A general organocatalytic enantioselective nitrocyclopropanation reaction

Article abstract of DOI:10.1055/s-2008-1042944

A general organocatalytic enantioselective synthesis of nitrocyclopropanes from bromonitromethane and a variety of cyclic and acyclic enones is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1042944

PAPER
1269
A General Organocatalytic Enantioselective Nitrocyclopropanation Reaction
Enantioselective
N
e
itrocyclopr
i
opanat
tion Reaction Wascholowski, Henriette M. Hansen, Deborah A. Longbottom, Steven V. Ley*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
Fax +44(1223)336442; E-mail: svl1000@cam.ac.uk
Received 21 December 2007
Br
NO2
Abstract: A general organocatalytic enantioselective synthesis of
nitrocyclopropanes from bromonitromethane and a variety of cyclic
3
O
and acyclic enones is described.
N
O
O
N
N
N
N
H
4
Key words: asymmetric catalysis, carbocycles, cyclisation, orga-
nocatalysis, nitrocyclopropane, tetrazole
H
H
H
HN
1
NO2
CH2Cl2
2
5
Since their first synthesis in 1884 by William Henry
Perkin,1 structures containing the cyclopropane motif
have been of great interest within the organic chemistry
community. They are widely distributed in a range of nat-
urally occurring compounds2 and biologically active
agents, for example, peptidomimetics,3 enzyme inhibi-
tors,4 and therapeutic agents.5 In addition, due to their
small, rigid structure and strain-driven reactivity, they
serve as versatile synthetic intermediates in a variety of
reactions.6 As a result, their stereoselective preparation is
a valuable goal and to date, many methods have been de-
veloped for this purpose.7
Scheme 1 Enantioselective nitrocyclopropanation
alyst 1. This new reaction sets up three new stereogenic
centres in a single operation yielding the product 5 in 80%
yield and 77% enantioselectivity after 24 hours in dichlo-
romethane (Scheme 1).19
However, when the five- and seven-membered-ring con-
geners were assessed in this reaction, while yields of the
products were high (73% and 93%, respectively), the
enantioselectivities were only moderate (35% and 40%).
Furthermore, with the acyclic example, non-3-en-2-one
(6) (Table 1), the yield was only moderate (45%), and di-
astereoselectivities (3 isomers, 4.6:1.3:1) and enantiose-
lectivities (14% to 42%) were disappointing (Table 1,
entry 1). Here, we report the evolution of these studies and
the resulting development of a more general and practical
enantioselective organocatalytic nitrocyclopropanation
reaction.
The presence of substituents on the cyclopropane ring af-
fects the properties, both physical and chemical.1,8 More-
over, they enable further transformations such as
functional group interconversions or couplings with other
molecules.9
More specifically, nitro-substituted cyclopropanes, which
are also present in natural products, like the peptidolac-
tone hormaomycin10 or intermediates in natural product
synthesis, such as the broad-spectrum antibiotic
Trovafloxacin11 are of potential utility. Furthermore,
nitro-substituted cyclopropanes may be converted into a
wide range of functionalities,12 and are prepared by a va-
riety of methods.13 However, these methods often have
drawbacks such as tedious procedures, the need for many
steps, and the separate and time-consuming preparation of
the starting material. Furthermore, the yields and enantio-
selectivities are mostly moderate.14
Table 1 Results of Nitrocyclopropanation on the Non-3-en-2-one
(6)a
Entry
Yield (%)b
Time (h) dr (a:b:c)
ee (%)c
1
2
3
4
5
6
45d
78
24
16
48
16
16
12
4.6:1.3:1
5.6:1.3:1
4.4:1.4:1
5.4:1.2:1
6.4:1.8:1
5.0:1.4:1
42, 14, 42
54, 34, 53
34, 16, 39
63, 33, 57
65, 31, 55
70, 37, 61
87
81e
47f
84g
Since the introduction of the pyrrolidinyl tetrazole deriv-
ative 1 in enantioselective organocatalysed reactions by
Arvidsson,15 Yamamoto,16 and ourselves17 its use is now
widely accepted.18 In recent studies in this area, after an
extensive screening of different organocatalysts, we de-
scribed an enantioselective nitrocyclopropanation process
between cyclohex-2-enone (2) and bromonitromethane
(3) in the presence of morpholine (4) and the tetrazole cat-
a Conditions: 6 (0.5 mmol), 3 (1.0 mmol), 4 (1.5 mmol), 1 (15 mol%),
CH2Cl2 (2 mL), r.t.
