The synthesis of substituted amino[2.2]paracyclophanes

Article abstract of DOI:10.1039/C6OB02150F

Two methodologies for the formation of substituted amino[2.2]paracyclophane derivatives were developed. The first involves the direct amination of bromo[2.2]paracyclophanes with sodium azide. This permits the synthesis of simple mono- and disubstituted de

Full text of DOI:10.1039/C6OB02150F

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Chem., 2016, DOI: 10.1039/C6OB02150F.
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DOI: 10.1039/C6OB02150F
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The synthesis of substituted amino[2.2]paracyclophanes
Krishanthi P. Jayasundera,a Disraëli N. M. Kusmus,a,b Lise Deuilhé,a,c Leonie Etheridge,a Zane
Farrow,a David J. Lun,a Gurpreet Kaur,a and Gareth J. Rowlandsa*
Received 00th January 20xx,
Accepted 00th January 20xx
Two methodologies for the formation of substituted amino[2.2]paracyclophane derivatives were developed. The first
involves the direct amination of bromo[2.2]paracyclophanes with sodium azide. This permits the synthesis of simple
mono- and disubstituted derivatives but fails to give sterically congested pseudo-gem derivatives. A ‘one-pot’ oxidation-
Lossen rearrangement of [2.2]paracyclophane oximes provides access to a range of amino[2.2]paracyclophanes including
DOI: 10.1039/x0xx00000x
www.rsc.org/
the
most
efficient
synthesis
of
the
pseudo-gem
planar
chiral
amino
acid
yet
reported.
The most direct route to 4-amino[2.2]paracyclophane is
Introduction
nitration followed by reduction but this sequence is notoriously
problematic. While moderate to high yields have been reported
these require very precise reaction times and conditions.8,12,13
More common routes to aminoparacyclophanes include the
Curtius rearrangement of the appropriate carboxylic acid9,14,15-18
or the electrophilic amination of bromoparacyclophanes.
Advantages of the former strategy include facile resolution of
the acid12,19 and the ability of acids to direct functionalisation of
paracyclophanes. The disadvantages include multiple steps and
the use of organic azides. Bromoparacyclophanes are
traditionally converted to amines by halogen-metal exchange
followed by reaction with an electrophilic amine.18,20-22,23-26 The
variable yields for these reactions, in conjunction with the
relatively harsh conditions, make this route less attractive.
The palladium-mediated Buchwald-Hartwig amination27 of
Derivatives of [2.2]paracyclophane offer an intriguing scaffold
for the preparation of enantiomerically enriched molecules
possessing a plane of chirality, a rigid backbone and unusual
electronic properties.1,2,3 These characteristics have been
exploited in asymmetric synthesis,1,4 as well as probes for the
study of through-bond and -space electronic interactions,5
interchromophore contact, π-π electron delocalisation,6
photonic applications7 as well as precursors to functionalised
coatings8,9
and
atypical
bioisosteres.10,11
While
amino[2.2]paracyclophanes (Figure 1) form the basis of many
of these functionalised molecules there are few simple, reliable
methods for the synthesis of substituted derivatives; most
reactions are substrate specific.
(pseudo)halides
offers
a
direct
route
to
R
NH2
NH2
NH2
R
aminoparacyclophanes.15,28,29,30-35 It would be reasonable to
think this was a general and reliable route but such aminations
are substrate specific. For example, the optimum ligand to
couple 4-bromo[2.2]paracyclophane with benzylic amines is
BINAP30 yet this ligand fails32 to give satisfactory yields when
anilines are used.‡ Ma and Song reported34 that a pre-made Pd-
dppf complex was the only reagent that coupled
4-amino
[2.2]paracyclophane
ortho
substituted
pseudo-gem
substituted
NH2
NH2
benzhydrylideneamine
to
pseudo-ortho-
R
R
dibromo[2.2]paracyclophane. And yet the amination of 4-
bromo[2.2]paracyclophane proceeded in a mere 15% yield
under identical conditions. The yield of a monoamination could
be increased to 80% by adding just 1 mol% of 4,12-
bis(benzhydrylideneamino)[2.2]paracyclophane, the product of
the diamination. When the Buchwald-Hartwig amination works
it is an excellent route but it is capricious.
pseudo-ortho
pseudo-para
substituted
substituted
Fig. 1 Substituted amino[2.2]paracyclophanes.
Considering the success of copper-mediated aminations,36
there is a dearth of reports of this methodology being used on
bromo[2.2]paracyclophane. Bolm indicated that the copper-
mediated coupling of 4-bromo[2.2]paracyclophane and
pyrazole failed31 although Paradies12 showed that analogous
conditions could give the pseudo-gem amino pyrazole but not
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the imidazole. We have briefly reported the copper-mediated
amination of 4-bromo[2.2]paracyclophane24 and present a more
detailed study below. Ortner has reported an interesting but low
yielding transition metal-free amination.10,35
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DOI: 10.1039/C6OB02150F
standard conditions:
NaN3 (1.3 eq), Cu2O (1.0 eq),
DL-proline (2.4 eq), 0.25M DMSO,
100°C, 48 hours, sealed vessel
Br
NH2
During our studies on [2.2]paracyclophane3,25,26,37,38,39 we
have tested many of the reactions outlined above. At best we
found the procedures to be substrate specific with a number
being fickle and, in our hands at least, not reproducible. It
would be beneficial to develop methodology that furnishes any
amino[2.2]paracyclophane regardless of other substituents.
Ideally the synthetic sequence should be simple and not involve
harsh reagents. The number of synthetic steps was unimportant;
rather the guarantee of access to each amine was paramount. In
this paper we outline our studies towards this goal. Two
methods were investigated, a copper-mediated amination and a
more general route based on the Lossen rearrangement.
61 - 69%
1
2
Deviation from standard:
1. Cu2O (0.5 eq) - 12% conversion*
2. CuI, CuBr or CuSO4•H2O & NaAscorbate - <10% conversion*
3. EtOH/H2O - 0%
4. DL-Proline (1.2 eq) - 25% conversion*
5. 90°C (48 hours) - 46% conversion*
6. 1 atmosphere Ar - 33% conversion*
*conversion measured by 1H NMR
Scheme 1 Optimisation of copper-mediated amination.
The
reaction
could
be
applied
to
Results and Discussion
dibromo[2.2]paracyclophanes. Both the pseudo-para and
pseudo-ortho dibromo[2.2]paracyclophanes (3 & 4) underwent
diamination in moderate yield (Scheme 2). Under conventional
heating it proved difficult to drive the reactions to completion
even with an excess of reagents. In all cases a mixture of the
desired diamine 6 or 7, the mixed amino bromide 8,
monoamine 2 and starting bromide 3 or 4 were isolated.
Extensive optimisation improved the yield so that 50 − 60% of
the diamine could be routinely isolated. Use of microwave
heating did not alter reaction time but permitted less reagent to
be used and resulted in good conversion to the diamine 6 or 7
with only a trace of the other products. The reaction time is
important; less than 48 hours and incomplete conversion is
observed while more than 48 hours results in the formation of
an unidentified side product. As has been noted previously,28
the diamines are not stable in solution; if the diamine is left in
the reaction mixture decomposition is observed.
Copper-mediated amination
Initially we were attracted to the copper-mediated conversion of
aryl bromides to aryl azides as a means of avoiding the use of
butyllithium. Previously, we had synthesised azides from 4-
lithio[2.2]paracyclophane and tosyl azide then converted this to
either a triazole24 or reduced it to an amine.25,38 We screened a
number of literature conditions, changing the source of copper,
the base, the solvent, and the temperature of the reaction
(Scheme 1).40,41 In each case only a trace of azide was observed
with the majority of material being unreacted bromide 1. One
set of conditions41 furnished an appreciable quantity of 4-
amino[2.2]paracyclophane 2 and we were able to optimise
these to give the amine 2 in moderate 61-69% yield. Deviation
from these conditions inevitably resulted in a dramatic drop in
1
conversion as determined by H NMR. Key to good yields was
using a sealed vessel with good stirring. Once the reaction has
cooled it should be stirred with an aqueous
ethylenediaminetetraacetic acid (EDTA) solution for 30
minutes. Failure to follow this procedure results in poor
recovery of amine suggesting that coordination with the copper
is a problem. Use of microwave irradiation did not decrease
reaction time but did result in a cleaner reaction. There is no
indication of kinetic resolution.§
X
Y
Br
X
Y
NH2
conditions
Z
Z
3; X=H; Y=Br; Z=H
4; X=Y=H; Z=Br
6; X=H; Y=NH2; Z=H
7; X=Y=H; Z=NH2
8; X=H; Y=Br; Z=H
5; X=CO2Me; Y=Z=H
conventional heating
NaN3 (6 eq), Cu2O (4 eq), DL-proline (10 eq), 0.05M
DMSO, 100°C, 48 hours, sealed vessel
50 - 60%
microwave heating
NaN3 (5.0 eq), Cu2O (2.2 eq), DL-proline (5.5 eq),
0.05M DMSO, 100°C, 48 hours, sealed vessel
61 - 68%
Scheme 2 Amination of substituted [2.2]paracyclophanes.
