Planar-Chiral [2.2]Paracyclophane-Based Amides as Proligands for Titanium- and Zirconium-Catalyzed Hydroamination

Article abstract of DOI:10.1002/ejoc.201700101

A synthetic route to racemic and enantiopure planar chiral [2.2]paracyclophanes with amide groups was developed to combine the well-established reactivity of amides as N,O-chelating ligands in hydroamination reactions with the planar chirality of the [2.2

Full text of DOI:10.1002/ejoc.201700101

A Journal of
Accepted Article
Title: Planar-chiral [2.2]Paracyclophane-based Amides as Proligands
for Titanium and Zirconium Catalyzed Hydroamination
Authors: Carolin Braun, Stefan Braese, and Laurel Schafer
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700101
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10.1002/ejoc.201700101
European Journal of Organic Chemistry
COMMUNICATION
Planar-chiral [2.2]Paracyclophane-based Amides as Proligands
for Titanium and Zirconium Catalyzed Hydroamination
Carolin Braun,[a] Stefan Bräse,*[a,b] and Laurel L. Schafer*[c]
Dedication ((optional))
Abstract: A synthetic route to racemic and enantiopure planar chiral
[2.2]paracyclophane containing amides was developed to combine
the well-established reactivity of amides as N,O-chelating ligands in
hydroamination reactions with the planar chirality of the
[2.2]paracyclophane backbone. A mono- as well as a tethered
bis(amide) were synthesized and investigated as ligands for titanium
and zirconium. Hydroamination reactivity studies showed their ability
to translate their planar chirality into central chirality in the product.
representatives of this special type of chirality and have been
exploited in other catalytic transformations such as hydrogenation
or coupling reactions.[7] [2.2]Paracyclophanes indeed have an
advantage over ferrocenes in that they are already chiral with only
one substituent. Chiral resolution can be achieved by
derivatization of the racemic [2.2]paracyclophane with an
enantiopure compound to give a diastereomeric product, which
can then be separated by column chromatography or fractional
recrystallization.[8] To date there is no general route to access
variously substituted [2.2]paracyclophanes in enantiopure form
and often chiral resolutions result in a limited number of resolved,
enantiopure derivatives.[8] However, they are a rigid ligand
framework with immense stability and significant steric bulk.[7a, 9]
Introduction
Nitrogen containing compounds, such as amines and enamines,
are widespread in nature and play a pivotal role not only as bulk
chemicals, but also as fine chemicals, agrochemicals and
pharmaceuticals. Therefore, an efficient and sustainable synthetic
approach to these compounds is required. In this context,
hydroamination[1] is the direct addition of an N–H bond across a
C–C multiple bond. This transformation has garnered significant
interest as it is 100% atom economic and uses simple starting
materials such as amines and alkynes/alkenes without any further
stoichiometric additives. The formation of pharmaceutical and
agrochemical agents is of particular interest in the field.
Interestingly, the formation of these products often requires a high
level of enantioselectivity. Numerous examples using metals such
as titanium[2], zirconium[2a, 2c-e, 3], lanthanides[3c, 4] and other early[2b,
2d, 3i, 5] or late[1c-e, 6] transition metals have been reported. However,
the disclosed ligand systems for asymmetric hydroamination
often usually central or axial chirality and amongst these reports
there is no ligand system that possesses exclusively planar
chirality. Although planar chirality is seldomly observed in classic
organic chemistry, disubstituted ferrocene or substituted
Notably,
reactivity
and
stereoselectivity
in
catalytic
hydroamination has been shown to be sensitive to steric and
electronic effects.
Ph
or
[Zr]
[Ti]
Ph
∗
NH2
Ph Ph
N
H
2
1
work:
work:
This
Previous
achiral amide
R2
chiral
planar
amide
iPr
Ph
ligands
ligands
Ph
iPr
HN
N
O
H
O
Scheme 1. Known achiral N,O-chelating amide[3j,
[2.2]paracyclophane containing ligands for intramolecular hydroamination.
and new planar chiral
10]
[2.2]paracyclophane
derivatives
are
quite
prominent
Therefore we combined the planar chirality of the
[a]
[b]
[b]
C. Braun, S. Bräse*
Institute of Organic Chemistry
Karlsruhe Institute of Technology (KIT)
Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
E-mail: braese@kit.edu
[2.2]paracyclophane backbone with amides as potent N,O-
11]
chelating proligands[3l,
for titanium and zirconium catalyzed
hydroamination (Scheme 1). These early transition metals are
advantageous in that they are earth-abundant and inexpensive
with low toxicity. Herein we report the racemic and enantiopure
synthesis of [2.2]paracyclophane containing mono- and
bisamides. Through catalytic investigation we have explored
transfer of their planar chirality into central chirality in the
hydroamination product.
