The synthesis of planar chiral pseudo-gem aminophosphine pre-ligands based on [2.2]paracyclophane

Article abstract of DOI:10.1039/c7ob02393f

The synthesis of three planar chiral pseudo-gem disubstituted [2.2]paracyclophane-derived P,N-pre-ligands is reported along with preliminary results of their activity in the amination of aryl bromides and chlorides. The pseudo-gem aminophosphines were capable of mediating the coupling reaction at a loading of 1 mol%.

Full text of DOI:10.1039/c7ob02393f

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DOI: 10.1039/C7OB02393F.
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DOI: 10.1039/C7OB02393F
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The synthesis of planar chiral pseudo-gem aminophosphine pre-
ligands based on [2.2]paracyclophane
Krishanthi P. Jayasundera,a Tim G. W. Engels,a,b David J. Lun,a Maulik N. Mungalpara,a Paul, G.
Received 00th January 20xx,
Accepted 00th January 20xx
Plieger,a and Gareth J. Rowlands*a
DOI: 10.1039/x0xx00000x
The synthesis of three planar chiral pseudo-gem disubstituted [2.2]paracyclophane-derived P,N-pre-ligands is reported along
with preliminary results of their activity in the amination of aryl bromides and chlorides. The pseudo-gem aminophosphines
were capable of mediating the coupling reaction at a loading of 1 mol%.
www.rsc.org/
improved results to be obtained from prototypical reactions as
well as the development of new synthetic transformations.
A highly successful class of P,N-ligands are the ‘DalPhos’
Introduction
The design and synthesis of bidentate ligands comprising of two
different donor atoms has been a successful avenue of
research.1 Each donor can interact with the metal centre
differently allowing modification of the properties of the
catalyst in order to aid distinct steps of the catalytic cycle.
compounds, such as
1 (Figure 1), developed by the Stradiotto
group.3c,3d,4 These are based on the ortho-P,N-phenylene
backbone and combine a bulky electron rich phosphine,
normally di(1-adamantyl)phosphine, with
a disubstituted
amine. While the adamantyl group is undoubtedly important to
the success of these pre-ligands, it is insufficient to explain their
remarkable reactivity; the amine moiety is equally important,
with the morpholine group of Mor-DalPhos proving particularly
effective.3a,5
O
PAd2
N
N
PAd2
TBSO
Chiral variants of DalPhos, such as
2, have been prepared
OTBS
(Figure 1) and applied to gold-mediated enantioselective
cyclopropanation reactions.6 These pre-ligands include
stereogenic centres on the amine substituents. This design
supposes that the P,N-ligands are bidentate during the
enantiodetermining step and that conformational changes keep
the stereogenic centres proximal to the metal centre.
An alternate approach to chiral DalPhos analogues would
incorporate the aromatic ring in a stereogenic unit. This could
be achieved by using [2.2]paracyclophane to introduce planar
chirality.7 [2.2]Paracyclophane’s rigid structure restricts
conformational freedom resulting in well-defined ligands such
as PhanePhos8 and GemPhos.9 These two ligands are isomeric,
with PhanePhos presenting the phosphine donors in the 4,12-
positions (pseudo-ortho) and GemPhos in the 4,13-positions
(pseudo-gem).
1
2
Mor-DalPhos
PPh2
NMe2
PPh2
N
iPr
O
3
(R)-MAP
Figure 1: Examples of reported P,N-Pre-ligands.
Ligands bearing phosphorus and nitrogen donors (P,N-ligands)
are amongst the most widely studied (Figure 1).2 and have
permitted challenging transformations to be achieved.2c,2g,3
Regardless of these past successes there is a continued need for
new P,N-ligands with different architectures. This will allow
We have studied a range of planar chiral heteroaromatic
monophosphines7d formed from the combination of
[2.2]paracyclophane with an imidazole ring (
or an indole (
) (Figure 2).12 While each of these pre-ligands
4 5
),10 a triazole ( ),11
6
showed potential it was clear that the [2.2]paracyclophane
moiety was a largely superfluous; if we wanted to exploit the
planar chirality of [2.2]paracyclophane we needed to design
bidentate derivatives.7d,13
Considering the potential of P,N-pre-ligands, there have been
surprisingly few based on [2.2]paracyclophane. A limited
This journal is © The Royal Society of Chemistry 20xx
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number of monophosphines with oxazoline (e.g.
Journal Name
3
),14 and range of temperatures all met with failure. In eVaiecwhArctiaclseeOntlhinee
pyridine15 substituents have been reported but in each case the starting material was recovered with excellent mass balance. To
donor atoms are separated from the [2.2]paracyclophane simplify the reaction, we attempted methylation either by
moiety by a linker. This changes the bite angle and potentially substitution or reductive amination but to no avail. Heating the
DOI: 10.1039/C7OB02393F
diminishes the effect of paracyclophane.
aniline-derivative to reflux in neat iodomethane, while
admittedly a relatively low temperature, resulted in the
complete recovery of the starting material. A variety of
acylations with anhydrides and acyl chlorides also returned
unreacted starting material. 12 proved to be remarkably
(a) Previous ligands
N
N
N
N
C5H11
N
N
P
P
R
R
P
unreactive.
R
R
X
R
R
Bräse
chemistry
ref. 17
O
O
4
5
6
(b) Proposed P,N-ligands
X
Br
X
R
N
N
N
10
NH2OH•HCl
NaOH
P
R
R
P
R
P
R
90 - 94 %
OTs
OH
R
I
7
8
9
OH
ortho
pseudo-gem
pseudo-ortho
N
Koser’s reagent
then NaOH
Figure 2: (a) Our previous planar chiral monophosphines and (b) proposed
aminophosphine [2.2]paracyclophane derivatives.
NH2
Br
55 - 56 %
Br
Therefore, we targeted planar chiral analogues of Mor-DalPhos.
There are three isomeric bidentate variants; the ortho
12
11
i. HBF4, NaNO2,
acetone, H2O
ii. morpholine
50%
substituted amino phosphine
the pseudo-ortho isomer ( ) (Figure 2). This communication
outlines the successful synthesis of the pseudo-gem isomer
7, the pseudo-gem isomer (8), and
9
8
,
and the obstacles encountered attempting to prepare 7.
R
N
O
N
N
R
N
Results and Discussion
Our initial target was the ortho-aminophosphine
Br
Br
7 as this most
closely mirrored the structure of Mor-DalPhos. The synthesis of
ortho-substituted [2.2]paracyclophanes can be problematic;
directed ortho-lithiations are notoriously fickle, being prone to
issues of regioselectivity (C2 versus C5 deprotonation)14c,16 and
chemoselectivity (1,4-addition versus 1,2-addition versus
deprotonation).14c By combining the elegant ortho-bromination
chemistry of Bräse17 with a modified Lossen rearrangement,18
we believed we could overcome these limitations and prepare
the key intermediate 12 (Scheme 1). Straightforward functional
group manipulations would then deliver the planar chiral
aminophosphine. Unfortunately, paracyclophane chemistry
frequently frustrates the best laid plans.
