C H Bond Arylation of Diamondoids Catalyzed by Palladium(II) Acetate

Article abstract of DOI:10.1002/adsc.201600156

We have developed an effective approach to 1,2-disubstituted diamondoids by palladium(II) acetate catalyzed functionalization of C H bond. Selective mono-arylation of the adamantane framework was achieved using picolylamide as a directing group in yields up to 87 %. Kinetic studies in combination with deuterium labeling experiments, competitive experiments and mass spectrometry contribute to the mechanistic understanding of the arylation process of alkanes with number of C H bonds neighboring the directing group. Triflic anhydride promoted cyclization of the directing group generates imidazo[1,5-a]pyridine derivatives. Acid-mediated removal of the directing group provides access to 2-aryl diamondoid carboxylic acids, which are common precursors for the synthesis of various bioactive compounds (drug candidates). (Figure presented.) .

Full text of DOI:10.1002/adsc.201600156

FULL PAPERS
DOI: 10.1002/adsc.201600156
ꢀ
C H Bond Arylation of Diamondoids Catalyzed by Palladium(II)
Acetate
a
b
b
b
Marta Larrosa, Sven Heiles, Jonathan Becker, Bernhard Spengler,
a,
and Radim Hrdina *
Department of Organic Chemistry, Justus-Liebig University, Heinrich-Buff-Ring 17, 35392 Giessen, Germany
E-mail: radim.hrdina@org.chemie.uni-giessen.de
Department of Inorganic and Analytical Chemistry, Justus-Liebig University, Heinrich-Buff-Ring 17, 35392 Giessen,
Germany
a
b
Received: February 4, 2016; Revised: April 20, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600156.
Abstract: We have developed an effective approach boring the directing group. Triflic anhydride promot-
to 1,2-disubstituted diamondoids by palladium(II) ed cyclization of the directing group generates imida-
acetate catalyzed functionalization of CꢀH bond. Se- zo[1,5-a]pyridine derivatives. Acid-mediated removal
lective mono-arylation of the adamantane frame- of the directing group provides access to 2-aryl dia-
work was achieved using picolylamide as a directing mondoid carboxylic acids, which are common precur-
group in yields up to 87%. Kinetic studies in combi- sors for the synthesis of various bioactive compounds
nation with deuterium labeling experiments, compet- (drug candidates).
itive experiments and mass spectrometry contribute
3
to the mechanistic understanding of the arylation Keywords: adamantane; arylation; C(sp )ꢀH func-
process of alkanes with number of CꢀH bonds neigh- tionalization; palladium(II) acetate
Introduction
was never applied to higher diamondoids and the re-
action conditions do not tolerate a variety of function-
[
1]
Adamantane derivatives have found numerous ap- al groups. The second strategy is based on directed re-
[
7]
plications in medicinal chemistry and drug develop- actions, such as intramolecular oxidations, or inser-
[2]
[8]
[9]
ment. Various adamantane modifications, added to tions of metal carbenoids or metal nitrenoids into
pharmacophores, were chosen to enhance lipophilicity the CꢀH bond and subsequent postfunctionalization
and stability of the drugs, improving their pharmaco- reactions. Palladium-catalyzed CꢀH functionalizations
[10,11]
kinetics.
have also been reported (Figure 2, eq. 2 and 3).
A number of such drug candidates contain a bond
between an aryl moiety and adamantane framework.
Several monosubstituted and disubstituted aryl ada-
mantane derivatives were synthesized and used for
[
3]
the modulation of biological processes (Figure 1).
Their syntheses rely on the undirected oxidation reac-
[4]
tions, which lead mostly to the substitutions of terti-
ary CꢀH bonds. The development of new synthetic
methods is required in order to reach different substi-
tution pattern on the adamantane framework. As
a consequence of the features of the adamantane
framework (Bredt’s rule), access to 1,2-disubstituted
[
5]
derivatives is synthetically demanding.
Two ap-
proaches were used to reach a 1,2-disubstitution pat-
tern. The first strategy involves the opening of the
adamantane cage to protoadamantanone and its fur-
[
6]
ther modifications (Figure 2, eq. 1). This strategy Figure 1. Aryl substituted bioactive adamantane derivatives.
Adv. Synth. Catal. 0000, 000, 0 – 0
1
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

FULL PAPERS
asc.wiley-vch.de
tion, which contribute to the general picture of
3
C(sp )ꢀH activation processes and reactivity of the
palladium complexes towards aryl iodides.
Results and Discussion
We chose 1-adamantanecarboxylic acid as the model
starting material for the synthesis of several amides
1
(Figure 3). The amide moiety serves as directing
group for the catalyst Pd(OAc) (10 mol%), in the
2
presence of 1.5 equiv of AgOAc and corresponding
coupling partner, 4-iodoanisole 2a (4 equiv). The first
tests were performed in toluene as a solvent at 1108C
(
Scheme 1).
Out of ten directing groups, amides with a pyridine
moiety 1g, 1h and 1i provided substitution of the sec-
ondary CꢀH bond in yields between 40% and 50%
(
Figure 3). The compound 1g (easy purification of the
product 3a from the starting material) was used for
further optimization studies (Scheme 2). The amount
of aryl iodide 2 was reduced to 1.5 equiv to suppress
Figure 2. Pd(OAc) catalyzed arylation of adamantane.
2
The development of catalytic methods for the func- the second arylation step on the adamantane frame-
3
[12]
tionalization of C ꢀH bonds
containing a metal
sp
substitution step (CꢀH activation) of an alkyl or cy-
cloalkyl chain is nowadays extensively studied. Vari-
[
13]
[14]
[15]
[16]
ous transition metals, such as Cu, Co, Fe, Ir,
[17]
[18]
[19]
[20]
[12e,21]
Ni,
Pt,
Rh,
Ru,
and mainly Pd,
have
been used in the reactions of alkanes, such as aryla-
[
22]
[23]
[24]
[25]
tion,
alkylation,
alkenylation,
alkynylation
[
26]
[27]
[28]
and oxidations to boron, nitrogen, oxygen, sul-
[
29]
[30]
phur
groups were developed for regioselective,
[33]
or halogen.