b Isolated yield.
c Determined by chiral GC.
d Conditions: 6 (0.5 mmol), 3 (0.5 mmol), 4 (0.5 mmol), 1 (15 mol%),
CH2Cl2 (2 mL), r.t.
e Solvent: CHCl3 (2 mL).
f Conditions: 6 (0.5 mmol), 3 (1.0 mmol), 4 (1.5 mmol), 1 (15 mol%),
Bu4NI (1.5 mol%), CHCl3 (2 mL), r.t.
g Conditions: 6 (0.5 mmol), 3 (1.0 mmol), 4 (1.5 mmol), 1 (15 mol%),
NaI (1.5 mol%), CHCl3 (2 mL), r.t.
SYNTHESIS 2008, No. 8, pp 1269–1275
x
x
.
x
x
.2
0
0
8
Advanced online publication: 18.03.2008
DOI: 10.1055/s-2008-1042944; Art ID: P14907SS
© Georg Thieme Verlag Stuttgart · New York

1270
V. Wascholowski et al.
PAPER
Br
NO2
N
3
O
N
NO2
N
H
4
N
H
O
O
HN
N
∗
1
∗
∗
CHCl3
6
7
Scheme 2 Nitrocyclopropanation of non-3-en-2-one (6)
NO2
O
Firstly, in the search for a general nitrocyclopropanation
procedure, the reaction of non-3-en-2-one (6) was careful-
ly monitored (Scheme 2). From this, the following con-
clusions could be drawn at the 12 hour time point. The
reaction had stopped and, while 50% of the starting mate-
rial remained, all the bromonitromethane was consumed.
Moreover, the reaction mixture had also become acidic
(pH £4).
NO2
O
7a
7b
NO2
O
Control experiments then revealed that, although there
was no side-reaction between bromonitromethane (3) and
the tetrazole catalyst 1, there was one between bromoni-
tromethane (3) and morpholine (4).20
7c
Figure 1 Stereochemical assignment by NOE experiments
were re-examined so as to obtain a comparison with the
previous conditions. It was most encouraging to see that
they did indeed react with generally high enantioselectiv-
ities and complete diastereoselection. Indeed, the reaction
with cyclohex-2-enone (2) now gave the product 5 in 87%
yield and impressive 90% ee in just two hours compared
to 77% ee in 24 hours with the previous conditions
(Table 2, entry 1).21 Furthermore, the seven-membered
congener (Table 2, entry 2) was formed in a similarly high
yield (91%), but with notably higher enantioselectivity
(70%) to the previously reported result. In fact, only the
five-membered cyclopent-2-enone (Table 2, entry 3) gave
a moderate enantioselectivity (48%), but retained the high
yield (87%). Steric and electronic effects were next exam-
ined, using the six-membered-ring system as the bench-
mark. Pleasingly, even the sterically hindered substrates
3-methylcyclohex-2-enone (Table 2, entry 4) and also the
4,4-diphenylcyclohex-2-enone (Table 2, entry 5), were
obtained with both good yields (74% and ~100%, respec-
tively) and enantioselectivities (76% and 77%). However,
a methoxy substituent in the 3-position of cyclohex-2-
enone (Table 2, entry 6) gave no reaction after 48 hours
and only starting material was recovered. It is postulated
that this is due to electronic rather than steric reasons, as
the methyl substituted example 10 works well. In this case
the donation of electrons from the oxygen into the a,b-un-
saturated system is probably deactivating enough to pro-
hibit the initial 1,4-addition of bromonitromethane (3),
and thus the final nitrocyclopropanation product forma-
tion. However, the optimised reaction conditions also
have limitations: for example, methyl substitution in the
2- or 3-position on the cyclopent-2-enone dramatically
decreased the speed of reaction and, as a result, also the
We speculated that this side-reaction was potentially the
source of the problems, and therefore the equivalents of
each compound were systematically increased. Conse-
quently with two equivalents of bromonitromethane (3)
and three of morpholine (4), a marked improvement was
seen: the yield of 7 was close to double and both diastereo-
and enantioselection had undergone significant improve-
ment with a reaction time of only 16 hours (Table 1, entry
2). Increase of the reaction time to 48 hours led to only a
slight improvement of yield, but interestingly, both the
diastereo- and enantioselectivity decreased (Table 1, en-
try 3). Closer examination of the reaction solvent revealed
that chloroform proved to be the optimal solvent in terms
of both yield and enantioselection (Table 1, entry 4). To
enhance the reaction rate, Finkelstein-type activation of
the bromonitromethane with iodide sources was exam-
ined. As expected, the reaction took place when tetrabu-
tylammonium iodide was added, but the yield
dramatically decreased, while the enantioselectivity was
retained (Table 1, entry 5). Furthermore, purification by
column chromatography became more difficult, due to the
formation of many by-products. Pleasingly, however the
use of sodium iodide achieved a further improvement in
yield and enantioselectivity. Indeed, the best result was
obtained with only 1.5 mol% of added sodium iodide
(Table 1, entry 6).