4-Bromo-5-formyl[2.2]paracyclophane 10 was readily prepared
following the literature procedures.17 Condensation with
hydroxylamine hydrochloride gave the oxime 11 in excellent
yield (Scheme 1). Treatment with Koser’s reagent,
hydroxy(tosyloxy)iodobenzene HTIB,19 initiated a ‘one-pot’
oxidation-rearrangement that, under our optimised
conditions,18a delivered the desired amine 12 in acceptable
yield. Having installed the challenging ortho-substitution
pattern, all that was left to achieve was elaboration of the
amine. Attempts to alkylate the amine with bis(2-
bromoethyl)ether in the presence of a variety of bases, and at a
13
Scheme 1: Attempted synthesis of ortho-aminophosphine derivative 7.
Only diazotisation resulted in the formation of a new product.
The diazonium salt could be trapped with morpholine to give
the triazene 13 (Figure 3). Attempts to prepare either the
bromoiodo species or the dibromo derivative from the
diazonium salt met with failure; both gave the same, as of yet,
unidentified side product. Our inability to alkylate amine 12 is
surprising; while anilines are less basic than alkylamines they
are normally sufficiently nucleophilic to undergo derivatisation.
4-Amino[2.2]paracyclophane readily reacts with a variety of
electrophiles, while a limited number of ortho-substituted
amino[2.2]paracyclophanes have participated in cyclisation
reactions.10,18a,20 We speculate that the reduced activity is a
result of increased delocalisation of the nitrogen lone pair due
to the bromine substituent, and increased steric congestion
around the amine. Presumably, diazotisation proceeds as the
nitrosyl reagent is both highly reactive, being potentially
cationic, and is small. We have observed reduced amine
reactivity in pseudo-gem amino acids (and esters),18a and have
attributed this to increased delocalisation as well as steric
effects.
2 | J. Name., 2012, 00, 1-3
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A
shorter
route
to
pseudo-gem
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DOI: 10.1039/C7OB02393F
aminobromo[2.2]paracyclophane 16 has been reported by
Paradies, and involves nitration, followed by regioselective
bromination, and reduction (Scheme 3).26 The capricious nature
of the nitration necessitated a modification of the reaction
conditions; addition of a solution of [2.2]paracyclophane 19 in
CH2Cl2 to a mixture of nitric and sulfuric acid at 0 °C minimises
multiple nitrations. Careful work-up is essential as a dark orange
oil often forms during the reaction. By decanting the reaction
mixture from this prior to work-up avoids emulsions, which
lower
the
yield.
Under
these
conditions
4-
nitro[2.2]paracyclophane was obtained in 49 - 95 %, which is
more than satisfactory for the nitration of [2.2]paracyclophane.
Regioselective bromination exploiting the transannular effect to
give the pseudo-gem product followed by reduction was
Figure 3: X-Ray structure of triazene 13 (N17–N18 = 1.263(4) Å and N18–N19 = 1.351(4)
Å).21 Ellipsoids are drawn at a 50% probability level.
achieved following the conditions of Paradies.26
i. HNO3, H2SO4, CH2Cl2 (49 - 95 %)
The stubborn stability of the ortho-substituted aniline
necessitated a change in target and we turned our attention to
the synthesis of the pseudo-gem analogue 7. Two routes were
ii. Br2, Fe (30 - 70 %)
iii. Fe, HCl (76 - 82 %)
NH2
Br
used to prepare this compound. The first route involved a ‘one-
pot’ oxidation-rearrangement reaction (Scheme 2).18a The
attraction of this longer route was the potential to resolve the
planar chirality at either the acid,22 or aldehyde stage.23
[2.2]Paracyclophane-4-carboxylic acid was prepared from
[2.2]paracyclophane by Friedel-Crafts acylation.24 While this
chemistry can deliver the ester directly, we always isolated a
mixture of ester and acid and elected to perform the
esterification in a second step. Directed bromination gave the
pseudo-gem disubstituted derivative 14 exclusively.25 A two-
step reduction-reoxidation to the aldehyde was more reliable
than partial reduction of the ester with DIBAL. The latter gives a
mixture of aldehyde and alcohol. Quantitative oxime formation
19
Scheme 3: Shorter synthesis of pseudo-gem aminobromo derivative.
16
The phosphine was introduced by metal-halogen exchange and
addition to the appropriate chlorophosphine. Competing
protodebromination appears to be unavoidable, and the
diphenylphosphine 15 could only be obtained in 40 - 59 % yield
(Scheme 3). A similar conversion was observed by 1H NMR
spectroscopy for the dicyclohexylphosphine derivative but it
was unstable to purification, and just 8 % was isolated. In situ
protection with borane improved the yield to a modest 33% on
a small scale (< 0.1 mmol). The reaction did not proceed for di-
tert-butylchlorophosphine. Attempts to introduce the
phosphine by a palladium-mediated coupling of bromo-17 with
various disubstituted phosphines all met with failure. In keeping
with all of our studies on pseudo-gem disubstituted
[2.2]paracyclophanes18a we speculate that the presence of the
second substituent hinders displacement of the bromide, while
gave 15
, which was subjected to ‘one-pot’ oxidation-
rearrangement to give the key aniline derivative 16. This time
the amino group was alkylated to form either the morpholine
17 or piperidine 18 derivative (Scheme 2).
i. LiAlH4
ii. (COCl)2, DMSO
OH
then Et3N
iii. NH2OH•HCl,
NaOH
O
N
Br
Br
OMe
the
highly
electron
rich
nature
destabilise
of
the
aniline-like
incipient
76 - 90 %
(3 steps)
[2.2]paracyclophane
could
organometallic intermediate.
X
X
i. t-BuLi
ii. R2PCl
(iii. BH3•THF)
14
15
(2 or 3 steps from
N
N
[2.2]paracyclophane)24,25
Koser’s reagent
then NaOH
59 - 65 %
Br
R
X
17 X = O
18 X = CH2
20 X = O; R = PPh2; 40 - 59 %
21 X = O; R = PCy2; 4 - 8 %
22 X = O; R = PCy2•BH3; 15 - 33 %
23 X = CH2; R = PPh2; 19 %
Br
Br
(BrCH2CH2)2X
K2CO3
N
NH2
X = O; 55 - 62 %
X = CH2; 50 - 68 %
Scheme 4: Synthesis of pseudo-gem aminophosphine.
17 X = O
18 X = CH2
16
Applying the best conditions to the piperidine analogue
permitted the synthesis of the diphenylphosphine derivative 23
in less than satisfactory yield (19 %). More protodebromination
Scheme 2: Synthesis of pseudo-gem aminobromo derivative.