Several classes of directing
[21a,31]
diaste-
[32]
reoselective and even enantioselective CꢀH acti-
vations of aliphatic systems using palladium catalysts.
[
34]
Amide based bidentate groups belong to the most
utilized in the case of Pd catalysis.
II
Figure 3. Screening of directing groups, yield of 3 in paren-
theses.
[35]
Diamondoids represent special aliphatic systems,
where a number of CꢀH bonds are neighboring with
the selected directing group. A major challenge is to
achieve selective (mono)-substitution on this rigid ali-
phatic system in good yields.
There are only two examples of the directed aryla-
tion of the adamantane scaffold using palladium catal-
ysis, reflecting the difficulties in the functionalization
of this rigid tricyclic framework. The group of
Scheme 1. Pd(OAc) catalyzed arylation of carboxamide; in-
itial screening conditions.
2
[10]
Wang utilized perfluorinated tolylamide as a direct-
ing group for the Pd(0)-catalyzed arylation of two
symmetrical substrates, adamantane and 3,5-dimethy-
ladamantane 1-carboxylic acid derivatives (Figure 2,
eq. 2). The group of Zhang reported Pd(II)-catalyzed
diarylation of rimantadine derivatives (Figure 2, eq.
[11]
3).
Here, we present the Pd(II)-catalyzed mono-aryla-
tion of the adamantane scaffold of diamondoids utiliz-
ing available bidentate amide directing group, as well
as extensive mechanistic studies of this transforma- Scheme 2. Optimization of the reaction conditions.
Adv. Synth. Catal. 0000, 000, 0 – 0
2
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

FULL PAPERS
asc.wiley-vch.de
work. A survey of different bases (1.5 equiv) was Table 2. Scope of aryl halides.
tested in toluene as a solvent to find out that AgOAc
[
a]
Entry Aryl halide
Conversion Yield
3
Yield
(di)
was the most effective. Pd(TFA) in combination with
2
(mono)
AgOAc or AgTFA did not lead to significant changes
in the product formation, so the further studies were
1
2a p-MeO-
95%
3a 87%
7%
performed with Pd(OAc) . Finally, various solvents
C H I
6 4
2
2
3
4
5
2b p-CF -C H I 50%
3b 48%
3c 75%
3d 62%
3e 56%
n.d.
n.d.
5%
n.d.
were tested. The best conversions were obtained
3
6
4
[
36]
2c p-F-C H I
80%
70%
57%
6
4
using hexafluoroisopropanol (HFIP).
The amount
2d p-Br-C H I
6
4
of catalyst Pd(OAc) was reduced to 5 mol% with
2
2e p-MeO C-
2
just a slight decrease of conversion to 3a (Table 1,
entry 17). The optimized reaction conditions were
C H I
6
4
6
7
8
9
2 f p-NC-C H I 42%
2g PhI
2h 2-I-Py
2i p-MeO-
3 f 36%
3g 62%
3h 0%
3i 0%
n.d.
10%
0%
0%
6
4
Pd(OAc) (5 mol%) as the catalyst, 1.5 equiv of the
2
65%
0%
0%
aryl halide 2, AgOAc (1.3 equiv) as the base in HFIP
at 1108C. These conditions were used to determine
the scope of variously substituted aryl halides
C H Br
6 4
(
Table 2).
10
2j p-MeO-
0%
0%
3j 0%
3k 0%
0%
0%
C H OTf
The best yield of 3 is obtained for the substrates
6
4
1
1
2k p-MeO-
having functional groups in para position with a posi-
tive mesomeric effect (Table 2). Presence of electron
withdrawing substituents in para position decreases
the conversion as well as the isolated yield of 3. The
reaction does not proceed with 2-iodopyridine. Nitrile
as substituent in the para position gives a low isolated
yield of 36%. The reaction proceeds exclusively with
aryl iodides. Aryl bromides, chlorides and triflates are
unreactive and these groups can be incorporated
C H Cl
6
4
[a]
Yield of isolated compounds; mixtures of monoarylated
and diarylated products were detected by H NMR; the
low concentration of triarylated compounds were detect-
1
ed by HRMS; n.d.=not determined.
The developed strategy was used for the substitu-
within the substrate (aryl iodide) for further derivati- tion reaction of the CꢀH bond of various diamond-
zations (entry 4, Table 2).
oids. Diamondoid derived carboxylic acids were con-
densed with pycolylamine to introduce the directing
group and these amides 1 were used in the corre-
sponding arylation reactions with 4-iodoanisole 2a to
obtain compounds 4 (Figure 4). Substituents in hyper-
conjugation with the cleaved CꢀH bond influence
Table 1. Optimization of the reaction conditions to obtain
monoarylated adamantane derivative 3a.
[a]
Entry Base
AgOAc
Solvent T [8C] Yield of isolated [3a]
electronically the metal substitution step (see Sup-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
tBuOH 110
PhMe 110
tBuOH 110
tBuOH 110
AmOH 110
110
110
110
110
110
110
110
110
41%
39%
n.d.
[5,37]
porting Information, page 53).
This results in re-
Ag CO3
NaOAc
KOAc
2
gioselective arylation of the framework. In the case of
bromo derivative 1k, 1:1 mixture of epimers is ob-
tained for 4k in 50% isolated yield. In the case of di-
methyl substituted adamantane framework 1l a single
regioisomer 4l is formed in an excellent 95% yield.
Adamantane derivative 1m (presence of the oxo
group in this position on the adamantane framework
has no influence on the regioselectivity) gives a mix-
ture of three isomers 4m. Noradamantane derivative
n.d.
Cs CO3
10%
14%
25%
48%
41%
35%
43%
29%
11%
66%
traces
90%
87%
57%
n.d.
2
K CO3
2
AgTFA
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
[
b]
[
[
c]
0
1
2
3
4
5
6
7
8
9
0
1
2
b]
1
n contains three different hydrogens next to the di-
recting group. Due to the strain in the noradamantane
TFE
iPrOH 110
HFIP
HFIP
HFIP
110
3
cage, the formal sp hybridization of the tertiary CꢀH
bond is reduced (i.e., larger s-content) and the CꢀH
bond dissociation energy as compared to the secon-
dary position is higher. As a consequence, the secon-
dary position is favored for metal substitution reac-
tion and a 1 to 1 mixture of aryl containing product
110
110
80
110
110
110
[
c]
Cu(OAc)2 HFIP
AgOAc
AgOAc
AgOAc
DMA
DCE
traces
traces
n.d.
