Palladium-catalyzed C-H bond acetoxylation: An approach to ortho-substituted hydroxy[2.2]paracyclophane derivatives

Article abstract of DOI:10.1002/adsc.201200625

The palladium-catalyzed direct C-H bond acetoxylation of [2.2]paracyclophanes has been investigated. Various mono- and disubstituted [2.2]paracyclophanes were subjected to typical Sanford acetoxylation conditions. Oxime ethers, an oxime acetate, a pyridine, and a pyrazole with [2.2]paracyclophane cores underwent direct ortho-acetoxylation in good to excellent yields using 1-5 mol% of palladium(II) acetate in combination with iodobenzene diacetate as oxidant. The reactions could be performed on a multigram scale, and the ortho-acetoxylated [2.2]paracyclophanes were suitable for further functionalizations affording a hydroxy[2.2]paracyclophane derivative and a planar chiral benzoxazole. Copyright

Full text of DOI:10.1002/adsc.201200625

FULL PAPERS
DOI: 10.1002/adsc.201200625
À
Palladium-Catalyzed C H Bond Acetoxylation: An Approach to
ortho-Substituted Hydroxy[2.2]paracyclophane Derivatives
AHCTUNGTRENNUNG
Petra Lennartz,a Gerhard Raabe,a and Carsten Bolma,*
a
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax : (+49)-241-809-2391; e-mail: Carsten.Bolm@oc.rwth-aachen.de
Received: July 17, 2012; Revised: September 10, 2012; Published online: November 13, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200625.
À
Abstract: The palladium-catalyzed direct C H bond could be performed on a multigram scale, and the
acetoxylation of [2.2]paracyclophanes has been in- ortho-acetoxylated [2.2]paracyclophanes were suita-
vestigated. Various mono- and disubstituted ble for further functionalizations affording a hydroxy-
[2.2]para
G
ACHTUNGTREN[NGNU 2.2]paracyclophane derivative and a planar chiral
ford acetoxylation conditions. Oxime ethers, an benzoxazole.
oxime acetate, a pyridine, and a pyrazole with
[2.2]paracyclophane cores underwent direct ortho-
acetoxylation in good to excellent yields using 1– Keywords: ortho-acetoxylation; direct functionaliza-
5 mol% of palladiACTHNUTRGENNUGum(II) acetate in combination with tion; palladium; ACHUTNGTREN[NUGN 2.2]paracyclophanes; planar chirali-
iodobenzene diacetate as oxidant. The reactions ty
Introduction
For the latter, disubstituted [2.2]paracyclophanes,
which are planar chiral in most cases, proved particu-
Recently, the direct functionalization of C H bonds larly attractive.[7] Among the various disubstituted
by transition metal catalysis has gained significant at- [2.2]paracyclophanes, only those with ortho-, pseudo-
tention, and it is often valued as an established geminal- and pseudo-ortho-positioned substituents are
method for the synthesis of highly functionalized suitable for the chelation of a metal. Unfortunately,
compounds.[1,2] Because of the chemical similarity of the number of efficient synthetic approaches to such
À
À
the targeted C H bonds, site selectivity is one of the derivatives is rather low and, consequently, their po-
main challenges in direct functionalizations. In many tential applications are hampered by preparative limi-
cases, ortho-selectivity has been achieved by the use tations. The most established route towards ortho-sub-
of directing/chelating substituents.[2] Among other stituted [2.2]paracyclophanes involves an ortho-direct-
metals[3] palladium has shown high activity in such ed lithiation and subsequent addition of an electro-
transformations. Via an in-situ generated five- or six- phile (E+) to the in-situ generated carbanion. Un-
À
À
membered palladacycle, new C C and C heteroatom fortunately,
this
approach
is
restricted
to
bonds can be formed.[1,2,4] As efficient directing [2.2]paracyclophanes with N,N-diethylcarbamido[8] or
groups (DG) various substituents have been reported, amido[9] and alkylsulfinyl[10] substituents (Scheme 1,
and many of them have pyridine, oxime ether and a).
acetate, pyrrolidinone, benzoquinoline, aminoquino-
While the aforementioned stoichiometric metalla-
line, amide, sulfoximine, imine, pyrazole, pyrazine, tion approach via organolithium reagents is well in-
and pyrimidine cores.[5] Despite the large variety of vestigated, the development of metal-catalyzed direct
À
À
reported transformations and structures, direct C H functionalizations of [2.2]paracyclophane C H bonds
activations of more complex molecules have remained has attracted surprisingly limited attention. For us,
challenging. In this context, site-selective directed a useful starting point for such studies was the forma-
functionalizations of [2.2]paracyclophanes are of in- tion of a planar chiral palladacyle obtained from an
terest because various derivatives of this doubly oxazolinyl-substituted [2.2]paracyclophane that we re-
linked bisarene have found applications for coatings ported in 2002.[11] Depending on the reaction condi-
in material science[6] and have also been used as li- tions either an ortho or a benzylic substitution oc-
gands, catalysts or auxiliaries in asymmetric synthesis. curred. Since then, a few more examples of [2.2]para-
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2
À
Scheme 2. Regioselectivity in ortho-directed sp C H bond
activation of a) arenes and b) [2.2]paracyclophanes.
Scheme 1. Syntheses of ortho-disubstituted [2.2]paracyclo-
phanes.
cyclophane-based palladacycles have been de-
scribed,[12–14] but none of them has been used for cata-
lytic syntheses of 4,5-disubstituted [2.2]paracyclo-
phanes. In continuation of our studies on preparations
and applications of disubstituted [2.2]paracyclopha-
nes,[8b,c,11,15] we recently reported a new synthetic
method to planar chiral carbazoles, which involved
Scheme 3. Syntheses of [2.2]paracyclophane-based carbonyl
derivatives 2–4.
À
a palladium-mediated intramolecular double C H
bond activation as key step.[16] Now, those studies
have been expanded, and we developed the first pal-
À
ladium-catalyzed method for the synthesis of 4,5-dis- C H bonds due to the strained structure of the
ubstituted [2.2]paracyclophanes by ortho-directed [2.2]paracyclophane (Scheme 2).
direct functionalization (Scheme 1, b).
In 1996, Yoneyama and Crabtree reported the first
palladium-catalyzed direct acetoxylation of benzene
and derivatives thereof with iodobenzene diacetate.[20]
Since then this approach has significantly been im-
proved by Sanford and others, and it can now be ap-
Results and Discussion
At the outset of our studies we hypothesized that plied to a wide variety of arenes.[5] In particular, O-
compared to analogous reactions with simple arenes, methyl oxime ethers have shown good ortho-directing
2
À
direct sp C H bond functionalizations of [2.2]paracy- abilities, while revealing a broad functional group tol-
clophanes could be difficult due to various factors in- erance.[5a,c–e] On that basis, ketoxime ether 2a, which
cluding the boat-like distortion of the aromatic was
easily
accessible
from
4-acetyl-
rings,[17] the unique p-interactions between the ben-
[2.2]paracyclophane[21] (1a) in 98% yield (Scheme 3),
ACHTUNGTRENNUNG
zene moieties and a reduced aromaticity.[18,19] Further- was chosen as starting material for the initial reactivi-
more, to the best of our knowledge, there was no ty screening of palladium-catalyzed direct acetoxyla-
À
report of a ligand-directed C H functionalization of tion reactions.
a sterically demanding compound bearing a substitu-
To our delight, our early expectations were fulfilled,
ent in ortho and meta positions relative to the direct- and using slightly modified conditions as reported by
ing group. Finally, the desired activation of the ortho-
A
Sanford, ortho-acetoxylated ketoxime ether 5a
À
[2.2]paracyclophane C H bond was expected to com- was obtained in 79% yield after 16 h using 5 mol% of
pete with those of the benzylic[11] or pseudo-geminal Pd
A
AHCTUNGTRENNUNG
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Palladium-Catalyzed C H Bond Acetoxylation: An Approach
and acetic anhydride at 1008C (Scheme 4 and Table 1,
entry 1).[22] The regioselectivity was proven by
1H NMR, 13C NMR and MS. A benzylic activation
was excluded based on the presence of eight methyl-
1
ene protons (at d=2.74–3.25 ppm) in the H NMR
spectrum and four peaks for methylene carbons in the
13C NMR spectrum. The 6 aromatic protons (at d=
6.45–6.89 ppm) and the characteristic signal splitting
for ortho-disubstituted [2.2]paracyclophanes (four
doublets of doublets and two doublets) confirmed the
desired substitution pattern.
Scheme 4. Direct acetoxylation of [2.2]paracyclophane-
based oxime ether 2a.
In the absence of PdACTHNUTRGENN(UG OAc)2 or PhIACHTUGNTERN(NUGN OAc)2, ortho-
acetoxylated product 5a was not formed and ketox-
ime ether 2a was recovered. The catalyst loading
could be reduced to 1 mol% of PdACTHNUTRGNEUNG(OAc)2 and under
these conditions, 5a was obtained in 77% yield. With
Table 1. Scope of the palladium-catalyzed direct ortho-ace-
the goal to avoid the stoichiometric formation of
toxylation of [2.2]paracyclophanes.[a]
toxic phenyl iodide stemming from PhIACTHNUTRGNEUNG
(OAc)2,[5d]
oxone and K2S2O8 were tested as oxidants. Unfortu-
nately, however, both reagents proved less effective
and 5a was only obtained in 16% and 17% yield, re-
spectively.
Considering
that
4,5-disubstituted
[2.2]paracyclophanes such as 5a could be of interest
AHCTUNGTRENNUNG
in material science or catalysis, an up-scaled synthesis
[starting from 2 g (7.2 mmol) of 2a] was conduced. To
our delight, the catalyst loading could be significantly
reduced (from the commonly used 5 mol%) to
2 mol% of PdACTHUNRGTNEUNG(OAc)2, and under further optimized re-
action conditions (see Scheme 4) acetoxylated prod-
uct 5a was finally obtained in 74% yield.