Amination of the pseudo-gem substituted bromo ester 5 was
unsuccessful. Unreacted starting material was recovered from
the reaction. We speculate that substitution of this bromide is
hampered by the ester group located directly above the
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bromide; steric hindrance could slow or prevent the insertion 56% yield. For consistency a number of precautions are needed;
View Article Online
step by preventing the bromide participating in a three or four all reagents should be dried and fDinOeI:ly10.1g0r3o9u/Cn6dOBb02e1f5o0rFe
atom transition state analogous to that proposed in palladium addition.46,47,49
systems.42
It is assumed that the reaction proceeds by oxidation of the
oxime to a hydroxamic acid. This latter species undergoes
Lossen rearrangement on treatment with sodium hydroxide. It
‘One-pot’ oxidation-rearrangement entry to amines
While the copper methodology furnishes both mono- and has been possible to stop the reactions prematurely and isolate
diamines, we were unhappy with the lack of generality. the hydroxamic acid. Treatment of the hydroxamic acid with
Therefore, a second route was developed. For this we returned sodium hydroxide gives the desired amine in comparable yield
to classic functional group transformations and a ‘one-pot’ to the ‘one-pot’ method.47,49
oxidation-Lossen rearrangement that would convert an oxime
The generality of the methodology was confirmed by
to an amine. Three ideas guided our thinking; we knew that the preparing a number of disubstituted paracyclophanes starting
formyl group was readily introduced in a controlled manner with the known pseudo-gem amino ester 15,16 and amino
through either the Rieche formylation17,43 or nucleophilic attack bromide 12.33,50,51 Exploiting the transannular effect, the
on a formyl amide.23,25,44 Secondly, the formyl group provides a pseudo-gem aldehyde 1317 could be prepared by directed
means to resolve the planar chirality of [2.2]paracyclophane as Rieche formylation of ester 12 (Scheme 3).52 Oxime (14)
demonstrated by Bräse’s recent chemistry.43,45 Finally there was formation followed by the oxidation–rearrangement sequence
literature precedent to suggest that an aldehyde could be gave the desired amine 15 in moderate to good yield. Key to
transformed to an amine through the intermediacy of an oxime reproducibility is the use of finely ground and dry reagents; if
and/or hydroxamic acid.46,47 This chemistry is complementary these precautions are not taken the reaction can stall after the
to the Curtius rearrangement commonly used in paracyclophane oxidation, furnishing the hydroxamic acid instead of the amine.
chemistry but with the advantage that the Rieche formylation
The synthesis of the pseudo-gem amino ester compares
permits the direct introduction of an aldehyde in a highly favourably with literature routes. The ester was first synthesised
regioselective manner using standard aromatic directing effects by the nitration of the ester 12 followed by reduction. The yield
and/or the transannular effect.§§
of the nitration was 15%.13,53 Pelter later improved the yield by
pseudo-gem-bromination of an oxazoline followed by halogen-
metal exchange, reaction with carbon dioxide, Curtius
rearrangement and hydrolysis of the oxazoline. The route was 8
steps from 4-bromo[2.2]paracyclophane and gave the amino
O
R
CH3OCHCl2, TiCl4
R
10 82-85%
13 80-94%
acid in 36% yield.16 Our route is just
5 steps from
[2.2]paracyclophane and gives the amino ester in 44% yield.†
9 R = H
12 R = CO2Me
10 R = H
13 R = CO2Me
HONH2•HCl,
1. LiAlH4
O
O
2. (COCl)2, DMSO
then Et3N
NaOH
Br
O
Br
11 90-94%
14 91-95%
80-92%
(over 2 steps)
OH
Koser's reagent, DMSO
then NaOH
N
16
17
HONH2•HCl,
NH2
R
R
NaOH
98%
11 = 50-56%
14 47-53%
OH
Br
H
Koser's reagent
then NaOH
N
2 R = H
11 R = H
14 R = CO2Me
Br
H
N
15 R = CO2Me
65%
Scheme 3 Synthesis of amino[2.2]paracyclophanes by ‘one-pot’ oxidation-
rearrangement.
19
18
The ease of this sequence was demonstrated by the
synthesis of 4-amino[2.2]paracyclophane (Scheme 3). 4-
Formyl[2.2]paracyclophane 10 was prepared by Rieche
formylation of 9 with dichloromethyl methyl ether and titanium
tetrachloride. Formation of the oxime 11 was followed by a
‘one-pot’ oxidation–rearrangement sequence.46,47 Treating a
solution of 11 in DMSO with Koser’s reagent,
hydroxy(tosyloxy)iodobenzene HTIB,48 for 30 minutes at room
temperature and 1 hour at 80°C followed by the addition of
sodium hydroxide heating for a further 1.5 hours gave 2 in 50-
Scheme 4 Synthesis of pseudo-gem amino-bromo[2.2]paracyclophane.
4-Amino-13-bromo[2.2]paracyclophane 19 was prepared
from ester 12. Aldehyde 17 was synthesised via 16 by
regioselective bromination18 followed by reduction and Swern
oxidation (Scheme 4).
A more direct route by either
regioselective bromination of 4-formyl[2.2]paracyclophane or
direct reduction of the ester proved unsatisfactory. The
aldehyde was subjected to the standard sequence, oxime 18
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formation followed by ‘one-pot’ oxidation–rearrangement to
give 19 in moderate yield. While there are shorter routes to this
amine,33,50,51 our goal was to prove the generality of the
chemistry. Arguably, this route has the advantage of avoiding a
challenging nitration or the use of azides required for the
Curtius rearrangement.
Two ortho substituted amino[2.2]paracyclophanes, 5-
amino-4-methoxy[2.2]paracyclophane 25 and 4-amino-5-
bromo[2.2]paracyclophane 28, were also prepared (Scheme 5).
The former was synthesised from the readily available
salicylaldehyde analogue 20.54 Initially we tried to form 5-
amino-4-hydroxy[2.2]paracyclophane 2221 but the oxidation–
rearrangement of 21 failed. Amino alcohol 22 is unstable and it
is possible that it decomposed under the reaction conditions.21
The methyl ether 25 is stable and the standard reaction
sequence, aldehyde 23 to amine 25 via oxime 24, proceeded
satisfactorily.
View Article Online
DOI: 10.1039/C6OB02150F
It is known that hydrogen bond donor catalysts and Brønsted
acids can promote the Friedel-Crafts-type alkylation of indole
with trans-β-nitrostyrene.12,18,56 We were curious if the planar
chiral amino acid formed would mediate this reaction. Pseudo-
gem amino ester 15 was converted to the sulfonamides 31-33
(Scheme 7). It was hoped that the sulfonamide would increase
the potential for hydrogen bonding and create a chiral pocket.
Enantiomerically enriched acids 31 were prepared by resolution
of the planar chirality through selective recrystallisation of the
diastereomeric cinchonium salts. While resolution of the
pseudo-gem formyl ester 13 should be possible through the
formation of a chiral imine it was more expedient to perform a
late stage resolution. Analysis by HPLC, using Chiralpak(R)
AD-H column (20:80 iPrOH:Hex @ 1.0 ml/min), revealed that
neutralisation of the insoluble salt gave the acid with 91:9 er.
The other enantiomer could be obtained by
a single
4-Amino-5-bromo[2.2]paracyclophane 28 was prepared
from 26, which is readily available through the elegant
chemistry of Bräse.55 Once again, ‘one-pot’ oxidation–
rearrangement of oxime 27 delivered the desired amine 28 in an
acceptable yield (Scheme 5). It should be noted that bromo
amine 28 is stunningly unreactive; virtually all attempts to
elaborate the amine met with failure; various alkylations,
reductive aminations, and acylations with anhydrides or acyl
chlorides (catalysed and non-catalysed) all returned unreacted
starting material. Even heating a mixture of 28 and base in neat
iodomethane failed. The only reaction that gave an identifiable
new product was diazotisation followed by reaction with
morpholine, which furnished triazene 29 (Scheme 6). Attempts
to react the diazonium salt with other nucleophiles, such as KI
and KBr, resulted in the same unidentified product in low yield.
The synthesis of ortho substituted [2.2]paracyclophanes is
notoriously problematic.
recrystallisation of the mother liquor as a 6:94 er mixture. Two
amides were prepared from the enantiomerically enriched
sulfonamides, the bis((3,5-trifluoromethyl)anilide 32 and the N-
trifluorosulfonamide 33. These were prepared to alter the steric
environment and the acidity of the amide proton compared to
the acid proton.
1. HBF4, NaNO2,
O
acetone, H2O
NH2
N
N
2. morpholine
N
Br
50%
Br
28
Scheme 6 Synthesis of triazene.
29
We then screened (±)-[2.2]paracyclophane-4-carboxylic
acid, sulfonamide 31, and the two amides 32 and 33 in the
Friedel-Crafts-type addition of indole to trans-β-nitrostyrene
(Scheme 8). The reactions were evaluated by mixing the
O
1
substrates and catalyst in CDCl3 then shaking for 24 hours. H
R = OH ref. 54
R
R = Br ref. 55
NMR of the crude reaction mixture gives the conversion while
HPLC analysis of the isolated product give the
enantioselectivity.
9
20 R = OH
23 R = OCH3
26 R = Br
CH3I, K2CO3
>95%
HONH2•HCl,
NaOH
OH
Koser's reagent
then NaOH
N
R
NH2
R
22 R = OH; 0%
25 R = OCH3; 59%
28 R = Br; 56%
21 R = OH; 62%
24 R = OCH3; 83%
27 R = Br; 94%
Scheme 5 Synthesis of ortho-substituted amino[2.2]paracyclophanes.