4
n was obtained in 68% yield. Diamantane deriva-
dioxane 110
tives display the same reactivity as adamantane con-
geners. Directing group in the secondary position of
the adamantane framework 1o enables the arylation
of the tertiary CꢀH bond to 4o. In the case of dia-
[
[
[
a]
reaction time 18 h; n.d.=not detected.
b]
Pd(TFA) 10 mol%.
2
c]
Pd(OAc) 5 mol%.
2
Adv. Synth. Catal. 0000, 000, 0 – 0
3
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

FULL PAPERS
asc.wiley-vch.de
Figure 5. Properties of the directing group, arylation of car-
boxylic acid derivatives and arylation of amine derivatives
with stated yields of monoarylation vs diarylation; Ar=p-
MeO-C H .
6
4
al features of the directing group. The conversions to
the aryl substituted derivatives take place when the
palladium is incorporated within two five-membered
rings (Figure 5). The structural arrangement of these
two five-membered rings can be inverted and in the
same manner it is possible to derivatize amines in the
[11]
ß position as well to obtain 2-aryl derivatives 5.
Compound 5 was prepared from N-(1-adamantylme-
thyl)pyridine-2-carboxamide using the optimized ary-
lation conditions (see Supporting Information, page
3
3).
The model reaction (1g to 3a; Scheme 2) was per-
Figure 4. Scope of diamondoids, yields of isolated products 4 formed under inert conditions to exclude the involve-
and ratio of isomers in parentheses; Ar=p-MeO-C H ; R=
6
4
ment of oxygen in the catalytic cycle. No change in
the yield of 3a was observed. Water hinders the reac-
tion significantly. The reaction carried out with
CH Py.
2
10 equiv of water provides 3a in just 16% yield.
mantane derivative 1q the apical position is exclusive-
The arylation of adamantane derivative 1g contains
ly arylated and product 4q is obtained in 40% yield. consecutive steps. The first arylation to monoarylated
To shed light on the reaction mechanism compound 3a, which is involved in the second aryla-
(
Scheme 3) we focused on the structural and function- tion step to diarylated adamantane derivative 6,
which can undergo further arylation (Scheme 4).
Scheme 4. Arylation of the adamantane framework under
II
Pd catalysis; Ar=p-MeO-C H , R=CH Py; mono-, di- and
6
4
2
tri arylated derivatives detected by MS.
First, we focused on the description of the catalytic
cycle of the first arylation. This cycle can be formally
divided into two steps: formation of the palladacycle
(
CꢀH activation) and reaction of the palladacycle
with an aryl iodide (arylation event).
Using Fourier-transform ion cyclotron resonance
mass spectrometry experiments (FT-ICR MS), we
were able to detect key intermediate complexes in
1g
1g
the catalytic cycle. Following complexes C1 , C2
1
g
and C3
were found in the reaction mixture
Scheme 3. Proposed mechanism of arylation of diamond-
oids; intermediates C and side products 7 and 8 detected by (Figure 6). It is suggested that C1 is first converted to
MS; complex C4 as last missing intermediate.
C2 with acetic acid. The role of acetate, for the actual
Adv. Synth. Catal. 0000, 000, 0 – 0
4
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

FULL PAPERS
asc.wiley-vch.de
with almost no incorporation of deuterium in the ada-
mantane framework; the same was observed for start-
ing material 1g. Preliminary kinetic studies, varying
the concentration of the starting material 1g, aryl
iodide 2a and Pd(OAc) revealed that the arylation
2
step is much slower than the palladacycle formation.
The kinetic data suggest that the reaction rate is in-
dependent on the concentration of the starting mate-
rial 1g and dependent on the concentration of the cat-
alyst Pd(OAc) and on the concentration of the aryl
2
iodide 2a at initial rates (see Supporting Information,
page 67). Competitive experiment (Scheme 5) using
equimolar amounts of aryl iodides containing me-
thoxy group or CF group in the para position pro-
3
duced a mixture of products 3 in ratio 2.2:1, 3a/3b.
Scheme 5. Competitive experiment between two electroni-
cally different para-substituted aryl iodides.
This experiment in addition to the results summar-
+
ized in Table 2 shows positive effect of M substitu-
1
g
ents on the arylation (C3 to C5) process. Based on
Figure 6. Experimental nanoESI FT-ICR mass spectra with the obtained results three transition states may be
the simulated isotope distributions and corresponding mass proposed for the arylation event (Figure 7). TS1:
1
g
1g
errors for the protonated positive ions of C1 , C2 and direct insertion of palladium (C3 complex) into the
1
g
IV
[40]
IV
C3 .
CꢀI bond (leading to Pd complex
C4 ); TS2:
IV
ipso oxidative substitution (leading to Pd complex
C4 ) or TS3: ipso substitution, which would lead to
IV
II
II
palladium CꢀH insertion step has been previously Pd complex C4 and upon reductive elimination, for-
[
32e,38]
0
proposed by several research groups.
mation of arylꢀcarbon bond, to Pd complex, that
1g
The palladacycle C3 was isolated and fully charac- would be internally re-oxidized by formed NꢀI spe-
terized (see Supporting Information, page 58). To cies.
1
g
support the hypothesis that the palladacycle C3 is
a competent reaction intermediate, the isolated C3
1
g
was subjected to the reaction with aryl iodide 2a in
HFIP at 1108C to observe the formation of the de-
sired product 3a (for details see Supporting Informa-
tion, page 59).
[
39]
Deuterium-labelling experiments revealed the re-
versibility of the palladacycle formation. The aryla-
tion reaction carried out in HFIP-d with 10 equiv of
2
AcOD produced deuterated 1g (b position of the
adamantane framework 4H/2D ratio) as well as deu-
terated 3a (4H/2D ratio) (see Supporting Informa-
tion, page 64).