S. Bräse
Institute of Toxicology and Genetics
Karlsruhe Institute of Technology (KIT)
Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen,
Germany
L. L. Schafer*
Department of Chemistry
University of British Columbia
2036 Main Mall, Vancouver, BC, V6T 1Z1, Canada
E-mail: schafer@chem.ubc.ca
Results and Discussion
First we explored the synthetic route towards the racemic
[2.2]paracyclophanyl benzamides, using methods similar to those
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201700101
European Journal of Organic Chemistry
COMMUNICATION
established for our achiral amide ligands[12] (Scheme 2). The
racemic 4-amino[2.2]paracyclophane is accessible from the
commercially available, unsubstituted parent compound 3 via
Fortunately we could develop a transformation of this enantiopure
[2.2]paracyclophane derivative into the desired amide, although
efficient transformations of benzaldehyde derivatives into aniline
derivatives are rare. Nevertheless Bols et al. reported a radical
azidonation to carbamoyl azides and subsequent hydrolysis as a
route for accessing the appropriate amines.[19] We could use
these conditions to access our desired, enantiopure
[2.2]paracyclophane amine (SP)-5 in 43% yield (Scheme 3, see
supporting information for safety issues).Despite the common use
of chiral resolution to access enantiopure [2.2]paracyclophanes,
these protocols are expensive and time intensive and typically
give access to only one enantiomer in pure form.[8] Therefore, we
developed an alternative route based on preparative HPLC with
commercially available chiral stationary phase (chiralpak® AZ-H
column) to separate the two enantiomers of the racemic bromide
4. Afterwards, the same synthetic route as for the racemic
compound (Scheme 2) can be applied in the synthesis of the
enantiopure ligand (SP)-6.
iron-catalyzed bromination[13] to give
4 in excellent yield.
Subsequent lithiation of bromide 4 and treatment with tosyl
azide[14] gives the 4-azido[2.2]paracyclophane that can be
reduced with NaBH4 under slightly modified reaction conditions to
give amine 5[13c, 15] in an overall yield of 44% over three steps. The
amine 5 can undergo a condensation reaction with benzoyl
chloride to give the desired amide 6[16]
,
which can be
recrystallized in high yield (83%).
cat
Br
Fe
,
2
r.t.
overnight
DCM
,
Br
4
3
(rac)/(SP)-
99 %
or
reflux
µwave
triglyme,
dmf,
n
BuLi,
azide,
p-tosyl
Br
Br
1)
r.t.,
-78 °C
thf,
overnight
Br
NaBH
thf/MeOH
,
2)
4,
h
5
reflux,
Br
chiralpak
AZ-H
8
9
%
(rac)-
65
O
O
-tosyl
p
azide,
20h,
r.t.
Ph
Cl
Ph
9
(SP)-
t
BuLi,
thf,
NEt
DCM,
NH
,
r.t., 3
-78 °C
NH2
4
h
6
5
NH2
N3
(rac)/(SP)-
(rac)/(SP)-
44
NaBH4
thf/MeOH reflux,
83%
%
5
h
,
Scheme 2. Synthesis of the [2.2]paracyclophane containing benzamide 6 via
amine 5. For resolution, see text and supporting information.
NH2
N3
NEt
DCM,
,
3 r.t.,
11
10
(rac)/(SP)-
(rac)/(SP)-
4
h
75%
79%
O
Ph
NH
With a synthetic procedure for the racemic proligand in hand, we
wanted to extend this protocol to synthesize enantiopure, planar-
chiral proligands. Our most reliable results for the chiral resolution
were obtained with racemic formyl[2.2]paracyclophane 7[17] via
condensation reaction with enantiopure (R)-phenylethyl amine
and fractional recrystallization of the resulting diastereomeric
imines to get, after imine hydrolysis, the enantiopure (SP)-4-
formyl[2.2]paracyclophane (7).[18]
O
Ph
Cl
NH
12
(rac)/(SP)-
93%
Ph
O
Scheme 4. Synthesis of the pseudo-ortho bisamide 12.