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was observed than before suggesting that the organolithium (dppf), and t-Bu3P•HBF4, failed. Only [2.2]paracyclophane was
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intermediate of the piperidine derivative was even less stable isolated. Protodebromination suggests DtOhIa:t10t.1h0e39/mC7oOrpB0h2o3l9in3eF
than its morpholine counterpart. The yield is not helped by the complex is undergoing β-hydride elimination more rapidly than
similarity in both the Rf and solubility of the product and reductive elimination.27b,29
Ph
debromo derivative.
The efficacy of the new P,N-pre-ligands (20-23) in the amination
Br
N
R
H
conditions
of various aryl halides with morpholine was ascertained
(Scheme 5).27 Initial screening reactions suggested that the
optimum conditions employed palladium(π-cinnamyl) chloride
dimer (1 mol%), ligand (2 mol%), and sodium tert-butoxide (150
mol%) as base in toluene at 110 °C for 3 hours. The palladium
source could be changed with a small decrease in yield. The
base could not be altered without a dramatic drop in yield.
H
Br
N
R
Ph
24
25
19
conditions: [Pd(CH2CHCHPh)Cl]2 (1 mol%), ligand (2 mol%), HNR1R2
(150 mol%), t-BuONa (150 mol%), toluene, 110 °C, 12 hours.
yields: HNR1R2 = morpholine; [2.2]paracyclophane 19 R = H; > 90%
HNR1R2 = aniline; ligand = 22; di-25 37 % & 19 > 50%
R2
HNR1R2 = aniline; ligand = 20; di-25 21 % & 19 > 50%
X
R2
R3
conditions
N
R1
+
HNR1R2 = aniline; ligand = dppf; di-25 30 % & 19 > 50%
R3
N
H
R1
Scheme 6: Trial aminations of pseudo-ortho dibromo[2.2]paracyclophane 24.
conditions: [Pd(CH2CHCHPh)Cl]2 (1 mol%), ligand (2
mol%), t-BuONa (150 mol%), toluene, 110 °C, 3 hours
yields for ligand 20 (values in brackets used piperidine
derivative 23 as ligand)
To avoid β-hydride elimination we screened a number of
nitrogen nucleophiles without the problematic hydrogen
atoms. The only successful coupling was observed with aniline.
Dppf and pre-ligands 20 and 22 furnished the pseudo-ortho
dianiline adduct in low yield (30 %, 21 %, and 37 % respectively)
along with [2.2]paracyclophane. The slight increase in yield with
the dicyclohexyl derivative 22 suggests that the electron rich
bulky ligand improves reactivity. Unfortunately, until a more
efficient synthesis of this derivative can be developed it is
unclear if this is true. No other combination of amine, amide or
sulfonamide, with any of the pre-ligands tested gave any
O
MeO
O
O
N
N
N
N
X = Br; 99%
(51%)
X = Cl; 58%
(34%)
X = Cl; 99%
(51%)
Bn
N
MeO
Bn
N
Bn
N
N
product other than [2.2]paracyclophane 19
.
X = Br; 99%
(72%)
X = Cl; 80%
(31%)
X = Cl; 99%
(82%)
Conclusion
Scheme 5: Illustrative Buchwald-Hartwig aryl aminations.
We have synthesised three new planar chiral pseudo-gem
aminophosphine pre-ligands. These added to the limited
number of P,N-ligands-based on the [2.2]paracyclophane
moiety. The ligands displayed promising activity in the
Buchwald-Hartwig coupling reaction; they mediated the
coupling of deactivated aryl chlorides in good yields at low
catalyst loadings. Future work will investigate their resolution
and application to enantioselective transformations.
Additionally, we will study the pseudo-ortho derivative in order
to ascertain its ease of synthesis, and to investigate any effect
changing the separation of the two donor groups may have on
catalytic activity.
As Scheme 5 indicates morpholine and N-benzylmethanamine
could be coupled with electron rich (hetero)aryl bromides and
chlorides in moderate to excellent yields with low catalyst
loadings, and in relatively short reaction times. The range of
coupling partners does appear to be limited; sterically
demanding anilines, such as 2,6-dimethylaniline, fail to couple.
A
range
of
amide-like
substrates
including
p-
toluenesulfonamide, benzamide, and tert-butyl carbamate also
failed to react. It is unclear if the problem arises from an
incompatibility with the strong base required for the reaction or
that a κ2-complex is formed that deactivates the palladium
centre.27b
One of the ongoing aims of our research is to identify reaction
conditions that permit the controlled amination of
(di)bromo[2.2]paracyclophane derivatives. There are a number
of reports achieving this goal,20a,28 but as we have detailed in an
earlier publication, we have had issues reproducing many of
these.18a As a result, we studied the amination of pseudo-ortho
dibromo[2.2]paracyclophane 24 under our standard conditions
(Scheme 6). Initially, we studied the monoamination of pseudo-
Experimental
General Information
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),
ortho-dibromo[2.2]paracyclophane with morpholine as
means of preparing the third aminophosphine ( ). All ligands
screened, 20 22, (±)-BINAP, bis(diphenylphosphino)ferrocene
a
9
,
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potassium permanganate, ethanolic phosphomolybdic acid or 13C NMR (125 MHz, CDCl3): δ (ppm) 142.7, 140.5,V1ie3w8A.r3ti,cl1e 3O8nl.in2e,
DOI: 10.1039/C7OB02393F
ninhydrin when applicable. NMR spectra were recorded at 133.3, 132.8, 132.5, 127.7, 126.4, 126.0, 124.0, 116.0, 35.8,
room temperature on Bruker-400 and Bruker-500 Avance 33.1, 33.2, 32.4
instruments, with the use of the residual solvent proton as an HRMS (EI): m/z found: [M+H]+, 302.0539. C16H1679BrN requires
internal standard (CHCl3 = 7.26 ppm). Melting points were [M+H]+, 302.0534.
recorded on a Gallenkamp melting point apparatus and are
uncorrected. Mass spectra and high resolution mass 4-(4-Bromo[2.2]paracyclophan-5-yldiazenyl)morpholine (13)
spectrometry were performed at the Waikato Mass To a solution of 4-bromo-5-amino[2.2]paracyclophane (75 mg,
Spectrometry Facility, The University of Waikato, New Zealand 0.25 mmol, 1.0 eq.) in acetone (0.1 ml), acetonitrile (0.2 ml), and
or at Massey University, using a Thermo Scientific Q Exactive H2O (0.5 ml) at 0°C was added a solution of 50% aqueous HBF4
Focus Hybrid Quadrupole-Orbitrap Mass Spectrometer.