An excess of acetic acid slightly decreases the reac-
tion rate (Scheme 2; 1g to 3a conversion after 4 h):
no additional AcOH 84%; 1 equiv ~76%; 5 equiv
~
60%; 10 equiv ~58%. The arylation reaction carried Figure 7. Suggested transition state models for the formation
out in HFIP-d with 1 equiv of AcOD produced 3a of C4 complexes.
2
Adv. Synth. Catal. 0000, 000, 0 – 0
5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

FULL PAPERS
asc.wiley-vch.de
A detailed look at the MS spectra for intermediates the undesired by-products 7 and 8 (detected by MS)
0
or side products did not allow us to distinguish be- and Pd , which can be re-oxidized by AgOAc. The
tween these proposals.
The reaction follows saturation kinetics. The prod- polarity of the solvent (HFIP) probably shifts the
solubilizing power and low nucleophilicity along with
1
g
1g
uct 3a is involved in the second arylation step, which equilibrium towards formation of C2 from C1 .
is in this case much slower than the first arylation of The last part of the work contains applications of
g. Isolated product 3a was subjected to the same re- the developed method. The directing group can be
action conditions to compare the rate of the second converted into imidazo[1,5-a]pyridine derivatives
1
[
44]
arylation event to obtain 6 (Scheme 6). This reaction (Scheme 7). The treatment of the substrate 3a with
2
8
-fluoropyridine and Tf O affords derivative 9 in
1% yield.
2
Scheme 6. Arylation of the monoarylated derivative.
Scheme 7. Intramolecular condensation reaction to imida-
zo[1,5-a]pyridine derivative 9.
is in order of magnitude slower (calculated ratio of k
constants kfirst arylation/ksecond arylation equals 26, see Sup-
porting Information, page 73). This observation can
be attributed to the fact that corresponding com-
Cleavage of the protecting group to reach carboxyl-
ic acid derivatives was performed under acidic condi-
3a
3a
[40b]
plexes C2 and C3 have reduced electrophilicity
due to the presence of the aryl moiety. In the next ex- tions to get compound 10. The structure of 10 was
periment starting material 1g and product 3a were confirmed by single crystal X-ray diffraction analysis
mixed in equimolar ratio and the rate of conversion (Scheme 8).
of starting material 1g was measured. The product 3a
[
41]
does not inhibit the first arylation reaction.
From
all kinetic data it is possible to conclude that there is
1g
3a
no significant difference in formation of C2 vs C2 .
[
42]
The second arylation step
mixture of three epimers of diarylated product 6
51% yield) is obtained, when 3a is used as starting
material.
The overall proposed simplified mechanism is the
is not regioselective. A
(
following: The first step is the fast deprotonation of
the directing group by the AgOAc to the silver com-
plex C (see Supporting Information, page 74). Conse- ylic acid derivative 10 (X-ray structure).
Scheme 8. Cleavage of the directing group to reach carbox-
a
quently, it follows transmetalation to the palladium
1g
complex C1 , which reacts with acetic acid and pro-
1g
duces complex C2 . “Elimination” of acetic acid from
Finally, we carried out the preparation of the car-
C2 (CꢀH activation step) produces the palladacycle boxylic acid 12, intermediate in the synthesis of bioac-
C3 . The mechanism of the palladacycle formation tive compounds (Scheme 9). Adamantane-2-carbox-
assistance of acetate in the insertion of Pd into the ylic acid was condensed with picolylamine to obtain
CꢀH bond) on similar systems was recently proposed the amide 1o in 97% yield. An arylation reaction
computationally and by MS studies. Acidoly- using the developed conditions was performed with
1g
1g
[45]
(
[32e,38a–c]
[43]
sis of the palladacycle C3 to C2 is the slowest step in phenyl iodide 2g to obtain 11 in 43% yield. The last
the reaction cycle. Complex C3 reacts with aryl iodide step, hydrolysis of the directing group, afforded the
2
to complex C4 (not detected/proposed on similar desired compound 12 in 52% yield.
systems) and upon reductive elimination produces
compound C5, which exchanges an iodide anion for
the acetate and can be detected in MS. Transmetala- Conclusions
b
tion with silver acetate produces product C and re-
generates the Pd(OAc) . Workup of the reaction mix- In conclusion, catalytic monoarylation of adamantane
2
ture provides the desired compound 3. The palladacy- derivatives was achieved using a CꢀH activation strat-
1g
cle C3 undergoes reductive elimination to produce egy. The described synthetic method provides direct
Adv. Synth. Catal. 0000, 000, 0 – 0
6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

FULL PAPERS
asc.wiley-vch.de
The resulting mixture was concentrated under reduced pres-
sure. The crude product was purified by chromatography to
afford products 3a–4o.
Characterization data for 3a
Purification by silica gel chromatography: 10!40% ace-
tone/hexane. White solid; yield (0.74 mmol scale): 242 mg
1
(
87%); R 0.15 (40% acetone/hexane); H NMR (400 MHz,
f
CDCl ): d/ppm=1.48–1.52 (m, 1H), 1.73–2.18 (m, 11H),
3
2
.54–2.57 (m, 1H), 3.34 (br s, 1H), 3.72 (s, 3H), 4.31–4.44
(
m, 2H), 6.69 (d, J=8.0 Hz, 2H), 6.82 (d, J=7.7 Hz, 1H),
7
1
.08–7.11 (m, 1H), 7.23 (d, J=8.0 Hz, 2H), 7.46–7.50 (m,
13
H), 8.40–8.43 (m, 1H); C NMR (101 MHz, CDCl ): d/
3
Scheme 9. New pathway to the common precursor 12 (pre-
cursor in the synthesis of compounds in Figure 1, second
line).
ppm=27.8 (CH), 28.3 (CH), 30.4 (CH ), 33.5 (CH ), 35.5
2
2
(
(
(
CH), 37.2 (CH ), 39.2 (CH ), 44.0 (C), 44.1 (CH ), 44.2
2
2
2
CH ). 50.9 (CH), 55.0 (CH ), 113.2 (CH), 121.9 (CH), 122.0
2
3
CH), 129.6 (2CH), 135.5 (CH), 136.6 (CH), 148.6 (CH),
57.0 (C), 157.4 (C), 177.0 (C); HRMS(ESI): m/z calculated
1
+
access to 1,2-disubstituted diamondoids. Crystalliza- for C H N O [M+H] : 377.2228, found 377.2227; IR
2
4
28
2
ꢀ1
2
IV
tion of palladacycle and attempts to detect the Pd / (neat): n˜ /cm =3334, 2911, 2853, 1636, 1529, 1512, 1471,
0
1
455, 1436, 1407, 1292, 1251, 1180, 1035, 1005, 815, 752, 671.