IN
5
h
MeCN, reflux,
,
1)
2)
3
O
H
Achiral amide proligands used in titanium or zirconium
catalysed hydroamination catalysis have been prepared as
bis(amidate) metal complexes.[11b, 11d, 20] Thus, the other targeted
proligand structure was a tethered bisamide based on a pseudo-
ortho disubstituted [2.2]paracyclophane backbone (Scheme 4).
This substitution pattern[21] is well investigated in
[2.2]paracyclophane chemistry in catalysis due to the well-
established PhanePhos[22] ligand. The synthetic approach to
those phosphine compounds is based on the unselective iron-
NaOH,
1,4-dioxane,
r.t., overnight
NH2
H
O
,
2
7
5
(SP)-
(SP)-
43
%
Scheme 3. Radical azidonation of (SP)-4-formyl[2.2]paracyclophane to get the
enantiopure amine (SP)-5 as precursor for the enantiopure amide ligand (SP)-6
(see supporting information for safety issues).
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10.1002/ejoc.201700101
European Journal of Organic Chemistry
COMMUNICATION
catalyzed double bromination of the [2.2]paracyclophane
backbone which yields various regioisomers but has the
piperidine 2. The enantioselective formation of 2 is known to be
more challenging than the asymmetric synthesis of the related
and more common five-membered pyrrolidine ring products,
which are furnished in good ee (90 - 99%) with several group 4
catalysts.[2a, 3f, 3g, 3j] As an illustration of the challenge presented by
advantage that the pseudo-para isomer 8 has the lowest
23d, 23f, 24]
solubility.[23] Afterwards, a thermal[23a,
or microwave-
induced[25] isomerization reaction of 8 gives the desired racemic
pseudo-ortho dibromide 9. Separation of the enantiomers could
be achieved by preparative HPLC using the commercially
available chiralpak® AZ-H column. This strategy provides easy
access to a homo-disubstituted [2.2]paracyclophane derivative
with defined stereochemistry, which is not the case for the
nitration[26] or acylation[27] approach from the unsubstituted
[2.2]paracyclophane. The transformation to the bisamide 12 was
performed following the same lithiation and reaction with tosyl
azide strategy (Scheme 2). The bisazide 10 was then reduced
with NaBH4 in THF/methanol under reflux conditions to give the
bisamine 11[28] in good yield. The last step included condensation
with benzoyl chloride to give the tethered desired bisamide 12 in
excellent yield (93%) after recrystallization. This synthesis has the
main advantage of giving a reliable access to the mono- as well
as the homo-disubstituted amides 5 and 12, which can sometimes
be challenging for homo-disubstituted [2.2]paracyclophane
derivatives due to solubility problems and low to modest yields.
After the successful synthesis of our amide proligands, we tested
them in the intramolecular alkene hydroamination.
substrate
1 only a few reported catalytic systems give
approximately 25%ee for titanium[2c-e] and select systems with
21–82 %ee have been reported for zirconium.[2a, 2c-e, 2g, 3a-h, 3k-n]
Furthermore, piperidine product formation often requires high
reaction temperatures of over 100 °C and long reaction times of
several days. Note that previously reported chiral catalysts are
largely based upon the use of chelate ligands with axial chirality
with a few examples incorporating point chirality into the ligand
set.[2a, 3e, 3g, 3n] Furthermore, it has also been shown that catalysts
are challenged by aminoalkene 1 in that a side reaction can occur
under catalytic hydroamination conditions to give the hydroamino-
alkylation[30] product 13 resulting from α-C–H-activation. Such
reactivity has been observed with both titanium[30b-e] and
zirconium[31] catalysts. The more commonly tested, shorter 2,2-
disubstituted-pent-4-en-1-amine substrate readily undergoes
hydroamination to give 5-membered pyrrolidine products and no
hydroaminoalkylation side-products are observed. Substrate 1
allows for insights into relative reactivity, stereoselectivity and
chemoselectivity
(between
hydroamination
and
hydroaminoalkylation) in one reaction that can be monitored by
NMR spectroscopy. Thus substrate 1 is our preferred test
substrate for catalyst development efforts.
