An enantioselective tandem reduction/nitro-Mannich reaction of nitroalkenes using a simple thiourea organocatalyst

Article abstract of DOI:10.1039/c3sc50613d

There is a continual need for ever more effective and operationally simpler methods for the asymmetric synthesis of nitrogen containing molecules. We report here a generally efficient synthesis of stereochemically defined β-nitroamine building blocks which, through the combination of two catalytic transformations into one tandem process, results in the use of a simpler asymmetric catalyst, less reaction materials, shorter reaction times, circumvents the need for moisture sensitive reaction partners and leads to a wider substrate scope. Using para-methoxy-phenyl (PMP) protected imines, a Hantzsch ester as hydride source and a simple and economic thiourea organocatalyst, we have promoted the nitro-Mannich reaction with a nitroalkene to form anti-β-nitroamines. After protection as their trifluoroacetamides the products can be isolated in good yields (32-83percent), high diastereomeric ratios (90:10 to >95:5) and excellent enantioselectivity (73-99percent ee).

Full text of DOI:10.1039/c3sc50613d

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An enantioselective tandem reduction/nitro-Mannich
reaction of nitroalkenes using a simple thiourea
organocatalyst†
Cite this: DOI: 10.1039/c3sc50613d
*
James C. Anderson and Paul J. Koovits
There is a continual need for ever more effective and operationally simpler methods for the asymmetric
synthesis of nitrogen containing molecules. We report here
a generally efficient synthesis of
stereochemically defined b-nitroamine building blocks which, through the combination of two catalytic
transformations into one tandem process, results in the use of a simpler asymmetric catalyst, less
reaction materials, shorter reaction times, circumvents the need for moisture sensitive reaction partners
and leads to a wider substrate scope. Using para-methoxy-phenyl (PMP) protected imines, a Hantzsch
ester as hydride source and a simple and economic thiourea organocatalyst, we have promoted the
Received 5th March 2013
Accepted 2nd May 2013
nitro-Mannich reaction with
a nitroalkene to form anti-b-nitroamines. After protection as their
DOI: 10.1039/c3sc50613d
trifluoroacetamides the products can be isolated in good yields (32–83%), high diastereomeric ratios
(90 : 10 to >95 : 5) and excellent enantioselectivity (73–99% ee).
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complex molecular architectures with high operational effi-
Introduction
ciencies has led to the development of many complex asym-
metric catalysts.9 One way of simplifying these procedures is to
combine catalytic reactions in a tandem process.10 We report a
Functional groups containing nitrogen are present in 75% of all
drug molecules, in every major drug class and in a wide variety
of biologically active natural products.1 The b-nitroamine
functionality has emerged as a privileged building block due to
its complimentary synthetic exibility available from the two
different nitrogen atom oxidation states. As such it has been
applied in the synthesis of many nitrogen containing functional
groups including a-amino carbonyls,2 1,2-diamines,3 peptido-
mimetics,4 natural products5 and many heterocyclic small
molecules6 of importance to drug discovery. This stereodened
bifunctional building block is most commonly made by an
enantioselective nitro-Mannich (or aza-Henry) reaction (Scheme 1).
Enantioselective reactions have been controlled by asym-
metric metal centered Lewis acids; chiral hydrogen bond
donors, in particular by the use of asymmetric thiourea orga-
nocatalysts; chiral Brønsted acids; phase transfer catalysts and
Brønsted base catalysts.7 However, many enantioselective nitro-
Mannich reactions largely suffer from several limitations
including a requisite for a large excess of nitroalkane and/or
long reaction times;8 limited availability of complex nitro-
alkanes; and in the majority of cases the use of moisture
sensitive N-Boc imines (Scheme 1a). The demand for making
Department of Chemistry, University College London, 20 Gordon Street, WC1H 0AJ,
UK. E-mail: j.c.anderson@ucl.ac.uk; Tel: +44 (0)20 7679 5585
† Electronic supplementary information (ESI) available: Method of determining
absolute stereochemistry, detailed catalyst screen, full experimental details, 1H
and 13C NMR spectra for all new compounds and HPLC data. See DOI:
10.1039/c3sc50613d
Scheme 1 Comparison of previous work.