Entry
1
Product: Yield
Entry
5
Product: Yield
With the goal to investigate acetoxylations of relat-
ed [2.2]paracyclophanes, other substrates were tested
under the developed reaction conditions. The structur-
al variations concerned the substituent at the oxime
ether, which was altered from methyl to hydrogen
and phenyl (as in 2b and 2c, respectively) as well as
an entire change of the directing ligand (from the
oxime ether unit to other chelating entities as shown
in Scheme 5 and Table 1). Furthermore, disubstituted
[2.2]paracyclophane 3 was applied.
2
3
6
7
4
[a]
Reaction scale: 200 mg of [2.2]paracyclophane in AcOH/
Ac2O (0.1M).
[b]
[c]
1 mol% of Pd
N
Scheme 5. Other [2.2]paracyclophane-based substrates for
direct acetoxylation reactions.
Reaction time: 3 h, after 16 h: 23% yield.
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For the preparation of the starting materials various
routes were developed. Thus, aldoxime ether 2b and
the phenyl-substituted ketoxime ether 2c were pre-
pared in a similar manner as 2a with yields of 96%
and 32%, respectively. Bromination of 2a with NBS
in acetonitrile at 1008C afforded pseudo-geminal dis-
ubstituted [2.2]paracyclophane 3 in 91% yield. The
observed regioselectivity in the bromination was con-
firmed by hydrolysis of 3 under acidic conditions,
which provided ketone 4 in 41% yield. Its NMR data
were identical to those reported in the literature.[23]
Acetylated oxime 6 was obtained from the corre-
sponding known ketoxime[24] by reaction with acetic
anhydride in acetic acid,[25] and the preparation of 4-
pyridinyl-substituted [2.2]paracyclophane 7 followed
a protocol recently reported by Rowlands and co-
workers (Scheme 5).[26] The hitherto unknown planar
chiral pyrazole 10 was synthesized as shown in
Scheme 5. Initially, we tried to prepare 10 by com-
À
monly applied copper-catalyzed C N cross coupling
reactions starting from bromide 8 and pyrazole (9).[27]
However, all attempts failed. Finally, the use of Pd2
ACHTUNGTRENNUNG(dba)3 in combination with Buchwaldꢁs t-Bu-XPhos
(2-di-tert-butylphosphino-2’,4’,6’-triisopropylbiphenyl)
led to success providing pyrazole 10 by Buchwald–
Hartwig-type amination[28] in 84% yield.
Figure 1. Molecular structure of trisubstituted [2.2]paracy-
clophane 11 in the solid state as determined by X-ray crystal
structure analysis.
wave function did not indicate any donation of elec-
The results of the palladium-catalyzed direct ace- tron density into the C-11/C-12 antibonding orbital,
toxylation reactions with substrates 2a–c, 3, 6, 7 and which significantly exceeds that for the other bonds of
10 are summarized in Table 1.
this aromatic ring, the elongation of this bond is not
Like oxime ether 2a, the structural analogous al- the result of a hyperconjugative interaction. Exchange
doxime ether 2b and phenyl-substituted ketoxime of the bromine atom for hydrogen has only a small
ether 2c reacted well too, providing the corresponding effect on the length of the C-11/C-12 bond in that it
ortho-acetoxylated products 5b and 5c in 68% and causes only a minute decrease to 1.420 ꢂ. Similarly, if
88% yield, respectively (Table 1, entries 2 and 3). The the substituent at C-10 is replaced by a hydrogen
high yield of trisubstituted 11 (87%; Table 1, entry 4) atom the C-11/-C12 bond length remains essentially
showed that the bromo substituent in the pseudo- the same (1.424 ꢂ). Replacement of the substituent at
geminal position of the directing moiety of [2.2]para- C-11 by hydrogen, however, results in a bond length
cyclophane 3 was tolerated well. The molecular struc- of 1.402 ꢂ, which is comparable to those of the other
ture of 11 was determined by X-ray crystallography bonds in the aromatic rings. It, therefore, appears that
and is depicted in Figure 1.
a repulsive interaction between the oxime substituent
The X-ray crystal structure of 11 revealed that the at C-11 with the neighboring CH2 group of the ethyl-
aromatic rings of the [2.2]paracylophanes are non- ene bridge accounts for the length of the C-11/C-12
planar showing structural features which are typical bond.
for this class of compounds. Thus, the para carbon
Use of acetyl-protected oxime 6 as starting material
atoms (C-9, C-12 and C-2, C-5) of both rings deviate for the palladium-catalyzed direct acetoxylation led to
from the least-squares planes defined by the other ortho-substituted [2.2]paracyclophane 12 in 61% yield
ring atoms by 0.14–0.19 ꢂ. Non-planarity of the aro- (Table 1, entry 5). In this case, the reaction had to be
matic systems is also reflected by the sums of bond terminated after 3 h because longer reaction times re-
angles which amount to about 1198 in each ring. Sur- sulted in decomposition and significantly lower yields
prising is the length of the C-11/C-12 bond of 12. Finally, both heterocylic substitutents, the pyri-
[1.425(2) ꢂ] which significantly exceeds that of the dinyl of 7 and the pyrazolyl of 10 directed well, and
other bonds in both aromatic rings (1.38–1.40 ꢂ). products 13 and 14 were obtained in 61% and 53%,
Structural optimization of an isolated molecule in the yield, respectively (Table 1, entries 6 and 7). The
gas phase at the B3LYP/6-31G* level reproduces this structure of the former compound was confirmed by
elongation (1.425 ꢂ). It can, therefore, not be the NMR spectroscopy of the phenolic product (13 with
result of intermolecular interactions in the solid state. OH instead of OAc), which was prepared in 86%
Moreover, since an NBO analysis of the moleculeꢁs yield by hydrolysis of 13 with methanolic K2CO3.
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Palladium-Catalyzed C H Bond Acetoxylation: An Approach
aminoACHTNUGRTNEUNG
[2.2]paracyclophane[30] (17) and 4-chlorobutano-
ic acid chloride by amidation and subsequent cycliza-
tion.
The limitations of the palladium-catalyzed direct
acetoxylation of [2.2]paracyclophanes became appar-
ent, when substrates with other potential directing
groups were tested. Figure 2 shows the derivatives
that could not be functionalized in this manner. Thus,
ketone 1a did not react indicating the essential re-
quirement of the oxime ether moiety (as in 2a). The
same was true for imine 19,[31] which hydrolyzed to al-
dehyde 1b under the given reaction conditions. Be-
cause other studies had identified amino and carbami-
do substituents as strong ortho-directing groups,
[2.2]paracyclophanes 20 and 21 were tested. However,
neither of them led to acetoxylated products. The
same was true for attempts to convert N-acetyl-pro-
tected 4-aminoACTHNUTRGNEUNG[2.2]paracyclophane 16 and pyrrolidi-
none 18. The latter appeared particularly promising
because good results had been reported with pyrroli-
2
3
À
dinones in other direct sp and sp C H functionaliza-
tions.[2] Here, however, pyrrolidinone 18 did neither
react under standard reaction conditions nor at ele-
vated temperature or after an extended reaction time.
Presumably, the steric hindrance of the [2.2]paracyclo-
phane skeleton was too pronounced hampering the
Figure 2.
ACHTUNGTRENNUNG[2.2]Paracyclophanes which did not undergo the
palladium-catalyzed direct acetoxylation.
Figure 2 shows substrates which could not be con- reaction in analogy to observations made in attempt-
verted by the developed palladium-catalyzed direct ed acetoxylations of sterically demanding benzo[h]-
acetoxylation. Some of them were prepared by new quinoline derivatives.[5l] For 16, also the use of K2S2O8
routes, others were unknown. Scheme 6 summarizes as oxidant instead of the commonly applied PhI-
two applied syntheses. Accordingly, the preparation
ACHTUNGRTEN(NUNG OAc)2 did not lead to success. Based on the fact that
of N-acetyl-protected 4-aminoACTHNUGTRNE[GUN 2.2]paracyclophane 16 in palladium-catalyzed direct functionalizations of
involved a Beckmann rearrangement[29] of the free simple arenes carboxyl[32] and chelating amido groups
oxime 15 using zinc chloride and para-toluenesulfonic derived from 8-aminoquinoline[5g] or 2-aminobenzo-
acid (PTSA). Pyrrolidinone 18 was prepared from 4- phenone[5m] were effective directing ligands, [2.2]para-
cyclophane-based acid 22 and amides 23 and 24 were
applied.[33] Unfortunately, however, none of those
compounds could be acetoxylated here.
With the goal to demonstrate the synthetic value of
the prepared acetoxylated [2.2]paracyclophanes, vari-
ous conversions of 5a were examplified (Scheme 7).
First, the acetyl ester group was cleaved, which oc-
curred under basic conditions with K2CO3 in metha-
nol to give [2.2]paracyclophane-based phenol 25 in
91% yield. There, the oxime ether moiety was re-
tained. Also under acidic conditions this heterocar-
bonyl substituent proved remarkably stable. Hence,
even after an extensive optimization the highest yield
in
the
release
of
5-acetyl-4-hydroxy-
AHCTUNGTRENNUNG
[2.2]paracyclophane (AHPC)[7c] (26) from 5a was only
12%.[34] Concurrently, the formation of planar chiral
benzoxazole 27 was observed. By treatment of 5a
with etheral HCl at elevated temperature 27 was fi-
nally obtained in 94% yield.[35] Apparently, 5a under-
went a facile Beckmann rearrangement, which was
terminated by an intramolecular trapping with the
neighboring phenol group formed by ester hydroly-
Scheme 6. Preparation of [2.2]paracyclophane derivatives 16
and 18.
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À
Scheme 8. Other attempted palladium-catalyzed C H bond
functionalizations of oxime ether 2a.
for the direct acetoxylation.[5b,d] An analogous ap-
proach was successful here, and with K2S2O8 instead
of PhIACTHNURTGNENG(U OAc)2 as oxidant product 31 was obtained
from oxime ether 2a by direct methoxylation. Un-
fortunately, the yield of 31 was only 18%.