Cyclohydroamination of aminoalkene 1 with bis-N,O-chelated
10a, 29]
complexes of Ti and Zr is well established,[3m,
with Zr
complexes generally displaying shorter reaction times to give
Table 1 Results for the in situ intramolecular hydroamination reaction[a] of 1 to yield 2 (and 13).
Ph
Ph
or
Ti(NMe2)4 Zr(NMe2)4
Ph
Ph
and or
6
12
+
∗
NH2
t
T,
d -toluene,
Ph Ph
8
N
H
NH2
1
2
13
HA
HAA
product
product
Entry
Ligand
Metal
M:lig ratio[b]
Temperature
Reaction Time
Conversion [d]
Yield 2[e] (13)[d]
ee[f]
Precursor
1
2
3
4
5
6
7
8
9
-
Ti(NMe2)4
Ti(NMe2)4
Ti(NMe2)4
Zr(NMe2)4
Zr(NMe2)
Ti(NMe2)4
Zr(NMe2)
Ti(NMe2)4
Zr(NMe2)
-
55 °C
55 °C
55 °C
55 °C
55 °C
55 °C
55 °C
100°C
100 °C
22 h
22 h[c]
22 h[c]
22 h
22 h
46 h
22 h
12 h
12 h
80%
quant.
quant.
30%
28%
43%
44%
90%
96%
72% (7%)
95%
0
(rac)-6
(SP)-6
(SP)-6
(SP)-6
(SP)-12
(SP)-12
(SP)-12
(SP)-12
1:1
1:1
1:1
1:2
1:1
1:1
1:1
1:1
0
95%
9%ee
0
29%
26%
0
36% (6%)
43%
68%ee
33%ee
15%ee
12%ee
75% (12%)
95%
[a] Reaction conditions: aminoalkene (1 equiv), Ti(NMe2)4 or Zr(NMe2)4 (10mol%), amide ligand (10 or 20 mol%), internal standard (250 µmol), d8-toluene, T, t,
N2 atmosphere. [b] Metal precursor to ligand ratio. [c] Determined by 1H NMR spectroscopy as time that was necessary for complete conversion. [d] Consumption
of 1 and yield of 13 determined by 1H NMR spectroscopy of the crude reaction mixture with an internal standard (1,3,5-trimethoxybenzene). [e] Isolated Yield. [f]
Determined by analytical HPLC with chiral stationary phase.
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10.1002/ejoc.201700101
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COMMUNICATION
For all hydroamination reactions, the catalyst system was Conclusions
prepared in situ via a protonolysis reaction by mixing the
commercially available metal precursors Ti(NMe2)4 or Zr(NMe2)4
and the proligands 6 or 12 (Table 1). First, we tested our racemic
ligand (rac)-6 under our reaction conditions at 55 °C, a
compromise between modest temperatures and reasonable
reaction times. After 22 h full conversion was observed by 1H
NMR spectroscopy with 95% isolated yield and without any
detectable hydroaminoalkylation side product (Table 2, entry 2).
Afterwards we wanted to clarify that in situ preparation of the
metal complexes gave the same results compared to isolated
compounds. Therefore we compared isolated racemic
6-Ti(NMe2)3 as catalyst (see supporting information) with the in
situ prepared example showing the same results and therefore
the usefulness of the in situ screening. Unfortunately, use of
enantiopure ligand imparts only a low ee of 9% (entry 3). This
result cannot be improved upon by using Zr(NMe2)4 as metal
precursor. On the contrary, the catalyst system comprised of
Zr(NMe2)4 and (SP)-6, prepared in situ with one or two equivalents
of ligand (entries 4–5), shows a decreased reactivity of only 30%
and 28% conversion, respectively, after the same reaction time,
and gives racemic reaction products. Seemingly, the flexible
ligand (SP)-6 is unable to give satisfying results, presumably due
to the fact that the steric bulk of the [2.2]paracyclophane
backbone can rotate freely even when the 1,3-N,O-ligand is
chelated to the metal centre. It is noteworthy that we also tested
the metal precursor Ti(NMe2)4 without any ligand as its activity for
hydroamination reactions is known in literature.[1a, 32] (entry 1).
Nevertheless, 7% of the hydroaminoalkylation side product 13
was detected by the characteristic doublet for the methyl
substituent at 0.91 ppm showing that without a specific ligand,
total chemoselectivity for hydroamination is not observed.
