A new family of cinchona-derived bifunctional asymmetric phase-transfer catalysts: Application to the enantio- and diastereoselective nitro-Mannich reaction of amidosulfones

Article abstract of DOI:10.1021/ol300779x

A new family of bifunctional H-bond donor phase-transfer catalysts derived from cinchona alkaloids has been developed and evaluated in the enantio- and diastereoselective nitro-Mannich reaction of in situ generated N-Boc-protected imines of aliphatic, aromatic, and heteroaromatic aldehydes. Under optimal conditions, good reactivity and high diastereoselectivities (up to 24:1 dr) and enantioselectivities (up to 95% ee) were obtained using a 9-amino-9- deoxyepiquinidine-derived phase-transfer catalyst possessing a 3,5-bis(trifluoromethyl)phenylurea H-bond donor group at the 9-position.

Full text of DOI:10.1021/ol300779x

ORGANIC
LETTERS
2012
Vol. 14, No. 10
2492–2495
A New Family of Cinchona-Derived
Bifunctional Asymmetric Phase-Transfer
Catalysts: Application to the Enantio- and
Diastereoselective Nitro-Mannich
Reaction of Amidosulfones
Kayli M. Johnson,† Matt S. Rattley,† Filippo Sladojevich, David M. Barber,
~
Marta G. Nunez, Anna M. Goldys, and Darren J. Dixon*
Department of Chemistry, Chemistry Research Laboratory, University of Oxford,
Mansfield Road, Oxford OX1 3TA, U.K.
darren.dixon@chem.ox.ac.uk
Received March 26, 2012
ABSTRACT
A new family of bifunctional H-bond donor phase-transfer catalysts derived from cinchona alkaloids has been developed and evaluated in the
enantio- and diastereoselective nitro-Mannich reaction of in situ generated N-Boc-protected imines of aliphatic, aromatic, and heteroaromatic
aldehydes. Under optimal conditions, good reactivity and high diastereoselectivities (up to 24:1 dr) and enantioselectivities (up to 95% ee) were
obtained using a 9-amino-9-deoxyepiquinidine-derived phase-transfer catalyst possessing a 3,5-bis(trifluoromethyl)phenylurea H-bond donor
group at the 9-position.
For an efficient, enantioselective union of enolizable pro-
nucleophiles to reactive electrophiles such as imines and
Michael acceptors, two particularly successful classes
of catalysts are bifunctional Brønsted base/H-bond donor
organocatalysts1 and asymmetric phase-transfer (APT)
† These authors contributed equally to this work.
(1) For selected recent reviews, see: (a) Marcelli, T.; Hiemstra, H.
(4) (a) Greenaway, K.; Dambruoso, P.; Ferrali, A.; Hazelwood, A. J.;
Sladojevich, F.; Dixon, D. J. Synthesis 2011, 1880–1886. (b) Jakubec, P.;
Cockfield, D. M.; Hynes, P. S.; Cleator, E.; Dixon, D. J. Tetrahedron:
Asymmetry 2011, 22, 1147–1155. (c) Kyle, A. F.; Jakubec, P.; Cockfield,
D. M.; Cleator, E.; Skidmore, J.; Dixon, D. J. Chem. Commun. 2011, 47,
10037–10039. (d) Sladojevich, F.; Trabocchi, A.; Guarna, A.; Dixon,
D. J. J. Am. Chem. Soc. 2011, 133, 1710–1713. (e) Jakubec, P.; Kyle,
A. F.; Calleja, J.; Dixon, D. J. Tetrahedron Lett. 2011, 52, 6094–6097.
(f) Wang, Y.; Yu, D. F.; Liu, Y. Z.; Wei, H.; Luo, Y. C.; Dixon, D. J.; Xu,
P. F. Chem.;Eur. J. 2010, 16, 3922–3925. (g) Moss, T. A.; Alonso, B.;
Fenwick, D. R.; Dixon, D. J. Angew. Chem., Int. Ed. 2010, 49, 568–571.
(h) Wang, Y.; Han, R. G.; Zhao, Y. L.; Yang, S.; Xu, P. F.; Dixon, D. J.