Pd intermediates are currently under investigation.
General procedure for directing group removal
Experimental Section
A solution of the corresponding amide 3 (0.14 mmol) in
H SO (0.9 mL, 40% aqueous solution) and p-xylene
2
4
Synthesis of adamantane based amide 1g
(0.90 mL) was stirred at 1308C for 24 h. The reaction mix-
ture was allowed to reach 258C and it was poured into H O
2
(
COCl) (1.50 mL, 17.73 mmol) was added dropwise to a so-
2
(
20 mL). The product was extracted with EtOAc (10 mL)
lution of 1-adamantanecarboxylic acid (3.00 g, 16.64 mmol)
and then the organic layer was dried over Na SO , filtered
2
4
in CH Cl (40 mL) and DMF (70 mL) at 08C. The reaction
2
2
and concentrated. The product was purified by flash chro-
matography on silica gel.
mixture was stirred at 258C and monitored by TLC analysis.
After 1 h the solvent was evaporated in vacuo and the 1-
adamantanecarbonyl chloride was used in the next step
without further purification. 2-Picolylamine (1.60 mL,
Characterization data for 12
1
5.52 mmol) was dropwise added to a solution of 1-adaman-
Purification by silica gel chromatography: 5!20% EtOAc/
tanecarbonyl chloride in CH Cl (50 mL) at 08C. After
1
action mixture was allowed to reach 258C. After 16 h, the
reaction mixture was diluted with CH Cl (30 mL) and
poured into H O (120 mL). The organic layer was dried
2
2
hexane. White solid; Yield: 15 mg (52%); R 0.3 (20%
f
0 min. Et N (4.20 mL, 30.17 mmol) was added and the re-
1
3
EtOAc/hexane); H NMR (600 MHz, CD OD): d/ppm=
3
1
.62–1.69 (m, 2H), 1.75–1.85 (m, 2H), 1.92–2.06 (m, 6H),
2
2
2.1–2.15 (m, 1H), 2.31–2.34 (m, 1H), 2.92–2.95 (m, 1H),
2
3.20 (s, 1H), 7.11 (t, J=7.4 Hz, 1H), 7.25 (t, J=7.8 Hz, 2H),
over Na SO , filtered and concentrated. The crude residue
13
2
4
7.35 (d, J=7.4 Hz, 2H); C NMR (150 MHz, CDCl ): d/
3
was flash chromatographed on silica gel: 0!10% acetone/
ppm=29.7 (CH), 30.5 (CH), 32.8 (CH ), 33.5 (CH), 36.4
2
hexane to furnish 1g as a white solid (4.10 g, Yield: 99%);
(
CH ), 38.1 (CH ), 38.8 (C), 39.3 (CH ), 48.4 (CH ), 55.3
2 2 2 2
1
Rf 0.20 (40% acetone/hexane); H NMR (400 MHz,
(CH), 126.1 (2CH), 126.6 (CH), 129.0 (2CH), 150.4 (C),
[D ]DMSO): d/ppm=1.60–1.75 (m, 6H), 1.80–1.84 (m, 6H),
6
177.3 (C); HRMS(ESI): m/z calculated for C H O [M+
1
7
20
2
1
1
1
.99 (s, 3H), 4.33 (d, J=5.9 Hz, 2H), 7.15 (d, J=7.9 Hz,
+
ꢀ1
Na] : 279.1361; found 279.1361; IR (neat): n˜ /cm =2910,
H), 7.21–7.24 (m, 1H), 7.73–7.78 (m, 1H), 8.04–8.07 (m,
2
850, 1696, 1497, 1445, 1418, 1231, 1205, 915, 762, 694.
1
3
H), 8.46–8.49 (m, 1H); C NMR (101 MHz, [D ]DMSO):
6
CCDC-1053886, CCDC-1053887, CCDC-1053888, CCDC-
d/ppm=27.7 (3CH), 36.1 (3CH ), 38.7 (3CH ), 39.9 (C), 44.0
2
2
1053889, CCDC-1053890, CCDC-1053891, and CCDC-
1053892 contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(CH ), 120.2 (CH), 121.8 (CH), 136.6 (CH), 148.7 (CH),
2
159.3 (C), 177.1 (C); HRMS(ESI): m/z calculated for
+
C H N O[M+H] : 271.1810, found 271.1809; IR (neat): n˜ /
17
ꢀ
22
2
1
cm =3318, 2902, 2847, 1632, 1586, 1532, 1469, 1413, 1353,
285, 1260, 1004, 746, 671.
1
General synthesis of aryl substituted derivative 3 and
4
Acknowledgements
Pd(OAc) (0.009 mmol), AgOAc (0.24 mmol), aryl iodide 2
This work was supported by the LOEWE “SynChemBio”
project, funded by the State of Hesse and by DFG project Sp
314/12–1. S. H. is grateful to the German National Academy
2
(
0.277 mmol) and the corresponding amide 1 (0.18 mmol) in
anhydrous HFIP (3.0 mL) were stirred at 1108C for 18 h.
Adv. Synth. Catal. 0000, 000, 0 – 0
7
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

FULL PAPERS
asc.wiley-vch.de
of Sciences Leopoldina (LPDR 2014–01) for a post-doctoral
scholarship. The authors would like to thank Prof. P. R.
Schreiner, Prof. A. A. Fokin, Dr. S. Ward and Ing. J. Je rˇ ꢀbek
for fruitful discussions, J.-P. Berndt, F. M. Metz, J. M. Schꢁ-
mann and S. Rçsel for generous gift of diamondoids, and Dr.
