Phenyliodine diacetate-mediated para-functionalizations of amido- and amino-substituted [2.2]paracyclophanes

Article abstract of DOI:10.1002/adsc.201300547

The reaction of N-[2.2]paracyclophanyl-substituted amides or amines with phenyliodine diacetate (PIDA) and protic nucleophiles affords mixed para-substituted [2.2]paracyclophane derivatives in moderate to good yields. As protic nucleophiles carboxylic aci

Full text of DOI:10.1002/adsc.201300547

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DOI: 10.1002/adsc.201300547
Phenyliodine Diacetate-Mediated para-Functionalizations of
Amido- and Amino-Substituted [2.2]Paracyclophanes
Petra Schaal (nꢀe Lennartz),+a Hannah Baars,+a Gerhard Raabe,a
Iuliana Atodiresei,a and Carsten Bolma,*
a
Institut fꢁr Organische Chemie der RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax : (+49)-241-8092391; e-mail: Carsten.Bolm@oc.rwth-aachen.de
+
Both authors contributed equally to this project.
Received: June 20, 2013; Published online: August 29, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300547.
Abstract: The reaction of N-[2.2]paracyclophanyl-
substituted amides or amines with phenyliodine di-
acetate (PIDA) and protic nucleophiles affords
mixed para-substituted [2.2]paracyclophane deriva-
tives in moderate to good yields. As protic nucleo-
philes carboxylic acids and alcohols as well as pyri-
dine hydrobromide can be used. 4-Hydroxy-
ents),[9,10] or electrophilic aromatic substitution of
[2.2]paracyclophane derivatives with activating
methyl or methoxy groups.[11,12] A general approach
providing para-substituted [2.2]paracyclophanes is still
lacking.
During our investigation of the palladium-catalyzed
ortho-acetoxylation of donor-substituted [2.2]paracy-
clophanes,[7f] we noticed an interesting reaction var-
ACHTUNGTRENNUNG[2.2]paracyclophane reacts in an analogous manner.
iant. With N-acetylaminoACTHNURGTNE[UNG 2.2]paracyclophane (1a) as
Keywords: cyclophanes; hypervalent iodine com-
pounds; metal-free synthesis; planar chirality; syn-
thetic methods
substrate and phenyliodine diacetate (PIDA) as oxi-
dant, a selective para-acetoxylation occurred and 2aa
(instead of the expected ortho-substituted product)
was isolated in 41% yield (Scheme 1). Although
Cram and co-workers described this compound al-
ready in 1966,[13] we noted to our surprise that no fur-
ther reports about 2aa or structurally related com-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
has been a continuous interest in determining their [bisACHTNUTRGENN(UG acyloxy)iodo]arenes [ArIAHCTUNGTERNN(UNG O2CR)2] were applied
properties and finding synthetic applications.[2,3] Uti- as mild oxidants and arylating agents for para-selec-
À
lizing their planar chirality, substituted [2.2]paracyclo- tive C H oxygenations, fluorinations and arylations
phanes have been used as auxiliaries, ligands and cat- under metal-free conditions.[15,16] Based on those re-
alysts in stereoselective synthesis.[4] In addition, appli- ports and in the light of our initial finding
cations in polymer and material science have been de- (Scheme 1), we decided to investigate the preparation
scribed.[5]
of other para-functionalized [2.2]paracyclophanes by
Although the regioselective functionalization of
monosubstituted [2.2]paracyclophanes is a major chal-
lenge in [2.2]paracyclophane chemistry, there are vari-
ous methods for the synthesis of pseudo-ortho,
pseudo-geminal, pseudo-meta and ortho-substituted
derivatives.[6,7] In contrast, only a few reports focus on
accessing para-substituted [2.2]paracyclophanes, de-
spite the fact that such derivatives proved promising
for applications in material science.[8] Most of the
para-substituted [2.2]paracyclophanes reported so far
have either been prepared by a de-novo synthesis
Scheme 1. Initial observation of a para-acetoxylation of
(providing products with two identical substitu- planar chiral amide 1a.
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Phenyliodine Diacetate-Mediated para-Functionalizations of Amido- and Amino-Substituted [2.2]Paracyclophanes
Table 1. Optimization of reaction conditions.[a]
Entry
t [h]
T [8C]
Oxidant (equiv.)