Scheme 7. Chemical modifications of ortho-acetoxylated
oxime ether 5a.
sis.[36] Site-selective deprotonation of benzoxazole 27 Conclusions
with butyllithium and subsequent reaction of the in-
situ formed anion with benzophenone gave 28 in 66% We developed a protocol for the palladium-catalyzed
À
yield, which appears like a promissing planar chiral direct C H bond acetoxylation of mono- and disubsti-
N,O- or O,O-chelator for asymmetric catalysis.
tuted [2.2]paracyclophanes leading to ortho-substitut-
Finally, we tried to extend the approach to other ed derivatives with high site selectivities. Benzylic
À
direct C H bond functionalizations, which were re- functionalizations, as observed before, did not occur.
ported for aryl oxime ethers (Scheme 8). Unfortu- The catalyst loading could be as low as 1 mol% [of
nately, however, the desired direct ortho-bromination PdACTHNUTRGNENUG(OAc)2], and the conditions were applicable for
of oxime ether 2a under Sanford conditions[37] did not multigram-scale reactions. For one representative
afford bromide 29, but gave pseudo-geminal oxime product subsequent functionalizations leading to at-
ether 3, presumably by favored electrophilic aromatic tractive synthetic intermediates have been demon-
substitution. All attempts to change the selectivity by strated. For future work the substrate reactivity pat-
À
adding silver salts or using acidic reaction conditions tern of the direct C H bond functionalization will be
(AcOH or presence of PTSA) remained unsuccesful. of interest: High reactivities have only been observed
Also the direct arylation of 2a with phenyl iodide with [2.2]paracyclophanes bearing directing groups
2
3
À
under palladium catalysis in the presence of silver that are commonly applied in sp and sp C H bond
salts[2a] failed. Only when dibenzoyl peroxide activations such as oxime ether and oximine ester
(DBPO)[38] was added were traces of the desired phe- groups, pyridinyl and pyrazolyl substituents. In con-
nylated compound 30 detected (by GC-MS). Until trast, substrates with carboxyl, amino, amido and re-
now, it remained impossible to isolate 30 in pure lated substituents, which have mainly been used in ac-
2
À
form. Sandford established a direct alkoxylation tivations of standard arene sp C H bonds, did not
under reaction conditions similar to those reported react. This result can be explained by the geometry of
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Palladium-Catalyzed C H Bond Acetoxylation: An Approach
(50 mL) and washed with water (50 mL) and brine (50 mL),
dried over MgSO4 and the solvent evaporated. Purification
by column chromatography (DCM) provided the ketoxime
ether 2a as a white solid; yield: 6.532 g (23.38 mmol, 98%);
the [2.2]paracyclophane core presenting bent aromat-
ic rings with C H bonds having a slight sp character.
As a consequence, the starting material (core/ligand)
has to be well composed, and our findings may serve
as a useful guideline for such molecular design.
3
À
1
mp 79–808C. H NMR (400 MHz, CDCl3): d=6.71 (d, J=
8.2 Hz, 1H), 6.59–6.54 (m, 3H), 6.49 (s, 2H), 6.42 (d, J=
8.0 Hz, 1H), 4.08 (s, 3H), 4.64–3.57 (m, 1H), 3.18–2.89 (m,
7H), 2.18 (s, 3H); 13C NMR (100 MHz, CDCl3): d=155.6,
139.7, 139.4, 139.2, 138.0, 137.3, 135.8, 133.0, 132.7, 132.5,
132.4, 131.7, 131.0, 61.8, 35.3, 35.2, 35.2, 35.1, 15.7; MS (EI):
m/z (%)=279 ([M]+, 49), 175 (26), 174 (27), 144 (100), 105
Experimental Section
General Methods
˜
(33), 104 (23), 103 (15), 78 (11), 77 (13); IR (ATR): n=
Unless otherwise stated, all starting materials were commer-
cially available and used as received. 4-Acetyl-
2927, 2851, 1591, 1460, 1434, 1366, 1308, 1170, 1068, 1041,
878, 852, 799, 725, 659 cmÀ1; elemental analysis calcd. for
C19H21NO: C 81.68, H 7.58, N 5.01; found: C 81.66, H 7.59,
N 5.01.
ACHTUNGTRENNUNG
[2.2]paracyclophane 1a[21] [purified by column chromatogra-
phy (DCM)], 4-formyl
column chromatography: pentane/ethyl acetate=19:1), 2-
([2.2]paracyclophane-4-yl)pyridine 7[26]
4-bromo[2.2]para-
cyclophane 8[40] (purified by column chromatography: pen-
tane/DCM=9:1), 4-acetyl
[2.2]paracyclophane oxime 15,[24]
4-amino cyclophanyl)
[2.2]paracylophane 17,[30] O-(4-[2.2]para
diethylcarbamate 21[8a] and 4-carboxy
[2.2]paracyclophane
[2.2]paracyclophane 1b[39] (purified by
ACHTUNGTRENNUNG
,
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
4-BenzoylACTHNUGRTNEUNG[2.2]paracyclophane-O-methyloxime (2c)
A
ACHTUNGTRENNUNG
Ketone 1c (1.874 g, 6.000 mmol, 1 equiv.) and H2NOMe·HCl
(1.002 g, 12.00 mmol, 2 equiv.) were heated under reflux for
64 h in ethanol (25 mL)/pyridine (25 mL). The solution was
poured into ice/water, the solid was filtered off and purified
by column chromatography (pentane/DCM=3:2). The title
compound was isolated as a white solid; yield: 645 mg
(1.89 mmol, 32%); mp 177–1788C. 1H NMR (600 MHz,
CDCl3): d=7.36 (s, 5H), 7.01 (d, J=7.9 Hz, 1H), 6.64 (s,
1H), 6.58–6.54 (m, 3H), 6.47–6.43 (m, 2H), 4.13 (s, 3H),
3.17–3.11 (m, 2H), 3.03–2.92 (m, 5H), 2.69–2.63 (m, 1H);
13C NMR (150 MHz, CDCl3): d=156.3, 139.7, 139.5, 139.3,
139.2, 136.7, 135.6, 134.7, 133.5, 133.2, 132.6 (2C), 132.4,
130.5, 129.3 (2C), 128.7, 127.7 (C-2), 62.4, 35.3, 35.3, 35.1,
35.0; MS (EI): m/z (%)=341 ([M]+, 100), 310 (34), 237 (23),
236 (21), 206 (77), 178 (11), 104 (19), 103 (11), 78 (14), 77
AHCTUNGTRENNUNG
22[41] were prepared as reported in the literature. All
[2.2]paracyclophane derivatives are used and prepared as
racemates. Toluene, THF, and diethyl ether were freshly dis-
tilled with sodium/benzophenone ketyl radical under nitro-
gen. DCM was freshly distilled over CaH2 and methanol
was distilled over molecular sieves 3 ꢂ. Reactions were
monitored by thin layer chromatography (TLC) using silica
gel 60 F254 plates and visualized with UV radiation at
254 nm. Column chromatography was performed using silica
1
gel (Acros, 60–200 mm, 60 ꢂ). H NMR and 13C NMR spec-
tra were recorded on a Varian Mercury 300, a Varian
VNMR 400 or a Varian VNMR 600 spectrometer in CDCl3,
C6D6 or DMSO-d6 using TMS as an internal standard. Mass
spectra were recorded on a Finnigan SSQ 7000 spectrometer
and HR-MS were recorded on a Finnigan MAT 95. IR spec-
tra were acquired on a Perkin-Elmer Spectrum FT-IR 100
spectrometer. Elemental analyses were performed on an El-
ementar Vario EL instrument. Melting points were mea-
sured with a Bꢃchi Melting Point B-540 apparatus.
˜
(26); IR (ATR): n=2925, 2893, 1493, 1442, 1147, 1107, 1046,
997, 871, 776, 698 cmÀ1
;
elemental analysis calcd. for
C24H23NO: C 84.42, H 6.79, N 4.10; found: C 84.09, H 6.76,
N 3.77.
13-Acetyl-O-methyloxime-4-bromoACTHNUTRGNEU[GN 2.2]para-
cyclophane (3)
General Procedure for the ortho-Acetoxylation
In a typical experiment the monosubstituted [2.2]paracyclo-
phane (200 mg), 1–5 mol% of Pd
ACHTUNGRTEN(NUNG OAc)2 and 1.1–1.5 equiv.
Oxime ether 2a (800 mg, 2.86 mmol, 1 equiv.) and NBS
(550 mg, 3.09 mmol, 1.1 equiv.) were heated at 1008C in
a sealed Schlenk tube in MeCN (20 mL) for 16 h. The title
compound was isolated after column chromatography (pen-
tane/ethyl acetate=97:3) as a white solid; yield: 929 mg
(2.59 mmol, 91%); mp 153–1558C. 1H NMR (400 MHz,
CDCl3): d=6.71 (d, J=1.8 Hz, 1H), 6.64–6.60 (m, 2H),
6.55–6.48 (m, 3H), 4.11–4.02 (m, 1H), 4.01 (s, 3H), 3.46
(ddd, J=13.5 Hz, 9.6 Hz and 2.3 Hz, 1H), 3.18–3.02 (m,
4H), 2.96–2.81 (m, 2H), 2.34 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=155.5, 141.0, 139.4, 137.9, 137.7, 136.2, 136.1,
136.0, 134.9, 133.4, 131.1, 129.5, 126.0, 61.8, 36.5, 35.0, 34.6,
of PhI(OAc)2 were dissolved in AcOH/Ac2O (0.1M with re-
ACHTUNGTRENNUNG
spect to [2.2]paracyclophane) and the solution was stirred at
1008C for the indicated time in a sealed Schlenk tube. The
reaction mixture was cooled to room temperature and dilut-
ed with ethyl acetate (20 mL), washed with water, saturated
NaHCO3 solution and brine and dried over MgSO4. The an-
alytically pure 4,5-disubstituted [2.2]paracyclophanes were
obtained by silica gel chromatography.