E. Rçcker for ESI measurements.
[12] a) M. S. Khan, A. Haque, M. K. Al-Suti, P. R. Raithby,
J. Organomet. Chem. 2015, 793, 114–133; b) Z. Chen,
B. Wang, J. Zhang, W. Yu, Z. Liu, Y. Zhang, Org.
Chem. Front. 2015, 2, 1107–1295; c) C. Zheng, S.-L.
You, RSC Adv. 2014, 4, 6173–6214; d) A. F. M. Noisier,
M. A. Brimble, Chem. Rev. 2014, 114, 8775–8806; e) N.
Dastbaravardeh, M. Christakakou, M. Haider, M.
Schnꢁrch, Synthesis 2014, 46, 1421–1439; f) G. Rouquet,
N. Chatani, Angew. Chem. 2013, 125, 11942–11959;
Angew. Chem. Int. Ed. 2013, 52, 11726–11743; g) J. Ya-
maguchi, A. D. Yamaguchi, K. Itami, Angew. Chem.
References
2
8
012, 124, 9092–9142; Angew. Chem. Int. Ed. 2012, 51,
960–9009; h) J. Wencel-Delord, T. Droge, F. Liu, F.
[
[
[
[
1] R. C. Fort, P. v. R. Schleyer, Chem. Rev. 1964, 64, 277–
00.
2] G. Lamoureux, G. Artavia, Curr. Med. Chem. 2010, 17,
967–2978.
3] L. Wanka, K. Iqbal, P. R. Schreiner, Chem. Rev. 2013,
13, 3516–3604.
4] a) A. A. Fokin, B. A. Tkachenko, N. A. Fokina, H.
Hausmann, M. Serafin, J. E. P. Dahl, R. M. K. Carlson,
P. R. Schreiner, Chem. Eur. J. 2009, 15, 3851–3862;
b) N. A. Fokina, B. A. Tkachenko, A. Merz, M. Serafin,
J. E. P. Dahl, R. M. K. Carlson, A. A. Fokin, P. R.
Schreiner, Eur. J. Org. Chem. 2007, 2007, 4738–4745;
c) P. R. Schreiner, N. A. Fokina, B. A. Tkachenko, H.
Hausmann, M. Serafin, J. E. P. Dahl, S. Liu, R. M. K.
Carlson, A. A. Fokin, J. Org. Chem. 2006, 71, 6709–
3
Glorius, Chem. Soc. Rev. 2011, 40, 4740–4761; i) O.
Baudoin, Chem. Soc. Rev. 2011, 40, 4902–4911; j) J. A.
Labinger, J. E. Bercaw, Nature 2002, 417, 507–514;
k) A. E. Shilov, G. B. Shul’pin, Chem. Rev. 1997, 97,
2
1
2
879–2932.
13] a) X. Wu, Y. Zhao, H. Ge, Chem. Sci. 2015, 6, 5978–
983; b) Z. Wang, J. Ni, Y. Kuninobu, M. Kanai,
[
5
Angew. Chem. 2014, 126, 3564–3567; Angew. Chem. Int.
Ed. 2014, 53, 3496–3499.
[
[
[
14] X. Wu, K. Yang, Y. Zhao, H. Sun, G. Li, H. Ge, Nat.
Commun. 2015, 6, 6462.
15] M. Sekine, L. Ilies, E. Nakamura, Org. Lett. 2013, 15,
7
14–717.
16] a) B. Li, M. Driess, J. F. Hartwig, J. Am. Chem. Soc.
014, 136, 6586–6589; b) E. M. Simmons, J. F. Hartwig,
6
720; d) A. A. Fokin, P. R. Schreiner, N. A. Fokina,
2
B. A. Tkachenko, H. Hausmann, M. Serafin, J. E. P.
Dahl, S. Liu, R. M. K. Carlson, J. Org. Chem. 2006, 71,
Nature 2012, 483, 70–73.
[
[
17] S.-Y. Yan, Y.-J. Liu, B. Liu, Y.-H. Liu, Z.-Z. Zhang, B.-
F. Shi, Chem. Commun. 2015, 51, 7341–7344.
18] a) M. Lee, M. S. Sanford, J. Am. Chem. Soc. 2015, 137,
8
532–8540; e) P. R. Schreiner, O. Lauenstein, E. D.
Butova, P. A. Gunchenko, I. V. Kolomitsin, A. Witt-
kopp, G. Feder, A. A. Fokin, Chem. Eur. J. 2001, 7,
1
2796–12799; b) N. F. Golꢂdshlger, V. V. Eskova, A. E.
4
996–5003.
Shilov, A. A. Shteinman, Zh. Fiz. Khim 1972, 46, 1353.
19] X. Wang, D.-G. Yu, F. Glorius, Angew. Chem. 2015,
[5] R. Hrdina, F. M. Metz, M. Larrosa, J.-P. Berndt, Y. Y.
[
[
[
Zhygadlo, S. Becker, J. Becker, Eur. J. Org. Chem.
2
1
1
27, 10419–10422; Angew. Chem. Int. Ed. 2015, 54,
0280–10283.
015, 6231–6236.
6] A. N. Abdel-Sayed, L. Bauer, Tetrahedron 1988, 44,
873–1882.
7] a) J. K. Chakrabarti, S. S. Szinai, A. Todd, J. Chem. Soc.
C 1970, 1303–1309; b) W. V. Curran, R. B. Angier, J.
Org. Chem. 1969, 34, 3668–3670; c) W. H. W. Lunn,
W. D. Podmore, S. S. Szinai, J. Chem. Soc. C 1968,
[
[
20] S. D. Bergman, T. E. Storr, H. Prokopcovꢃ, K. Aelvoet,
1
G. Diels, L. Meerpoel, B. U. W. Maes, Chem. Eur. J.
2
012, 18, 10393–10398.
21] a) Y.-F. Zhang, H.-W. Zhao, H. Wang, J.-B. Wei, Z.-J.
Shi, Angew. Chem. 2015, 127, 13890–13894; Angew.