4 | J. Name., 2012, 00, 1-3
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H
N
H
sterically demanding pseudo-gem derivatives. TheVsieiwmAprtlicilceiOtynlionef
NaH,
TsCl
CO2Me
H
CO2R
Ts
N
DOI: 10.1039/C6OB02150F
the reaction is offset by a use of an excess of sodium azide and
a laborious work-up. An alternative reaction sequence is more
general. This second route permits the electrophilic aromatic
chemistry of [2.2]paracyclophane, and both ortho and
transannular directing effects, to be exploited. It has provided
the shortest published route to the pseudo-gem planar chiral
amino acid. In the future we intend to develop more efficient
routes to amino[2.2]paracyclophanes including directed
nitrations and to exploit these in the synthesis of planar chiral
amino acids for use in asymmetric catalysis.
49%
KOH, EtOH
(±)-30 R = Me
(±)-31 R = H
(±)-15
75%
H
i. cinchonine,
acetone
ii. separation
iii. HCl
OH
N
N
H
H
N
Experimental
General information
CO2H
Ts
i. (COCl)2, DMFcat., DCM
ii. 3,5-(CF3)2C6H3NH2, tol
or
All starting compounds and solvents were used as received
from commercial sources without further purification unless
otherwise noted. All reactions were performed in oven-dried
glassware under an atmosphere of argon or nitrogen unless
otherwise stated. Column chromatography was carried out on
silica gel (grade 60, mesh size 230-400, Scharlau).
Visualisation techniques employed included using ultraviolet
light (254 nm), potassium permanganate, ethanolic
phosphomolybdic acid or ninhydrin when applicable. NMR
spectra were recorded at room temperature on Bruker-400 and
Bruker-500 Avance instruments, with the use of the solvent
proton as an internal standard. Melting points were recorded on
a Gallenkamp melting point apparatus and are uncorrected.
Mass spectra and high resolution mass spectrometry were
performed at the Waikato Mass Spectrometry Facility, The
University of Waikato, New Zealand.
ii. CF3SO2NH, NaH
R
31
H
NH
N
51-60%
Ts O
H
32; R=3,5-(CF3)2C6H3
33; R=SO2CF3
N CO2H
Ts
31
Scheme 7 Resolution of planar chiral amino acids. Absolute configuration of the
two enantiomers is unknown.
The results show that both the amine and the carboxylic
acid
functionality
are
necessary
for
catalysis;
[2.2]paracyclophane-4-carboxylic acid is a poor catalyst. The
trifluorosulfonamide 33 gives the most reactive catalyst,
permitting over 50% conversion in 24 hours; presumably as it is
the most acidic catalyst.57 Unfortunately, none of the reactions
occurred with any enantioselectivity. The best results was
52.5:47.5 er (5% ee) with the simple amino acid derivative 31.
Copper methodology
4-Amino[2.2]paracyclophane (2).20,39 A suspension of 4-
bromo[2.2]paracyclophane 1 (1.0 g, 3.48 mmol, 1.0 eq.), NaN3
(0.45 g, 6.96 mmol, 2.0 eq.), Cu2O (0.50 g, 3.48 mmol, 1.0 eq.)
and DL-proline (0.96 g, 8.36 mmol, 2.4 eq.) in DMSO (14 ml)
in a round bottomed flask sealed with a rubber septum was
heated to 100 °C for 48 hours. The initially red solution became
black after 24 hours. After heating the reaction mixture was
cooled to rt and poured into a saturated aqueous solution of
EDTA (30 ml). The deep blue biphasic mixture was stirred for
30 minutes and filtered through Celite®. The filtrate was
extracted with EtOAc (3 x 20 ml). The combined organic layers
were dried (MgSO4) and concentrated. The residue was purified
by column chromatography eluting Hex/EtOAc 4/1 to afford 4-
amino[2.2]paracyclophane as a pale yellow solid (0.48 g, 62%).
Rf (4/1 Hex/EtOAc) 0.375
1H NMR (500 MHz, CDCl3): δ 7.17 (1H, dd, J = 7.8 Hz), 6.59
(1H, dd, J = 1.8, 7.8 Hz), 6.39 (2H, d, J = 7.8 Hz), 6.27 (1H, d,
J = 7.8 Hz), 6.13 (1H, dd, J = 1.7, 7.8 Hz), 5.38 (1H, d, J = 1.7
Hz), 3.45 (2H, brs), 3.15-2.93 (7H, m), 2.86-2.79 (1H, m). 13C
NMR (125 MHz, CDCl3): δ 145.1, 141.2, 139.1, 139.0, 135.4,
133.6, 132.6, 131.6, 126.9, 124.6, 123.0, 122.4, 35.5, 35.1,
33.2, 32.4. Data comparable to that reported in the
literature.20,39
catalyst,
Ph
24 hours
NO2
CDCl3
NO2
Ph
N
H
N
H
35
34
catalyst conversion (34:35)
no catalyst 100:0
[2.2]paracyclophane-4-carboxylic acid 85:15
31 66:34
32 96:4
33 43:57
Scheme 8 Acid catalysis of Friedel-Crafts alkylation.
Conclusions
In conclusion, we have developed two routes to substituted
amino[2.2]paracyclophanes. The direct amination of
bromo[2.2]paracyclophane gives moderate to good yields of
simple amino[2.2]paracyclophanes but fails to give the more
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Copper methodology – conventional heating
residue was dissolved in EtOAc (10 ml) and washed with H2inOe
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(10 ml) and brine (10 ml), dried (MgDSOOI:4)10.a1n0d39/tCh6eOBs0o2lv15e0nFt
removed to give the desired product 11 as a colourless solid
(0.235 g, 94%).
4,12-Diamino[2.2]paracyclophane (6) and 12-bromo-4-
amino[2.2]paracyclophane (8).34
A suspension of 4,12-
dibromo[2.2]paracyclophane 3 (0.10 g, 0.27 mmol, 1.0 eq.),
NaN3 (0.11 g, 1.64 mmol, 6.0 eq.), Cu2O (0.16 g, 1.09 mmol,
4.0 eq.) and DL-proline (0.31 g, 2.73 mmol, 10.0 eq.) in DMSO
(5.5 ml) in a round bottomed flask sealed with a rubber septum
was heated to 100 °C for 48 hours. The reaction mixture was
cooled to rt and poured into a saturated aqueous solution of
EDTA (15 ml). The deep blue biphasic mixture was stirred for
30 minutes and filtered through Celite®. The filtrate was
extracted with EtOAc (3 x 10 ml). The combined organic layers
were dried (MgSO4) and concentrated. The residue was purified
by column chromatography using gradient elution starting from
Hex/EtOAc; 3/1 to Hex/EtOAc 0/100 to afford 12-bromo-4-
Rf (4/1 Hex/EtOAc) 0.43
1H NMR (500 MHz, CDCl3): δ 8.16 (1H, s), 7.48 (1H, brs),
6.77 (1H, d, J = 1.1 Hz), 6.66 (1H, d, J = 7.8 Hz), 6.56 (1H, dd,
J = 7.8, 1.9 Hz), 6.53-6.43 (4H, m), 3.62-3.56 (1H, m), 3.20-
2.84 (7H, m). 13C NMR (125 MHz, CDCl3):
δ 149.6, 140.3, 139.5, 139.4, 139.3, 135.4, 134.1, 133.2, 132.9,
132.1, 131.8, 131.7, 131.0, 35.43, 35.1, 35.0, 33.9.
comparable to that reported in the literature.58
Data
4-Amino[2.2]paracyclophane (2).20,39 A mixture of 4-
(hydroxyimino)[2.2]paracyclophane 11 (0.50 g, 2.0 mmol, 1.0
eq.) and Koser’s reagent (1.09 g, 2.8 mmol, 1.4 eq.) in DMSO
(2 ml) was allow to stirred at rt for 30 min and then heated at
80oC for 1h. Sodium hydroxide (120 mg, 3.0 mmol, 1.5 eq.)
was added and heating was continued for further 1.5h. The
mixture was allowed to cool to rt, water (1 mL) was added and
then extracted with ethyl acetate (2 x 20 mL). The combined
organic layer was washed with water (20 mL), brine and dried
over MgSO4 and the solvent was removed under reduced
pressure. The resulting residue was separated by column
chromatography eluting Hex/EtOAc 9/1 to afford the 4-
amino[2.2]paracyclophane as a pale yellow solid (240 mg,
54%). Data as before (see above).
Methyl 13-formyl[2.2]paracyclophane-4-carboxylate (13).17
To a solution of methyl [2.2]paracyclophane-4-carboxylate 12
(0.266 g, 1.0 mmol, 1.0 eq.) in dry CH2Cl2 (10 ml) was added
TiCl4 (0.220 ml, 2.0 mmol, 2.0 eq.), and 1,1-dichloromethyl
methyl ether (0.093 ml, 1.05 mmol, 1.05 eq.), at -10 °C. The
reaction mixture was warmed to rt overnight. Ice (15 ml) was
added and the reaction mixture stirred for 30 min. The aqueous
layer was extracted with CH2Cl2 (2 x 20 ml). The combined
organic layers were washed with a sat. aqueous NaHCO3
solution (15 ml), H2O (15 ml) and dried (MgSO4). The solvent
was removed to afford the desired aldehyde 13 as a colourless
solid (0.280 g, 94%).
amino[2.2]paracyclophane
6 (0.018 g, 22%) and 4,12-
Diamino[2.2]paracyclophane 8 (0.033, 51%).
4,12-Diamino[2.2]paracyclophane 6. 1H NMR (400 MHz,
CDCl3): δ 6.39 (2H, d, J = 7.7 Hz), 6.20 (2H, d, J = 1.2 Hz),
6.07 (2H, dd, J = 7.7, 1.3 Hz), 3.36 (4H, brs), 3.09-3.03 (2H,
m), 2.98-2.89 (4H, m), 2.68-2.60 (2H, m). 13C NMR (125 MHz,
CDCl3): δ 144.7, 141.3, 135.2, 124.3. 123.1, 116.3, 32.7, 32.0.