Additive (equiv.)
Yield [%]
1[b]
2[b]
3
16
16
16
1
1
1
7
2
2
0.5
100
100
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
PIDA (1.1)
PIDA (1.1)
PIDA (1.1)
PIDA (1.1)
PIDA (1.1)
PIDA (1.1)
PIDA (1.1)
PIDA (1.5)
PIDA (1.5)
PIFA (1.5)
Pd
–
–
–
–
G
41
45
60
67
60
60
32
32
4
5[c]
6[d]
7[e]
8
–
AcOH (10)
TFA (1.0)
BF3·OEt2 (1.0)
–
9
10
40
<28[f]
[a]
Reaction conditions: amide 1a (0.500 mmol), oxidant and additive were stirred under air in AcOH ([1a]=0.1M).
In AcOH/Ac2O.
[1a]=0.5M.
[1a]=0.05M.
[b]
[c]
[d]
[e]
[f]
In MeCN.
Containing traces of an unknown by-product.
PIDA-promoted
[2.2]paracyclophane derivatives such as amide 1a.
reactions of monosubstituted
Increasing the amount of PIDA from 1.1 equiv. to
2.2 equiv. led to over-oxidation, and the two planar
An early screening of the reaction conditions chiral para-benzoquinone derivatives 3 and 4 were
showed that the presence of Pd(OAc)2 was not obtained in 54% and 2% yield, respectively
needed for the para-acetoxylation of 1a (Table 1, (Scheme 2).
entry 2). Performing the reaction at room tempera- The para-selectivity of the C O bond formation in
AHCTUNGTRENNUNG
À
ture and shortening the reaction time from 16 h to 1 h the conversion of amide 1a was revealed by mass
was beneficial allowing us to isolate para-acetoxylated spectrometry, NMR spectroscopy, and X-ray crystal
acetamide 2aa in 67% yield (Table 1, entry 4). Chang- structure analysis of product 2aa. Crystals suitable for
ing the reagent concentrations had no major effect X-ray crystal structure analysis were grown from
(Table 1, entries 4–6). With the goal to avoid product ethyl acetate at room temperature and the structure
decomposition leading to undefined side reactions, of para-substituted amide 2aa is shown in Figure 1.[17]
the addition of MeCN as co-solvent with 10 equiv. of
In general, [2.2]paracyclophanes have two very
AcOH as protic nucleophile was tried. Under those characteristic features: (i) non-planar aromatic rings
À
conditions, however, the yield of 2aa dropped to 32% and (ii) significantly elongated C C bonds in the eth-
even after an extended reaction time of 7 h (Table 1, ylene bridges. Here, the carbon atoms bonded to the
À
À
À
entry 7). In contrast to observations made in para- bridging CH2 CH2 groups (C-1, C-4 and C-9, C-12)
acet
ACHTUNGTRENNUNG
yield was observed when TFA or BF3·OEt2 was added squares planes defined by atoms C-2, C-3, C-5, C-6
to a reaction with N-[2.2]paracyclophanylamide 1a
(Table 1, entries 8 and 9). Substituting PIDA by the
more reactive iodine
ACHTUNGTRNE(NUNG III) reagent [bis(trifluoroacet-
ACHTUNGTRENNUNGoxy)iodo]benzene (PIFA) led to a lower yield of 2aa
also due to the formation of an unknown by-product,
which could not be separated from 2aa (Table 1,
entry 10). In summary, the optimized conditions in-
volved the use of 1.1 equiv. of PIDA to be applied in
AcOH as solvent for 1 h at ambient temperature pro-
viding para-acetoxylated amide 2aa in 67% yield.
Scheme 2. Synthesis of planar chiral para-benzoquinone de-
rivatives 3 and 4.
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anilide derivatives.[15a,c] Being less acidic, methanol
and ethanol could only be applied when K2CO3 was
added as base (Table 2, entries 7–10). Under those
conditions, amides 1a and 1b showed a straight reac-
tion behaviour leading to para-alkoxylated products
2ac, 2bc, and 2ad in yields up to 64% (Table 2, en-
tries 7, 8 and 10). As observed in the acetoxylation of
1d presented before, the PIDA-mediated reaction of
this 2-pyridinyl-substituted aniline derivative with
methanol led to a cyclohexadiene-type product (5dc),
which could be isolated in 65% yield (Table 2,
entry 9). None of the expected fully aromatized
[2.2]paracyclophane 2dc was observed.