Chem. Int. Ed. 2015, 54, 13686–13690; b) I. Franzoni,
C. Mazet, Org. Biomol. Chem. 2014, 12, 233–241.
22] a) P.-X. Ling, S.-L. Fang, X.-S. Yin, K. Chen, B.-Z. Sun,
B.-F. Shi, Chem. Eur. J. 2015, 21, 17503–17507; b) P.
Hu, T. Bach, Synlett 2015, 26, 2853–2857.
23] a) N. Hoshiya, K. Takenaka, S. Shuto, J. I. Uenishi,
Org. Lett. 2016, 18, 48–51; b) K. Chen, X. Li, S.-Q.
Zhang, B.-F. Shi, Chem. Commun. 2016, 52, 1915–1918.
1
657–1660.
[
8] K. C. Nicolaou, A. F. Stepan, T. Lister, A. Li, A. Mon-
tero, G. S. Tria, C. I. Turner, Y. Tang, J. Wang, R. M.
Denton, D. J. Edmonds, J. Am. Chem. Soc. 2008, 130,
[
1
3110–13119.
[
[
9] J. J. Rohde, M. A. Pliushchev, B. K. Sorensen, D.
Wodka, Q. Shuai, J. Wang, S. Fung, K. M. Monzon,
W. J. Chiou, L. Pan, X. Deng, L. E. Chovan, A. Ram-
aiya, M. Mullally, R. F. Henry, D. F. Stolarik, H. M.
Imade, K. C. Marsh, D. W. A. Beno, T. A. Fey, B. A.
Droz, M. E. Brune, H. S. Camp, H. L. Sham, E. U. Fre-
vert, P. B. Jacobson, J. T. Link, J. Med. Chem. 2007, 50,
[24] G. Shan, G. Huang, Y. Rao, Org. Biomol. Chem. 2015,
13, 697–701.
[25] a) B. Wang, G. He, G. Chen, Sci. China Chem. 2015, 58,
1345–1348; b) V. G. Landge, M. K. Sahoo, S. P. Midya,
G. Jaiswal, E. Balaraman, Dalton Trans. 2015, 44,
15382–15386.
1
49–164.
[
[
10] Y.-X. Lao, J.-Q. Wu, Y. Chen, S.-S. Zhang, Q. Li, H.
Wang, Org. Chem. Front. 2015, 2, 1374–1378.
[26] a) J. He, H. Jiang, R. Takise, R.-Y. Zhu, G. Chen, H.-X.
Dai, T. G. M. Dhar, J. Shi, H. Zhang, P. T. W. Cheng, J.-
Q. Yu, Angew. Chem. 2016, 128, 795–799; Angew.
Chem. Int. Ed. 2016, 55, 785–789; b) I. A. I. Mkhalid,
J. H. Barnard, T. B. Marder, J. M. Murphy, J. F. Hart-
wig, Chem. Rev. 2010, 110, 890–931.
11] During the preparation of this manuscript the excellent
work dealing with diarylation of rimantadine deriva-
tives appeared utilizing a similar directing motif as we
present in our article: Z. Fan, S. Shu, J. Ni, Q. Yao, A.
Zhang, ACS Catal. 2016, 6, 769–774.
Adv. Synth. Catal. 0000, 000, 0 – 0
8
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

FULL PAPERS
asc.wiley-vch.de
[
[
27] a) Q. Gou, G. Liu, Z.-N. Liu, J. Qin, Chem. Eur. J.
015, 21, 15491–15495; b) Q. Zhang, K. Chen, B.-F. Shi,
[35] a) M. A. Gunawan, J.-C. Hierso, D. Poinsot, A. A.
Fokin, N. A. Fokina, B. A. Tkachenko, P. R. Schreiner,
New J. Chem. 2014, 38, 28–41; b) H. Schwertfeger,
A. A. Fokin, P. R. Schreiner, Angew. Chem. 2008, 120,
1038–1053; Angew. Chem. Int. Ed. 2008, 47, 1022–1036.
[36] a) N. Dastbaravardeh, T. Toba, M. E. Farmer, J.-Q. Yu,
J. Am. Chem. Soc. 2015, 137, 9877–9884; b) A. Berkes-
sel, S. S. Vormittag, N. E. Schlçrer, J.-M. Neudçrfl, J.
Org. Chem. 2012, 77, 10145–10157; c) A. Berkessel,
J. A. Adrio, D. Hꢁttenhain, J. M. Neudçrfl, J. Am.
Chem. Soc. 2006, 128, 8421–8426.
2
Synlett 2014, 25, 1941–1945.
28] a) Z.-L. Tao, X.-H. Li, Z.-Y. Han, L.-Z. Gong, J. Am.
Chem. Soc. 2015, 137, 4054–4057; b) Q. Gou, Z.-F.
Zhang, Z.-C. Liu, J. Qin J. Org. Chem. 2015, 80, 3176–
3
186.
[29] H.-Y. Xiong, T. Besset, D. Cahard, X. Pannecoucke, J.
Org. Chem. 2015, 80, 4204–4212.
[
30] a) Q. Zhu, D. Ji, T. Liang, X. Wang, Y. Xu, Org. Lett.
2
015, 17, 3798–3801; b) W. Liu, L. Tan, P. Zhou, C.
Chen, Q. Zhang, Synthesis 2013, 45, 2600–2604.
31] C. Wang, L. Zhang, C. Chen, J. Han, Y. Yao, Y. Zhao,
Chem. Sci. 2015, 6, 4610–4614.
[
37] A. A. Fokin, B. A. Tkachenko, P. A. Gunchenko, D. V.
[
[
Gusev, P. R. Schreiner, Chem. Eur. J. 2005, 11, 7091–
7
101.
38] a) Q. Zhang, H. Yu, Y. Fu, Sci. China Chem. 2015, 58,
316–1322; b) G.-J. Cheng, P. Chen, T.-Y. Sun, X.
Zhang, J.-Q. Yu, Y.-D. Wu, Chem. Eur. J. 2015, 21,
1180–11188; c) M. Anand, R. B. Sunoj, H. F. Schaefer,
32] a) J. Wencel-Delord, F. Colobert, Synlett 2015, 26,
[
2
644–2658; b) B. Gopalakrishnan, S. A. Babu, R. Pad-
1
mavathi, Tetrahedron 2015, 71, 8333–8349; c) D. Dail-
ler, G. Danoun, B. Ourri, O. Baudoin, Chem. Eur. J.