In order to determine the stereochemical outcome of this
reaction, NOE experiments were conducted on each sin-
gle diastereomer of 7 (Figure 1), and it was interesting to
see that the major diastereomer 7a has the same relative
stereochemistry as the cyclic example, cyclohex-2-
enone.19
With such a dramatic improvement in the results for the enantioselectivity and yield (Table 2, entries 7 and 8). In-
acyclic non-3-en-2-one (6) example, application of these terestingly, in the case of methyl substitution in the 3-po-
optimised reaction conditions to alternative substrates sition on the cyclopent-2-enone two diastereomers were
was investigated (Table 2). First, the cyclic examples isolated (Table 2, entry 8), whereas all other cyclic exam-
Synthesis 2008, No. 8, 1269–1275 © Thieme Stuttgart · New York

PAPER
Enantioselective Nitrocyclopropanation Reaction
1271
Table 2 Results of Nitrocyclopropanation on the Cyclic Enonesa
Table 3 Results of Nitrocyclopropanation on the Acyclic Enonesa
Entry
Product
Yield (%)b Time (h) ee (%)c
Entry Product
Yield dr (a:b:c) ee (%)c
(%)b
O
H
NO2
87
90
∗ O
1
NO2
NO2
2
(80)d
(77)d
1
84d
72d
5:1.4:1
4.6:1:1
70, 37, 61
75, 41, 68
∗
H
∗
5
8
7
O
H
NO2
91e
70
∗ O
2
3
4
16
2
2
(93)d
(40)d
∗
H
∗
15
NO2
H
NO2
O
∗ O
87
48
3
4
63d
5.9:1.3:1 76, 31, 60
(73)d
(35)d
∗
H
∗
9
16
17
O
NO2
H
∗ O
56f
74g
no reaction in 48 h
24
76
77
NO2
∗
10
11
NO2
O
∗ O
H
H
∗
∗
5
69
6.9:1.3:1 63, 41, 51
NO2
∗
5
6
~100
8
18
19
20
NO2
∗ O
6
7
no reaction in 48 h
O
O
∗
H
O
no reaction in 48 h
NO2
NO2
NO2
∗ O
47
42
4.6:1
1.6:1
63, 37
42, 29
∗
12
∗
O
7
8
11
24
14
NO2
H
∗ O
∗
13
8
∗
H
NO2
16h
8h
24
24
34
28
O
21
a Conditions: substrate (0.5 mmol), 3 (1.0 mmol), 4 (1.5 mmol), 1 (15
mol%), NaI (1.5 mol%), CHCl3 (2 mL), 16 h, r.t.
b Isolated yield.
14
a Conditions: substrate (0.5 mmol), 3 (1.0 mmol), 4 (1.5 mmol), 1 (15
mol%), NaI (1.5 mol%), CHCl3 (2 mL), r.t.
b Isolated yield.
c Determined by chiral GC.
d Reaction time was 10 h.
c Determined by chiral GC.
d Results from the previous publication.19
e A syringe pump was used to add bromonitromethane over the indi-
cated time.
apart from the optimised example, non-3-en-2-one (6,
Table 3, entry 1), the hept-3-en-2-one (Table 3, entry 2)
and pent-3-en-2-one (Table 3, entry 3) also worked well
and were obtained in good yields, retaining the good dia-
stereo- and enantioselectivity.
f Total isolated yield.
g Yield based on recovered starting material.
h Two diastereomers: 14a and 14b were isolated in a dr of 2:1.
ples showed complete diastereoselection. Further trials to
optimise these reactions with cyclopent-2-enone have so
far been unsuccessful.