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solution to these problems using an asymmetric tandem enantioselectivity due to retro-addition (Table 1, entry 4).
reductive nitro-Mannich strategy, with nitroalkenes and N-PMP Interestingly, when using ethyl ester substituted Hantzsch ester
imines, catalysed by
a simple thiourea organocatalyst 4b only 10% nitroalkene reduction was observed and <5%
(Scheme 1b).11 The combination of these two catalytic trans- conversion to desired product 3 (Table 1, entry 5).16 Before
formations into one tandem process led to the use of a simpler undertaking a catalyst screen, the stoichiometry of the reaction
asymmetric catalyst, less equivalents of nitroalkene and was examined and it was discovered that by employing 2
reductant, shorter reaction times and circumvented the need equivalents each of the nitroalkene and hydride source the
for moisture sensitive N-Boc imines. This concept generally may reaction was faster and higher yielding with little effect on the
simplify other catalytic systems and specically will allow the enantioselectivity of the reaction (Table 1, entry 6). Increasing
wider synthesis of this versatile building block.
the stoichiometry of imine had no effect on the relative rate of
reaction (Table 1, entry 7) suggesting that the reduction of the
nitroalkene is the rate limiting step. The reaction was also
attempted in a stepwise manner where imine 2 was charged
aer complete reduction of 1 (Table 1, entry 8). This resulted in
no formation of desired product 3 prompting us speculate that
the two reactions occur in tandem.
Results and discussion
Proof of concept and reaction optimisation
Both nitro-Mannich reactions12,13 and reductions of nitro-
alkenes14 have been shown to be amenable to asymmetric
thiourea organocatalysis, so a tandem reaction appeared plau-
sible. Initially, we tested catalyst 5a, previously shown by
Jacobsen to be effective for nitro-Mannich reactions,13b in a
tandem reduction/nitro-Mannich reaction with b-nitrostyrene
1a and Hantzsch ester 4 as hydride source (Table 1). The reac-
tion with N-Boc protected imine failed to give the desired
product, instead preferentially reducing N-Boc imine (Table 1,
Entry 1). However by switching to the less electrophilic N-PMP
protected imine we were able to promote the desired tandem
reductive nitro-Mannich reaction. Due to the instability of the b-
nitroamine products, an in situ triuoroacetamide protection
was performed,15 and 3 was isolated in 29% yield and in 58% ee
aer 1 h (Table 1, entry 2). Extended reaction times initially gave
an increase in the reaction yield, up to 9 h when b-nitrostyrene
1a had been fully consumed (Table 1, entry 3). Further ageing
of the reaction however gave a decreased yield and lower
Optimisation of asymmetric catalyst
Using these optimised conditions we then screened the reaction
with a variety of thiourea organocatalysts (Table 2).17 Take-
moto's catalyst 5b,18 failed to reduce nitroalkene 1a and
Table 2 Optimisation of asymmetric catalysta
87% yield, 95 : 5 dr, 50% ee
25% yield, >95 : 5 dr, 86% ee
36% yield, >20 : 1 dr, À65% ee
No reaction
Table 1 Optimisation of reductive nitro-Mannich reaction
48% yield, >95 : 5 dr, 90% ee
37% yield, 95 : 5 dr, 76% ee
Entry PG
R
Rxn time (h) Yield (%) dra
eeb (%)
t
1
2
3
4
Boc
CO2 Bu 16
<5
29
45
23
<5
77
30
<5
—
95 : 5
95 : 5
90 : 10 34
—
95 : 5
95 : 5
—
—
58
52
t
PMP CO2 Bu
1
9
t
PMP CO2 Bu
t
PMP CO2 Bu 22
5
PMP CO2Et
22
2
1
—
50
57
—
6c
7d
8e
PMP CO2 Bu
t
t
72% yield, >95 : 5 dr, 90% ee
75% yield, 90 : 10 dr, 90% ee 81%
yield, 95 : 5 dr, 90% eeb
PMP CO2 Bu
t
PMP CO2 Bu
9
a
a
b
Determined by 1H NMR analysis. Determined by chiral HPLC see
Reaction of N-PMP imine (0.14 mmol) with 1a (2 equiv.), 4a (2 equiv.)
and 5 (10 mol%) in toluene (1 mL) at rt for 2 h. b Reaction performed at
À20 ꢀC over 24 h.
c
d
e
ESI. 2 equiv. of 1 and 4a. 2 equiv. of 2. Reaction performed using
a stepwise addition.
