Selective ortho-Functionalization of Adamantylarenes Enabled by Dispersion and an Air-Stable Palladium(I) Dimer

Article abstract of DOI:10.1002/anie.202001326

Contrary to the general belief that Pd-catalyzed cross-coupling at sites of severe steric hindrance are disfavored, we herein show that the oxidative addition to C?Br ortho to an adamantyl group is as favored as the corresponding adamantyl-free system due

Full text of DOI:10.1002/anie.202001326

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Accepted Article
Title: Selective Ortho Functionalization of Adamantylarenes enabled by
Dispersion and an Air-Stable Pd(I) Dimer
Authors: Indrek Kalvet, Kristina Deckers, Ignacio Funes-Ardoiz,
Guillaume Magnin, Theresa Sperger, Marius Kremer, and
Franziska Schoenebeck
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202001326
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10.1002/anie.202001326
Angewandte Chemie International Edition
DOI: 10.1002/anie.201((will be filled in by the editorial staff))
Synthetic Methods
Selective Ortho Functionalization of Adamantylarenes enabled by
Dispersion and an Air-Stable Pd(I) Dimer
Indrek Kalvet, Kristina Deckers, Ignacio Funes-Ardoiz, Guillaume Magnin, Theresa Sperger, Marius
Kremer and Franziska Schoenebeck*
In memory of Professor Dieter Enders
Abstract: Contrary to the general belief that Pd-catalyzed cross-
couplings at sites of severe steric hindrance are disfavored, we
herein show that the oxidative addition to C-Br ortho to an
adamantyl group is as favored as the corresponding adamantyl-
free system due to attractive dispersion forces. This enabled the
development of a fully selective arylation and alkylation of C-Br
in ortho position to an adamantyl group, even if challenged with
competing non-hindered C-OTf or C-Cl sites. The method makes
use of an air-stable Pd(I) dimer and allows for a straightforward
access to diversely substituted therapeutically important
adamantylarenes in 5-30 min.
regioisomers),[6] the process requires harsh conditions (concentrated/
strong acids, elevated temperature) and will strongly depend on the
electronic bias of the particular substrate, precluding late-stage
applications.[7]
We therefore set out to address the ortho-functionalization
challenge and focused on ortho-bromo adamantylarenes as coupling
motif. More specifically, to maximize the potential for downstream
diversification, we initially targeted a poly(pseudo)halogenated
adamantyl-arene as modular platform. The selective manipulation of
e.g. C-Br vs. C-OTf would ultimately deliver a library of diversely
substituted adamantyl-derivatives with an ortho/meta relationship
that is not yet accessible in a general manner. The key requirements
for success of this strategy are (i) that selective C-Br vs. C-OTf
functionalization can be realized and (ii) that coupling ortho to the
large adamantyl group is possible.
O
wing to its exceptional liphophilicity and stability enhancing
properties, the adamantyl group has found widespread applications in
materials science,[1] medicinal chemistry and drug development.[2] In
fact, the only other hydrocarbon moiety that was similarly successful
in generating active therapeutics is the methyl group.[2] Adamantane
derivatives are used in the fighting of viral infections, such as
Influenza, Herpes, Hepatitis C, HIV, of Malaria or Parkinson’s
disease and as retinoid antibiotics (see Figure 1).[2-3] Yet, the synthetic
access to densely functionalized adamantyl containing molecules is
still challenging,[4] especially the diversification via arylation or
alkylation ortho to the adamantyl group is currently out of reach.
However, the future discovery of superior therapeutics or antibiotics
would vastly benefit from synthetic methodology that allows access
to a larger chemical space of diversely substituted adamantyl
derivatives. Ideally, this is achieved in a modular and rapid fashion
that allows to introduce various potential arene substituents late in the
synthesis and with complete site-control, as the nature of the
substituents and their relative positioning will ultimately control the
function of the final target molecule. While the introduction of the 1-
adamantyl group to an arene has significantly advanced in recent
years, particularly due to successes in devising radical-based or
organometallic methodology,[4c,4e-h,5] these approaches predominant-
ly deliver the adamantyl in meta or para-position relative to an
alternative substituent in the arene, but not ortho. Similarly, although
electrophilic adamantylations (Friedel-Crafts) could in principle
deliver an ortho substitution pattern (along with alternative
[]
I. Kalvet, K. Deckers, Dr. I. Funes-Ardoiz, G. Magnin, T. Sperger, Marius
Kremer, Prof. Dr. Franziska Schoenebeck
Institute of Organic Chemistry, RWTH Aachen University,
Landoltweg 1, 52074 Aachen, Germany
Figure 1. Medicinally relevant adamantyl compounds (top), current synthetic
E-mail: franziska.schoenebeck@rwth-aachen.de
Homepage: http://www.schoenebeck.oc.rwth-aachen.de/
approaches to adamantylarenes and this work (bottom).
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/anie.201xxxxxx.