4-AcetylACHTUNGTRENNUNG[2.2]paracyclophane-O-methyloxime (2a)
Ketone 1a (6.000 g, 23.97 mmol, 1 equiv.), H2NOMe·HCl
(2.402 g, 28.76 mmol, 1.2 equiv.), pyridine (7.7 mL) and mo-
lecular sieves 4 ꢂ (1.0 g) were heated under reflux in metha-
nol (60 mL) overnight. The solution was cooled to room
temperature, filtered over Celite and concentrated under re-
duced pressure. The reaction mixture was diluted with DCM
32.4, 15.1; MS (EI): m/z (%)=184 ([M
AHCTUNGTRENNUNG
(81Br)]+, 5), 182 ([M-
ACHTUNGTRENNUNG
˜
IR (ATR): n=2931, 2896, 2855, 1585, 1471, 1434, 1392,
1370, 1066, 1040, 868, 843, 727, 710 cmÀ1; elemental analysis
calcd. for C19H20NOBr: C 63.70, H 5.63, N 3.91; found: C
63.65, H 5.98, N 3.79.
Adv. Synth. Catal. 2012, 354, 3237 – 3249
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3243

Petra Lennartz et al.
FULL PAPERS
(2.9 mL/2.9 mL) within 16 h. Purification by column chroma-
tography (pentane/ethyl acetate=9:1) provided 5c as
a white solid; yield: 207 mg (0.506 mmol, 88%); mp 141–
4-Acetoxy-5-acetyl-O-methyloximeACTHNUTRGNE[NUG 2.2]para-
cyclophane (5a)
1
Oxime ether 2a (200 mg, 0.716 mmol, 1 equiv.), Pd
ACHTUNGERTN(NUNG OAc)2
1438C. H NMR (400 MHz, CDCl3): d=7.31–7.28 (m, 2H),
(8.0 mg, 0.036 mmol, 0.05 equiv.) and PhI(OAc)2 (346 mg,
AHCTUNGTRENNUNG
7.25–7.22 (m, 3H), 7.15 (d, J=7.9 Hz, 1H), 6.72 (d, J=
7.9 Hz, 1H), 6.67 (dd, J=7.8 Hz and 1.4 Hz, 1H), 6.60 (dd,
J=7.8 Hz and 1.4 Hz, 1H), 6.57 (d, J=7.9 Hz, 1H), 6.49 (d,
J=7.9 Hz, 1H), 4.18 (s, 3H), 3.39–3.24 (m, 2H), 3.13–3.04
(m, 2H), 2.99–2.73 (m, 4H), 1.87 (s, 3H); 13C NMR
(100 MHz, DMSO-d6): d=167.4, 151.5, 146.9, 140.7, 139.2,
138.8, 135.3, 133.8, 132.6, 132.4, 132.2, 132.1, 130.8, 129.2,
129.0 (2C), 128.7, 128.0, 127.4 (2C), 62.1, 35.0, 33.7, 33.0,
29.7, 20.0; MS (EI): m/z (%)=399 ([M]+, 100), 358 (10), 357
(35), 326 (33), 310 (12), 295 (14), 253 (29), 252 (94), 223
(15), 222 (70), 221 (34), 220 (14), 194 (38), 193 (18), 165
1.074 mmol, 1.5 equiv.) were treated according to the gener-
al procedure for 16 h. The title compound was isolated after
column chromatography (pentane/ethyl acetate=17:1) as
a white solid; yield: 192 mg (0.569 mmol, 79%); mp 97–
1
988C. H NMR (400 MHz, CDCl3): d=6.89 (dd, J=7.9 Hz
and 1.8 Hz, 1H), 6.72 (dd, J=7.9 Hz and 1.8 Hz, 1H), 6.63
(dd, J=7.8 Hz and 1.8 Hz, 1H), 6.57 (dd, J=7.8 Hz and
1.8 Hz, 1H), 6.51 (d, J=7.9 Hz, 1H), 6.45 (d, J=7.9 Hz,
1H), 4.08 (s, 3H), 3.25–2.87 (m, 7H), 2.81–2.74 (m, 1H),
2.29 (s, 3H), 1.93 (s, 3H); 13C NMR (100 MHz, CDCl3): d=
168.9, 152.7, 146.4, 140.3, 139.4, 139.3, 135.2, 132.7, 132.4,
132.3, 131.7, 131.6, 130.1, 129.6, 61.9, 35.4, 34.3, 33.5, 30.5,
20.9, 16.8; MS (EI): m/z (%)=337 ([M]+, 89), 295 (27), 265
(10), 264 (12), 248 (17), 233 (16), 191 (40), 190 (100), 161
(18), 160 (84), 159 (26), 132 (14), 130 (15), 105 (17), 104
˜
(12), 104 (28), 78 (10), 77 (10); IR (ATR): n=2934, 1761,
1365, 1197, 1057, 1026, 1004, 876, 798, 692 cmÀ1; elemental
analysis calcd. for C26H25NO3: C 78.17, H 6.31, N 3.51;
found: C 77.99, H 6.23, N 3.18.
˜
(34), 103 (12), 78 (9); IR (ATR): n=2934, 1756, 1436, 1367,
4-AcetylACTHNUGRTNEUNG[2.2]paracyclophane-O-acetyloxime (6)
1200, 1146, 1111, 1037, 930, 883, 850, 794, 721 cmÀ1; elemen-
tal analysis calcd. for C21H23NO3: C 74.75, H 6.87, N 4.15;
found: C 74.40, H 6.97, N 4.03.
Oxime 15 (1.499 g, 5.649 mmol) was stirred for two hours at
room temperature in AcOH (25 mL)/Ac2O (25 mL). The
excess of Ac2O was quenched with water and the title com-
pound extracted with ethyl acetate (100 mL). The organic
layer was washed with saturated NaHCO3 solution and
brine, dried over MgSO4 and the solvent evaporated. The
protected oxime 6 was isolated as a white solid after column
chromatography (pentane/diethyl ether=2:1); yield: 1.625 g
(5.286 mmol, 94%); mp 95–968C. 1H NMR (400 MHz,
CDCl3): d=6.75 (d, J=8.0 Hz, 1H), 6.63 (d, J=1.7 Hz, 1H),
6.57–6.51 (m, 4H), 6.42 (d, J=7.9 Hz, 1H), 3.55 (ddd, J=
12.5 Hz, 9.4 Hz and 2.6 Hz, 1H), 3.18–2.94 (m, 7H), 2.34 (s,
3H), 2.29 (s, 3H); 13C NMR (100 MHz, CDCl3): d=169.2,
163.5, 139.8, 139.6, 139.2, 138.7, 135.9, 135.6, 134.2, 132.7,
132.4, 132.4, 131.9, 131.1, 35.3, 35.2, 35.1, 35.1, 20.0, 17.4;
MS (EI): m/z (%)=307 ([M]+, 9), 265 (29), 161 (33), 160
(30), 144 (100), 105 (17), 104 (29), 103 (13), 78 (10), 77 (11);
4-Acetoxy-5-formyl-O-methyloximeACTHNUTRGNE[NUG 2.2]para-
cyclophane (5b)
The title compound was obtained according to the general
procedure from aldoxime ether 2b (200 mg, 0.754 mmol,
ACHTUNGTRENNUNG(OAc)2 (8.5 mg, 0.038 mmol, 0.05 equiv.) and
PhI(OAc)2 (267 mg, 0.829 mmol, 1.1 equiv.) in AcOH/Ac2O
(3.8 mL/3.8 mL) in 16 h. After purification by column chro-
matography (pentane/ethyl acetate=17:1) 5b was isolated as
a pale yellow solid; yield: 166 mg (0.514 mmol, 68%); mp
159–1608C. 1H NMR (600 MHz, CDCl3): d=7.94 (s, 1H),
6.80 (dd, J=7.8 Hz and 1.7 Hz, 1H), 6.59–6.52 (m, 4H), 6.49
(dd, J=7.7 Hz and 1.6 Hz, 1H), 4.01 (s, 3H), 3.79 (ddd, J=
13.2 Hz, 10.1 Hz and 1.5 Hz, 1H), 3.18–3.14 (m, 1H), 3.07–
2.99 (m, 4H), 2.86–2.81 (m, 1H), 2.76–2.71 (m, 1H), 2.34 (s,
1 equiv.), Pd
ACHTUNGTRENNUNG
˜
IR (ATR): n=2929, 1765, 1615, 1367, 1301, 1206, 1000, 932,
1
891, 854, 795, 719 cmÀ1
;
elemental analysis calcd. for
3H); H NMR (400 MHz, C6D6): d=8.16 (s, 1H), 6.81 (dd,
J=7.8 Hz and 1.9 Hz, 1H), 6.62 (dd, J=7.8 Hz and 1.9 Hz,
1H), 6.34 (dd, J=7.8 Hz and 1.8 Hz, 1H), 6.25 (dd, J=
7.9 Hz and 1.8 Hz, 1H), 6.24 (d, J=8.0 Hz, 1H), 6.21 (d, J=
8.0 Hz, 1H), 3.81 (s, 3H), 3.80–3.75 (m, 1H), 2.92–2.68 (m,
5H), 2.56–2.48 (m, 1H), 2.43–2.36 (m, 1H), 1.80 (s, 3H);
13C NMR (150 MHz, CDCl3): d=168.7, 147.4, 144.8, 141.5,
139.1, 139.1, 135.3, 133.4, 132.8, 132.7, 132.2, 130.3, 129.0,
125.3, 62.0, 34.2, 34.0, 33.9, 30.7, 20.9; MS (EI): m/z (%)=
323 ([M]+, 36), 281 (30), 250 (10), 234 (34), 219 (9), 177
(32), 176 (88), 146 (100), 118 (23), 117 (13), 91 (15), 78 (14);
C20H21NO2: C 78.15, H 6.89, N 4.56; found C 78.19, H 6.95,
N 4.53.