In the oxidative dearomatization of phenols a mix-
Figure 1. ORTEP diagram of the molecular structure of
amide 2aa as determined by X-ray single crystal structure ture of MeCN/H2O was used for the introduction of
a hydroxy substituent.[19] Applying analogous condi-
analysis.
tions here remained unsuccessful, and in the attempt
to para-hydroxylate amide 1a with PIDA and aqueous
and C-10, C-11, C-13, C-14 by 0.15 ꢃ resulting in MeCN only para-benzoquinone imine 3 was isolated
À À
sums of C C C bond angles within the rings of in 40% yield. Recently, a para-selective fluorination
values close to 7178. The lengths of the bridging C C of anilides using HF/pyridine was reported.[15d] Con-
À
bonds in 2aa are 1.591(2) and 1.588(2), respectively. sidering the interest in parylene F, which is a fluoro-
À
Compared with the average value of a C C bond in substituted polymer derived from [2.2]paracyclophane
the solid state [1.530(15) ꢃ[18]] this amounts to an showing high stability at elevated temperatures,[20]
elongation of 0.05–0.06 ꢃ. Mixing of the p orbitals in- a para-selective fluorination of 1a was tried. Unfortu-
volving the ring atoms bonded to the bridges into nately, treatment of 1a with HF/pyridine and PIDA in
their s* orbital might contribute to this elongation.
MeCN only resulted in decomposition of the starting
Next, the reaction behavior of other [2.2]paracyclo- material and formation of an unidentified compound.
phane derivatives was investigated (Table 2). Smooth In contrast, a combination of HBr/pyridine reacted
acetoxylations with 1.1 equiv of PIDA in AcOH as well affording para-brominated amide 2ae in 46%
solvent also occurred using [2.2]paracyclophanes 1b yield (Table 2, entry 11). This regioselectivity is note-
and 1c as substrates providing the corresponding worthy because common brominations of monosubsti-
para-acetoxylated products (amide 2ba and carbamate tuted [2.2]paracyclophanes predominately occur in
2ca) in 58% and 41% yield, respectively (Table 2, en- a pseudo-geminal position due to a transannular
tries 2 and 3). To our surprise, cyclohexadiene-type effect.[21] Thus the here reported PIDA-promoted
products (5da and 5ea) were predominantly formed strategy gives access to a product (2ae), which might
when N-(het)aryl-substituted amines 1d and 1e were also prove useful for subsequent para-functionaliza-
applied under the same conditions. Whereas 1d bear- tions of [2.2]paracyclophane achievable by transition
ing a 2-pyridinyl group exclusively led to 5da in 59% metal-catalyzed cross-coupling or metal/bromine ex-
yield, 1e having a phenyl substituent gave a mixture change reactions.
of para-acetoxylated product 2ea and cyclohexadiene-
Paracetamol (acetaminophen, 6) is a widely used
type product 5ea in 23% and 53% yield, respectively drug against pain and fever with only minor side ef-
(Table 2, entries 4 and 5). In both cases, para-func- fects.[22] Overdose, however, can cause liver damage
tionalizations had occurred, but apparently the re-aro- and death. Amide 2af can be considered as structural-
matization was hampered. Presumably, the strained ly extended analogue of paracetamol. As already dis-
[2.2]paracyclophane backbone contributed to the un- cussed, the attempted direct para-hydroxylation of
expected stability of the observed products. To the amide 1a using the newly developed PIDA-promoted
best of our knowledge these reactions represent the strategy had failed. To our delight, however, 2af
first examples of para-selective functionalizations of (named “phanacetamol”) could be obtained in 87%
N-(het)aryl-substituted anilines with hypervalent yield by selective ester hydrolysis of amide 2aa under
iodine
(III) reagents.
acidic conditions (Scheme 3).