However, in contrast to the cyclic enone with a b-methyl
substituent, the linear 4-methylpent-3-en-2-one (Table 3,
entry 4) gave no reaction in 48 hours and only starting ma-
terial was recovered. If the branching is not directly at the
double bond, good yields and enantioselectivities were
The nitrocyclopropanation reaction was then applied to
acyclic systems (Table 3). It was pleasing to find that
Synthesis 2008, No. 8, 1269–1275 © Thieme Stuttgart · New York

1272
V. Wascholowski et al.
PAPER
1-[(1S,2S,3R)-2-Nitro-3-pentylcyclopropyl]ethanone (7a)
obtained (Table 3, entry 5). Similar to the cyclic example
12, methoxy substitution directly at the double bond
(Table 3, entry 6) gave no reaction, again probably due to
the electron-donating substituent, which deactivates the
system to nucleophilic attack.
(Major Diastereomer)
Yield: 0.056 g (57%); colourless oil; Rf = 0.68 (CH2Cl2);
[a]D25 +42.3 (c = 1, CHCl3).
1H NMR (600 MHz, CDCl3): d = 0.85–0.87 (m, 3 H, CH3), 1.21–
1.44 (m, 7 H, 3 × CH2, CH2a), 1.53–1.58 (m, 1 H, CH2b), 2.33 (s, 3
H, CH3CO), 2.40–2.45 (m, 1 H, CH), 3.16 (dd, J = 11.0, 3.5 Hz, 1
H, CH), 4.60 (t, J = 3.9 Hz, 1 H, CHNO2).
13C NMR (100 MHz, CDCl3): d = 13.83 (CH3), 22.31 (CH2), 23.71
(CH2), 28.48 (CH2), 31.07 (CH2), 31.61 (CH3), 34.29 (CH), 36.97
(CH), 64.37 (CHNO2), 200.90 (C=O).
In addition, replacing the a-methyl with alternative
groups was also studied. Interestingly, with more bulky
groups only two diastereomers were isolated. It is thought
that the third diastereomer is not formed because in these
cases a unfavoured interaction with the nitro group takes
place. However, in both cases (ethyl, and phenyl, Table 3,
entries 7 and 8) a greater amount of side-reactions and by-
product formation was observed, unfortunately leading to
decreased yields and enantioselectivities.
HRMS-ESI: m/z calcd for C10H17NO3 + Na [M + Na]+: 222.1100;
found: 222.1101.
1-[(1S,2S,3S)-2-Nitro-3-pentylcyclopropyl]ethanone (7b)
(1st Minor Diastereomer)
Yield: 0.016 g (16%); colourless oil; Rf = 0.64 (CH2Cl2); [a]D
–25.0 (c = 0.15, CHCl3).
25
In summary, a general enantioselective organocatalytic
nitrocyclopropanation reaction process has been devel-
oped. The reaction is efficiently catalysed by the simple
pyrrolidinyl tetrazole catalyst 1. Results with cyclic sub-
strates are good to excellent and with linear examples,
yields are high with slightly reduced enantio- and diaste-
reoselectivites. Mechanistic studies and synthetic applica-
1H NMR (400 MHz, CDCl3): d = 0.86–0.89 (m, 3 H, CH3), 1.27–
1.47 (m, 6 H, 3 × CH2), 1.54–1.74 (m, 2 H, CH2), 1.91–1.99 (m, 1
H, CH), 2.53 (s, 3 H, CH3CO), 3.01 (dd, J = 7.0, 3.3 Hz, 1 H, CH),
4.66 (dd, J = 8.5, 3.5 Hz, 1 H, CHNO2).
13C NMR (100 MHz, CDCl3): d = 13.86 (CH3), 22.34 (CH2), 23.72
tions of this transformation are ongoing in our laboratory. (CH2), 24.95 (CH2), 28.28 (CH2), 31.10 (CH3), 33.24 (CH), 36.10
(CH), 64.37 (CHNO2), 200.90 (C=O).
HRMS-ESI: m/z calcd for C10H17NO3 + Na [M + Na]+: 222.1100;
found: 222.1108.