Angew. Chem., Int. Ed. 2009, 48, 9834–9838. (i) Yang, T.; Ferrali, A.;
Sladojevich, F.; Campbell, L.; Dixon, D. J. J. Am. Chem. Soc. 2009, 131,
9140–9141. (j) Jakubec, P.; Cockfield, D. M.; Dixon, D. J. J. Am. Chem.
Soc. 2009, 131, 16632–16633. (k) Hynes, P. S.; Stupple, P. A.; Dixon,
D. J. Org. Lett. 2008, 10, 1389–1391. (l) Moss, T. A.; Fenwick, D. R.;
Dixon, D. J. J. Am. Chem. Soc. 2008, 130, 10076–10077. (m) Rigby,
C. L.; Dixon, D. J. Chem. Commun. 2008, 3798–3800. (n) Hynes, P. S.;
Stranges, D.; Stupple, P. A.; Guarna, A.; Dixon, D. J. Org. Lett. 2007, 9,
2107–210. (o) Ye, J.; Dixon, D. J.; Hynes, P. S. Chem. Commun. 2005,
4481–4483.
Synthesis 2010, 1229–1279. (b) Takemoto, Y. Chem. Pharm. Bull. 2010,
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58, 593–601. (c) Palomo, C.; Oiarbide, M.; Lopez, R. Chem. Soc. Rev.
2009, 38, 632–653. (d) Connon, S. J. Synlett 2009, 354–376. (e) Connon,
S. J. Chem. Commun. 2008, 2499–2510. (f) Yu, X.; Wang, W. Chem.
Asian J. 2008, 3, 516–532. (g) Doyle, A. G.; Jacobsen, E. N. Chem. Rev.
2007, 107, 5713–5743. (h) Taylor, M. S.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 2006, 45, 1520–1543. (i) Takemoto, Y. Org. Biomol. Chem. 2005,
3, 4299–4306.
(2) For recent reviews, see: (a) Hashimoto, T.; Maruoka, K. Chem.
Rev. 2007, 107, 5656–5682. (b) Ooi, T.; Maruoka, K. Angew. Chem., Int.
Ed. 2007, 46, 4222–4226.
(3) For a recent example with a bifunctional Brønsted base/H-bond
donor organocatalyst, see: (a) Huang, X.; Broadbent, S.; Dvorak, C.;
Zhao, S. H. Org. Process Res. Dev. 2010, 14, 612–616. For a recent
example with a phase-transfer catalyst, see: (b) Mazzotta, S.; Gramigna,
L.; Bernardi, L.; Ricci, A. Org. Process Res. Dev. 2010, 14, 687–691. For
recent reviews of asymmetric phase-transfer catalysis in organic process
research and development, see: (c) Howell, G. P. Org. Process Res. Dev.
2012, DOI: 10.1021/op200381w. (d) Ikunaka, M. Org. Process Res. Dev.
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r
10.1021/ol300779x
Published on Web 05/01/2012
2012 American Chemical Society

catalysts2 (Figure 1). Both continue to attract signifi-
cant attention from the research community and
show potential for industrial and scale-up applications.3
However, neither class is without their limitations, a
number of which we have observed during the course of
our own research investigations.4 For example, with cinchona-
derived bifunctional Brønsted base/H-bond donor
catalysis, although high levels of enantiocontrol can be
observed with a range of pro-nucleophiles and electro-
philes, poor reactivity can often be witnessed.1c,5 This is
particularly apparent for high pKa pro-nucleophiles where
long reaction times, high reaction temperatures, and/or
high catalyst loadings are commonly required. With APT
catalysis, higher levels of reactivity can be achieved (for
example, relatively nonacidic carbon-centered acids can be
employed in conjunction with strong external bases).