1
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10.1002/anie.202001326
Angewandte Chemie International Edition
The adverse impact of steric hindrance on the efficiency of Pd-
catalyzed cross coupling has been widely documented.[8] For
example, although 4-bromoaryl triflate can be selectively coupled at
C-Br with a [PdCl2{P(o-tol)3}2]-catalyzed Kumada reaction, the
introduction of two relatively small methyl substituents ortho to the
C-Br (in 3- and 5-positions) resulted in erosion of selectivity and
mixtures of products.[9] The vast majority of literature concludes that
the oxidative addition step controls the site-selectivity[10] and that this
step is most likely inhibited by steric hindrance.[11]
In this context, we wondered about the feasibility of oxidative
addition ortho to the adamantyl group. Although the adamantyl group
is large, it has also been ascribed to be a privileged dispersion
donor.[12] Attractive dispersion forces have previously been found to
outweigh steric effects, counterintuitively stabilizing more crowded
molecules over their less crowded counterparts.[13]
general belief of steric effects on the oxidative addition step - the
adamantyl substituent should not impede oxidative addition.
We therefore next set out to experimentally target compound 1.
The required substitution pattern has so far been synthetically
inaccessible. There is one patent that claims the synthesis of 3-
(adamantan-1-yl)-4-bromo-5-methoxyphenol (2a) in a single step
(see Scheme 1).[6a] However, our follow up investigation revealed that
these claims are incorrect and the alternative isomer, 4-(adamantan-
1-yl)-2-bromo-5-methoxyphenol (2e) was instead generated. As
such, previous C-Br coupling attempts of starting materials prepared
by this method instead yielded derivatives of 2e.[9b,26b,19] [We hence
embarked on developing a synthetic route to 1 which would establish
the 3-(adamantan-1-yl)-2-bromo-phenol substitution pattern for the
first time.
We focused on compound 1 (see Scheme 1), which bears a C-
Br ortho to adamantyl and allows for further meta-derivatization via
C-OTf coupling. The methoxy group is representative of a potential
linkage to biomolecules.[14]
As a theoretical exercise, we computationally assessed the
impact of the adamantyl group on oxidative addition step, utilizing
Pd(0)(PtBu3)2 as a model system, which should be particularly prone
to engage in attractive C-H•••H-C dispersion attraction with the
adamantyl group.[15] To this end, we calculated the activation free
energy barrier for the oxidative addition of 2-adamantyl-6-
methoxybromoarene (Figure 2, C) vs. the corresponding adamantyl-
free systems (Figure 2, A and B). The lowest energy pathway of
oxidative addition involves an initial ligand loss, followed by
oxidative addition to C-Br by the monophosphine Pd(0)(PtBu3)
complex.[15,17b,c,30] The barriers for oxidative addition to Ar-Br were
compared using DFT methods[16] with and without dispersion-
corrections. The results are illustrated in Figure 2.
Scheme 1. Structural revision of previously claimed ortho-bromo-
adamantylarene (2a) and synthesis of 4-Br-5-methoxy-3-adamantyl-phenyl
triflate (1) from 1,3-dimethoxyphenol 3. See SI for detailed reaction conditions.
Scheme 1 presents our successful synthesis. The 1-adamantyl
group was introduced to 1,3-dimethoxyphenol 3 via Friedel-Crafts
alkylation with 1-adamantanol.[20] The free OH group of 4 was then
protected as a diethyl phosphate ester (5) and subsequently reduced
under Li/NH3 conditions to 5-adamantylresorcinol dimethyl ether 6.
Selective removal of one of the methyl groups was accomplished with
BBr3, followed by the introduction of a TIPS protecting group. This
allowed for predominant reaction at the 6-position in the electrophilic
bromination with NBS.[21] The structure of 1 was unambiguously
confirmed through single crystal X-ray diffraction analysis (Scheme
1),[22] and 2D NMR analyses were conducted on all intermediates and
the target compound 1.[23]
We subsequently set out to study the functionalization of 1. In
the context of Pd(0)/Pd(II) catalysis, the relative reactivity of aryl
triflates and bromides is frequently referred to be roughly the same,[24]
and the selectivities therefore have historically been a result of a
subtle interplay of reaction conditions, catalyst, coupling partner and
the steric and electronic effects imposed by the substrate.[9a,10e,10f,24-25]
Figure 2. Computational study of activation free energies and enthalpies (in
parentheses) for C-Br oxidative addition relative to Pd(PtBu3)2 in kcal/mol;
calculated at CPCM (THF) B3LYPD3/Def2TZVP// B3LYP-D3/6-31G(d)/
LanL2DZ level of theory. See SI for additional computational data with alternative
methods on this trend, including D4 dispersion results.[17,30]
Interestingly, while the classical DFT methods (that do not
account for dispersion) predict activation barriers in accord with
expected steric effects, i.e. with barriers A < B < C, inclusion of
dispersion in turn predicts roughly the same activation free energy
barriers for A, B and C of approximately 26 kcal/mol,[17] suggesting
that attractive dispersion between the adamantyl and tert-butyl
substituent of the Pd-catalyst outweigh steric clashes. As such,
although computational challenges exist in unambiguously capturing
this
phenomenon
relative
to
solute-solvent
dispersive
interactions,[12a,15,18] these calculations suggest that - as opposed to the
2
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10.1002/anie.202001326
Angewandte Chemie International Edition
By contrast, we recently established a substrate independent and a
priori predictable Csp2-Csp2 and Csp2-Csp3 functionalization
exclusively at C-Br in competition with C-OTf and C-Cl sites.[9b, 26]
Key to this exquisite selectivity was the employment of an air- and
moisture stable Pd(I) dimer that facilitated the couplings in ≤ 5min at
room temperature.[27] As such, we envisioned that if the privileged
reactivity for C-Br also applies to the adamantyl motif 1, we would
then be in a position to diversify C-Br at will, leaving possibilities for
functionalization at the remaining C-OTf with any type of
methodology.
