Creation through immobilization: A new family of high performance heterogeneous bifunctional iminophosphorane (BIMP) superbase organocatalysts

Article abstract of DOI:10.1021/ol5029942

An immobilized chiral bifunctional iminophosphorane superbase organocatalyst has been developed and applied in a range of challenging enantioselective reactions. A unique feature of this novel catalytic system is that the final step creation of the iminophosphorane occurs at the point of immobilization. The utility of the immobilized catalyst system was demonstrated in the nitro-Mannich reaction of ketimines as well as the conjugate addition of high pK_a 1,3-dicarbonyl pro-nucleophiles to nitrostyrene. Catalyst recycling was also demonstrated.

Full text of DOI:10.1021/ol5029942

Letter
pubs.acs.org/OrgLett
Creation through Immobilization: A New Family of High Performance
Heterogeneous Bifunctional Iminophosphorane (BIMP) Superbase
Organocatalysts
Anna M. Goldys, Marta G. Nunez, and Darren J. Dixon*
́
̃
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, United
Kingdom
S
* Supporting Information
ABSTRACT: An immobilized chiral bifunctional iminophos-
phorane superbase organocatalyst has been developed and
applied in a range of challenging enantioselective reactions. A
unique feature of this novel catalytic system is that the final
step creation of the iminophosphorane occurs at the point of
immobilization. The utility of the immobilized catalyst system
was demonstrated in the nitro-Mannich reaction of ketimines as well as the conjugate addition of high pKa 1,3-dicarbonyl pro-
nucleophiles to nitrostyrene. Catalyst recycling was also demonstrated.
eterogeneous catalytic processes employing catalytically
competent species attached to insoluble supports can
commercial material, we saw the opportunity to utilize it as a
replacement for the soluble triarylphosphine component. Thus,
we envisaged the synthesis of a novel heterogeneous bifunctional
organocatalytic system through a practically convenient
formation of the iminophosphorane superbase at the point of
immobilization (Figure 1). Although the tether-free formation of
H
bring distinct advantages over homogeneous catalysis such as
facilitating simple separation of the catalyst from the product and
reaction mixture, catalyst recycling, and, in certain cases,
applications in flow chemistry. In pursuit of these benefits,
many organocatalysts such as proline-based nucleophilic
catalysts,1 MacMillan-type imidazolidinones,2 chiral phosphoric
acids,3 cinchona alkaloids,4−6 and bifunctional organocatalysts
such as Takemoto’s catalyst,7 Jacobsen’s thioureas,8 or
squaramides9−11 have been immobilized on a diverse range of
solid supports. However, catalyst immobilization often has severe
detrimental effects on inherently modest catalyst reactivity and
stereoselectivity and often necessitates the incorporation of a
linker into the catalyst structure through additional synthetic
steps.12 Arguably, an ideal immobilized organocatalyst should
retain high reactivity and stereoselectivity without the need for
additional synthetic steps to attach it to the solid support.
The use of organic superbases, instead of tertiary amine bases,
offers one potential solution to the problem of low catalyst
reactivity in bifunctional Brønsted base/H-bond donor organo-
catalysis.13,14 Accordingly, the immobilization of a chiral
superbase-derived bifunctional organocatalyst would be antici-
pated to result in a solid-supported organocatalyst that possesses
superior activity. However, to the best of our knowledge, in this
class only one chiral guanidine organocatalyst has been
immobilized to date,15,16 and its performance in any type of
challenging enantioselective transformations has yet to be
proven.
Figure 1. Simultaneous catalyst formation and immobilization concept
(PS = polystyrene; R* = chiral scaffold).
an organocatalyst immobilised via the H-bond donor in a 2-step
process has been recently reported,9 this would constitute an
unprecedented one-step formation of a solid-supported organo-
catalyst immobilised via the formation of the Brønsted base. We
believed this combined method of catalyst creation/immobiliza-
tion would greatly assist catalyst synthesis, handling, library
generation and heterogeneous enantioselective bifunctional
organocatalysis applications in general.
The enantioselective nitro-Mannich reaction of diphenylphos-
phinoyl-protected ketimines, already known to be successful
under bifunctional iminophosphorane catalysis,13 was chosen to
demonstrate proof of concept in the formation of the
immobilized bifunctional catalyst from azides 2 and 3, derived
from phenylglycine and tert-leucine, respectively (Scheme 1).