1-([2.2]Paracyclophane-4-yl)-1H-pyrazole (10)
In modification of a literature procedure:[28] Pd
(23 mg, 0.025 mmol, 0.025 equiv.), tBuX-Phos (42 mg,
0.10 mmol, 0.1 equiv.), bromide (287 mg, 1.00 mmol,
2ACHTUNGTRENNUNG(dba)3
8
1.0 equiv.), pyrazole (9, 89 mg, 1.30 mmol, 1.3 equiv.) and
NaO-t-Bu (ground before use, 144 mg, 1.50 mmol,
1.5 equiv.) were placed in a dry Schlenk tube. The tube was
evacuated and filled with argon three times and dry toluene
(2 mL) was added. The solution was heated to 808C for
6.5 h, filtered over Celite and evaporated under reduced
pressure. The title compound was isolated as a white solid
after column chromatography (pentane/ethyl acetate=
19:1); yield: 229 mg (0.825 mmol, 84%); mp 125–1268C.
1H NMR (400 MHz, CDCl3): d=7.80 (d, J=1.8 Hz, 1H),
7.72 (d, J=2.4 Hz, 1H), 6.69–6.55 (m, 7H), 6.49 (t, J=
2.1 Hz, 1H), 3.50 (ddd, J=12.2 Hz, 9.5 Hz and 2.1 Hz, 1H),
3.21–2.84 (m, 6H), 2.63–2.56 (m, 1H); 13C NMR (100 MHz,
CDCl3): d=141.3, 140.8, 139.8, 139.5, 139.1, 136.6, 132.9,
˜
IR (ATR): n=2933, 1744, 1466, 1426, 1360, 1224, 1188,
1053, 1012, 902, 872, 794, 720, 658 cmÀ1; elemental analysis
calcd. for C20H21NO3: C 74.28, H 6.55, N 4.33; found: C
74.32, H 6.63, N 4.19.
4-Acetoxy-5-benzoyl-O-methyloximeACHTUNGTRNE[NUNG 2.2]para-
cyclophane (5c)
The title compound was obtained according to the general
procedure from oxime ether 2c (200 mg, 0.586 mmol,
1 equiv.), PdACHTUNGTRENNUNG
PhIACHTUNGTRENNUNG
3244
asc.wiley-vch.de
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 3237 – 3249

À
Palladium-Catalyzed C H Bond Acetoxylation: An Approach
132.6, 132.5, 132.3, 132.2, 130.5, 129.7, 126.8, 106.7, 35.3,
35.0, 34.7, 33.6; MS (EI): m/z (%)=274 ([M]+, 63), 170
(100), 169 (56), 143 (6), 142 (5), 115 (5), 104 (9); IR (KBr):
4-Acetoxy-5-(pyridine-2’-yl)ACTHNUGTRNEUNG[2.2]paracyclophane (13)
The title compound was prepared from pyridine derivative 7
(200 mg, 0.701 mmol, 1.0 equiv.), Pd(OAc)2 (7.9 mg,
0.035 mmol, 0.05 equiv.) and PhI(OAc)2 (248 mg,
AHCTUNGTRENNUNG
˜
n=3060, 2932, 2849, 1594, 1560, 1501, 1427, 1391, 1326,
AHCTUNGTRENNUNG
1214, 1124, 1091, 1040, 944, 890, 835, 716 cmÀ1; HR-MS
(ESI): m/z=275.1542, calcd. for C19H19N2 [M+ +H]:
275.1543.
0.771 mmol, 1.1 equiv.) in AcOH/Ac2O (3.5 mL/3.5 mL) in
16 h and isolated as a white solid after column chromatogra-
phy
(pentane/ethyl
acetate=3:1);
yield:
147 mg
(0.428 mmol, 61%); mp 99–1018C. 1H NMR (600 MHz,
CDCl3): d=8.78 (s, 1H), 7.72 (t, J=7.7 Hz, 1H), 7.39–7.37
(m, 1H), 7.24–7.22 (m, 1H), 6.94–6.93 (m, 1H), 6.88–6.86
(m, 1H), 6.67–6.64 (m, 2H), 6.59 À6.56 (m, 2H), 3.17–3.03
(m, 4H), 2.94–2.88 (m, 3H), 2.85–2.80 (m, 1H), 2.06 (s,
3H); 13C NMR (150 MHz, CDCl3): d=168.8, 155.8, 149.4,
146.2, 141.2, 139.7, 139.4, 135.4, 135.3, 133.0, 132.9, 132.9,
132.5, 131.6, 131.2, 129.6, 125.6, 121.6, 35.0, 34.4, 33.4, 30.7,
20.7; MS (EI): m/z (%)=344 (37), 343 ([M]+, 100), 301 (14),
239 (24), 238 (13), 197 (85), 196 (100), 168 (33), 167 (22),
4-Acetoxy-5-acetyl-O-methyloxime-12-bromoACTHNUGTRNEUNG[2.2]-
paracyclophane (11)
The title compound was prepared according to the general
procedure from oxime ether (200 mg, 0.558 mmol,
1 equiv.), Pd(OAc)2 (6.3 mg, 0.028 mmol, 0.05 equiv.) and
PhI(OAc)2 (198 mg, 0.614 mmol, 1.1 equiv.) in AcOH/Ac2O
3
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
(2.8 mL/2.8 mL) for 15 h. Purification by column chromatog-
raphy (pentane/ethyl acetate=17:1) provided the title com-
pound as a white solid; yield: 0.202 g (0.485 mmol, 87%);
mp 1278C. 1H NMR (600 MHz, CDCl3): d=6.81 (d, J=
1.7 Hz, 1H), 6.69 (d, J=8.0 Hz, 1H), 6.65 (dd, J=7.8 Hz
and 1.3 Hz, 1H), 6.59 (d, J=8.0 Hz, 1H), 6.55 (dd, J=
7.8 Hz and 0.8 Hz, 1H), 3.97 (s, 3H), 3.53–3.43 (m, 2H),
3.18–3.04 (m, 3H), 2.92–2.67 (m,3H), 2.28 (s, 3H), 2.27 (s,
3H); 13C NMR (150 MHz, CDCl3): d=168.4, 153.3, 146.4,
141.2, 140.9, 139.0, 135.6, 135.3, 133.5, 132.9, 131.1, 130.4,
129.7, 124.9, 61.9, 36.7, 33.5, 31.6, 31.6, 21.0, 18.1; MS (EI):
˜
154 (8), 104 (6), 78 (6). IR (ATR): n=2929, 1750, 1586,
1473, 1412, 1362, 1191, 1087, 1014, 901, 792, 755, 717,
659 cmÀ1; elemental analysis calcd. for C23H21NO2: C 80.44,
H 6.16, N 4.08; found: C 80.40, H 6.37, N 3.97.
4-Hydroxy-5-(pyridine-2’-yl)ACTHUNTGRNEUNG[2.2]paracyclophane (13
with OH instead of OAc)
m/z (%)=417 ([MACTHNUTRGNENGU ACHTUGNTRENNUGN
(81Br)]+, 18), 415 ([M(79Br)]+, 19), 375
Acetyl-protected
[2.2]paracyclophane
13
(112 mg,
0.326 mmol) and K2CO3 (6.8 mg, 0.050 mmol) in methanol
(1 mL) were stirred overnight at room temperature. The
product was isolated as a yellow solid after column chroma-
tography (pentane/ethyl acetate=9:1); yield: 84 mg
(0.28 mmol (86%); mp 93–958C. 1H NMR (400 MHz,
CDCl3): d=13.18 (s, 1H), 8.64–8.62 (m, 1H, 1H), 7.78–7.73
(m, 1H), 7.52 (dt, J=8.3 Hz and 1.0 Hz, 1H), 7.24–7.21 (m,
1H), 7.16 (dd, J=8.0 Hz and 2.0 Hz, 1H), 6.62 (dd, J=
7.6 Hz and 2.0 Hz, 1H), 6.54 (dd, J=8.0 Hz and 2.0 Hz,
1H), 6.46 (d, J=7.6 Hz, 1H), 6.36 (d, J=7.6 Hz, 1H), 6.26
(dd, J=7.6 Hz and 2.0 Hz, 1H), 3.66–3.59 (m, 1H), 3.49
(ddd, J=12.9 Hz, 10.3 Hz and 2.7 Hz, 1H), 3.28–3.21 (m,
1H), 3.11–3.05 (m, 1H), 2.96–2.88 (m, 2H), 2.62–2.45 (m,
2H); 13C NMR (150 MHz, CDCl3): d=157.9, 157.1, 146.4,
140.1, 139.1, 138.1, 137.0, 135.9, 132.6, 132.1, 130.4, 128.6,
127.7, 127.0, 126.4, 122.2, 120.9, 35.5, 34.8, 34.0, 30.6; MS
(EI): m/z (%)=301 ([M]+, 40), 198 (14), 197 (100), 196 (34),
(14), 373 (13), 336 (8), 233 (16), 191 (44), 190 (100), 184 (7),
182 (7), 160 (96), 132 (17), 130 (19), 103 (13), 77 (11); IR
˜
(ATR): n=2958, 1753, 1368, 1199, 1107, 1050, 1027, 929,
888, 845, 799, 707, 669 cmÀ1; elemental analysis calcd. for
C21H22BrNO3: C 60.59, H 5.33, N 3.36; found: C 60.61, H
5.23, N 3.25.
4-Acetoxy-5-acetyl-O-acetyloximeACTHNUTRGNE[NUG 2.2]para-
cyclophane (12)
The title compound was prepared according to the general
procedure from acetyl-protected oxime (200 mg,
0.651 mmol, 1.0 equiv.), Pd(OAc)2 (7.3 mg, 0.033 mmol,
0.05 equiv.) and PhI(OAc)2 (231 mg, 0.717 mmol, 1.1 equiv.)