All reactions were carried out under argon. Petroleum ether (PE) re-
fers to the 40–60 °C boiling point fraction of petroleum. Anhydrous
CHCl3 was bought from Sigma-Aldrich. All other reagents and sol-
vents were used as supplied. Flash column chromatography was
1-[(1R,2S,3R)-2-Nitro-3-pentylcyclopropyl]ethanone (7c)
(2nd Minor Diastereomer)
Yield: 0.011 g (11%); colourless oil; Rf = 0.61 (CH2Cl2); [a]D
–10.0 (c = 0.2, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.90 (t, J = 7.1 Hz, 3 H, CH3),
1.23–1.33 (m, 4 H, 2 × CH2), 1.38–1.47 (m, 4 H, 2 × CH2), 2.25–
2.30 (m, 1 H, CH), 2.29 (s, 3 H, CH3CO), 2.48–2.50 (m, 1 H, CH),
4.24 (q, J = 4.2 Hz, 1 H, CHNO2).
13C NMR (100 MHz, CDCl3): d = 13.88 (CH3), 22.41 (CH2), 27.74
(CH2), 28.47 (CH3), 30.06 (CH2), 30.64 (CH), 31.08 (CH2), 37.91
(CH), 65.51 (CHNO2), 199.12 (C=O).
carried out using Merck Kieselgel (230–400 mesh). 1H NMR spec-
tra were recorded on a Bruker DRX-400 or Bruker DRX-600 spec-
trometer. The residual protic solvent CHCl3 (dH = 7.26) in CDCl3
was used as an internal standard. 13C NMR spectra were recorded
on the same spectrometers at 100 and 150 MHz, using central reso-
nance of CDCl3 (dC = 77.0). Accurate mass data were obtained on
Micromass Q-TOF by electrospray ionisation (ESI). Optical rota-
tions were measured on a PerkinElmer 343 polarimeter at 25 °C;
concentrations (c) are reported in g/100 mL. Melting points were
measured on a Reichert hot stage apparatus, and are uncorrected.
The enantiomeric excess (ee) of the products was determined by
chiral stationary phase GC (Chiraldex G-TA column).
25
HRMS-ESI: m/z calcd for C10H17NO3 + Na [M + Na]+: 222.1100;
found: 222.1109.
Nitrocyclopropanation of Enones; General Procedure
To a stirred suspension of the enone starting material (0.5 mmol)
and pyrrolidinyl tetrazole 1 (15 mol%) in CHCl3 (2 mL) were added
NaI (1.5 mol%), morpholine (4; 1.5 mmol) and bromonitromethane
(3; 1.0 mmol) at r.t. during the indicated time. The mixture was di-
luted with CH2Cl2 (10 mL) and washed with H2O (10 mL). The
aqueous phase was extracted with CH2Cl2 (3 × 10 mL). The com-
bined organic phases were dried (MgSO4), concentrated in vacuo,
and the residue was purified by flash chromatography (Tables 2
and 3).
(1R,7S,8R)-8-Nitrobicyclo[5.1.0]octan-2-one (8)
Yield: 0.077 g (91%); colourless oil; Rf = 0.62 (CH2Cl2); [a]D
–16.0 (c = 0.5, CHCl3).
25
1H NMR (400 MHz, CDCl3): d = 1.29–1.75 (m, 5 H, 2 CH2, CH2a),
2.15–2.23 (m, 1 H, CH2b), 2.37–2.48 (m, 2 H, CH, CH2c), 2.56–2.68
(m, 1 H, CH2d), 3.11 (dd, J = 12.1, 3.7 Hz, 1 H, CH), 4.62 (t, J = 3.9
Hz, 1 H, CHNO2).
13C NMR (100 MHz, CDCl3): d = 24.42 (CH2), 25.57 (CH2), 26.96
(CH2), 27.29 (CH), 39.86 (CH), 43.12 (CH2), 62.91 (CHNO2),
203.24 (C=O).
(1R,6S,7R)-7-Nitrobicyclo[4.1.0]heptan-2-one (5)
Yield: 0.067 g (87%); white solid; mp 70–71 °C; Rf = 0.48
(CH2Cl2); [a]D25 –53.5 (c = 0.4, CHCl3).
HRMS-ESI: m/z calcd for C8H11NO3 + Na [M + Na]+: 192.0631;
found: 192.0640.
1H NMR (400 MHz, CDCl3): d = 1.46–1.58 (m, 1 H, CH2a), 1.80–
1.88 (m, 1 H, CH2b), 1.93–2.02 (m, 1 H, CH2c), 2.09–2.18 (m, 2 H,
CH2d, CH2e), 2.28–2.35 (m, 1 H, CH2f), 2.62–2.67 (m, 1 H, CH),
2.80 (dd, J = 9.6, 2.6 Hz, 1 H, CH), 4.66 (t, J = 3.1 Hz, 1 H,
CHNO2).