Our research group has recently introduced a novel class of
bifunctional iminophosphorane (BIMP) organocatalysts.13,17
These catalysts are synthesized via a Staudinger reaction between
a triarylphosphine and a chiral azide bearing the H-bond donor
motif, forming the active iminophosphorane moiety in the final
step. As solid-supported triphenylphosphine is a widely available
Received: October 12, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol5029942 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Formation of Immobilized Bifunctional
Iminophosphorane Organocatalysts from Azide Precursors
Figure 2. Gel-phase 31P NMR (CDCl3) of polystyrene-supported
triphenylphosphine 1a (red, top) and polystyrene-supported catalyst 5
(blue, bottom).
Conversion to product and high enantiomeric ratio were taken as
evidence of catalyst formation. In initial experiments, we
compared commercial polystyrene-supported triphenylphos-
phine (PS−PPh3) with PS−PPh3 prepared from poly(4-
bromostyrene) using the method of Spring and co-workers.18
This procedure was appealing as it opened the possibility of
preparing a variety of differently substituted polystyrene-
supported phosphines. In-house prepared PS−PPh3 generated
catalysts gave higher conversion in the nitro-Mannich reaction
when compared to commercial material (Table 1) and
accordingly was selected for the remainder of this study.
Table 2. Nitro-Mannich Reaction of Diphenylphosphinoyl-
a
Protected Ketimines
b
c
7
R1
R2
conv (%)
yield (%)
er
d
7a
phenyl
Me
Me
Me
Me
Me
Me
Et
99
94
88
98
99
99
95
99
73
82
75
96
88
87
71
95
98:2
97:3
96:4
97:3
97:3
95:5
97:3
93:7
Table 1. Formation of Immobilized Bifunctional
7b
7c
7d
7e
7f
4-methylphenyl
4-methoxyphenyl
2-methoxyphenyl
4-chlorophenyl
3,4-dichlorophenyl
phenyl
Iminophosphoranes and Use in the Nitro-Mannich Reaction
a
of Ketimine 6a
7g
7h
3-pyridyl
Me
a
Absolute stereochemistry determined by comparison with literature
b
c
compounds (see Supporting Information).13 Conversion determined
by H NMR analysis of the crude reaction mixture. Enantiomeric
ratio (er) was determined by HPLC analysis on a chiral stationary
b
PS−PPh3 source
catalyst
conversion (%)
er
c
1
commercial
in-house
4
4
5
54
65
88
6:94
5:95
98:2
d
phase. The reaction time for 7a was 24 h.
in-house
a
Catalyst was formed in situ by reaction of PS−PPh3 and azide 2 or 3.
also prepared;18 however, PS−PPh3 gave the best compromise
between results and ease of preparation (see Supporting
Information). The yields and enantiomeric ratios of the nitro-
Mannich products were comparable to those obtained previously
with the homogeneous bifunctional iminophosphorane under
similar conditions.13 A variety of diphenylphosphinoyl-protected
ketimines were subjected to the nitro-Mannich reaction using the
immobilized catalyst−electron withdrawing (7e−f) as well as
electron donating (7b−d) substituents were all well-tolerated, as
were heterocyclic substrates (7h) and extension of the methyl
substituent of the ketimine to an ethyl group (7g). Performing
the reaction under identical conditions with the corresponding
homogeneous catalyst and ketimine 6a, we obtained the product
in 92% conversion and 97:3 er in 14 h (see Supporting
Information).
Substituted malonates are an example of a synthetically useful
class of high pKa pro-nucleophile. Isolated examples of the
organocatalyzed addition of substituted malonates to nitro-
styrenes have been reported,19−22 most notably using highly
basic chiral guanidine catalysts.23 However, the scope of this
reaction has not been systematically explored, therefore justifying
the need for further in-depth studies. After optimization studies
we observed that by using 5 mol % of catalyst 5 at −20 °C in THF
we were able to perform the conjugate addition of a variety of
substituted malonates to nitrostyrene in very good to excellent
Compound 6a and nitromethane were then added to the reaction
b
mixture. Determined by 1H NMR analysis of crude reaction mixture.
c
Enantiomeric ratio (er, R:S) was determined by HPLC analysis on a
chiral stationary phase.