However, the levels of enantioinduction are highly depen-
dent on the exact structure of the pro-nucleophile and/or
electrophile, and small variations can result in substantial
loss of enantiofacial selectivity.2b
One design concept that could simultaneously address
these issues is to link a (variable) H-bond donor group to
an appropriate quaternary ammonium salt via a chiral
scaffold (Figure 1).6 Potentially, this would combine pro-
nucleophile activation (under strong base promotion) with
substrate control, preorganization, and activation and thus
lead to desirable levels of reactivity and stereoselectivity in a
broad range of reactions. Tactically, we envisaged that a
short and effective route to such catalysts would be to
alkylate the nucleophilic bridgehead nitrogen atom of
cinchona-derived bifunctional Brønsted base/H-bond donor
catalysts. In turn, these would be readily prepared on
scale in one step from 9-amino-9-deoxyepicinchona alka-
loids. The late stage introduction of these two key catalyst
features, namely the alkyl group of the quaternary ammo-
nium salt and the H-bond donor group, would enable
focused libraries of catalysts to be easily accessed, thus
facilitating rapid optimization in any reaction of interest.
Herein we describe the synthesis of a new family of APT
catalysts bearing ureas, amides, and sulfonamides as
H-bond donor groups, and we also present an evaluation
of their performance in the nitro-Mannich reaction of
amidosulfones.
Figure 1. Concept and design of a new family of cinchona-
derived bifunctional asymmetric phase-transfer catalysts.
by reaction of 9-amino-9-deoxyepicinchona-derived ureas,
amides, and sulfonamides with benzyl bromide, p-(trifluo-
romethyl)benzyl bromide, and (9-anthracenyl)methyl
chloride in toluene at 65 °C for 12 h (Scheme 1).
The new family of asymmetric phase-transfer catalysts
was tested in the enantioselective nitro-Mannich reaction
of in situ generated N-Boc-protected imines of aliphatic,
aromatic, and heteroaromatic aldehydes, introduced
by Herrera and Bernardi,6e and Palomo.6d This reac-
tion is known to proceed well under asymmetric phase-
transfer catalysis conditions.7 However, we believed that
A library of cinchonium/H-bond donor bifunctional
asymmetric phase-transfer catalysts 2À9was readily formed
(7) (a) Kumaraswamy, G.; Pitchaiah, A. Tetrahedron 2011, 67, 2536–
2541. (b) Bzaszczyk, R.; Gajda, A.; Zawadzki, S.; Czubacka, E.; Gajda,
T. Tetrahedron 2010, 66, 9840–9848. (c) Jiang, X.; Zhang, Y.; Wu, L.;
Zhang, G.; Liu, X.; Zhang, H.; Fu, D.; Wang, R. Adv. Synth. Catal.
(5) Oh, S. H.; Rho, H. S.; Lee, J. W.; Lee, J. E.; Youk, S. H.; Chin, J.;
Song, C. E. Angew. Chem. Int. Ed. 2008, 47, 7872–7875.
(6) For selected recent examples, see: (a) Wei, Y.; He, W.; Liu, Y.;
Liu, P.; Zhang, S. Org. Lett. 2012, 14, 704–707. (b) Fiandra, C. D.; Piras,
L.; Fini, F.; Disetti, P.; Moccia, M.; Adamo, M. F. A. Chem. Commun.
2012, 48, 3863–3865. (c) Maciver, E. E.; Knipe, P. C.; Cridland, A. P.;
Thompson, A. L.; Smith, M. D. Chem. Sci. 2012, 3, 537–540. For
representative examples, see: (d) Ohmatsu, K.; Kiyokawa, M.; Ooi, T.
J. Am. Chem. Soc. 2011, 133, 1307–1309. (e) Gomez-Bengoa, E.; Linden,
ꢀ
2009, 351, 2096–2100. (d) Palomo, C.; Oiarbide, M.; Laso, A.; Lopez, R.
J. Am. Chem. Soc. 2005, 127, 17622–17623. (e) Fini, F.; Sgarzani, V.;
Pettersen, D.; Herrera, R. P.; Bernardi, L.; Ricci, A. Angew. Chem. Int.
Ed. 2005, 44, 7975–7978.
(8) (a) Bai, S.; Liang, X.; Song, B.; Bhadury, P. S.; Hu, D.; Yang, S.