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Table 3 Scope of the enantioselective reductive nitro-Mannich reaction with
consequently no nitro-Mannich reaction was observed. Using
catalyst 5c, which has been previously used for asymmetric
reductions of nitroalkenes,14 we obtained a high degree of
enantioselectivity (86% ee) but in a poor yield (25%, extended
reaction times did not lead to an improvement in yield). Tol-
uenesulfonamide catalyst 5d gave the desired product with
excellent enantioselectivity (90% ee) and a moderate yield of
48% (extended reaction times led to a maximum yield of 75%
with an 88% ee). To explore which chiral group was responsible
for stereoinduction, we screened catalyst 5e, which gave the
opposite enantiomer to that obtained with 5d with 64% ee; and
diastereomeric catalyst 5f, which gave the same enantiomer as
that obtained with 5d, albeit with a slightly reduced yield and
enantioselectivity (37%, 76% ee). These two results suggest that
the diaminocyclohexane group is not responsible for the high
degree of stereoselectivity. Due to the relatively high cost of un-
natural amino acid L-tert-leucine, we also synthesised catalyst 5g
using the signicantly cheaper L-valine and were surprised to
observe the same high levels of enantioselectivity (90% ee).
Combining these results we replaced the diaminocyclohexane
moiety with an aryl group to give catalyst 5h which achieved a
high level of enantioinduction (90% ee) and yield (75%). With
catalyst 5h showing good potential we conducted a solvent
screen that conrmed toluene as the best choice (see ESI†).
Further investigation of the reaction in toluene at rt showed
complete consumption of the imine aer 30 min and imme-
diate protection enabled isolation of 3 in 74% yield with an
impressive 94% ee. This result suggested that stereoselectivity
was probably being eroded at rt due to the reversibility of the
nitro-Mannich reaction. In order to retard the retro-addition
reaction we performed the reaction at lower temperatures (see
respect to imines
Entry R1
Product Yielda (%) drb
eec (%)
1
2
3
4
5
6
7
8
Ph
3aa
81
75
83
74
66
75
70
77
76
59
>95 : 5 (>95 : 5) 98
p-MeOPh 3ab
o-MeOPh 3ac
p-F3CPh
o-F3CPh
o-MePh
o-BrPh
2-Furyl
2-Pyridyl
nPentyl
>95 : 5 (>95 : 5) 97
>95 : 5 (>95 : 5) 99
90 : 10 (90 : 10) 94
>95 : 5 (80 : 20) 80 (4)
>95 : 5 (85 : 15) 90 (34)
>95 : 5 (80 : 20) 92 (10)
90 : 10 (90 : 10) 97
>95 : 5 (>95 : 5) 96
>95 : 5 (>95 : 5) 73
3ad
3ae
3af
3ag
3ah
3ai
9
10d
3aj
a
b
Isolated yield of 3. dr of isolated 3 calculated by 1H NMR,
c
parentheses indicate dr of crude product. Determined by chiral
HPLC, parenthesis indicate ee of syn-diastereomer if isolated.
d
Reaction performed at rt over 1 h.
without any noticeable effect on the enantioselectivity allowing
isolation of 3aj in 59% yield.
Reaction optimisation with respect to nitroalkenes 1
The nitroalkene partner tolerated alkyl substituents,
substituted aromatics and heterocyclic analogues exceptionally
well giving high yields and excellent stereoselectivity (Table 4,
entries 1–7). A decrease in the rate of the reaction was observed
ꢀ
ESI†). At À20 C the desired product was isolated in excellent
yield and stereoselectivity (81% yield, >95 : 5 dr and 98% ee)
aer 20 h. Prolonged reaction at À20 ꢀC did not lead to a
decrease in enantioselectivity suggesting no retro-addition
occurs (see ESI†).
Table 4 Scope of the enantioselective reductive nitro-Mannich reaction with
respect to nitroalkenes
Reaction optimisation with respect to imines 2
With these optimised conditions we examined the scope of the
reaction, initially with respect to imines 2 (Table 3). Both elec-
tron rich and electron poor aromatic imines (Table 3, entries 2–
7) gave uniformally high yields and excellent stereoselectivities,
although the ortho-triuoromethyl substituted electron de-
cient imine (Table 3, entry 5) was less enantioselective (80% ee).
The crude diastereoselectivities for all the ortho-substituted
substrates (Table 3, entries 5–7) were lower than that of the
puried products. All of the syn-diastereoisomers isolated from
these analogues were of low enantiopurity which may suggest
that there are different transition states in operation for each
diastereoisomer. The reaction worked well for heterocyclic
imines (Table 3, entries 8–9), but less so for an alkyl npentyl
substituted product 3aj which was formed in moderate 73% ee
(Table 3, entry 10).