Data comparable to that reported in the literature.34
4-Amino-12-bromo[2.2]paracyclophane 8. 1H NMR (500
MHz, CDCl3): δ 7.29 (1H, d, J = 1.5 Hz), 6.60 (1H, d, J = 7.8
Hz), 6.44 (1H, dd, J = 7.8, 1.4 Hz), 6.37 (1H, d, J = 7.7 Hz),
6.16 (1H, dd, J = 7.7, 1.5 Hz), 6.11 (1H, d, J = 1.4), 3.53 (2H,
brs), 3.39 (1H, ddd, J = 12.4, 9.8, 2.0 Hz), 3.15-3.11 (1H, m),
3.09-2.91 (4H, m), 2.82 (1H, ddd, J = 13.1, 10.0, 6.6 Hz), 2.68
(1H, ddd, J = 13.5, 9.4, 7.5 Hz). 13C NMR (125 MHz, CDCl3):
δ 144.9, 141.3, 141.1, 138.3, 135.3, 134.4, 131.9, 131.0, 125.9,
124.3, 122.7, 117.6, 35.5, 32.9, 32.3, 32.1. Data comparable to
that reported in the literature.34
Copper methodology – microwave heating
4,16-Diamino[2.2]paracyclophane (7).28,34 Data comparable
to that reported in the literature.28,34 It should be noted that this
diamine is the least stable amine we have prepared. Purification
is best achieved by recrystallisation from hot 1,4-dioxane with
the addition of hexane. The amine is best used directly after
synthesis. In solution decomposition observable in less than 24
hours. 1H NMR (500 MHz, CDCl3): δ 6.64 (2H, d, J = 7.9 Hz),
6.23 (2H, d, J = 7.7 Hz), 5.51 (2H, s), 3.19 (2H, ddd, J = 12.4,
9.7, 1.6 Hz), 3.05 (2H, ddd, J = 15.6, 9.9, 5.9 Hz), 2.91 (2H,
ddd, J = 12.7, 10.8, 1.9 Hz), 2.69 (2H, ddd, J = 16.4, 10.7, 5.7
Hz). 13C NMR (125 MHz, DMSO): δ 147.3, 139.9, 134.2,
122.5, 121.7, 118.9, 32.8, 31.6.
Rf (4/1 Hex/EtOAc) 0.63
1H NMR (500 MHz, CDCl3): δ 9.92 (1H, s), 7.07 (2H, t, J =
2.4, Hz), 6.70 (2H, ddd, J = 8.7, 6.7, 1.8 Hz), 6.64 (1H, d, J =
15.6 Hz), 6.63 (1H, d, J = 15.6 Hz), 4.20-4.02 (2H, m), 3.81
(3H, s), 3.20-3.08 (5H, m), 3.03-2.98 (1H, m). 13C NMR (125
MHz, CDCl3): δ190.9, 174.9, 144.0, 143.7, 142.3, 140.3, 139.9,
138.4, 136.4, 136.2, 135.9, 134.9, 134.7, 133.9, 52.1, 35.2,
34.9, 34.8, 31.3. Data comparable to that reported in the
literature.17
Methyl 13-((hydroxyimino)methyl)[2.2]paracyclophane-4-
carboxylate (14). To
a
mixture of hydroxylamine
‘One-pot’ oxidation-rearrangement methodology
hydrochloride (0.208 g, 3.0 mmol, 3.0 eq.) and NaOH (0.124 g,
3.1 mmol, 3.1 eq.) in ethanol (10 ml) at reflux was added a
solution of methyl 13-formyl[2.2]paracyclophane-4-carboxylate
13 (0.294 g, 1.0 mmol, 1.0 eq.) in EtOH (30 ml). The resulting
mixture was heated to reflux for 30 min. The reaction was
cooled to rt and the solvent removed. The residue was extracted
with EtOAc (10 ml) and the organic layer washed with H2O (10
[2.2]Paracyclophane-4-carbaldehyde oxime (11).58 A mixture
of hydroxylamine hydrochloride (0.208 g, 3 mmol, 3.0 eq.) and
NaOH (0.124 g, 3.1 mmol, 3.1 eq.) in EtOH (5 ml) was heated
to reflux and a solution of 4-formyl[2.2]paracyclophane43
(0.236 g, 1.0 mmol, 1.0 eq.) in EtOH (5 ml) was added. The
resulting mixture was heated at reflux for 30 min. The
suspension was cooled to rt and the solvent was removed. The
6 | J. Name., 2012, 00, 1-3
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ml), and brine (10 ml), dried (MgSO4) and the solvent removed 131.7, 128.6, 127.3, 51.7, 35.3, 35.0, 34.7,Vie3w3A.r7tic.le ODnalintea
to give 14 as a colourless solid (0.288 g, 93%).
Rf (4/1 Hex/EtOAc) 0.15
comparable to that reported in the literatuDreO.1I:810.1039/C6OB02150F
13-Bromo-4-hydroxymethyl[2.2]paracyclophane. To
a
1H NMR (500MHz, CDCl3): δ 8.11 (1H, s), 7.26 (1H, d, J = 2.0 suspension of LiAlH4 (84 mg, 2.2 mmol, 2.2 eq.) in THF (4 ml)
Hz), 6.86 (1H, d, J = 1.3 Hz), 6.71 (1H, dd, J = 7.8, 2.0 Hz), was added a solution of methyl 13-bromo[2.2]paracyclophane-
6.63 (1H, d, J = 7.8 Hz), 6.61-6.57 (2H, m), 4.30-4.25 (1H, m), 4-carboxylate 16 (345 mg, 1.0 mmol, 1.0 eq.) in THF (6 ml)
3.91 (3H, s), 3.72-3.68 (1H, m), 3.19-3.01 (6H, m). 13C NMR over 10 min at rt. The reaction mixture was heated to reflux for
(125 MHz, CDCl3): δ 167.1, 149.3, 142.7, 139.8, 139.6, 139.5, 2h and then cooled to rt. The excess hydride was destroyed by
136.5, 136.3, 135.1, 134.5, 134.3, 132.2, 130.5, 129.5, 51.9, the addition of aqueous 2M HCl (5 ml). The suspension was
34.9, 34.8, 34.8, 32.4. HRMS (EI) found: [M+Na]+ 332.1260. filtered through celite, washing with CH2Cl2 and diluted with
C19H19N1O3Na requires [M+Na]+ 332.1257.
Methyl 4-amino[2.2]paracyclophane-13-carboxylate (15).16 (2 x 10 ml). The combined organic layers were washed with
mixture of finely ground methyl 13- sat. aqueous NaHCO3 (10 ml), H2O (10 ml), brine (10 ml), and
CH2Cl2 (20 ml). The aqueous layer was extracted with CH2Cl2
A
((hydroxyimino)methyl)[2.2]paracyclophane-4-carboxylate 14 dried (MgSO4). The solvent was removed to afford the 13-
(0.155 g, 0.5 mmol, 1.0 eq.) and finely ground Koser’s reagent bromo-4-hydroxymethyl[2.2]paracyclophane as a colourless
(0.272 g, 0.7 mmol, 1.4 eq.) in DMSO (1 ml) was stirred at rt solid, which was used for the next reaction without further
for 30 min and then heated to 80 °C for 1h. Finely ground purification (315 mg, quant.).
NaOH (0.028 g, 0.7 mmol, 1.4 eq.) was added and the heating Rf (9/1 Hex/EtOAc) 0.1
continued for 1.5h. The mixture was cooled to rt and H2O (10 1H NMR (500 MHz, CDCl3): δ 6.60 (1H, dd, J = 7.8, 1.9 Hz),
ml) added. The aqueous layer was extracted with EtOAc (3 x 6.55-6.45 (4H, m), 6.39 (1H, d, J = 1.5 Hz), 4.71 (1H, d, J =
10 ml) and the combined organics washed with H2O (5 ml) and 12.7 Hz), 4.38 (1H, d, J = 12.7 Hz), 3.40 (1H, ddd, J = 13.1,
brine (5 ml). The combined organic layers were dried (MgSO4) 10.2, 2.3 Hz), 3.17-2.97 (6H, m) 2.87 (1H, ddd, J = 16.7, 10.8,
and the solvent removed. The resulting residue was separated 5.8 Hz). 13C NMR (125 MHz, CDCl3): δ 140.4, 139.9, 139.7,
by column chromatography eluting Hex/EtOAc; 9/1 to afford 139.4, 137.4, 137.6, 135.2, 133.5, 133.4, 132.5, 132.3, 132.2,
the methyl 4-amino[2.2]paracyclophane-13-carboxylate 15 as a 129.2, 64.7, 35.4, 35.2, 34.5, 32.9.
colourless solid (0.075 g, 53%).