(1 ml, excess). A solution of NaNO2 (18 mg, 0.25 mmol, 1.0 eq.)
in ice cold water (0.2 ml) was added dropwise at 0 °C. Within 10
minutes dark yellow precipitate had formed. The solid was
4-Bromo[2.2]paracyclophane-5-carbaldehyde oxime 11
(
)
To a mixture of hydroxyl amine hydrochloride (156mg, 2.25 removed by filtration and washed with cold Et2O. The solid was
mmol, 3.0 eq.) and sodium hydroxide (93 mg, 2.325 mmol, 3.1 mixed with morpholine (2 ml) for 2 h. The solution was diluted
eq.) in ethanol (5 ml) at reflux was added a solution of 4-bromo- with CH2Cl2 (10 ml) and H2O (10 ml). The layers were separated
5-formyl[2.2]paracyclophane (236 mg, 0.75 mmol, 1.0 eq.) in and the organic layer washed with H2O (2 x 10 ml), dried
ethanol (3 ml). The resulting mixture was heated at reflux for 30 (MgSO4) and concentrated. The resulting solid was
min. The mixture was cooled to rt and the solvent removed. The recrystallized from CDCl3 (50 mg, 50%).
product was dissolved in EtOAc (10 ml) and washed with H2O Rf (9:1 Hex:EtOAc) 0.70
and brine, dried (MgSO4) and the solvent removed under 1H NMR (500 MHz, CDCl3): δ (ppm) 7.06 (1H, dd, J = 6.8, 1.2 Hz),
reduced pressure to give the product as a colourless solid (233 6.69 (1H, dd, J = 6.8, 1.2 Hz), 6.58-6.53 (3H, m), 6.41 (1H, d, J =
mg, 94%).
Rf (9:1 Hex:EtOAc) 0.25
7.7 Hz), 3.94-3.82 (8H, m), 3.49 (1H, ddd, J = 13.1, 10.3, 2.5 Hz),
3.29 (1H, ddd, J = 12.5, 9.8, 2.4 Hz), 3.17 (1H, ddd, 15.6, 10.3,
1H NMR (500 MHz, CDCl3): δ (ppm) 8.24 (1H, s), 7.65 (1H, brs), 5.2 Hz), 3.08-3.00 (2H, m), 2.89-2.80 (2H, m), 2.67 (1H, ddd, J =
7.26 (1H, s), 6.98 (1H, dd, J = 7.8, 1.8 Hz), 6.61 (1H, d, J = 7.8 Hz), 16.3, 10.2, 6.1 Hz)
6.60 (1H, dd, J = 7.8, 1.8 Hz), 6.53 (2H, d, J = 7.8 Hz), 6.52 (1H, 13C NMR (125 MHz, CDCl3): δ (ppm) 146.8, 140.7, 139.3, 138.8,
dd, J = 7.8, 1.8 Hz), 3.77 (1H, ddd, J = 13.0, 10.1, 2.6 Hz), 3.50 133.9, 133.3, 132.9, 132.7, 131.3, 129.9, 123.9, 66.6, 48.01 (br),
(1H, ddd, J = 13.0, 10.3, 3.4 Hz), 3.30-2.98 (4H, m), 2.90-2.82 (2H, 35.6, 34.4, 33.5, 32.9
m)
HRMS (EI): m/z found: [M+H]+, 400.1048. C20H2179BrN3O
13C NMR (125 MHz, CDCl3): δ (ppm) 151.7, 141.7, 140.1, 139.6, requires [M+H]+, 400.1025.
139.1, 135.1, 134.1, 133.4, 133.0, 131.7, 130.3, 129.4, 128.4,
36.1, 34.8, 34.6, 33.3
X-Ray data of the compound 13 was recorded at low
HRMS (EI): m/z found: [M+Na]+, 352.0307. C17H1679BrNO temperature (153 K) with a Rigaku-Spider X-ray diffractometer,
requires [M+Na]+, 352.0313.
comprising a Rigaku MM007 microfocus copper rotating-anode
generator, high-flux Osmic monochromating, and focusing
multilayer mirror optics (CuKα radiation, λ 1.5418 Å), and a
5-Amino-4-bromo[2.2]paracyclophane (12)
A mixture of finely ground 4-bromo[2.2]paracyclophane-5- curved image-plate detector. CrystalClear30 was utilised for data
carbaldehyde oxime (165 mg, 0.5 mmol, 1.0 eq.) and ground collection and FSProcess in PROCESS-AUTO31 for cell refinement
Koser’s reagent (272 mg, 0.7 mmol, 1.4 eq.) in DMSO (1 ml) was and data reduction. Using Olex2,32 the structure was solved
allow to stirred at rt for 30 min and then heated at 80 °C for 1h. with the Superflip structure solution program using Charge
Sodium hydroxide (28 mg, 0.7 mmol, 1.4 eq.) was added and Flipping33 and refined with the ShelXL34 refinement package
heating was continued for further 1.5 h. The mixture was cooled using least-squares minimisation. Hydrogen atoms were placed
to rt, H2O (1 ml) was added and the aqueous layer extracted at calculated positions.
with EtOAc (2 x 20 ml). The combined organic layers were
washed with H2O (20 ml), dried (MgSO4), and the solvent was Crystal structure determination of 13
removed under reduced pressure. The resulting residue was Crystal Data for C20H22BrN3O (M = 400.31 g/mol): monoclinic,
separated by column chromatography eluting Hex:EtOAc 9:1 to space group P21/n (no. 14), a = 7.368(3) Å, b = 10.812(3) Å, c =
afford the 5-amino-4-bromo[2.2]paracyclophane as a pale 22.597(5) Å, β = 95.146(17)°, V = 1792.8(10) Å3, Z = 4, T = 123 K,
yellow solid (85 mg, 56%).
Rf (9:1 Hex:EtOAc) 0.425
μ(CuKα) = 3.221 mm-1, Dcalc = 1.483 g/cm3, 17115 reflections
measured (11.35° ≤ 2Θ ≤ 130.154°), 2883 unique (Rint = 0.0739,
1H NMR (500 MHz, CDCl3): δ (ppm) 6.98 (1H, dd, J = 7.8, 1.8 Hz), Rsigma = 0.0566) which were used in all calculations. The
6.92 (1H, dd, J = 7.8, 1.8 Hz), 6.58 (1H, d, J = 7.8 Hz), 6.50 (1H, final R1 was 0.0495 (I > 2σ(I)) and wR2 was 0.1228 (all data).