Rxn time
Product (h)
Entry R1
Yielda (%) drb
eec (%)
1
2
3
4
5
6
7
8
nPentyl
Cyclohexyl 3ca
o-BrPh
o-F3CPh
2-Pyridyl
o-MePh
o-MeOPh
2-Furyl
3ba
20
20
20
20
28
48
72
240
71
75
79
73
68
70
64
32
>95 : 5 97
>95 : 5 95
3da
3ea
3fa
3ga
3ha
3ia
>95 : 5 98
>95 : 5 95
>95 : 5 98
>95 : 5 98
>95 : 5 98
>95 : 5 95
The yield of the reaction was also reduced due the instability
of the npentyl substituted imine 2j, even at À20 ꢀC. It was found
that the yield was best at rt, where the reaction was rapid,
Isolated yield of 3. dr of crude 3 calculated by 1H NMR, which
a
b
remained unchanged aer purication. c Determined by chiral HPLC.
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enantiomer. Conversely, to obtain the opposite enantiomer the
iso-propyl group would be required to be in the same plane as
the C]S bond (TS-2). Such a conformation would have a large
steric penalty and would as such be unfavorable.
Preliminary investigations into forming three contiguous
stereocentres
Pleased with the results using simple nitrostyrene derivatives
we wished to examine the potential of this reaction to form
nitro-Mannich products containing three contiguous stereo-
centres. Using nitroalkene 6 and our thiourea catalyst 5h we
were pleasingly able to obtain 7a in high enantiopurity (84% ee)
and excellent diastereoselectivity (95 : 0 : 5 : 0 dr) aer 17 h at
room temperature, albeit in a low yield of 37% (Table 5, entry 3).
Interestingly, the reaction initially favoured formation of the
syn, anti-diastereomer 7b before converting to 7a. We are
currently unsure as to the mechanism of this interconversion
but believe it may be formed via a retro addition/nitro-Mannich
sequence.20 Further investigations and optimisations of this
intriguing reaction are currently underway.
Scheme 2 Origin of enantioselectivity.
when using more electron rich nitroalkenes (Table 4, entries
6–8). This effect was most evident when using 2-furyl nitroal-
kene 1i which required a reaction time of 10 days to consume all
of imine 2a (Table 4, entry 8). This increased reaction time also
led to decreased yields due to competitive reduction of imine 2.
This result also suggests that the reduction is the rate deter-
mining step of the reaction.
Conclusions
We have developed the rst asymmetric tandem reductive nitro-
Mannich reaction using a simple thiourea organocatalyst and a
Hantzsch ester as hydride source. The reaction uses the
simplest thiourea organocatalyst applied to a nitro-Mannich
reaction yet and in general does not suffer from the long reac-
tion times or large excess of reagents required of previous
reports. The reductive nitro-Mannich strategy provides an
opportunity for more diverse substrates and the reaction is
tolerant of a variety of different nitroalkenes and imines. To the
best of our knowledge this is also the rst organocatalysed
nitro-Mannich reaction using PMP-imines, which signicantly
simplies the experimental conditions of the reaction and
should enable wider use in synthesis. We are currently begin-
ning detailed experimental and computational investigations
into the origin of the exceptionally high levels of enantiose-
lectivity considering the simplicity of the catalyst.
Mechanistic hypothesis
Our current working hypothesis is that the high enantiose-
lectivity originates from a H-bond stabilised transition state
(Scheme 2). This six-membered transition state consists of two
H-bonds between the thiourea and nitro group as well as an
amide H-bond with the iminium species.
If we assume from the detailed work of Jacobsen on a similar
catalyst that the most stable conformation of catalyst 5h is when
the highlighted C–H bond is in the same plane as the large C]S
bond,19 the amide can freely H-bond to the iminium species in a
pseudo equatorial position (TS-1) giving rise to the observed
Table 5 Preliminary investigations into forming three contiguous stereocentres
Acknowledgements
Financial support was provided by the EPSRC (DTG) and UCL,
we thank Dr L. Harris and Mr J. Hill for mass spectra, and Ms
J. Maxwell for microanalytical data.
Notes and references
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Rxn time
(h)
Conv. to 7a
(%)
Yieldb
(%)
drc
eed
(%)
Entry
(a : b : c : d)
1
2
3
0.5
2.5
17
10
30
55
n.d.
n.d.
37
10 : 80 : 10 : 0
65 : 5 : 30 : 0
95 : 0 : 5 : 0
n.d.
n.d.
84
2 (a) R. Ballini and M. Petrini, Tetrahedron, 2004, 60, 1017; (b)
Calculated by 1H NMR. b Isolated yield of 7. c dr of crude 7 calculated
a
´
C. Palomo, M. Oiarbibe, R. Halder, A. Laso and R. Lopez,
by 1H NMR. d Determined by chiral HPLC.
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´
´
E. Marquez-Lopez, P. Merino, T. Tejero and R. P. Herrera,
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8 Most examples require 5–10 equivalents of nitroalkane or
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