Rf (4/1 Hex/EtOAc) 0.38
13-Bromo-4-formyl[2.2]paracyclophane (17). To a solution
of oxalyl chloride (0.10 ml, 1.15 mmol, 1.15 eq.) in dry CH2Cl2
1H NMR (500 MHz, CDCl3): δ 7.23 (1H, d, J = 1.9 Hz), 6.68 ( 5 ml) at -78 °C was added DMSO (0.17 ml, 2.40 mmol, 2.40
(1H, dd, J = 7.7, 1.9 Hz), 6.41 (1H, d, J = 7.8 Hz), 6.34 (1H, d, eq.). The solution was stirred for 15 min at this temperature. A
J = 7.8 Hz), 6.18 (1H, dd, J = 7.7, 1.9 Hz), 5.48 (1H, d, J = 1.5 solution of 13-bromo-4-hydroxymethyl[2.2]paracyclophane
Hz), 4.28 (1H, ddd, J = 13.5, 9.8, 5.2 Hz), 3.88 (3H, s), 3.16 (0.32 g, 1.00 mmol, 1.00 eq.) in CH2Cl2 (5 ml) was slowly
(1H, ddd, J = 13.0, 9.8, 2.9 Hz), 3.07-2.90 (5H, m), 2.74 (1H, added and the reaction stirred for a 15 min at -78 °C. Et3N (0.70
ddd, J = 14.0, 10.7, 5.2Hz). 13C NMR (125 MHz, CDCl3): ml, 5.00 mmol, 5.00 eq.) was added and the reaction mixture
δ 169.2, 142.0, 140.8, 138.9, 136.4, 135.5, 135.0, 133.8, 127.5, stirred for a further 1h at -78 °C and then warmed to rt. The
124.9, 122.9, 121.3, 51.8, 35.0, 34.8, 31.9, 31.5. Data reaction mixture was partitioned between CH2Cl2 (10 ml) and
comparable to that reported in the literature.16
H2O (10 ml). The aqueous layer extracted with CH2Cl2 (2 x 10
Methyl 13-bromo[2.2]paracyclophane-4-carboxylate (16).18 ml). The combined organic layers were washed with H2O (20
To a two-necked round bottom flask charged with iron filings ml), dried (MgSO4) and the solvent was removed. The resulting
(0.067 g, 1.2 mmol, 0.3 eq.) covered with foil was fitted a residue was purified by column chromatography eluting with
dropping funnel filled with Br2 (0.206 ml, 4.0 mmol, 1.0 eq.) in Hex/EtOAc
9/1
to
afford
the
13-bromo-4-
CH2Cl2 (20 ml) (the stock solution). Stock solution (2 ml) was formyl[2.2]paracyclophane 17 as a colourless solid (0.29 g,
added to the iron filings and stirred for 30 min at rt. A solution 92%).
of methyl [2.2]paracyclophane-4-carboxylate 12 (1.06 g, 4.0 Rf (9/1 Hex/EtOAc) 0.43
mmol, 1.0 eq) in dry CH2Cl2 (20 ml) was added and the stock 1H NMR (500 MHz, CDCl3): δ 10.3 (1H, s), 7.10 (1H, d, J =
solution was then added dropwise over 1h. The resulting 1.9 Hz), 6.77 (1H, dd, J = 7.8, 1.5 Hz), 6.63 (1H, dd, J = 7.8,
mixture was stirred for 1h at rt. The mixture was washed with 1.5 Hz), 6.58 (1H, d, J = 7.8 Hz), 6.53 (1H, d, J = 7.8 Hz), 6.50
sat. aqueous Na2S2O3 (30 ml) and brine (30 ml) and dried (1H, d, J = 1.5 Hz), 4.16 (1H, ddd, J = 10.1, 7.3, 4.2 Hz), 3.55
(MgSO4). The solution was filtered and the solvent was (1H, ddd, J = 10.1, 6.3, 3.2 Hz), 3.18-2.93 (6H, m). 13C NMR
removed under reduced pressure to afford the desire product 16 (125 MHz, CDCl3): δ 190.9, 143.0, 141.8, 140.2, 138.9, 138.1,
as a pale yellow solid (1.28 g, 93%).
Rf (9/1 Hex/EtOAc) 0.45
136.9, 136.4, 136.1, 135.2, 134.0, 131.5, 128.3, 35.6, 35.1,
34.9, 30.4. HRMS (EI) found: [M+Na]+ 337.0208.
1H NMR (500 MHz, CDCl3): δ 7.35 (1H, d, J = 1.9 Hz), 6.69 C17H15BrONa requires [M+Na]+ 337.0198.
(1H, dd, J = 7.8, 1.9 Hz), 6.60 (1H, d, J = 1.9 Hz), 6.57-6.54 13-Bromo[2.2]paracyclophane-4-carbaldehyde oxime (18).
(3H, m), 4.43-4.37 (1H, m), 3.89 (3H, s), 3.22-3.01 (1H, m), To a mixture of hydroxylamine hydrochloride (.21 g, 3.0 mmol,
3.15-2.92 (6H, m). 13C NMR (125 MHz, CDCl3): δ 167.5, 3.0 eq.) and NaOH (0.12 g, 3.1 mmol, 3.1 eq.) in EtOH (10 ml)
142.8, 141.4, 139.2, 139.2, 136.6, 136.5, 136.2, 134.9, 134.5, heated to reflux, was added a solution of 13-bromo-4-
formyl[2.2]paracyclophane 17 (0.32 g, 1.0 mmol, 1.0 eq.) in
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ethanol (40 ml). The resulting mixture was heated to reflux for CDCl3): δ 192.3, 163.6, 144.4, 141.1, 139.7, 139.4, 133.5,
View Article Online
30 min. The reaction was cooled to rt and the solvent removed. 132.6, 132.0, 131.6, 131.5, 130.0, 129.4,D6O2I.:51,0.31403.49,/C364O.5B,023145.00F,
The residue was dissolved in EtOAc (10 ml) and washed with 31.0. HRMS (EI) found: [M+Na]+ 289.1188. C18H18O2Na
H2O (10 ml) and brine (10 ml), dried (MgSO4) and the solvent requires [M+Na]+ 289.1199.
removed to give a colourless solid 18 that was used in the next 4-Methoxy[2.2]paracyclophane-5-carbaldehyde oxime (24).
reaction without further purification (0.33 g, 98%).
Rf (4/1 Hex/EtOAc) 0.15
A mixture of hydroxyl amine hydrochloride (0.21 g, 3.0 mmol,
3.0 eq.) and NaOH (0.12 g, 3.1 mmol, 3.1 eq.) in EtOH (5 ml)
1H NMR (500 MHz, DMSO-d6): δ 10.88 (1H, s), 8.25 (1H, s), was heated to reflux before a solution of 4-methoxy-5-
6.79 (1H, d, J = 1.6 Hz), 6.67-6.61 (3H, m), 6.59 (1H, dd, J = formyl[2.2]paracyclophane 23 (0.27 g, 1.0 mmol, 1.0 eq.) in
7.7, 1.6 Hz), 6.55 (1H, d, J = 7.4 Hz), 3.72 (1H, ddd, J = 17.0, EtOH (5 ml) was added. The resulting mixture was heated at
13.0, 3.3 Hz), 3.38 (1H, m), 3.03-2.95 (6H, m). 13C NMR (125 reflux for 30 min then cooled to rt and the solvent removed.
MHz, DMSO-d6): δ 148.4, 141.7, 139.2, 138.1, 137.6, 135.6, The residue was dissolved in EtOAc (10 ml) and washed with
135.5, 135.2, 133.7, 132.3, 132.1, 130.6, 125.3, 34.4, 34.3, H2O (10 ml) and brine (10 ml), dried (MgSO4) and the solvent
33.9, 31.5. HRMS (EI) found: [M+Na]+ 352.0307. removed to give the desired product 24 as a pale yellow solid
C17H16BrNONa requires [M+Na]+ 352.0313.
(0.24 g, 83%).
4-Amino-13-bromo[2.2]paracyclophane (19).51 A mixture of Rf (4/1 Hex/EtOAc) 0.43
finely ground 13-bromo[2.2]paracyclophane-4-carbaldehyde 1H NMR (500 MHz, CDCl3): δ 8.45 (1H, s), 8.20 (1H, s), 6.80
oxime 18 (0.17 g, 0.5 mmol, 1.0 eq.) and finely ground Koser’s (1H, dd, J = 10.0, 2.2 Hz), 6.51-6.59 (3H, m), 6.47 (1H, dd, J =
reagent (0.27 g, 0.7 mmol, 1.4 eq.) in DMSO (1 ml) was stirred 8.7, 2.2 Hz), 6.43 (1H, d, J = 6.9 Hz), 3.83 (1H, ddd, J = 17.2,
at rt for 30 min then heated to 80 °C for 1h. Finely ground 10.0, 1.8,Hz), 3.65 (3H, s), 3.30 (1H, ddd, J = 13.4, 10.2, 3.4
NaOH (0.03 g, 0.7 mmol, 1.4 eq.) was added and heating was Hz), 3.15-3.09 (2H, m), 3.03-2.95 (2H, m), 2.82-2.68 (2H, m).
continued for 1.5h. The mixture was cooled to rt and H2O (1 13C NMR (125 MHz, CDCl3): δ 158.4, 148.2, 141.6, 139.5,
ml) was added. The mixture was extracted with EtOAc (2 x 20 139.2, 136.5, 133.3, 132.6, 131.8, 131.3, 130.5, 129.2, 126.0,
ml). The combined organic layers were washed with H2O (20 61.7, 34.6, 34.4, 34.0, 31.1. HRMS (EI) found: [M+Na]+
ml), dried (MgSO4) and the solvent removed. The resulting 304.1313. C18H19NO2Na requires [M+Na]+ 304.1308.
residue was purified by column chromatography eluting 5-Amino-4-methoxy[2.2]paracyclophane (25). A mixture of
Hex/EtOAc
9/1
to
afford
13-bromo-4- finely ground 4-methoxy[2.2]paracyclophane-5-carbaldehyde
amino[2.2]paracyclophane 19 as a pale yellow solid (98 mg, oxime 24 (0.23 g, 0.8 mmol, 1.0 eq.) and finely ground Koser’s
65%).
reagent (0.44 g, 1.1 mmol, 1.4 eq.) in DMSO (1.6 ml) was
stirred at rt for 30 min and then heated to 80 °C for 1h. Finely
Rf (4/1 Hex/EtOAc) 0.53
1H NMR (500 MHz, CDCl3): δ 6.83 (1H, d, J = 1.8 Hz), 6.47 ground NaOH (0.05 g, 1.1 mmol, 1.4 eq.) was added and the
(1H, dd, J = 17.7, 1.5 Hz), 6.43 (1H, d, J = 7.6 Hz), 6.40 (1H, d, reaction heated for further 1.5h. The mixture was cooled to rt
J = 7.6 Hz), 6.10 (1H, dd, J = 7.8, 1.8 Hz), 5.70 (1H, d, J = 1.8 and H2O (2 ml) was added and the aqueous layer extracted with
Hz), 3.69 (1H, ddd, J = 14.1, 9.7, 2.4 Hz), 3.33 (1H, ddd, J = EtOAc (2 x 20 ml). The combined organic layers were washed
13.8, 10.3, 2.4 Hz), 3.13-3.00 (2H, m), 2.95-2.83 (4H, m). 13C with H2O (20 ml), dried (MgSO4) and the solvent was removed.