dd, J = 7.8, 1.8 Hz), 6.37 (1H, d, J = 7.8 Hz), 6.18 (1H, d, J = 7.8
Hz), 3.95 (2H, brs), 3.35 (1H, ddd, J = 17.0, 10.1, 1.7 Hz), 3.15- Methyl 4-bromo[2.2]paracyclophane-13-carboxylate (14)
25
2.93 (5H, m), 2.72-2.83 (2H, m)
A two necked round bottom flask was charged with iron filings
(67 mg, 1.2 mmol, 0.3 eq.), covered with foil, and fitted with
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dropping funnel filled with a solution of Br2 (206 μL, 4 mmol, 1.0 was removed under reduced pressure. The resulting residue
View Article Online
DOI: 10.1039/C7OB02393F
eq.) in CH2Cl2 (20 ml) (the stock solution). Stock solution (2 ml) was separated by column chromatography eluting Hex:EtOAc
was added to the iron filings and stirred for 30 min at rt. A 9:1 to afford the 4-bromo-13-formyl[2.2]paracyclophane as a
solution of methyl [2.2]paracyclophane-4-carboxylate (1.06 g, 4 colourless solid (290 mg, 92%).
mmol, 1.0 eq.) in dry CH2Cl2 (20 ml) was added. The remaining Rf (9:1 Hex:EtOAc) 0.425
stock solution was added dropwise over 1h. The resulting 1H NMR (500 MHz, CDCl3): δ (ppm) 10.3 (1H, s), 7.10 (1H, d, J =
mixture was stirred for 1h at rt. The mixture was washed with 1.9 Hz), 6.77 (1H, dd, J = 7.8, 1.5 Hz), 6.63 (1H, dd, J = 7.8, 1.5
Na2S2O3 (30 ml) and brine (30 ml) then dried (MgSO4). The Hz), 6.58 (1H, d, J = 7.8 Hz), 6.53 (1H, d, J = 7.8 Hz), 6.50 (1H, d,
solution was filtered and the solvent was removed under J = 1.5 Hz), 4.16 (1H, ddd, J = 10.1, 7.3, 4.2 Hz), 3.55 (1H, ddd, J
reduced pressure to afford the desire product as a pale yellow = 10.1, 6.3, 3.2 Hz), 3.18-2.93 (6H, m)
solid (1.28 g, 93%).
Rf (9:1 Hex:EtOAc) 0.45
13C NMR (125 MHz, CDCl3): δ (ppm) 190.9, 143.0, 141.8, 140.2,
138.9, 138.1, 136.9, 136.4, 136.1, 135.2, 134.0, 131.5, 128.3,
1H NMR (500 MHz, CDCl3): δ (ppm) 7.35 (1H, d, J = 1.9 Hz), 6.69 35.6, 35.1, 34.9, 30.4
(1H, dd, J = 7.8, 1.9 Hz), 6.60 (1H, d, J = 1.9 Hz), 6.57-6.54 (3H, HRMS (EI): m/z found: [M+Na]+, 337.0208. C17H1579BrO requires
m), 4.43-4.37 (1H, m), 3.89 (3H, s), 3.22-3.01 (1H, m) 3.15-2.92 [M+Na]+, 337.0198.
(6H, m)
13C NMR (125 MHz, CDCl3): δ (ppm) 167.5, 142.8, 141.4, 139.2, 4-Bromo[2.2]paracyclophane-4-carbaldehyde oxime
(15)
139.2, 136.6, 136.5, 136.2, 134.9, 134.5, 131.7, 128.6, 127.3, To a solution of hydroxylamine hydrochloride (208 mg, 3 mmol,
51.7, 35.3, 35.0, 34.7, 33.7. Data comparable to that reported in 3.0 eq.) and sodium hydroxide (124 mg, 3.1 mmol, 3.1 eq.) in
the literature.25
ethanol (10 ml) at reflux was added a solution of 4-bromo-13-
formyl[2.2]paracyclophane (315 mg, 1 mmol, 1.0 eq.) in ethanol
(40 ml). The resulting mixture was heated to reflux for 30 min.
4-Bromo-13-hydroxymethyl[2.2]paracyclophane
To a suspension of LiAlH4 (84 mg, 2.2 mmol, 2.2 eq.) in THF (4 Then cooled to rt and the solvent removed. The residue was
ml) was slowly added solution of methyl 4- dissolved in EtOAc (10 ml) and washed with H2O (10 ml) then
a
bromo[2.2]paracyclophane-13-carboxylate (345 mg, 1.0 mmol, brine (10 ml), dried (MgSO4). The solvent removed under
1.0 eq.) in THF (6 ml) over 10 min at rt. The reaction mixture was reduced pressure to give a colourless solid that was used in the
heated to reflux for 2h then cooled to rt. The excess hydride was next reaction without purification (325 mg, 98%).
destroyed by addition of 2M HCl (5 ml). The reaction mixture Rf (4/1 Hex:EtOAc) 0.15
was filtered through celite and diluted with CH2Cl2 (20 ml). The 1H NMR (500 MHz, DMSO-d6): δ (ppm) 10.88 (1H, s), 8.25 (1H,
aqueous layer was extracted with CH2Cl2 (2 x 10 ml). The s), 6.79 (1H, d, J = 1.6 Hz), 6.67-6.61 (3H, m), 6.59 (1H, dd, J =
combined organic layers were washed with sat. aqueous 7.7, 1.6 Hz), 6.55(1H, d, J = 7.4 Hz), 3.72 (1H, ddd, J = 17.0, 13.0,
NaHCO3 (10 ml), H2O (10 ml), brine (10 ml), and dried (MgSO4). 3.3 Hz), 3.38 (1H, m), 3.03-2.95 (6H,m)
The solvent was removed under reduced pressure to afford 4- 13C NMR (125 MHz, DMSO-d6): δ (ppm) 148.4, 141.7, 139.2,
bromo-13-hydroxymethyl[2.2]paracyclophane as a colourless 138.1, 137.6, 135.6, 135.5, 135.2, 133.7, 132.3, 132.1, 130.6,
solid which was used in the next reaction without further 125.3, 34.4, 34.3, 33.9, 31.5.
purification (315 mg, quant.).
HRMS-EI
:
m/z found: [M+Na]+, 352.0307. C17H1679BrNO requires
Rf (9:1 Hex:EtOAc) 0.1
[M+Na]+, 352.0313.