Tetrahedron: Asymmetry 2011, 22, 518–523. (b) Zhang, H.; Syed, S.;
Barbas, C. F., III. Org. Lett. 2010, 12, 708–711. (c) Verkade, J. M. M.;
van Hemert, L. J. C.; Quaedflieg, P. J. L. M.; Rutjes, F. P. J. T. Chem.
Soc. Rev. 2008, 37, 29–41. (d) Song, J.; Shih, H. W.; Deng, L. Org. Lett.
2007, 9, 603–606. (e) Tillman, A. L.; Ye, J.; Dixon, D. J. Chem. Commun.
2006, 1191–1193. (f) Song, J.; Deng, L. J. Am. Chem. Soc. 2006, 128,
6048–6049. (g) Bode, C. M.; Ting, A.; Schaus, S. E. Tetrahedron 2006,
62, 11499–11505. (h) Bernardi, L.; Fini, F.; Herrera, R. P.; Ricci, A.;
Sgarzani, V. Tetrahedron 2006, 62, 375–380.
ꢀ
ꢀ
A.; Lopez, R.; Mugica-Mendiola, I.; Oiarbide, M.; Palomo, C. J. Am.
ꢀ
Chem. Soc. 2008, 130, 7955–7966. (f) Berkessel, A.; Guixa, M.; Schmidt,
€
F.; Neudorfl, J. M.; Lex, J. Chem.;Eur. J. 2007, 13, 4483–4498. (g)
Sohtome, Y.; Takemura, N.; Iguchi, T.; Hashimoto, Y.; Nagasawa, K.
Synlett 2006, 144–146. (h) Ooi, T.; Ohara, D.; Fukumoto, K.; Maruoka,
K. Org. Lett. 2005, 7, 3195–3197. (i) Ooi, T.; Ohara, D.; Tamura, M.;
Maruoka, K. J. Am. Chem. Soc. 2004, 126, 6844–6845. (j) Manabe, K.
Tetrahedron 1998, 54, 14465–14476.
Org. Lett., Vol. 14, No. 10, 2012
2493

good stereocontrol could arise from the linked H-bond
donor groups, as has been seen previously in Mannich
and nitro-Mannich reactions catalyzed by bifunctional
cinchona-derived (thio)ureas.8
Table 1. Nitro-Mannich Optimization with Substrate 10a
Scheme 1. Synthesis of Catalyst Library
X
concn temp time yielda eeb
cat. (%) base
solvent (M) (°C)
(h)
(%)
(%)
1
2
2
2
2
2
6
7
3
4
8
5
9
9
9
9
9
9
9
9
9
5
10 KOH
toluene
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
À20
À20
À20
À20
À20
À20
À20
À20
À20
À20
À20
À40
12
34
34
13
12
12
12
12
12
12
12
40
12
12
12
12
12
12
12
24
67
ndc
ndc
ndc
78
ndc
70
53
78
59
91
71
79
77
72
78
73
35
79
66
82
10 K2CO3 toluene
10 Cs2CO3 toluene
10 CsOH toluene
3
4
5
10 KOH
10 KOH
10 KOH
10 KOH
10 KOH
10 KOH
10 KOH
10 KOH
10 KOH
10 KOH
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
EtOAc
58
6
7
81
8
71
9
85d
80
10
11
12
13
14
15
16
17
18
19
20
85d
84d
85d
85d
85d
80d
84d
86d
89d,e
84
0.05 À20
0.2
0.1
0.1
0.1
À20
À20
À20
À20
À20
À20
À20
5
5
5
5
5
5
KOH
KOH
KOH
KOH
KOH
KOH
CH2Cl2
tol/CHCl3 0.1
TBME
TBME
0.1
0.1
a Isolated yield. b Determined by chiral stationary phase HPLC.
c Reaction did not proceed or proceeded very slowly to 12a. d Enantio-
meric (R)-12a was obtained. e The R configuration of (R)-12a was
established through comparison of its specific rotation with literature
data; see the Supporting Information.
a Made from pseudo-enantiomeric starting materials.