NMR (125 MHz, CDCl3): δ147.1, 141.1, 140.7, 138.3, 135.5, The resulting residue was separated by column chromatography
135.5, 135.3, 132.8, 123.6, 123.2, 122.6, 121.2, 35.0, 34.8, eluting Hex/EtOAc 9/1 to afford the 5-amino-4-
33.2, 31.6. HRMS (EI) found: [M+H]+ 302.0554. C16H17BrN methoxy[2.2]paracyclophane 25 as a colourless solid (0.12 g,
requires [M+H]+ 302.0539. Data comparable to that reported in 59%).
the literature.51
4-Methoxy-5-formyl[2.2]paracyclophane
Rf (4/1 Hex/EtOAc) 0.60
1H NMR (500 MHz, CDCl3): δ 6.97 (1H, dd, J = 7.8, 1.8 Hz),
(23).
To
a
suspension of 4-hydroxy-5-formyl[2.2]paracyclophane54 20 6.64 (1H, dd, J = 7.8, 1.8 Hz), 6.53 (1H, dd, J = 7.8, 1.8 Hz),
(0.25 g, 1.0 mmol, 1.0 eq.) and K2CO3 (0.41 g, 3.0 mmol, 3.0 6.43 (1H, dd, J = 7.8, 1.8 Hz), 6.18 (1H, d, J = 7.8 Hz), 6.10
eq.) in DMF (2 ml) was added iodomethane (0.19 ml, 0.43 g, (1H, d, J = 7.8 Hz), 3.62 (3H, s), 3.17 (1H, ddd, J = 13.3, 9.1,
3.0 mmol, 3.0 eq.). The reaction mixture was stirred at rt for 4.2 Hz), 3.09-2.90 (5H, m), 2.66-2.56 (2H, m). 13C NMR (125
12h then diluted with H2O (10 ml). The aqueous layer was MHz, CDCl3): δ 146.7, 139.1, 139.0, 138.1, 132.7, 132.3,
extracted with EtOAc (2 x 20 ml) and dried (MgSO4). The 132.2, 130.2, 128.3, 126.7, 125.9, 124.1, 60.2, 34.3, 33.0, 31.2,
solvent was removed and the resulting pale yellow solid was 30.7. HRMS (EI) found: [M+H]+ 254.1548. C16H16BrN
used for the next reaction without further purification (0.27 g, requires [M+H]+ 254.1539.
quant.).
[2.2]Paracyclophane-4-carbaldehyde O-methyl oxime.55 To
Rf (4/1 Hex/EtOAc) 0.70
a solution of methoxyamine hydrochloride (0.10 g, 1.2 mmol,
1H NMR (500 MHz, CDCl3): δ 10.11 (1H, s), 6.80 (1H, dd, J = 1.2 eq.) and dry pyridine (0.32 ml, 4.0 mmol, 4.0 eq.) in CH2Cl2
7.9, 1.9 Hz), 6.67 (1H, d, J = 7.9 Hz), 6.58 (1H, dd, J = 7.9, 1.8 (4 ml) was added 4-formyl[2.2]paracyclophane (0.24 g, 1.0
Hz), 6.43 (1H, dd, J = 7.9, 1.9 Hz), 6.42 (1H, d, J = 7.6 Hz), mmol, 1.0 eq.) and the reaction mixture stirred at rt for 12h.
6.37 (1H, dd, J = 7.9, 1.9 Hz), 4.06 (1H, ddd, J = 12.2, 10.1, 1.4 The solvent was removed under reduced pressure. The resulting
Hz), 3.33 (1H, ddd, J = 13.6, 10.1, 3.6 Hz), 3.20-3.12 (2H, m), crude residue was purified by column chromatography eluting
3.10-2.99 (2H, m), 2.80-2.73 (2H, m). 13C NMR (125 MHz, Hex/EtOAc 9/1 to afford the [2.2]paracyclophane-4-
8 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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carbaldehyde O-methyl oxime as a colourless solid (240 mg, formyl[2.2]paracyclophane 26 (0.24 g, 0.8 mmoVl,iew1A.0rticeleqO.)nlinine
DOI: 10.1039/C6OB02150F
91%).
ethanol (3 ml). The resulting mixture was heated to reflux for
30 min. The reaction was cooled to rt and the solvent was
Rf (9/1 Hex/EtOAc) 0.70
1H NMR (500 MHz, CDCl3): δ 8.10 (1H, s), 6.79 (1H, d, J = removed. The residue was dissolved in EtOAc (10 ml) and
1.8 Hz), 6.66 (1H, d, J = 8.0 Hz), 6.56-6.52 (3H, m), 6.53-6.43 washed with H2O (10 ml) and brine (10 ml), dried (MgSO4) and
(2H, m), 4.04 (3H, s), 3.62 (1H, ddd, J = 13.3, 10.0, 1.8 Hz), the solvent removed to give the desired product 27 as a
3.20-2.96 (6H, m), 2.87 (1H, ddd, J = 17.1, 10.3, 6.7 Hz). 13C colourless solid (0.23 g, 94%).
NMR (125 MHz, CDCl3): δ 148.0, 140.2, 139.4, 139.3, 139.2, Rf (9/1 Hex/EtOAc) 0.25
135.3, 133.9, 133.2, 133.0, 132.9, 132.2, 132.0, 131.0, 62.0, 1H NMR (500 MHz, CDCl3): δ 8.24 (1H, s), 7.65 (1H, brs),
35.4, 35.1, 34.9, 34.0. Data comparable to that reported in the 7.26 (1H, s), 6.98 (1H, dd, J = 7.8, 1.8 Hz), 6.61 (1H, d, J = 7.8
literature.55
Hz), 6.60 (1H, dd, J = 7.8, 1.8 Hz), 6.53 (2H, d, J = 7.8 Hz),
5-Bromo[2.2]paracyclophane-4-carbaldehyde
O-methyl 6.52 (1H, dd, J = 7.8, 1.8 Hz), 3.77 (1H, ddd, J = 13.0, 10.1, 2.6
oxime.55 To a solution of N-bromosuccinimide (0.64 g, 3.6 Hz), 3.50 (1H, ddd, J = 13.0, 10.3, 3.4 Hz), 3.30-2.98 (4H, m),
mmol, 1.2 eq.), Pd(OAc)2 (0.13 g, 0.6 mmol, 0.2 eq.) and 2.90-2.82 (2H, m). 13C NMR (125 MHz, CDCl3): δ151.7,
AgOTf (0.13 g, 0.6 mmol, 0.2 eq.) in DCE (60 ml), was added 141.7, 140.1, 139.6, 139.1, 135.1, 134.1, 133.4, 133.0, 131.7,
[2.2]paracyclophane-4-carbaldehyde O-methyl oxime XX (0.80 130.3, 129.4, 128.4, 36.1, 34.8, 34.6, 33.3. HRMS (EI) found:
g, 3.0 mmol, 1.0 eq.) and the reaction mixture was stirred at [M+Na]+, 352.0307. C17H1679BrNONa requires [M+Na]+,
100 °C for 8h. The reaction was cooled to rt and diluted with 352.0313.
CH2Cl2 (35 ml) and H2O (35 ml). Aqueous layer was extracted 4-Amino-5-bromo[2.2]paracyclophane (28). A mixture of
with CH2Cl2 (2 x 25 ml). The combined organic layers were finely ground 5-bromo[2.2]paracyclophane-4-carbaldehyde
dried (MgSO4) and filtered through celite. The solvent was oxime 27 (0.17 g, 0.5 mmol, 1.0 eq.) and ground Koser’s
removed and the resulting residue was separated by column reagent (0.27 g, 0.7 mmol, 1.4 eq.) in DMSO (1 ml) was stirred
chromatography eluting Hex/CH2Cl2 4/1 to afford 5- at rt for 30 min then heated to 80 °C for 1h. Finely ground
bromo[2.2]paracyclophane-4-carbaldehyde O-methyl oxime as NaOH (0.03 g, 0.7 mmol, 1.4 eq.) was added and heating was
a colourless solid (0.62 g, 60%).