6
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
in AcOH/Ac2O (3.3 mL/3.3 mL) for 3 h. After column chro-
matography (pentane/ethyl acetat=17:1) a yellow oil was
obtained; yield: 146 mg (0.400 mmol, 61%). 1H NMR
(600 MHz, CDCl3): d=6.97 (dd, J=7.9 Hz and 2.0 Hz, 1H),
6.73 (dd, J=7.9 Hz and 1.5 Hz, 1H), 6.63 (dd, J=7.9 Hz and
2.0 Hz, 1H), 6.58–6.56 (m, 2H), 6.49 (d, J=7.9 Hz, 1H),
3.28–3.23 (m, 1H), 3.19–3.15 (m, 1H), 3.13–3.08 (m, 1H),
3.04–2.91 (m, 4H), 2.82–2.77 (m, 1H), 2.32 (s, 3H), 2.31 (s,
3H), 2.03 (s, 3H); 13C NMR (150 MHz, CDCl3): d=168.9,
168.7, 161.4, 146.2, 140.3, 139.5, 139.1, 136.2, 132.7, 132.6,
132.2, 132.0, 132.0, 129.6, 128.7, 35.2, 34.3, 33.6, 30.5, 20.9,
20.0, 18.5; MS (EI): m/z (%)=365 ([M]+, 24), 323 (19), 282
(15), 281 (74), 264 (57), 263 (100), 248 (24), 219 (11), 218
(12), 202 (12), 177 (21), 176 (47), 160 (68), 159 (92), 130
˜
168 (31), 167 (16), 154 (12), 104 (3), 78 (5); IR (ATR): n=
2977, 2926, 2850, 1590, 1562, 1496, 1461, 1415, 1372, 1268,
1228, 1154, 1105, 1047, 996, 936, 787, 745, 711, 691,
658 cmÀ1; elemental analysis calcd. for C21H19NO: C 83.69,
H 6.35, N 4.65; found: C 83.64, H 6.37, N 4.56.
5-Acetoxy-4-(1H-pyrazole-1-yl)ACTHNUTRGNEUNG[2.2]paracyclophane
(14)
The title compound 14 was prepared according to the gener-
al procedure from pyrazole 12 (200 mg, 0.730 mmol,
˜
1 equiv.), Pd
AHCTUNGTRENNUNG
ACHTUNGRTEN(NUNG OAc)2 (8.2 mg, 0.037 mmol, 0.05) and PhI-
(14), 104 (32); IR (capillary): n=3017, 2934, 2856, 1763,
1426, 1368, 1301, 1198, 1028, 1000, 930, 882, 756, 664 cmÀ1
;
HR-MS (EI): m/z=365.1614, calcd. for C22H23NO4 [M+]:
(3.7 mL/3.7 mL) for 16 h and isolated as a pale yellow solid
after column chromatography (pentane/ethyl acetate=4:1);
yield: 129 mg (0.388 mmol, 53%); mp 138–1408C. H NMR
365.1622.
1
(400 MHz, CDCl3): d=7.77 (dd, J=1.8 Hz and 0.5 Hz, 1H),
7.65 (dd, J=2.4 Hz and 0.6 Hz, 1H), 6.92–6.88 (m, 2H), 6.66
(m, 2H), 6.61 (d, J=8.0 Hz, 1H), 6.57 (d, J=8.0 Hz, 1H),
Adv. Synth. Catal. 2012, 354, 3237 – 3249
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Petra Lennartz et al.
FULL PAPERS
6.44 (t, J=2.2 Hz, 1H), 3.17–3.08 (m, 3H), 3.94–2.75 (m,
5H), 2.11 (s, 3H); H NMR (300 MHz, C6D6): d=7.71 (d,
132.9, 132.7, 132.5, 131.4, 130.5, 124.4, 49.3, 35.3, 35.2, 34.9,
34.1, 32.2, 19.4; MS (EI): m/z (%)=291 ([M]+, 74), 187
(100), 158 (12), 144 (12), 117 (10), 104 (19), 103 (11), 78
1
J=1.8 Hz, 1H), 7.30–7.26 (m, 2H), 7.00 (d, J=8.1 Hz, 1H),
6.41 (s, 2H), 6.24 (d, J=8.0 Hz, 1H), 6.19 (d, J=8.0 Hz,
1H), 6.14 (t, J=2.0 Hz, 1H), 2.99–2.89 (m, 3H), 2.79–2.70
(m, 2H), 2.64–2.41 (m, 3H), 1.67 (s, 3H); 13C NMR
(100 MHz, CDCl3): d=167.8, 142.9, 140.5, 139.4, 139.5,
138.1, 135.0, 133.1, 133.0, 132.9, 132.5, 132.4, 131.3, 130.9,
129.6, 106.0, 34.7, 34.3, 32.0, 30.5, 20.5; MS (EI): m/z (%)=
332 (100, [M]+), 290 (19), 228 (24), 186 (72), 185 (60), 157
˜
(11), 77 (11); IR (ATR): n=2929, 1694, 1592, 1491, 1420,
1377, 1298, 1231, 1165, 1021, 944, 893, 817, 716, 659 cmÀ1; el-
emental analysis calcd. for C20H21NO: C 82.44, H 7.26, N
4.81; found: C 82.42, H 7.36, N 4.71.
N-(2’,4’,6’-Trimethylphenyl)-[2.2]paracyclophane-4-
carbaldimine (19)
˜
(18), 104 (17), 78 (9), 77 (8); IR (KBr): n=2929, 1756, 1508,
1447, 1369, 1195, 1147, 1068, 1043, 1020, 943, 890, 756 cmÀ1
;
HR-MS (ESI): m/z=333.1598, calcd. for C21H21N2O2 [M+ +
Aldehyde 1b (1.182 g, 5.000 mmol, 1.0 equiv.), 2,4,5-trime-
thylaniline (2.03 g, 15.0 mmol, 5 equiv.), Et2SnCl2 (258 mg,
1.00 mmol, 0.2 equiv.) and molecular sieves 4 ꢂ were heated
to reflux in toluene (15 mL) over night. The solution was fil-
tered and concentrated under reduced pressure. The ob-
tained solid was purified by column chromatography (pen-
tane/ethyl acetate=9:1) and recrystallized from ethyl ace-
tate/pentane providing imine 19 as a yellow solid; yield:
H]: 333.1598.
N-Acetyl-4-amino-[2.2]paracyclophane (16)
In modification of literature procedure for Beckmann rear-
rangement:[29] 4-acetyl
ACTHNUTRGNE[NUG 2.2]paracyclophane oxime (15)
(663 mg, 2.50 mmol, 1.0 equiv.) was treated with para-tolue-
nesulfonic acid (43 mg, 0.25 mmol, 0.1 equiv.) and ZnCl2
(41 mg, 0.30 mmol, 0.12 equiv.) in MeCN (12.5 mL) for 5 h
under reflux. Purification by column chromatography
(DCM/ethyl acetate=9:1) afforded amide 16 as a white
solid; yield: 543 mg (2.05 mmol, 80%); mp 206–2078C.
1H NMR (600 MHz, DMSO-d6): d=9.21 (s, 1H), 6.74 (d,
J=7.6 Hz, 1H), 6.51–6.49 (m, 2H), 6.44–6.39 (m, 3H), 6.35
(d, J=7.7 Hz, 1H), 3.33–3.29 (m, 1H), 3.01–2.95 (m, 4H),
2.91–2.84 (m, 2H), 2.66–2.61 (m, 1H), 2.12 (s, 3H);
13C NMR (150 MHz, DMSO-d6): d=167.3, 139.7, 139.1,
138.5, 136.9, 134.9, 132.8, 132.7, 132.2, 132.2, 128.7, 128.6,
126.9, 34.8, 34.5, 33.3, 33.3, 23.6; MS (EI): m/z (%)=265
([M]+, 100), 223 (3), 161 (93), 160 (14), 119 (70), 118 (11),
105 (32), 104 (30), 92 (13), 91 (27), 78 (20), 77 (13), 65 (13);
1
1.512 g (4.278 mmol, 86%); mp 1578C. H NMR (300 MHz,
CDCl3): d=8.28 (s, 1H), 7.30 (d, J=1.7 Hz, 1H), 6.95 (s,
2H), 6.67–6.51 (m, 6H), 3.82–2.72 (m, 1H), 3.28–2.91 (m,
7H), 2.33 (s, 3H), 2.24 (s, 6H); 13C NMR (75 MHz, CDCl3):
d=161.4, 149.3, 141.2, 140.5, 139.6, 139.2, 135.8 (2C), 135.4,
133.2, 132.9, 132.8, 132.3, 132.2, 131.8, 128.8 (2C), 127.2
(2C), 35.5, 35.4, 35.1, 33.2, 20.7, 18.6 (2CH3); MS (EI): m/z
(%)=353 ([M]+, 100), 249 (100), 249 (67), 134 (12), 104
˜
(13); IR (KBr): n=2921, 2853, 1616, 1480, 1435, 1375, 1279,
1200, 1140, 850, 800, 722 cmÀ1; elemental analysis calcd. for
C26H27N: C 88.34, H 7.70, N 3.96; found: C 88.45, H 7.80, N
3.82.
˜
IR (ATR): n=3266, 2927, 1653, 1596, 1533, 1488, 1365,
N-(Quinoline-8’-yl)-4-[2.2]paracyclophane-
carboxamide (23)
1294, 984, 896, 871, 793, 715 cmÀ1; elemental analysis calcd.
for C18H19NO: C 81.47, H 7.22, N 5.28; found: C 81.58, H
7.33, N 5.19.
4-CarboxyACTHNUTRGNEUG[N 2.2]paracyclophane (22) (1.267 g, 5.022 mmol,
1.0 equiv.) and SOCl2 (12 mL) were stirred at 608C for 3 h.