1H NMR (500 MHz, CDCl3): δ (ppm) 6.60 (1H, dd, J = 7.8, 1.9 Hz),
35
6.55-6.45 (4H, m), 6.39 (1H, d, J = 1.5 Hz), 4.71 (1H, d, J = 12.7 4-Bromo-13-amino[2.2]paracyclophane
(
16
)
Hz), 4.38 (1H, d, J = 12.7 Hz), 3.40 (1H, ddd, J = 13.1, 10.2, 2.3
Hz), 3.17-2.97 (6H, m) 2.87 (1H, ddd, J = 16.7, 10.8, 5.8 Hz)
A mixture of 4-bromo[2.2]paracyclophane-4-carbaldehyde
oxime (165 mg, 0.5 mmol, 1.0 eq.) and Koser’s reagent (272 mg,
13C NMR (125 MHz, CDCl3): δ (ppm) 140.4, 139.9, 139.7, 139.4, 0.7 mmol, 1.4 eq.) in DMSO (1 ml) was stirred at rt for 30 min
137.4, 137.6, 135.2, 133.5, 133.4, 132.5, 132.3, 132.2, 129.2, and then heated at 80 °C for 1h. Sodium hydroxide (28 mg, 0.7
64.7, 35.4, 35.2, 34.5, 32.9.
mmol, 1.4 eq.) was added and heating continued for further
1.5h. The mixture was cooled to rt, H2O (1 ml) was added. The
aqueous phase was extracted with EtOAc (2 x 20 ml). The
4-Bromo-13-formyl[2.2]paracyclophane
To a solution of oxalyl chloride (100 μL, 1.15 mmol, 1.15 eq.) in combined organic layer was washed with H2O (20 ml), dried
dry CH2Cl2 (5 ml) at -78 °C was added DMSO (170 μL, 2.4 mmol, (MgSO4) and the solvent was removed under reduced pressure.
2.4 eq.). The solution was stirred for 15 min. A solution of 4- The resulting residue was purified by column chromatography
bromo-13-hydroxymethyl[2.2]paracyclophane (315 mg,
1
(eluting Hex:EtOAc 9:1) to afford the 4-bromo-13-
mmol, 1 eq.) in CH2Cl2 (5 ml) was slowly added and stirred for a amino[2.2]paracyclophane as a pale yellow solid (98 mg, 65%).
further 15 min at -78 °C. Triethylamine (696 μL, 5 mmol, 5 eq.) Rf (4/1 Hex:EtOAc) 0.525
was added to the reaction and the solution stirred for a further 1H NMR (500 MHz, CDCl3): δ (ppm) 6.83 (1H, d, J = 1.8 Hz), 6.47
1h at -78 °C. The reaction mixture was warmed to rt and diluted (1H, dd, J = 17.7, 1.5 Hz), 6.43 (1H, d, J = 7.6 Hz), 6.40 (1H, d, J =
with CH2Cl2 (10 ml) and H2O (10 ml). The aqueous layer was 7.6 Hz), 6.10 (1H, dd, J = 7.8, 1.8 Hz), 5.70 (1H, d, J = 1.8 Hz), 3.69
extracted with CH2Cl2 (2 x 10 ml). The combined organic layers (1H, ddd, J = 14.1, 9.7, 2.4 Hz), 3.33 (1H, ddd, J = 13.8, 10.3, 2.4
were washed with H2O (20 ml), dried (MgSO4) and the solvent Hz), 3.13-3.00 (2H, m), 2.95-2.83 (4H, m)
6 | J. Name., 2012, 00, 1-3
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13C NMR (125 MHz, CDCl3): δ (ppm) 147.1, 141.1, 140.7, 138.3, reduced pressure. The resulting residue was purifiVeidewbAyrticcloelOunmlinne
DOI: 10.1039/C7OB02393F
135.5, 135.5, 135.3, 132.8, 123.6, 123.2, 122.6, 121.2, 35.0, chromatography (eluting Hex:EtOAc 9:1) to afford the 4-bromo-
34.8, 33.2, 31.6
13-amino[2.2]paracyclophane as a pale yellow solid (0.76 g,
HRMS-EI: m/z found: [M+H]+, 302.0554. C16H1679BrN requires 76%).
[M+H]+, 302.0539.
Data the same as outlined above.
Data comparable to that reported in the literature.35
4-(4-Bromo[2.2]paracyclophan-13-yl)morpholine
A mixture of 4-bromo-13-amino[2.2]paracyclophane (75.51 mg,
(17)
4-Nitro[2.2]paracyclophane26
To a solution of [2.2]paracylophane (4.0 g, 19.2 mmol, 1.0 eq.) 0.25 mmol, 1.0 eq.), bis(2-bromoethyl)ether (70 mg, 0.3 mmol,
in CH2Cl2 (380 ml) at 0 °C was added H2SO4 (95%; 4.31 ml, 76.9 1.2 eq.) and K2CO3 (76 mg, 0.55 mmol, 2.2 eq.) in DMF (2.5 ml)
mmol, 4.0 eq.) and HNO3 (70%; 2.29 ml, 38.5 mmol, 2.0 eq.). was heated to 80 °C for 12 hours. The mixture was cooled to rt,
The mixture was allowed to warm to rt overnight. The reaction then partitioned between CH2Cl2 (5 ml) and H2O (5 ml). The
mixture was decanted onto ice, leaving any dark orange tar in organic layer was removed and aqueous layer was extracted
reaction vessel. The biphasic mixture was stirred for 15 min. and with CH2Cl2 (3 x 5 ml). The combined organic layers were dried
the layers separated. The aqueous phase was extracted with (MgSO4) and the solvent was removed. The resulting residue
CH2Cl2 (3 x 50 ml). The combined CH2Cl2 layers were dried was separated by column chromatography eluting Hex:EtOAc
(MgSO4) and concentrated. Crude mixture purified by silica gel 6:1 to afford 4-(4-bromo[2.2]paracyclophan-13-yl)morpholine
chromatography (Hex:EtOAc 4:1) to give the title compound as as a pale yellow solid (58 mg, 62%).
a yellow powder (4.4 g, 91%).
Rf (4:1 Hex:EtOAc) 0.67
Rf (4:1 Hex:EtOAc) 0.55
1H NMR (500 MHz, CDCl3): δ (ppm) 6.57 (1H, m), 6.54 (2H, m),
1H NMR (500 MHz, CDCl3): δ (ppm) 7.22 (1H, d, J = 1.8 Hz), 6.79 6.51 (1H, d, J = 7.6 Hz), 6.30 (1H, dd, J = 7.6, 1.4 Hz), 5.93 (1H,
(1H, dd, J = 7.9, 1.8 Hz), 6.63 (2H, dd, J = 7.8, 2.4 Hz), 6.57 (2H, d, J = 1.2 Hz), 3.93-3.85 (4H, m), 3.74-3.57 (2H, m), 3.11-2.83
ddd, J = 14.0, 7.8, 1.7 Hz), 6.48 (1H, dd, J = 7.8, 1.8), 4.03 (1H, (10H, m)
ddd, J = 13.2, 9.5, 1.9 Hz), 3.24-3.04 (6H, m), 2.90 (1H, ddd, J = 13C NMR (125 MHz, CDCl3): δ (ppm) 152.4, 141.0, 140.3, 139.1,
13.2, 9.9, 7.2 Hz).
136.1, 135.7, 135.4, 132.0, 131.5, 128.3, 123.5, 119.5, 67.1,
53.0, 35.7, 35.3, 34.8, 32.1
Data comparable to that reported in the literature.26
HRMS-EI: m/z found: [M+H]+, 372.0950. C20H2279BrNO requires
[M+H]+, 372.0958.