Rf (9/1 Hex/EtOAc) 0.725
continued for 1.5h. The mixture was cooled to rt, H2O (1 ml)
was added and the aqueous layer was extracted with EtOAc (2
1H NMR (500 MHz, CDCl3): δ 8.15 (1H, s), 6.97 (1H, d, J = x 20 ml). The combined organic layers were washed with H2O
7.6 Hz), 6.60-6.49 (5H, m), 4.02 (3H, s), 3.62-3.46 (1H, m), (20 ml), dried (MgSO4) and the solvent removed. The resulting
3.52-3.46 (1H, m), 3.19-3.01 (4H, m), 2.90-2.87 (2H, m). 13C residue was separated by column chromatography eluting
NMR (125 MHz, CDCl3): δ 148.9, 141.6, 139.6, 139.0, 134.9, Hex/EtOAc 9/1 to afford 4-amino-5-bromo[2.2]paracyclophane
134.1, 133.4, 133.0, 131.7, 130.0, 129.5, 128.4, 62.3, 36.0, 28 as a pale yellow solid (0.09 g, 56%).
35.0, 34.5, 33.3. Data comparable to that reported in the Rf (9/1 Hex/EtOAc) 0.425
literature.55
1H NMR (500 MHz, CDCl3): δ 6.98 (1H, dd, J = 7.8, 1.8 Hz),
5-Bromo-4-formyl[2.2]paracyclophane (26).55 The solution 6.92 (1H, dd, J = 7.8, 1.8 Hz), 6.58 (1H, d, J = 7.8 Hz), 6.50
of 5-bromo[2.2]paracyclophane-4-carbaldehyde O-methyl (1H, dd, J = 7.8, 1.8 Hz), 6.37 (1H, d, J = 7.8 Hz), 6.18 (1H, d,
oxime (0.095 g, 0.28 mmol, 1.0 eq.), para-toluenesulfonic acid J = 7.8 Hz), 3.95 (2H, brs), 3.35 (1H, ddd, J = 17.0, 10.1, 1.7
(0.095 g, 0.55 mmol, 2.0 eq.), formaldehyde (37% in H2O; Hz), 3.15-2.93 (5H, m), 2.72-2.83 (2H, m). 13C NMR (125
0.207 ml, 2.76 mmol, 10.0 eq.) in toluene:H2O (10:1; 6ml) was MHz, CDCl3): δ142.7, 140.5, 138.3, 138.2, 133.3, 132.8, 132.5,
heated to reflux for 12h. The reaction was cooled to rt and the 127.7, 126.4, 126.0, 124.0, 116.0, 35.8, 33.1, 33.2, 32.4. HRMS
solvent removed. The resulting residue was purified by column (EI) found: [M+H]+, 302.0539. C16H1779BrN requires [M+H]+,
chromatography eluting Hex/EtOAc 10/1 to afford the 5- 302.0534.
bromo-4-formyl[2.2]paracyclophane 26 as a colourless solid 4-(5-Bromo[2.2]paracyclophan-4-yldiazenyl)morpholine
(0.080 g, 92%).
(29). To a solution of 5-bromo-4-amino[2.2]paracyclophane 28
Rf (9/1 Hex/EtOAc) 0.70
(0.075 g, 0.25 mmol, 1.0 eq.) in acetone (0.1 ml), acetonitrile
1H NMR (500 MHz, CDCl3): δ 10.08 (1H, s), 6.96 (1H, dd, J = (0.2 ml) and water (0.5 ml) at 0 °C was added a solution of 50%
7.8, 1.8 Hz), 6.65 (1H, d, J = 7.8 Hz), 6.61 (1H, dd, J = 7.8, 1.8 aqueous HBF4 (1 ml, excess). A solution of NaNO2 (0.0175 g,
Hz), 6.61 (1H, d, J = 7.8 Hz), 6.48 (1H, dd, J = 7.8, 1.8 Hz), 0.25 mmol, 1.0 eq.) in ice cold water (0.2 ml) was added
6.39 (1H, dd, J = 7.8, 1.9 Hz), 3.95-3.88 (1H, m), 3.62-3.56 dropwise at 0 °C. Within 10 minutes a dark yellow percipitate
(1H, m), 3.20-3.16 (3H, m), 3.11-3.04 (1H, m), 2.93-2.78 (2H, had formed. The solid was removed by filtration and washed
m). 13C NMR (125 MHz, CDCl3): δ 194.2, 144.9, 140.8, 139.8, with cold Et2O. The solid was mixed with morpholine (2 ml)
139.0, 138.6, 134.5, 134.2, 133.5, 132.9, 132.1, 131.2, 128.6, for 2 hours. The solution was diluted with CH2Cl2 (10 ml) and
35.3, 34.7, 34.5, 33.3. Data comparable to that reported in the H2O (10 mL). The layers were separated and the organic layer
literature.55
washed with H2O (2 x 10 mL), dried (MgSO4) and
5-Bromo[2.2]paracyclophane-4-carbaldehyde oxime (27). concentrated. The resulting solid was recyrstalised from CDCl3
To a mixture of hydroxylamine hydrochloride (0.16 g, 2.3 (50 mg, 50%).
mmol, 3.0 eq.) and NaOH (0.09 g, 2.3 mmol, 3.1 eq.) in ethanol Rf (9/1 Hex/EtOAc) 0.70
(5 ml) heated to reflux was added a solution of 5-bromo-4-
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J. Name., 2013, 00, 1-3 | 9
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OrgaPnleicas&e Bdoionmoot laedcjuulsatrmCahregimnsistry
Page 10 of 14
ARTICLE
Journal Name
1H NMR (500 MHz, CDCl3): δ 7.06 (1H, dd, J = 6.8, 1.2 Hz), 21.6. HRMS (EI) found: [M+Na]+, 444.1306. C2V H2ANNaO4nSe
4
iew 3rticle Onli
6.69 (1H, dd, J = 6.8, 1.2 Hz), 6.58-6.53 (3H, m), 6.41 (1H, d, J requires [M+Na]+, 444.1240.
= 7.7 Hz), 3.94-3.82 (8H, m), 3.49 (1H, ddd, J = 13.1, 10.3, 2.5
DOI: 10.1039/C6OB02150F
Resolution
Hz), 3.29 (1H, ddd, J = 12.5, 9.8, 2.4 Hz), 3.17 (1H, ddd, 15.6,
10.3, 5.2 Hz), 3.08-3.00 (2H, m), 2.89-2.80 (2H, m), 2.67 (1H, To a solution of 4-(p-toluenesulfonamido)[2.2]paracyclophane-
ddd, J = 16.3, 10.2, 6.1 Hz). 13C NMR (125 MHz, CDCl3): 13-carboxylic acid (1.0 g, 2.38 mmol, 1.0 eq.) in CH2Cl2 (5 ml),
δ146.8, 140.7, 139.3, 138.8, 133.9, 133.3, 132.9, 132.7, 131.3, a milky suspension of cinchonine in acetone (8 ml) was added
129.9, 123.9, 66.6, 48.01 (br), 35.6, 34.4, 33.5, 32.9. HRMS dropwise and the resulting mixture was stirred for 1.5h at rt.
(EI) found: [M+H]+, 400.1048. C20H2379BrN3O requires The resulting precipitate was filtered (0.60 g); this was the first
[M+H]+, 400.1025.
Methyl 4-(p-toluenesulfonamido)[2.2]paracyclophane-13- brownish solid (0.93 g); this was the second diastereomeric salt.
carboxylate (30). To solution of methyl 4- Separately, the salts were recrystalised from CH2Cl2.
diastereomeric salt. The filtrate was concentrated to give a
a
amino[2.2]paracyclophane-13-carboxylate (1.7 g, 6.0 mmol, Separately, the resulting salts were dissolved in MeOH (10 ml)
1.0 eq.) in THF (90 ml) at 0°C was added NaH (60%; 0.29 g, and 2M HCl(aq.) was added. Each mixture was allowed to stir at
12.0 mmol, 2.0 eq.) portionwise over 10 min. The suspension rt for several hours. The resulting precipitates were filtered
was stirred for 15 minutes whereupon p-toluenesulfonyl (first enantiomer 0.53 g, second enantiomer 0.31 g). HPLC
chloride (1.38 g, 7.2 mmol, 1.2 eq.) was added in several indicated that the acid dervied from the first diasteremoeric salt
portions. The suspension was warmed to rt and then heated at (the solid) had an enantiomeric excess of 82% while the acid
reflux overnight. In the morning the suspension was cooled to rt derived from the filtrate had an enantiomeric excess of 89%.
and washed with H2O (4 x 30 ml), dried (MgSO4) and A Chiralpak AD(-H) column was used with an isopropyl
concentrated. The residue was purified by column alcohol : hexane (20 : 80) mixture as eluent at a flow rate of 1.0
chromatography (SiO2; gradient 10:1 hexane:EtOAc to 2:1 ml min-1. Enantiomer 1 retention time = 13.18 min. Enantiomer
Hexane:EtOAc) to give the product 30 (1.29 g, 49%).
Rf (10:1 Hex:EtOAc) 0.53
1H NMR (500MHz, CDCl3): δ 7.36 (1H, dd, J = 8.3, 1.8 Hz), enantiomer 2 had an er = 10 : 90.
2: retention time = 17.75 min. See Supplementary Material for
reproduction of traces. Enantiomer 1 had an er = 83 : 17 and
7.35 (1H, dd, J = 8.3, 1.8 Hz), 7.12-7.09 (3H, m), 6.65 (1H, dd, N-(3,5-Bis(trifluoromethyl)phenyl)-4-(p-
J = 7.8, 1.8 Hz), 6.53 (1H, d, J = 5.2 Hz), 6.52 (1H, d, J = 10.4 toluenesulfonamido)[2.2]paracyclophane-13-carbamide
Hz), 6.43 (1H, dd, J = 7.8, 1.8 Hz), 6.33 (1H, brs), 5.94 (1H, d, (32).
