1/Q-1 is 17%.
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