4-Bromo-13-nitro[2.2]paracyclophane
A dropping funnel covered in foil was charged with Br2 (0.25 ml,
5.0 mmol, 1.3 eq.) and CH2Cl2 (10 ml) (the stock solution). A 4-(4-Bromo[2.2]paracyclophan-13-yl)piperidine (18)
suspension of iron filings (0.02 g, 0.4 mmol, 0.1 eq.) and 2 ml of A mixture of 4-bromo-13-amino[2.2]paracyclophane (100 mg,
the stock solution was stirred at rt for 1 h. A solution of 4- 0.33 mmol, 1.0 eq.), 1,5-dibromopentane (54 μl, 92 mg, 0.40
nitro[2.2]paracyclophane (1.0 g, 4.0 mmol, 1.0 eq.) in CH2Cl2 (15 mmol, 1.2 eq.) and K2CO3 (101 mg, 0.73 mmol, 2.2 eq.) in DMF
ml) was added. The remaining stock solution was added (4 ml) was heated to 80 °C for 12 hours. The mixture was cooled
dropwise over 1 h. The resulting mixture was stirred for 1 h at to rt, then partitioned between CH2Cl2 (5 ml) and H2O (5 ml).
rt then heated to reflux for 5 h. The mixture was washed with The organic layer was removed and aqueous layer was
Na2S2O3 (30 ml) and brine (30 ml) then dried (MgSO4). The extracted with CH2Cl2 (3 x 5 ml). The combined organic layers
solution was filtered and the solvent was removed under were dried (MgSO4) and the solvent was removed. The resulting
reduced pressure to afford the desire product as a pale yellow residue was separated by column chromatography eluting
solid (0.93 g, 70%).
Rf (4:1 Hex:EtOAc) 0.4
Hex:EtOAc 6:1 to afford 4-(4-bromo[2.2]paracyclophan-13-
yl)piperidine as a pale yellow solid (122 mg, 68%).
1H NMR (500 MHz, CDCl3): δ (ppm) 7.57 (1H, d, J = 1.8 Hz), 6.77 1H NMR (CDCl3, 500 MHz): δ (ppm) 6.62 (1H, s), 6.56 (2H, s), 6.51
(1H, dd, J = 7.8, 1.8 Hz), 6.71 (1H, d, J = 1.6 Hz), 6.65-6.61 (2H, (1H, d, J = 7.5 Hz), 6.27 (1H, d, J = 7.5 Hz), 5.97 (1H, s), 3.76-3.72
m), 6.59 (1H, dd, J = 7.8, 1.7 Hz), 4.38 (1H, ddd, J = 13.7, 9.6, 4.1 (1H, m), 3.65-3.61 (1H, m), 3.12-3.06 (1H, m), 3.05-2.97 (2H, m),
Hz), 3.67 (1H, ddd, J = 13.7, 9.9, 4.1 Hz), 3.20-3.03 (6H, m).
2.96-2.81 (8H, m), 1.78 (4H, quint, J = 5.1 Hz), 1.57-1.52 (2H, m)
13C NMR (CDCl3, 125 MHz): δ (ppm) 153.4, 140.7, 139.8, 139.2,
135.6, 135.1, 131.7, 127.4, 123.5, 119.3, 54.0, 35.6, 35.3, 34.7,
35
4-Bromo-13-amino[2.2]paracyclophane (16)
A solution of 4-bromo-13-nitro[2.2]paracyclophane (1.1 g, 3.32 32.0, 26.0, 24.5
mmol, 1.0 eq.) in EtOH (25 ml) and H2O (25 ml) was stirred for 1 HRMS-EI: m/z found [M+H]+, 370.1162. C21H24BrN requires
h at rt. Fe powder (2.23 g, 39.87 mmol, 12.0 eq.) was added and [M+H]+ 370.1170.
the suspension heated to reflux. Concentrated HCl (8 ml) was
added dropwise over 10 min. The suspension was stirred at this 4-(4-Diphenylphosphinyl[2.2]paracyclophan-13-
temperature for a further 300 minutes then cooled to rt. The yl)morpholine
suspension was poured into a mixture of ice and sat. NaHCO3 A solution of t-BuLi (1.6M in hexanes; 148 μl, 0.24 mmol, 2.2
(50 ml). The aqueous layer was extracted with EtOAc (3 x 30 ml). eq.) was added dropwise to solution of 4-(4-
(20)
a
Filtration of the suspension occasionally helped the work up. bromo[2.2]paracyclophan-13-yl)morpholine (40 mg, 0.11
The organic layers were dried (MgSO4), and concentrated under mmol, 1.0 eq.) in THF (10 ml) at -78 °C. The resulting clear
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orange solution was stirred at -78 °C for 25 min. by column chromatography (Hex:EtOAc 15:1) tVoiewaAffrtoicrledOntlhinee
Chlorodiphenylphosphine (30 μl, 33 mg, 0.15 mmol, 1.4 eq.) borane complex as a colourless solid (17 DmOgI,: 1303.1%03).9/C7OB02393F
was slowly added. The resulting mixture was warmed to rt Rf (25:1 Tol:EtOAc) 0.70
overnight. The reaction was quenched by the addition of H2O 1H NMR (500 MHz, CDCl3): δ (ppm) 6.59 (1H, d, J = 7.6 Hz ), 6.50-
(30 μl), and filtered through a small pad of silica. The solvent 6.49 (2H, m), 6.38-6.36 (2H, m), 5.62 (1H, d, J = 1.2 Hz), 4.12-
was evaporated and the resulting residue was purified by 4.05 (1H, m), 3.95-3.85 (4H, m), 3.47-3.44 (1H, m), 3.05-2.73
column chromatography (eluting Hex:EtOAc 9:1) to afford 4-(4- (9H, m), 2.23-0.96 (24H, m)
diphenylphosphinyl[2.2]paracyclophan-13-yl)morpholine as a 13C NMR (125 MHz, CDCl3): δ (ppm) 151.4, 144.8, 144.7, 140.5,
colourless solid (24 mg, 52%).
Rf (4:1 Hex:EtOAc) 0.575
136.5, 136.3, 135.3, 135.1, 133.9, 133.8, 132.7, 131.2, 130.3,
126.7, 117.5, 67.1, 52.5, 36.3, 36.2, 35.9, 35.8, 35.4, 35.3, 34.4,
1H NMR (500 MHz, CDCl3): δ (ppm) 7.35-7.18 (10H, m), 6.59 (1H, 34.2, 33.4, 33.2, 32.4, 32.2, 31.6, 31.4, 29.8, 29.0, 28.9, 28.5,
d, J = 7.6 Hz), 6.55-6.48 (2H, m), 6.37 (1H, dd, J = 7.6, 1.7 Hz), 28.0, 27.9, 27.8, 27.7, 27.6, 27.5
5.90 (1H, dd, J = 8.0, 1.7 Hz), 5.66 (1H, d, J = 1.6 Hz), 4.22-4.17 31P NMR (202 MHz, CDCl3): δ (ppm) -4.12.