To
a
suspension
of
4-(p-
J = 1.7 Hz), 4.05 (1H, ddd, J = 13.1, 10.0, 3.1 Hz), 4.00 (3H, s), toluenesulfonamido)[2.2]paracyclophane-13-carboxylic
acid
3.54 (1H, ddd, J = 13.1, 10.0, 5.2 Hz), 3.12-2.78 (6H, m), 2.33 (0.15 g, 0.36 mmol, 1.0 eq.) in CH2Cl2 (3.5 ml) was added
(3H, s). 13C NMR (125 MHz, CDCl3): δ167.4, 143.3, 142.1, oxalyl chloride (0.04 ml, 0.43 mmol, 1.2 eq.) and a drop of
140.7, 139.4, 136.4, 136.3, 136.2, 135.3, 135.2, 134.3, 131.8, DMF. The solution was allowed stirred for 3 hrs at rt. The
130.9, 129.3, 127.0, 52.6, 34.8, 34.5, 34.3, 31.5, 21.5. HRMS solvent was removed and the residue re-dissolved in toluene
(EI) found: [M+Na]+, 458.1333. C25H25NNaO4S requires (3.5 ml). 3,5-Bis(trifluoromethyl)aniline (0.07 ml, 0.43 mmol,
[M+Na]+, 458.1402.
4-(p-Toluenesulfonamido)[2.2]paracyclophane-13-
1.2 eq.) was added and the mixture heated to reflux overnight.
The solvent was removed. The resulting residue was purified by
carboxylic acid (31). To
a solution of methyl 4-(p- column chromatography eluting Hex/EtOAc 2/1 to afford the
toluenesulfonamido)[2.2]paracyclophane-13-carboxylate (0.44 N-(3,5-bis(trifluoromethyl)phenyl)-4-(p-
g, 1.0 mmol, 1.0 eq.) in EtOH (10 ml) was added a solution of toluenesulfonamido)[2.2]paracyclophane-13-carbamide 32 as a
2M KOH (5 ml). The resulting mixture was heated to reflux for pale yellow solid (0.13 g, 57%).
5h. The reaction was cooled in an ice bath, acidified to pH 5 Rf (2/1 Hex/EtOAc) 0.30
with 2M HCl and the resulting precipitate collected by 1H NMR (500 MHz, CDCl3): δ 8.15 (2H, s), 7.91 (1H, s), 7.80
filteration. The precipitate was dissolved in CH2Cl2 (10 (1H, s), 7.68 (1H, s), 7.43 (2H, d J = 8.2 Hz), 7.37 (1H, s), 7.12
ml),dried (MgSO4) and the solvent removed to give 4-(p- (2H, d, J = 8.2 Hz), 6.89 (1H, d, J = 1.8 Hz), 6.63 (1H, dd, J =
toluenesulfonamido)[2.2]paracyclophane-13-carboxylic acid 31 7.8, 1.8 Hz), 6.58 (1H, d, J = 7.8 Hz), 6.54-6.51 (2H, m), 5.95
as a brownish solid (0.32 g, 75%). The sample was sufficiently (1H, d, J = 1.4 Hz), 3.75-3.62 (2H, m), 3.13-2.94 (5H, m), 2.73
pure to use in the subsequent reactions.
Rf (20/1 DCM/MeOH) 0.30
(1H, ddd, J = 13.6, 10.8, 4.4 Hz), 2.34 (3H, s). 13C NMR (125
MHz, CDCl3): δ169.6, 143.1, 140.7, 140.2, 139.0, 138.7, 136.8,
1H NMR (500 MHz, CDCl3): δ 7.89 (1H, s), 7.50 (2H, d, J = 136.5, 136.2, 135.7, 135.2, 134.5, 132.7, 132.4, 132.2, 131.5,
8.2 Hz), 7.14 (1H, d, J = 1.8 Hz), 7.06 (2H, d, J = 8.2 Hz), 6.74 131.1, 129.3, 127.1, 127.0, 124.2, 122.4, 120.2, 118.2, 111.9,
(1H, dd, J = 7.8, 1.8 Hz), 6.62 (1H, d, J = 7.8 Hz), 6.53 (1H, d, 34.8, 34.5, 33.2, 32.5, 21.5. Splitting by the fluorine causes the
J = 7.8 Hz), 6.35 (1H, dd, J = 7.8, 1.8 Hz), 6.22 (1H, d, J = 1.8 13C NMR to be more complex than normal. HRMS (EI) found:
Hz), 4.45-4.38 (1H, m), 3.93-3.85 (1H, m), 3.15-2.86 (6H, m), [M+Na]+, 655.1410. C32H26F6N2NaO3S requires [M+Na]+,
2.28 (3H, s). 13C NMR (125 MHz, CDCl3): δ 172.2, 144.0, 655.1461.
143.4, 140.7, 139.6, 136.9, 136.5, 136.4, 136.1, 136.0, 135.4, 4-(p-Toluenesulfonamido)-N-
134.8, 131.2, 129.4, 128.2, 128.1, 127.4, 35.9, 34.9, 34.7, 31.2, ((trifluoromethyl)sulfonyl)[2.2]paracyclophane-13-
carbamide
(33).
To
a
suspension
of
4-(p-
10 | J. Name., 2012, 00, 1-3
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4
S. E. Gibson and J. D. Knight, Org. Biomol. Chem., 2003,
1, 1256; V. Rozenberg, E. SergDeeOvI:a10a.1n0d3V9ieH/wC.6AOrHticBol0ep2Of1,n5li0niFne
Modern Cyclophane Chemistry, eds. R. Gleiter and H.
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Organomet. Chem., 2012, 717, 14.
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toluenesulfonamido)[2.2]paracyclophane-13-carboxylic acid 31
(50 mg, 0.12 mmol, 1.0 eq.) in CH2Cl2 (1.2 ml) was added
oxalyl chloride (12 ml, 0.14 mmol, 1.2 eq.) and a drop of DMF.
The solution was stirred at rt for 3h. The solvent was removed
and the residue dissolved in THF (2 ml). To a solution of
trifluoromethanesulfonamide (21 mg, 0.14 mmol, 1.2 eq.) in
THF (1 ml) was added a suspension of NaH (60%; 6 mg, 0.24
mmol, 2.0 eq.) followed by the solution of 4-(p-
toluenesulfonamido)[2.2]paracyclophane-13-carbonyl chloride.
The reaction mixture was stired at rt for 3h. The reaction
mixture was cooled to 0 °C and H2O (two drops) added. The
reaction mixture was diluted with CH2Cl2 (10 ml) and dried
(MgSO4) before the solvent was removed. The resulting residue
was separated by column chromatography eluting Hex/EtOAc
5
6
7
8
9
2/1
to
afford
the
4-(p-toluenesulfonamido)-N-
10
11
((trifluoromethyl)sulfonyl)[2.2]paracyclophane-13-carbamide
33 as a brown solid (36 mg, 56%).
Rf (20/1; CH2Cl2/MeOH) 0.3
1H NMR (500 MHz, CDCl3): δ 7.68 (1H, s), 7.43 (2H, d, J =
8.2 Hz), 7.40 (1H, d, J = 1.8 Hz), 7.07 (2H, d, J = 8.2 Hz), 6.73
(1H, dd, J = 7.8, 1.8 Hz), 6.60 (1H, d, J = 7.8 Hz), 6.52 (1H, d,
J = 7.8 Hz), 6.36 (1H, dd, J = 7.8, 1.8 Hz), 6.24 (1H, d, J = 1.6
Hz), 4.43-4.35 (1H, m), 3.84-3.75 (1H, m), 3.17-2.86 (6H,m),
2.29 (3H, s). 13C NMR (125 MHz, CDCl3): δ 172.2, 143.9,
143.4, 140.8, 139.6, 137.0, 136.5, 136.4, 136.1, 135.8, 135.4,
134.6, 131.2, 129.4, 128.6, 128.2, 127.3, 35.5, 34.9, 34.8, 31.1,
21.6 (includes fluorine splitting).
12
13
14
Acknowledgements
The authors thank Massey University for financial support
(GJR), a Massey Vice Chancellor’s Doctoral Scholarship (LE),
a Massey University Technician Award (GK), and the Ecole
Nationale Supérieure de Chimie de Rennes for support (LD).
Notes and references
‡ We have previously found BINAP to be the optimum ligand for
the coupling of anilines to ortho-substituted [2.2]paracyclophane
triflates.59 This demonstrates the substrate sensitivity of
Buchwald-Hartwig couplings.
† This yield is based on a yield of 90% and 97% for the synthesis
of [2.2]paracyclophane-4-carboxylic acid and its methyl
esterification respectively (average yields) then the highest yields
for each of the subsequent steps.
§ We briefly studied the amination reaction with L-proline. We
noted a slight improvement in conversion but there was no
indication by HPLC or circular dichroism of the isolated amine
that there had been any enrichment.
§§ The transannular effect guides electrophilic aromatic
substitution to the pseudo-gem position.60 Bromination gives the
best results. There are examples of chloromethylation61 and the
Rieche formylation17 while pseudo-gem nitration met with
limited success.53
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Table of Contents entry
X = Br
1 step
H
N
H
N
X = CHO
2 steps
R1
H
X
R1
H
3 examples
R2, R3 = Br
and/or NH2
R2
5 examples
R1, R2 = Br,
R2
R2
R3
R3
CO2Me or OMe
Amino[2.2]paracyclophanes can be prepared by direct amination of
bromo[2.2]paracyclophanes or more generally by formylation–oxime formation–
oxidation–Lossen-like rearrangement sequence.