Gram-scale catalyst preparation was readily carried out and
spectroscopic evidence for the formation of the polystyrene-
supported catalyst in the form of gel-phase 31P NMR spectra of
PS−PPh3 1a and of tert-leucine-derived catalyst 5 was obtained
(Figure 2). These spectra distinctly show the disappearance of
the PPh3 peak at −5.0 ppm and the formation of a new, broad
peak at 23.8 ppm corresponding to the iminophosphorane (cf.
21.9 ppm for the corresponding homogeneous catalyst). A minor
peak at 30.0−31.0 ppm, which corresponds to a trace of polymer-
bound triphenylphosphine oxide, is visible in both spectra.
With sufficient quantities of immobilized catalysts in hand we
undertook to demonstrate their performance in a range of
challenging organocatalyzed reactions.
The immobilized bifunctional iminophosphorane organo-
catalysts had been demonstrated to be effective in the nitro-
Mannich reaction (Table 1); therefore, we chose to further
investigate the scope of this reaction (Table 2). Optimal reaction
conditions employed 10 mol % of catalyst 5 and 20 equiv of
nitromethane at 0 °C in toluene. Catalysts incorporating
differently substituted polystyrene-supported phosphines were
B
dx.doi.org/10.1021/ol5029942 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
yields and enantiomeric ratios (Table 3). Malonates with an
unbranched alkyl substituent gave the best reactivity and
substituted substrate (12h) required additional reaction time
and also gave a reduced dr but very good er. Performing the
reaction under identical conditions with the corresponding
homogeneous catalyst and keto-amide 11a, we obtained the
product 12a in 77% yield, 38:62 dr and 94:6 er (major
diastereomer) in 2 h at −20 °C followed by 24 h at 0 °C (see
Supporting Information).
Table 3. Conjugate Addition of Substituted Malonates to
a
Nitrostyrene
Having successfully applied our immobilized bifunctional
iminophosphorane to a range of enantioselective reactions, we
next demonstrated its recyclability. The nitro-Mannich reaction
of ketimine 6a with nitromethane was repeated using the same
catalyst (recovered by washing off the reaction product) over 11
runs. The conversion (as measured by H NMR analysis)
remained greater than 95% until the 11th run (Figure 3). The er
b
10
R
time
yield (%)
er
10a
10b
10c
10d
10e
10f
Me
Et
16 h
16 h
16 h
48 h
4 d
93
92
98
80
63
76
98:2
97:3
96:4
98:2
94:6
94:6
1
allyl
propyl chloride
isobutyl
Bn
4 d
a
Absolute stereochemistry determined by comparison with literature
compounds23 and by analogy (see Supporting Information).
b
Enantiomeric ratio (er) was determined by HPLC analysis on a
chiral stationary phase.
enantioselectivity (10a−c). Branching at the γ position of the
alkyl substituent is well-tolerated but led to a small reduction in
yield and enantiomeric ratio (10e,f).24 Performing the reaction
under identical conditions with the corresponding homogeneous
catalyst and malonate 9a, we obtained the product in 93% yield in
4 h and 97:3 er (see Supporting Information).
In a similar fashion to substituted malonates, β-keto amides are
a challenging class of high pKa pro-nucleophile. To the best of
our knowledge, only a single report exists on the use of acyclic β-
keto amides in organocatalyzed conjugate additions.25 By using
10 mol % of immobilized catalyst 5 in THF at −20 °C we were
able to add a number of N,N-dimethyl β-keto amides, bearing a
range of substituents at the ketone, to nitrostyrene in very good
yields and diastereo- and enantiomeric ratios (Table 4).
Substrates with primary or secondary alkyl substituents (12a,b)
gave the highest diastereo- and enantiomeric ratios. The use of
heteroatom-containing (12f) and aryl-substituted (12g) ketones
resulted in reduced dr but very good er. The tert-butyl-
Figure 3. Recycling of catalyst 5 in the nitro-Mannich reaction of
ketimine 6a. Reaction performed with 10 mol % catalyst and 20 equiv of
MeNO2 [8 M] in PhMe at room temperature (cf. 0 °C in Table 2), 24 h
1
reaction time. Blue columns represent conversion as measured by H
NMR; red columns represent ee. Error bars indicate typical error range
for the above measurements.
was observed to rise slightly over the course of the recycling
experiment, which we propose is due to decreased reversibility of
the nitro-Mannich reaction as the catalyst activity decreased (see
Supporting Information).