Amidosulfone 10a was chosen as a model substrate, and
its base-mediated reaction with nitromethane under solid/
liquid APT conditions with catalysts 2À9 was assessed for
efficiency and stereocontrol (Table 1). Initially, a reactivity
study was carried out using catalyst 2 in conjunction with
finely ground KOH, K2CO3, Cs2CO3, and CsOH with
toluene as solvent. Very pleasingly at À20 °C, KOH and
catalyst 2 gave the desired nitro-Mannich product (S)-12a
in 67% yield and 82% ee (entry 1). Interestingly, none of
the other three bases effectively promoted the reaction.
A range of cinchonidine-derived catalysts presenting
variations in both the H-bond donor group and N-alkyl
group were then screened in the reaction with KOH in
toluene at À20 °C (Table 1). With catalyst 6, possessing a
3,5-bis(trifluoromethyl)benzoylamide, good reactivity was
observed, but enantiocontrol was diminished (58% ee,
entry 5) relative to urea 2. On the other hand, sulfonamide
7 was incompetent as a phase-transfer catalyst in this
reaction (entry 6). Comparing the performance of a series
of ureas with variable ammonium salts, p-(trifluoro-
methyl)benzylammonium salt 3 gave similar results to
benzyl catalyst 2 (70% yield, 81% ee, entry 7), whereas
catalyst 4 possessing an anthracenyl group imparted
slightly diminished enantioselectivity and the product
was obtained in 53% yield (entry 8). From the above
results, it was concluded, at this stage, that for maximum
selectivity the combination of a urea atthe 9-position ofthe
9-amino-9-deoxyepicinchonidinescaffoldand anN-benzyl
group on the bridgehead nitrogen were required. Impor-
tantly, a simple cross-check using commerical N-benzyl-
cinchonidinium bromide as the catalyst, under identical
reaction conditions, afforded the enantiomeric product in
substantially reduced yield and with poor stereocontrol
[(R)-12a was obtained in 34% ee and 29% yield]. This
result confirmed that the urea functionality was playing a
key role in controlling the stereochemical course of the
reaction. The related cinchonine-, quinine- and quinidine-
derived catalysts 8, 5, and 9, respectively, were then sub-
jected to the reaction conditions and, pleasingly, gave rise
to good reactivity and similar levels of control across the
series(entries 9À11). Quinidine derivedcatalyst9 narrowly
out-performed the others and was therefore selected as
the catalyst of choice for the remainder of the optimiza-
tion studies. Lowering the temperature of the reaction to
À40 °C had no beneficial effect on enantiocontrol but did
significantly decrease the reaction rate (entry 12). Neither
concentrating nor diluting the reaction mixture, nor redu-
cing the catalyst loading to 5 mol %, deleteriously affected
2494
Org. Lett., Vol. 14, No. 10, 2012

the enantioselectivity (entries 13À15). Finally, a solvent
screen (entries 15À19) revealed TBME as the solvent
of choice and the optimal conditions employed KOH
(5 equiv) as base and 5 mol % catalyst 9 at À20 °C for
12 h; (R)-12a was obtained in 79% yield and 89% ee
(entry 19). Under the fully optimized conditions but
using pseudo-enantiomeric catalyst 5, the enantiomeric
product (S)-12a was obtained in 66% yield and 84% ee
(entry 20).
give product 12h in 83% yield with excellent diastereos-
electivity (24:1 anti:syn) and enhanced enantioselectivity
(94% ee, entry 7) relative to the analogous experiment
with nitromethane. This same enhancement was observed
with other substituted nitroalkanes such as nitropropane
(92% ee, 17:1 dr, entry 8) and 4-nitrobut-1-ene (95% ee,
6:1 dr, entry 9).