The excess of thionyl chloride was removed by azeotropic
distillation with toluene. The resulting acid chloride was dis-
solved in DCM (10 mL) and added to a solution of 8-amino-
quinoline (0.797 g, 6.98 mmol, 1.4 equiv.) and NEt3
(0.77 mL, 0.562 mg, 5.6 mmol, 1.1 equiv.) in DCM (10 mL)
and the solution stirred at room temperature for 3 h. After
treatment with water and extraction with DCM, the com-
bined organic organic phases were dried over MgSO4 and
purified by column chromatography (DCM) affording
amide 23 as a white solid; yield: 1.317 g (3.48 mmol, 69%);
N-[2.2]Paracylophane-4-yl-pyrrolidinone (18)
4-Chlorobutanoic acid chloride was slowly added to a sus-
pension of amine 17 (1.210 g, 5.418 mmol) and Na2HPO4
(1.538 g, 10.84 mmol) in CHCl3 (30 mL). The solution was
stirred overnight at room temperature, filtered over Celite
and the solvent was removed under reduced pressure. This
solid was added in small portions to a sodium ethanolate so-
lution (sodium 1.2 g, 52.4 mmol in 35 mL of ethanol), the so-
lution was stirred over night and acidified with concentrated
HCl. Then, ethanol was removed under vacuum. The ob-
tained solid was dissolved in DCM (80 mL), washed with
water (80 mL) and the aqueous layer extracted twice with
DCM. The combined organic phases were dried over
MgSO4, filtered and concentrated. Column chromatography
(DCM/ethyl acetate=9:1) provided pyrrolidinone 18 as
a white solid; yield: 1.336 g (4.585 mmol, 85%); mp 1528C.
1H NMR (400 MHz, CDCl3): d=6.62 (d, J=7.9 Hz, 1H),
6.58 (d, J=7.9 Hz, 1H), 6.53 (d, J=7.8 Hz, 1H), 6.47 (s,
2H), 6.39 (dd, J=7.8 Hz and 1.8 Hz, 1H), 6.29 (d, J=
1.8 Hz, 1H), 3.99–3.93 (m, 1H), 3.89–3.84 (m, 1H), 3.22–
3.16 (m, 1H), 3.10–3.06 (m, 3H), 3.02–2.92 (m, 4H), 2.62–
2.50 (m, 2H), 2.26–2.20 (m, 2H); 13C NMR (100 MHz,
CDCl3): d=173.0, 139.8, 139.8, 139.1, 136.5, 136.0, 134.4,
1
mp 2028C. H NMR (600 MHz, CDCl3): d=10.17 (br, 1H),
8.97 (dd, J=7.6 Hz and 1.3 Hz, 1H), 8.81–8.80 (m, 1H), 8.19
(dd, J=8.3 Hz and 1.7 Hz, 1H), 7.63 (t, J=8.0 Hz, 1H), 7.56
(dd, J=8.3 Hz and 1.3 Hz, 1H), 7.47–7.45 (m, 1H), 6.99 (d,
J=2.0 Hz, 1H), 6.90 (d, J=7.6 Hz, 1H), 6.69 (dd, J=7.6 Hz
and 1.7 Hz, 1H), 6.63–6.60 (m, 4H), 3.93–3.89 (m, 1H),
3.27–3.19 (m, 3H), 3.15–3.06 (m, 3H), 3.03–2.98 (m, 1H);
13C NMR (100 MHz, CDCl3): d=167.2, 148.2, 140.3, 139.9,
139.7, 139.3, 138.7, 136.3, 136.3, 136.0, 135.3, 135.0, 132.8,
132.7, 132.4, 131.8, 131.6, 128.0, 127.4, 121.6, 121.5, 116.2,
35.4, 35.3, 35.2, 35.0; MS (EI): m/z (%)=378 ([M]+, 86), 274
(100), 234 (14), 131 (21), 105 (22), 104 (28), 77 (19); IR
˜
(ATR): n=3335, 3031, 2971, 2923, 2849, 2200, 1675, 1585,
1520, 1479, 1421, 1384, 1304, 1259, 1198, 1094, 905, 827, 796,
3246
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 3237 – 3249

À
Palladium-Catalyzed C H Bond Acetoxylation: An Approach
752 cmÀ1; elemental analysis calcd. for C26H22N2O: C 82.51,
H 5.86, N 7.40; found: C 82.24, H 5.87, N 7.29.
16 h. After cooling to room temperature the resulting solu-
tion was diluted with ethyl acetate (30 mL), washed with sa-
turated NaHCO3 solution (80 mL) and brine (20 mL), dried
over MgSO4 and the solvent removed under reduced pres-
sure. After column chromatography (pentane/ethyl ace-
tate=4:1) benzoxazole 27 was isolated as an off-white solid;
N-(2’-Benzoylphenyl)-4-[2.2]paracyclophane-
carboxamide (24)
1
The acid chloride was prepared as described for compound
23 from 4-carboxyACTHNUTRGNE[NUG 2.2]paracyclophane (22) (1.281 g,
yield: 221 mg (0.839 mmol, 94%); mp 158–1608C. H NMR
(600 MHz, CDCl3): d=6.57 (d, J=7.8 Hz, 1H), 6.55 (d, J=
7.8 Hz, 1H), 6.46 (dd, J=7.7 Hz and 1.5 Hz, 1H), 6.42 (dd,
J=7.7 Hz and 1.4 Hz, 1H), 6.19 (dd, J=7.8 Hz and 1.5 Hz,
1H), 6.11 (dd, J=7.8 Hz and 1.6 Hz, 1H), 3.62–3.58 (m,
1H), 3.42–3.38 (m, 1H), 3.00–2.95 (m, 4H), 2.88–2.81 (m,
2H), 2.70 (s, 3H); 13C NMR (150 MHz, CDCl3): d=161.7,
151.1, 143.1, 138.5, 138.0, 132.5, 132.2, 131.9, 129.9, 129.3,
126.6, 124.8, 122.9, 34.4, 33.9, 30.6, 29.7, 14.6; MS (EI): m/z
(%)=263 ([M]+, 38), 160 (11), 159 (100), 130 (16), 104 (24),
5.656 mmol, 1.0 equiv.). Pyridine (0.55 mL, 6.79 mmol,
1.2 equiv.) was slowly added to a solution of the acid chlo-
ride and 2-aminobenzophenone (1.339 g, 6.788 mmol,
1.2 equiv.) in DCM (55 mL) at 08C and the solution stirred
at room temperature for 5 h. After treatment with water
and extration with DCM the combined organic phases were
dried over MgSO4 and the solvent evaporated. The resulting
solid was washed several times with hot diethyl ether afford-
ing amide 24 as
a pale yellow solid; yield: 1.410 g
˜
89 (9), 78 (6); IR (KBr): n=2924, 2847, 1601, 1568, 1497,
1
(3.267 mmol, 58%); mp 1768C. H NMR (600 MHz, CDCl3):
d=11.14 (br, 1H), 8.90 (d, J=8.4 Hz, 1H), 7.73 (d, J=
8.4 Hz, 2H), 7.67 (t, J=7.9 Hz, 1H), 7.62–7.58 (m, 2H), 7.49
(t, J=7.7 Hz, 2H), 7.13 (t, J=7.4 Hz, 1H), 6.93 (s, 1H), 6.76
(d, J=7.4 Hz, 1H), 6.64 (d, J=7.4 Hz, 1H), 6.60–6.56 (m,
4H), 3.90 (t, J=10.9 Hz, 1H), 3.26–2.94 (m, 7H); 13C NMR
(150 MHz, CDCl3): d=199.6, 167.7, 141.0, 140.4, 140.2,
139.9, 139.3, 138.7, 136.5, 135.6, 135.5, 134.3, 133.8, 132.7,
132.6, 132.6, 132.4, 131.6, 131.6, 129.9 (2C), 128.3 (2C),
123.5, 122.0, 121.3, 35.5, 35.3, 35.3, 35.1; MS (EI): m/z (%)=
432 ([M]+, 19), 327 (8), 234 (10), 131 (21), 105 (100), 104
1434, 1388, 1324, 1264, 1193, 1147, 1049, 925, 874, 797, 757,
718, 681 cmÀ1; elemental analysis calcd. for C18H17NO: C
82.10, H 6.51, N 5.32; found C 81.92, H 6.33, N 5.16.
1-1-Diphenyl-2{[2]paracyclo[2]ACTHNUTRGNEUNG(4’,7’)benzoxazolo-
phane-2’-yl-}ethanol (28)
Benzoxazole 27 (120 mg, 0.456 mmol, 1.0 equiv.) was dis-
solved under an argon atmosphere in THF (10 mL), treated
with n-BuLi (1.6M in hexane, 0.34 mL, 0.547 mmol,
1.2 equiv.) at À788C and the orange solution stirred at
À788C for 2 h. Benzophenone (104 mg, 0.570 mmol,
1.25 equiv.) was added in one portion and the solution
slowly warmed to room temperature. After treatment with
NH4Cl solution and extraction with DCM, the combined or-
ganic phases were dried over MgSO4 and the solvent evapo-
rated. The title compound 28 was isolated after column
chromatography (pentane/ethyl acetate=9:1) as a white
˜
(39), 103 (35), 78 (11), 77 (35); IR (ATR): n=3324, 2927,
1670, 1626, 1577, 1509, 1439, 1293, 1262, 1159, 1067, 941,
807, 773, 750, 697 cmÀ1
; elemental analysis calcd. for
C30H25NO2: C 83.50, H 5.84, N 3.25; found C 83.12, H 5.43,
N 3.04.