In conclusion, we have described the development and
application of a high-performance immobilized bifunctional
iminophosphorane superbase organocatalyst. Because of its
strong basicity the catalyst remains highly active despite
immobilization, and the efficient, one-step catalyst creation/
immobilization via Staudinger reaction avoids the need for
additional synthetic steps to affect immobilization. The catalyst
was successfully applied to three challenging enantioselective
reactions: the nitro-Mannich reaction of diphenylphosphinoyl-
protected ketimines and to the conjugate addition of substituted
malonates and N,N-dimethyl β-keto amides to nitrostyrene.
Catalyst recycling without significant loss of activity or
stereoselectivity was demonstrated over 10 cycles. Further
work to broaden the range of reactions catalyzed by 5 and
related catalysts, and to demonstrate its utility in flow chemistry,
is underway and will be reported in due course.
Table 4. Conjugate Addition of β-Keto Amides to
a
Nitrostyrene
yield
(%)
b
c
12
R
temp (°C)
time (h)
dr
er
12a
12b
12c
12d
12e
12f
Me
Bu
Bn
iPr
−20 then 0 4 then 20
20:80
90:10
94:6
74
67
58
71
82
64
54
70
96:4
93:7
96:4
96:4
93:7
94:6
96:4
95:5
−20
−20
−20
24
24
24
24
24
24
48
96:4
cyclohexyl −20
CH2OMe
95:5
−20
−20
−20
74:26
65:35
75:25
ASSOCIATED CONTENT
* Supporting Information
■
12g
12h
Ph
S
tBu
Experimental procedures, NMR spectra, and HPLC traces of
novel compounds. Details of immobilized catalysts with variation
at the phosphine, demonstration of reversibility of nitro-
Mannich reaction, absolute stereochemistry determination, and
comparisons with homogeneous system. This material is
available free of charge via the Internet at http://pubs.acs.org.
a
Absolute stereochemistry determined by comparison with literature
compounds25 and by analogy (see Supporting Information).
b
Determined by 1H NMR analysis of the crude reaction mixture.
c
Enantiomeric ratio (er) of major diastereomer was determined by
HPLC analysis on a chiral stationary phase.
C
dx.doi.org/10.1021/ol5029942 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(17) Goldys, A. M.; Dixon, D. J. Macromolecules 2014, 47, 1277.
(18) Thomas, G. L.; Ladlow, M.; Spring, D. R. Org. Biomol. Chem.
2004, 2, 1679.
AUTHOR INFORMATION
■
Corresponding Author
(19) Andres
5116.
́
, J. M.; Manzano, R.; Pedrosa, R. Chem.−Eur. J. 2008, 14,
*E-mail: darren.dixon@chem.ox.ac.uk.
Notes
(20) Raimondi, W.; Lettieri, G.; Dulcere, J.-P.; Bonne, D.; Rodriguez, J.
Chem. Commun. 2010, 46, 7247.
The authors declare no competing financial interest.
(21) Comer, E.; Rohan, E.; Deng, L.; Porco, J. A. Org. Lett. 2007, 9,
2123.
ACKNOWLEDGMENTS
■
(22) Wang, Y.; Luo, Y.-C.; Zhang, H.-B.; Xu, P.-F. Org. Biomol. Chem.
2012, 10, 8211.
(23) Terada, M.; Ube, H.; Yaguchi, Y. J. Am. Chem. Soc. 2006, 128,
1454.
(24) Attempts to perform the reaction with β-branched substrates such
as dimethyl 2-isopropylmalonate or dimethyl 2-cyclopentyl malonate
were not successful.
We gratefully acknowledge the EPSRC (Leadership Fellowship
to D.J.D. and Postdoctoral Fellowship to M.G.N.), the
Clarendon Fund in conjunction with Magdalen College,
University of Oxford (graduate scholarship to A.M.G.), and the
EC (IEF to M.G.N. [PIEF-GA-2009-254637]).
(25) Du, H.; Rodriguez, J.; Bugaut, X.; Constantieux, T. Chem.Eur. J.
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