1
2
015, 21, 9370–9379; d) R. Parella, B. Gopalakrishnan,
J. Am. Chem. Soc. 2014, 136, 5535–5538; d) Y. Bouta-
dla, D. L. Davies, S. A. Macgregor, A. I. Poblador-Ba-
hamonde, Dalton Trans. 2009, 5820–5831; e) J. Ox-
gaard, W. J. Tenn, R. J. Nielsen, R. A. Periana, W. A.
Goddard, Organometallics 2007, 26, 1565–1567; f) D.
Garcꢄa-Cuadrado, P. de Mendoza, A. A. C. Braga, F.
Maseras, A. M. Echavarren, J. Am. Chem. Soc. 2007,
S. A. Babu, J. Org. Chem. 2013, 78, 11911–11934; e) R.
Giri, Y. Lan, P. Liu, K. N. Houk, J.-Q. Yu, J. Am.
Chem. Soc. 2012, 134, 14118–14126.
[
[
33] a) S.-B. Yan, S. Zhang, W.-L. Duan, Org. Lett. 2015, 17,
2458–2461; b) J. Pedroni, N. Cramer, Angew. Chem.
2015, 127, 11992–11995; Angew. Chem. Int. Ed. 2015,
54, 11826–11829; c) D. Katayev, E. Larionov, M. Naka-
1
29, 6880–6886; g) M. Lafrance, C. N. Rowley, T. K.
nishi, C. Besnard, E. P. Kꢁndig, Chem. Eur. J. 2014, 20,
5021–15030.
Woo, K. Fagnou, J. Am. Chem. Soc. 2006, 128, 8754–
1
8
2
756; h) M. Lafrance, K. Fagnou, J. Am. Chem. Soc.
006, 128, 16496–16497; i) L.-C. Campeau, M. Parisien,
34] a) X. Yang, G. Shan, L. Wang, Y. Rao, Tetrahedron
Lett. 2016, 57, 819–836; b) S.-K. Zhang, X.-Y. Yang, X.-
M. Zhao, P.-X. Li, J.-L. Niu, M.-P. Song, Organometal-
lics 2015, 34, 4331–4339; c) H. Tang, X.-R. Huang, J.
Yao, H. Chen, J. Org. Chem. 2015, 80, 4672–4682;
d) R. K. Rit, M. R. Yadav, K. Ghosh, A. K. Sahoo, Tet-
rahedron 2015, 71, 4450–4459; e) O. Daugulis, J. Roane,
L. D. Tran, Acc. Chem. Res. 2015, 48, 1053–1064; f) Q.
Gu, H. H. Al Mamari, K. Graczyk, E. Diers, L. Acker-
mann, Angew. Chem. 2014, 126, 3949–3952; Angew.
Chem. Int. Ed. 2014, 53, 3868–3871; g) S. De Sarkar, W.
Liu, S. I. Kozhushkov, L. Ackermann, Adv. Synth.
Catal. 2014, 356, 1461–1479; h) G. He, S.-Y. Zhang,
W. A. Nack, Q. Li, G. Chen, Angew. Chem. 2013, 125,
A. Jean, K. Fagnou, J. Am. Chem. Soc. 2006, 128, 581–
90.
5
[
39] G. He, G. Chen, Angew. Chem. 2011, 123, 5298–5302;
Angew. Chem. Int. Ed. 2011, 50, 5192–5196.
[40] a) N. D. Ball, J. B. Gary, Y. Ye, M. S. Sanford, J. Am.
Chem. Soc. 2011, 133, 7577–7584; b) P. Sehnal, R. J. K.
Taylor, I. J. S. Fairlamb, Chem. Rev. 2010, 110, 824–889.
[41] D. G. Blackmond, Angew. Chem. 2005, 117, 4374–4393;
Angew. Chem. Int. Ed. 2005, 44, 4302–4320.
[42] a) J. Liu, Y. Xie, W. Zeng, D. Lin, Y. Deng, X. Lu, J.
Org. Chem. 2015, 80, 4618–4626; b) W. R. Gutekunst,
P. S. Baran, J. Org. Chem. 2014, 79, 2430–2452; c) D. S.
Roman, A. B. Charette, Org. Lett. 2013, 15, 4394–4397.
[43] C. L. Boeser, J. C. Holder, B. L. H. Taylor, K. N. Houk,
B. M. Stoltz, R. N. Zare, Chem. Sci. 2015, 6, 1917–1922.
1
1330–11334; Angew. Chem. Int. Ed. 2013, 52, 11124–
1
1128; i) F.-J. Chen, S. Zhao, F. Hu, K. Chen, Q. Zhang,
S.-Q. Zhang, B.-F. Shi, Chem. Sci. 2013, 4, 4187–4192;
j) A. Garcꢄa-Rubia, M. ꢅ. Fernꢃndez-IbꢃÇez, R. Gꢆme-
z Arrayꢃs, J. C. Carretero, Chem. Eur. J. 2011, 17, 3567–
[
44] G. Pelletier, A. B. Charette, Org. Lett. 2013, 15, 2290–
293.
2
3
570; k) D. Shabashov, O. Daugulis, J. Am. Chem. Soc.
[
45] I. Papanastasiou, A. Tsotinis, N. Kolocouris, S. Nikas,
2
010, 132, 3965–3972; l) V. G. Zaitsev, D. Shabashov, O.
A. Vamvakides, Med. Chem. Res. 2014, 23, 1966–1975.
Daugulis, J. Am. Chem. Soc. 2005, 127, 13154–13155.
Adv. Synth. Catal. 0000, 000, 0 – 0
9
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

FULL PAPERS
1
0 CꢀH Bond Arylation of Diamondoids Catalyzed by
Palladium(II) Acetate
Adv. Synth. Catal. 2016, 358, 1 – 10
Marta Larrosa, Sven Heiles, Jonathan Becker,
Bernhard Spengler, Radim Hrdina*
Adv. Synth. Catal. 0000, 000, 0 – 0
10
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!