5-Acetyl-O-methyloxime-4-hydroxyACHTUNGTREN[NGNU 2.2]paracyclo-
1
phane (25)
solid; yield: 133 mg (0.299 mmol, 66%); mp 708C. H NMR
(400 MHz, CDCl3): d=7.82–7.79 (m, 2H), 7.61–7.58 (m,
2H), 7.42–7.39 (m, 2H), 7.35–7.31 (m, 2H), 7.25–7.21 (m,
2H), 6.52 (s, 2H), 6.40–6.36 (m, 3H), 5.72 (d, J=8.0 Hz,
1H), 5.07 (d, J=8.0 Hz, 1H), 4.12 (d, J=16.6 Hz, 1H), 3.81
(d, J=16.6 Hz, 1H), 3.54–3.49 (m, 1H), 3.41–3.34 (m, 1H),
2.95–2.70 (m, 6H); 13C NMR (100 MHz, CDCl3): d=162.3,
150.0, 146.3, 146.1, 141.9, 138.5, 137.9, 132.3, 132.3, 131.9,
130.4, 129.7, 128.5 (2C), 128.3 (2C), 127.4, 127.2, 127.1,
125.8 (2C), 125.6 (2C), 125.3, 123.0, 39.8, 34.4, 34.0, 30.5,
29.6 (one Cq was not resolved); MS (EI): m/z (%)=445
([M]+, 1), 427 (2), 323 (4), 263 (23), 183 (24), 159 (100), 130
Treatment of ortho-substituted oxime ether 5a (200 mg,
0.593 mmol, 1.0 equiv.) with K2CO3 (12 mg, 0.089 mmol,
0.15 equiv.) in methanol (1.2 mL) at room temperature over-
night afforded the free hydroxyACTHNUGRTNEUNG[2.2]paracylophane 25 after
column chromatography (pentane/ethyl acetate=9:1) as
a colorless solid; yield: 160 mg (0.542 mmol, 91%); mp 94–
1
958C. H NMR (400 MHz, CDCl3): d=10.30 (br, 1H), 6.96
(dd, J=8.0 Hz and 2.0 Hz, 1H), 6.60–6.57 (m, 2H), 6.49 (dd,
J=8.0 Hz and 1.6 Hz, 1H), 6.41 (d, J=8.0 Hz, 1H), 6.28 (d,
J=7.7 Hz, 1H), 4.08 (s, 3H), 3.39 (ddd, J=12.6 Hz, 10.0 Hz
and 2.7 Hz, 1H), 3.20–3.11 (m, 2H), 3.07–2.98 (m, 2H),
2.93–2.86 (m, 1H), 2.81–2.74 (m, 1H), 2.59–2.52 (m, 1H),
2.17 (s, 3H); 13C NMR (100 MHz, CDCl3): d=158.0, 154.4,
140.8, 140.0, 137.9, 135.6, 132.5, 132.3, 129.5, 127.9, 127.4,
126.9, 122.2, 62.4, 35.7, 35.0, 33.9, 30.7, 18.2; MS (EI): m/z
(%)=295 ([M]+, 31), 264 (2), 248 (12), 191 (33), 190 (33),
160 (100), 132 (32), 117 (25), 115 (13), 105 (18), 104 (32),
˜
(27), 105 (99), 104 (37), 77 (51); IR (ATR): n=3382, 2929,
1594, 1562, 1494, 1447, 1397, 1262, 1181, 1053, 1016, 876,
752, 697 cmÀ1; elemental analysis calcd. for C31H27NO2: C
83.57, H 6.11, N 3.14; found: C 83.24, H 5.81, N 3.01.
5-Acetyl-O-methyloxime-4-methoxy-[2.2]para-
cyclophane (31)
˜
103 (19), 91 (13), 78 (15), 77 (12); IR (ATR): n=3013, 2960,
2926, 2850, 1599, 1411, 1291, 1232, 1051, 1017, 922, 792, 756,
714 cmÀ1; elemental analysis calcd. for C19H21NO2: C 77.26,
H 7.17, N 4.74; found: C 77.09, H 7.05, N 4.62.
In a dry sealable tube oxime ether 2a (200 mg, 0.716 mmol,
1.0 equiv.) was treated with PdACHTUNRGTNEUNG(OAc)2 (16 mg, 0.072 mmol,
0.1 equiv.), K2S2O8 (387 mg, 1.43 mmol, 2 equiv.) and molec-
ular sieves 3 ꢂ (250 mg) in dry methanol (7.2 mL) at 1008C
for 24 h. Then, the solution was filtered over Celite, concen-
trated under reduced pressure, and compound 31 was isolat-
ed as a white solid after column chromatography (pentane/
[2]Paracyclo[2]2-methyl-(4,7)benzoxazolophane (27)
Oxime ether 5a (300 mg, 0.889 mmol) was treated with HCl
(5 mL) in diethyl ether (5 mL) in a sealable tube at 608C for
Adv. Synth. Catal. 2012, 354, 3237 – 3249
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3247

Petra Lennartz et al.
FULL PAPERS
ethyl acetate=97:3); yield: 39 mg (0.13 mmol, 18%); mp References
85–878C. 1H NMR (600 MHz, CDCl3): d =6.75 (dd, J=
À
7.9 Hz and 1.5 Hz, 1H), 6.69 (dd, J=7.9 Hz and 1.5 Hz,
1H), 6.65 (dd, J=7.9 Hz and 1.9 Hz, 1H), 6.60 (dd, J=
7.9 Hz and 1.6 Hz, 1H), 6.44 (d, J=7.9 Hz, 1H), 6.33 (d, J=
7.9 Hz, 1H), 4.04 (s, 3H), 3.66 (s, 3H), 3.29–3.24 (m, 2H),
3.18–3.13 (m, 1H), 3.11–3.06 (m, 1H), 3.01–2.96 (m, 2H),
2.90–2.85 (m, 1H), 2.82–2.77 (m, 1H), 2.15 (s, 3H);
13C NMR (150 MHz, CDCl3): d=157.1, 154.6, 140.4, 139.6,
139.3, 136.2, 132.5, 132.3, 131.7, 130.9, 130.7, 130.0, 129.4,
61.7, 61.7, 35.4, 34.6, 33.4, 30.6, 16.8; MS (EI): m/z (%)=
309 ([M]+, 57), 278 (10), 260 (18), 219 (12), 204 (87), 190
(11), 174 (97), 159 (18), 144 (28), 130 (26), 104 (100), 89
[1] For selected reviews on direct C H functionalization,
see: a) D. Alberico, M. E. Scott, M. Lautens, Chem.
Rev. 2007, 107, 174–238; b) L.-C. Campeau, D. R.
Stuart, K. Fagnou, Aldrichimica Acta 2007, 40, 35–41;
c) X. Chen, K. M. Engle, D.-H. Wang, J.-Q. Yu, Angew.
Chem. 2009, 121, 5196–5217; Angew. Chem. Int. Ed.
2009, 48, 5094–5115; d) K. Godula, D. Sames, Science
2006, 312, 67–72; F. Kakiuchi, N. Chatani, Adv. Synth.
Catal. 2003, 345, 1077–1101; e) J. Wencel-Delord, T.
Droge, F. Liu, F. Glorius, Chem. Soc. Rev. 2011, 40,
4740–4761.
˜
(10), 78 (23). IR (ATR): n=2929, 1553, 1457, 1397, 1296,
À
[2] For selected reviews on ligand directed C H function-
1241, 1151, 1029, 885, 846, 795, 711 cmÀ1; HR-MS (ESI): m/
z=310.1803, calcd. for C20H24O2N (M+ +H): 310.1802.
alization, see: a) O. Daugulis, H.-Q. Do, D. Shabashov,
Acc. Chem. Res. 2009, 42, 1074–1086; b) B.-J. Li, S.-D.
Yang, Z.-J. Shi, Synlett 2008, 949–957; c) T. W. Lyons,
M. S. Sanford, Chem. Rev. 2010, 110, 1147–1169;
d) S. R. Neufeldt, M. S. Sanford, Acc. Chem. Res. 2012,
45, 939–946.
X-Ray Crystal Structure Determination of 4-Acetoxy-
5-acetyl-O-methyloxime-12-bromoACHTUNGTRNE[NUNG 2.2]para-
cyclophane (11)
[3] V. Ritleng, C. Sirlin, M. Pfeffer, Chem. Rev. 2002, 102,
1731–1770.
[4] For a review on the application of palladacycles, see: J.
Dupont, C. S. Consorti, J. Spencer, Chem. Rev. 2005,
105, 2527–2572.
Crystals suitable for X-ray structure determination were ob-
tained from ethyl acetate. The compound (C21H22NO3Br)
crystallizes in monoclinc space group P21/c (14) with cell
constants a=7.8042(3), b=12.0712(4), c=19.6794(7) ꢂ, a=
g=908, and b=90.999(2)8. The molecular weight of 416.31,
a cell volume of 1853.64(11) ꢂ3, and Z=4 result in a density
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of 1.492 gcmÀ3 and
a linear absorption coefficient of
3.191 mmÀ1, respectively. Diffraction data were collected at
200 K on a Bruker APEX-II CCD diffractometer employing
graphite-monochromated CuKa radiation (l=1.54179 ꢂ).
46334 reflections were collected in the range À9ꢀhꢀ9,
À14ꢀkꢀ14, and À23ꢀlꢀ 23 (qmax =67.18), merged to give
3269 independent reflections [Rint =0.02(1)]. The structure
was solved by direct methods as implemented in the
XTAL3.7 package of crystallographic programs[42] employ-
ing GENSIN[42] to generate structure-invariant relationships
and GENTAN[42] for the general tangent phasing procedure.
3209 observed reflections [I>2s (I)] were included in a full-
matrix least squares refinement of 324 parameters converg-
ing at R(Rw)=0.027(0.033; w=1/ACHTUNGTRNEUNG
[7.0s2(F)], a final goodness
of fit of 1.085, a maximum shift/error <0.001, and a residual
electron density of À0.42/+0.41 eꢂÀ3. All hydrogen atoms
could be located in difference Fourier maps and were re-
fined isotropically
CCDC 889165 contains the supplementary crystallograph-
ic 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.
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