Finally, we investigated the performance of amidosul-
fones derived from aliphatic aldehydes. Good results were
obtained withsterically hindered amidosulfones;tert-butyl
amidosulfone 10h yielded the expected product with ex-
cellent enantiocontrol (90% ee, entry 10). Less hindered
aliphatic amidosulfones such as cyclohexyl amidosulfone
10i led to a slight decrease in enantioinduction (84% ee), but
as with aromatic amidosulfones, an enhancement in enan-
tiocontrol was also observed when larger nitroalkanes were
used. The reactions of 10i with nitroethane (95% ee, entry 12)
and 4-nitrobut-1-ene (93% ee, entry 13) proceeded with
excellent enantioselectivity and good diastereoselectivity.
In summary, we have developed a new family of cinch-
onium/H-bond donor bifunctional asymmetric phase-
transfer catalysts. Their straightforward two-stage synthe-
sis from 9-amino-9-deoxyepicinchona alkaloids readily
allows variation of both the alkyl group of the quaternary
ammonium salt and the H-bond donor group and thus
rapid access to focused libraries of novel catalysts. These
catalysts combine the good reactivity profile of previously
reported asymmetric phase-transfer catalysts with the tun-
able stereocontrol of bifunctional Brønsted base/H-bond
donor catalysts. We have also successfully demonstrated the
application of this new family of catalysts to the enantio-
and diastereoselective nitro-Mannich reaction of in situ
generated N-Boc-protected imines of aliphatic, aromatic,
and heteroaromatic aldehydes. Other applications of cata-
lysts 2À9, and their analogues, are under active investiga-
tion in our laboratories and will be reported in due course.
Table 2. Scope of the Nitro-Mannich Reaction
yielda dr anti: eeanti
c
10
R1
11
R2
12 (%)
synb
(%)
1 b p-Me-Ph
2 c p-OMe-Ph
3 d p-F-Ph
a
a
a
a
a
a
b
c
H
b
c
d
e
f
64
84
91
90
90
91
92
92
94
92
95
90
84
95
93
90
H
H
65
4 e p-CF3-Ph
5 f 2-naphthyl
6 g 3-pyridyl
7 a Ph
H
65
H
87
H
g
h
i
73
Me
Et
83
24:1
17:1
6:1
8 a Ph
94
9 a Ph
d
a
a
b
d
b
CH2CHdCH2
j
64
10 hd tert-butyl
11 i cyclohexyl
12 i cyclohexyl
13 i cyclohexyl
14 j iso-butyl
H
k
l
63
H
100
75
Me
m
n
o
9:1
CH2CHdCH2
82
11:1
13:1e
Me
100
a Isolated yield. b Determined by 1H NMR or chiral stationary phase
HPLC analysis. c Determined by chiral stationary phase HPLC. d To-
luenesulfinic acid-derived amidosulfone was used. e See the Supporting
Information for proof of absolute and relative stereochemistry.
Acknowledgment. We thank the EPSRC (Leadership
Fellowship to D.J.D., postdoctoral fellowship to F.S., and
studentship to D.M.B.), the EC [IEF to F.S. (PIEF-GA-
2009-254068) and to M.G.N. (PIEF-GA-2009-254637)],
AstraZeneca (studentship to D.M.B.), the NSERC of
Canada (postgraduate scholarship to K.M.J.), the Rhodes
Trust (postgraduate award to K.M.J.), and the University
of Oxford Clarendon Fund (studentship to A.M.G).
With optimal conditions in hand, the scope of the
reaction with respect to the amidosulfone was surveyed
(Table 2). A variety of amidosulfones derived from aro-
matic aldehydes proved effective, with substitution in the
para position being well-tolerated with excellent enantio-
selectivities observed with both electron-rich (90À91% ee,
entries 1 and 2) and electron-poor (90À91% ee, entries 3
and 4) aromatics. Polycyclic aromatic and heteroaromatic
amidosulfones also proved effective, with 2-naphthyl and
3-pyridinyl amidosulfones both giving their respective
products in 92% ee (entries 5 and 6). Next, we set out to
assess the generality of the reaction with other nitroalkane
pro-nucleophiles. Pleasingly, the reaction of phenyl ami-
dosulfone 10a with nitroethane proceeded smoothly to
Supporting Information Available. Experimental pro-
cedures and spectral data for compounds 1c, 2À9, 10h,
and 12aÀo. This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 10, 2012
2495