As such, both arylation and alkylation could be accomplished
selectively ortho to the adamantyl group, even in the presence of the
additional and deactivating methoxy substituent. With this stern test
passed, we next investigated the wider scope of functionalization of a
range of 2-bromo adamantylarenes (11, see Table 2). We were able
to couple the C-Br within 5 min at room temperature, and successfully
introduced the alkyl substituents methyl, butyl, cyclopropyl and
CH2TMS (12a-d, Table 2). Arylations were similarly effective, and
electron-rich (12i,j) as well as -deficient (12h) groups coupled
equally efficiently. Even the introduction of the more hindered 2-
methyl phenyl (12f) and the heterocyclic thiophene substituents (12g)
proceeded smoothly.
Table 1. Pd(I) I-dimer catalyzed Br-selective cross-coupling reactions with 1.[28]
Table 2. Pd(I) I-dimer catalyzed Br-selective cross-coupling reactions with 11.
Reaction conditions: 11 (0.2 mmol), organometallic reagent (0.3 mmol in THF),[29]
Pd(I) iodo dimer (0.01 mmol), toluene (0.8 mL), r.t. [a] Organomagnesium was
used. [b] Yield obtained by quantitative 1H NMR analysis of the crude.
Reaction conditions: 1 (0.1 mmol), organometallic reagent (0.7 mmol in THF),[29]
Pd(I) iodo dimer (0.01 mmol), toluene (0.6 mL), 50 °C, slow addition of
organometallic reagent over 12 minutes. [a] 1 (0.05 mmol), organometallic
reagent (0.15 mmol in THF), Pd(I) iodo dimer (0.0013 mmol), toluene (0.3 mL),
r.t., slow addition of organometallic reagent over 4 minutes. [b] As in a, with 0.25
mmol of organometallic reagent.
In summary, we showcased the C-Br selective ortho-
functionalization in adamantylarenes, while leaving the less sterically
encumbered C-OTf or C-Cl sites fully untouched. Our computational
studies indicated that oxidative addition to C-Br ortho to the
adamantyl group is just as facile as to the corresponding adamantyl-
free arene, suggesting that attractive PtBu3•••adamantyl dispersion
forces override steric repulsion and stabilize the transition state for
oxidative addition, which is at odds with current expectations in metal
catalyzed cross-coupling chemistry. Given the pronounced
therapeutic potential of adamantyl containing motifs, we anticipate a
widespread interest in the herein reported unlocked ortho
diversification method in adamantylarenes.
When we explored the functionalization of 1 with the methyl-
or TMS-CH2-organozinc reagents in toluene with the air-stable Pd(I)
dimer (5 mol%), we saw efficient conversion to the corresponding
coupling products arising from exclusive C-Br coupling (10a and
10b) within ≤ 5min reaction time at r.t. (see Table 1). Similarly,
arylation and n-butylation were equally selective for C-Br and left C-
OTf untouched despite the need for slightly elevated temperatures
(50 °C), slower addition rates (12 min) and increased organozinc (5-
7 equiv.) as well as catalyst (10 mol%) loadings to reach high yields.
Under these conditions we were able to introduce phenyl (10d, Table
1), 2-thienyl (10f), n-butyl (10c), 4-chlorophenyl (10e) as well as 4-
methoxyphenyl groups (10g) under exclusive coupling at the C-Br
site, as unambiguously confirmed also through Xray crystallographic
analysis of 10g (see Table 1).
Acknowledgements
We thank the RWTH Aachen University, the European Research
Council (ERC-637993) and the Alexander von Humboldt foundation
(postdoctoral fellowship to I. F.-A.) for funding. Calculations were
3
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10.1002/anie.202001326
Angewandte Chemie International Edition
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Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff))
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Keywords: chemoselectivity • Csp2-Csp3 coupling • dinuclear Pd(I) •
DFT • catalysis
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Cambridge Crystallographic Data Centre.
[23] For details please refer to the Supporting Information.
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[29] Organometallic coupling partner was prepared from R-MgCl (1 equiv.),
LiCl (1 equiv.) and ZnCl2 (1.1 equiv.).
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10.1002/anie.202001326
Angewandte Chemie International Edition
Synthetic Methods
I. Kalvet, K. Deckers, I. Funes-Ardoiz, G.
Magnin, T. Sperger, M. Kremer, F.
Schoenebeck*
Page – Page
Selective Ortho Functionalization of
Adamantylarenes enabled by
Dispersion and an Air-Stable Pd(I)
Dimer
5
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