In summary, we have explored the potential use of a planar chiral
[2.2]paracyclophane system for asymmetric hydroamination. A
synthetic route to racemic and enantiopure [2.2]paracyclophane
containing amide proligands with different substitution patterns of
the [2.2]paracyclophane backbone is shown. The enantiopure
ligands are accessible via two different procedures, we
demonstrated that both chiral resolution and separation of the
enantiomers via preparative HPLC with chiral stationary phase,
are powerful tools to gain access to enantiopure [2.2]para-
cyclophane derivatives with various substituents. Most
importantly, we have demonstrated that these planar chiral ligand
systems possess the ability to impart enantioselectvity to the
respective central chiral products. Our preliminary results showed
that mono-ligated Ti systems display desirable chemoselective
reactivity giving uniquely the hydroamination product, making
further exploration of other planar chiral systems attractive. These
synthetic advances and reactivity insights provide a new platform
for on-going catalyst development efforts.
Experimental Section
General
procedure
for
NMR-tube
scale
intramolecular
hydroamination. All NMR-tube scale reactions were prepared in an N2-
filled glove box. The amide ligand (37 µmol, 10 mol%) and Ti(NMe2)4 or
Zr(NMe2)4 (37 µmol, 10 mol%) were dissolved in 300 µL d8-toluene and
stirred for 30 min. Then the internal standard (1,3,5-trimethoxybenzene)
(250 µmol) and 2,2-diphenylhex-5-en-1-amine (375 µmol, 1 eq.) were
added. The solution was transferred to a J.Young NMR-tube with a Teflon
screw cap and the reaction vial was rinsed with 200 µL d8-toluene. The
tube was then heated to and maintained at the appropriate temperature
for the stated duration of time. The NMR conversions and yields of 13 were
determined by comparing the integration of the internal standard with a
well-resolved signal for the starting material and the heterocyclic products.
Afterwards, the crude reaction mixture was purified using column
chromatography on silica.
Next we tested our tethered bisamide (SP)-12 under the same
reaction conditions with the two metal precursors (entries 6–9).
With Ti(NMe2)4 and at 55 °C, the reaction runs significantly slower
than with mono amidate 6 or without ligand. Even after prolonged
reaction time of 2 d, only 43% conversion could be observed
(entry 6). This behaviour can be easily explained regarding the
increased steric bulk around the metal centre with this tethered
ligand design. Despite the decreased reactivity and the fact that a
significant amount of side product 13 was detected, this ligand is
superior in terms of asymmetric induction, which is shown by
68%ee, which is a significant increase compared to other titanium
catalysts.[2c-e] Superior reactivity was observed when Zr(NMe2)4
was used, showing 43% conversion after only 22 h without side
product. This enhanced reactivity is consistent with previously
reported group 4 catalysts for alkene hydroamination[10a] derived
from the larger atomic radius of zirconium, which is less affected
and sterically shielded by the tethered ligand 12. Nevertheless,
with 33%ee the ee is significantly decreased and follows the often
observed trend that a higher reactivity goes hand in hand with a
lower selectivity. Nevertheless, the obtained ee is in a comparable
range with some other reported zirconium systems.[2a, 2c-e, 2g, 3a-c, 3f,
Acknowledgements
We thank Prof. Jan Paradies for lending of the preparative HPLC
column with chiral stationary phase and the SFB/TR 88 for
financial support. C.B. gratefully acknowledges the Evonik
Stiftung for financial support..
Keywords: [2.2]paracyclophanes; asymmetric intramolecular
hydroamination; amidate ligands
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10.1002/ejoc.201700101
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COMMUNICATION
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10.1002/ejoc.201700101
European Journal of Organic Chemistry
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[2.2]paracyclophane, hydroamination
Ph
or
[Ti] [Zr]
Ph
∗
NH2
Carolin Braun, Stefan Bräse*, and Laurel
L. Schafer*
Ph Ph
N
H
2
1
R2
Page No. – Page No.
chiral
planar
amide
ligands
Planar-chiral [2.2]Paracyclophane-
based Amides as Proligands for
Titanium and Zirconium Catalyzed
Hydroamination
R1
N
O
H
This article is protected by copyright. All rights reserved.