(2H, m), 4.06-4.01 (2H, m), 3.61-3.54 (2H, m), 3.05-2.83 (7H, m),
2.81-2.68 (3H, m)
4-(4-Diphenylphosphinyl[2.2]paracyclophan-13-yl)piperidine
23
13C NMR (125 MHz, CDCl3): δ (ppm) 143.9, 143.8, 140.7, 140.6,
(
)
140.6, 138.5, 137.8, 136.7, 136.6, 136.3, 135.9, 135.7, 134.0, t-BuLi (1.6M solution in hexanes; 1.32 ml, 2.11 mmol, 2.2 eq.)
133.4, 133.4, 133.3, 132.9, 132.7, 131.6, 129.4, 128.7, 128.6, was added dropwise over 10 min. to a solution of 4-(4-
128.3, 128.3, 128.2, 127.1, 119.2, 67.3, 67.2, 52.7, 35.1, 35.0, bromo[2.2]paracyclophan-13-yl)piperidine (355 mg, 0.96
33.8, 33.7
mmol, 1.0 eq.) in THF (10 ml) at -78 °C. The resulting yellow
solution was stirred for 40 min. at -78 °C.
31P NMR (202 MHz, CDCl3): δ (ppm) -5.9
HRMS-EI: m/z found: [M+O+H]+, 494.2243. C32H32NOP requires Chlorodiphenylphosphine (0.17 ml, 0.96 mmol, 1.0 eq.) was
[M+O+H]+, 494.2171.
added dropwise to the resulting solution over 5 min. The
solution was warmed to rt overnight. The reaction mixture was
quenched by the addition of H2O (15 μl). The resulting organic
phase was separated and aqueous phase was extracted with
4-(4-Dicyclohexanylphosphinyl[2.2]paracyclophan-13-
yl)morpholine (21)
A solution of t-BuLi (1.6M in hexanes; 148 μl, 0.24 mmol, 2.2 EtOAc (3 × 15 ml), the combined organics dried (MgSO4) and
eq.) was added dropwise to solution of 4-(4- concentrated under reduced pressure to yield a yellow residue.
bromo[2.2]paracyclophan-13-yl)morpholine (40 mg, 0.11 Purification by column chromatography on silica gel
mmol, 1.0 eq.) in THF (10 ml) at -78 °C. The mixture was stirred (CH2Cl2:Pentane 13:87) gave white powder of 4-(4-
a
a
at -78 °C for 25 min. To the resulting clear orange solution, Diphenylphosphinyl[2.2]paracyclophan-13-yl)piperidine
chlorodicyclohexylphosphine (34 μl, 36 mg, 0.15 mmol, 1.4 eq.) mg, 19%).
(85
was slowly added. The resulting mixture was warmed to rt 1H NMR (CDCl3, 500 MHz): δ (ppm) 7.38-7.19 (10H, m), 6.58 (1H,
overnight. The reaction was quenched with H2O (30 μl), and d, J = 7.5 Hz), 6.55 (1H, dd, J = 7.6, 1.3 Hz), 6.52 (1H, dd, J = 7.6,
filtered through a small pad of silica. The solvent was removed 5.3 Hz), 6.33 (1H, dd, J = 7.4, 1.5 Hz), 5.91 (1H, dd, J = 7.8, 1.4
and the resulting residue was separated by column Hz), 5.67 (1H, d, J = 1.4 Hz), 3.64-3.63 (2H, m), 3.03 (1H, ddd, J =
chromatography (Hex:EtOAc 15:1) to afford the 4-(4- 13.0, 10.1, 4.0 Hz), 2.96-2.70 (10H, m), 2.10-2.06 (2H, m), 1.92-
dicyclohexanylphosphinyl[2.2]paracyclophan-13-yl)morpholine 1.85 (2H, m), 1.64 (2H, quint, J = 5.7 Hz), 1.46-1.32 (2H, m), 0.97-
as an oil (5 mg, 8%).
Rf (4:1 Hex:EtOAc) 0.55
0.90 (1H, m)
13C NMR (CDCl3, 125 MHz): δ (ppm) 152.8, 144.0, 140.7, 140.3,
1H NMR (500 MHz, CDCl3): δ (ppm) 6.74-6.70 (1H, m), 6.61-6.52 138.6, 137.6, 136.6, 135.9, 135.8, 133.9, 133.2, 133.1, 132.7,
(3H, m), 6.36 (1H, dd, J = 7.6, 1.2 Hz), 5.67 (1H, d, J = 1.2 Hz), 131.8, 129.1, 128.4, 128.0, 126.2, 119.0, 53.8, 35.0, 33.6, 33.5,
4.22-4.17 (1H, m), 3.95-3.85 (4H, m), 3.57-3.50 (1H, m), 3.20- 26.2, 24.7
3.14 (1H, m), 3.05-2.73 (9H, m), 2.23-0.96 (22H, m).
31P NMR (CDCl3, 202 MHz) δ (ppm) -6.57
HRMS-EI: m/z [M+H]+, 476.2502. C33H34NP requires [M+H]+
476.2507.
4-(4-Dicyclohexanylphosphinyl[2.2]paracyclophan-13-
yl)morpholine borane complex
A solution of t-BuLi (1.6M in hexanes; 148 μl, 0.24 mmol, 2.2
eq.) was added dropwise to solution of 4-(4-
(22)
Acknowledgements
a
bromo[2.2]paracyclophan-13-yl)morpholine (40 mg, 0.11
mmol, 1.0 eq.) in THF (10 ml) at -78 °C. The mixture was stirred
at -78 °C for 25 min. To the resulting clear orange solution,
chlorodicyclohexylphosphine (34 μl, 36 mg, 0.15 mmol, 1.4 eq.)
was slowly added. The resulting mixture was warmed to rt
overnight. A solution of borane in THF (267 μL, 0.267 mmol, 2.5
eq.) was added to the reaction mixture and stirred for 3 h at rt.
The solvent was removed and the resulting residue was purified
The authors thank Massey University for financial support (GJR,
KPJ & DJL), and the Institute of Fundamental Sciences (Massey
University) for a Graduate Assistant (MNM) position.
Notes and references
8 | J. Name., 2012, 00, 1-3
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Table of Contents entry
two
X
R R
P
complimentary
routes
N
R = Ph, Cy
X = O, CH2
We have synthesized three pseudo-gem [2.2]paracyclophane-derived P,N-ligands
and report preliminary activity studies for the amination of aryl bromides and
chlorides.