Next, para-functionalizations of 1a with other nu-
As other [2.2]paracyclophane derivatives have al-
cleophiles were studied. Instead of acetic acid, formic ready shown interesting bioactivities,[23] we hypothe-
acid could be applied, and [2.2]paracyclophane 2ab size that due to the increased lipophilicity and extend-
was isolated in 59% yield (Table 2, entry 6). Attempts ed three-dimensional structure of phanacetamol (2af)
to use trifluoroacetic acid or p-toluenesulfonic acid as compared to paracetamol (6), alternative metabolic
failed, which contrasts with the behaviour of simple pathways are activated leading to a safer and less hep-
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Phenyliodine Diacetate-Mediated para-Functionalizations of Amido- and Amino-Substituted [2.2]Paracyclophanes
Table 2. Substrate scope of the PIDA-promoted para-functionalization of [2.2]paracyclophanylamides and -amines.[a]
Entry
1
R
NucH
Products
Yield [%]
67
COMe (1a)
AcOH
2
3
COEt (1b)
Boc (1c)
AcOH
AcOH
58
41
4
2-pyridinyl (1d)
AcOH
0 (2da); 59 (5da)
5
Ph (1e)
AcOH
23 (2ea); 53 (5ea)
6
COMe (1a)
COMe (1a)
HCOOH
MeOH
59
64
7[b]
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Table 2. (Continued)
Entry
R
NucH
Products
Yield [%]
52
8[b]
COEt (1b)
MeOH
9
2-pyridinyl (1d)
COMe (1a)
MeOH
0 (2dc); 65 (5dc)
10[b]
EtOH
56
46
11[c,d]
COMe (1a)
HBr/pyridine
[a]
Reaction conditions: [2.2]paracyclophane 1 (0.500 mmol) in acid or alcohol (0.1M).
Addition of K2CO3 (1.1 equiv.).
Performed at 08C.
Performed in MeCN.
[b]
[c]
[d]
atotoxic drug with potentially useful analgesic proper- ing from 4-hydroxy
ties. Studies along those lines are in progress, and re- neither the use of 1.1 equiv. nor applying 2.2 equiv. of
sults will be reported in due course. PIDA led to the expected product, para-benzoqui-
ACHTUNGTRNE[NUNG 2.2]paracyclophane (7). However,
The oxidative functionalization of phenol deriva- none 4. Instead, planar chiral cyclohexadienone 8 was
tives with PIDA results in the formation of cyclohexa- obtained in 77% yield (Scheme 4). Also in this case,
dienones.[19,24] Having observed para-benzoquinone no aromatization had occurred revealing an unusual
derivatives 3 and 4 in PIDA-mediated para-acetoxyla- stability of the resulting acetoxylated planar chiral cy-
tions of amide 1a (Scheme 2), we assumed the latter clohexadienone derivative 8.
product to be dominant in analogous reactions start-
In line with findings by Rozenberg and co-workers,
who had shown that the nucleophilic attack of planar
chiral benzoquinone 4 always proceeds from the less
shielded top face,[25] the acetoxy substituent of cyclo-
Scheme 3. Paracetamol (6) and synthesis of phanacetamol
(2af).
Scheme 4. PIDA-promoted
AHCTUNGERTG[NNUN 2.2]paracyclophane (7).
oxidation
of
4-hydroxy-
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Phenyliodine Diacetate-Mediated para-Functionalizations of Amido- and Amino-Substituted [2.2]Paracyclophanes
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General Procedure for PIDA-Promoted para-
Acetoxylation/Etherification
To a stirred solution of amide or amine 1 (0.500 mmol) in
acetic acid (5 mL) or alcohol (5 mL) was added PhIACTHNUTRGNEUNG(OAc)2
(177 mg, 0.55 mmol, 1.1 equiv.). If alcohols were used,
K2CO3 (76 mg, 0.55 mmol, 1.1 equiv.) was added to the reac-
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Acknowledgements
This work was supported by the Deutsche Forschungsgemein-
schaft through the International Research Training Group
Seleca (IGRK 1628) and the Forschungscluster SusChemSys.
SusChemSys is co-financed by the Regional Development
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[26] The carbonyl O atom in the molecule is disordered
over two positions with site occupation factors of
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hydrogen atoms, including the disordered O atom,
were refined anisotropically. The hydrogen atoms were
placed at idealised positions and refined isotropically
using the riding model. CCDC 945027 contains the sup-
plementary crystallographic data of the X-ray structure
analysis of compound 8. 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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Adv. Synth. Catal. 2013, 355, 2506 – 2512