13C NMR (100 MHz, CDCl3): d = 18.70 (CH2), 20.09 (CH2), 27.28
(CH), 35.66 (CH), 37.71 (CH2), 61.02 (CHNO2), 201.57 (C=O).
(1R,5S,6R)-6-Nitrobicyclo[3.1.0]hexan-2-one (9)
Yield: 0.062 g (87%); light yellow solid; mp 62 °C; Rf = 0.50
(CH2Cl2); [a]D25 +6.4 (c = 0.5, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.91–2.01 (m, 1 H, CH2a), 2.16–
2.36 (m, 3 H, CH2b, CH2), 2.77 (d, J = 6.7 Hz, 1 H, CH), 2.94–2.97
(m, 1 H, CH), 4.40 (t, J = 1.9 Hz, 1 H, CHNO2).
13C NMR (100 MHz, CDCl3): d = 22.48 (CH2), 31.29 (CH), 32.93
(CH2), 38.01 (CH), 62.34 (CHNO2), 207.99 (C=O).
HRMS-ESI: m/z calcd for C7H9NO3 + Na [M + Na]+: 178.0474;
found: 178.0479.
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PAPER
Enantioselective Nitrocyclopropanation Reaction
1273
HRMS-ESI: m/z calcd for C6H7NO3 + Na [M + Na]+: 164.0318;
HRMS-ESI: m/z calcd for C7H9NO3 + Na [M + Na]+: 178.0474;
found: 164.0323.
found: 178.0474.
(1R,6S,7R)-6-Methyl-7-nitrobicyclo[4.1.0]heptan-2-one (10)
Yield: 0.048 g (56%); yield based on recovered starting material:
0.062 g (74%); colourless solid; mp 39 °C; Rf = 0.39 (CH2Cl2);
[a]D25 +43.5 (c = 0.7, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.41 (s, 3 H, CH3), 1.49–1.61 (m,
1 H, CH2a), 1.78–1.90 (m, 2 H, CH2b, CH2c), 2.02–2.11 (m, 1 H,
CH2d), 2.17–2.23 (m, 1 H, CH2e), 2.32–2.38 (m, 1 H, CH2f), 2.88 (d,
J = 3.2 Hz, 1 H, CH), 4.78 (d, J = 3.3 Hz, 1 H, CHNO2).
13C NMR (100 MHz, CDCl3): d = 17.86 (CH2), 17.91 (CH3), 28.76
(CH2), 32.95 (Cq), 36.75 (CH2), 40.79 (CH), 65.79 (CHNO2),
202.36 (C=O).
HRMS-ESI: m/z calcd for C8H11NO3 + Na [M + Na]+: 192.0631;
found: 192.0626.
1-(2-Nitro-3-propylcyclopropyl)ethanone (15) (Mixture of 15a
and 15b)
Yield: 0.052 g (61%); colourless oil; Rf = 0.76 (CH2Cl2)
1H NMR (400 MHz, CDCl3): d (inseparable mixture of isomers, mi-
nor isomer 15b starred) = 0.88–0.94 (m, 3 H, CH3 and 3 H, CH3*),
1.24–1.58 (m, 4 H, 2 × CH2 and 4 H, 2 × CH2*), 1.92–2.00 (m, 1 H,
CH*), 2.34 (s, 3 H, CH3CO), 2.35 (s, 3 H, CH3*CO), 2.40–2.50 (m,
1 H, CH), 3.01 (dd, J = 7.1, 3.5 Hz, 1 H, CH*), 3.16 (dd, J = 11.0,
3.4 Hz, 1 H, CH), 4.61 (dd, J = 4.8, 3.3 Hz, 1 H, CHNO2), 4.66 (dd,
J = 8.6, 3.4 Hz, 1 H, CH*NO2).
13C NMR (100 MHz, CDCl3): d (inseparable mixture of isomers,
minor isomer 15b starred) = 13.41 (CH3), 13.44 (CH3*), 21.33
(CH2*), 22.03 (CH2), 25.69 (CH2), 26.92 (CH2*), 30.97 (CH3*),
31.62 (CH3), 32.98 (CH*), 34.03 (CH), 36.03 (CH*), 36.89 (CH),
64.38 (CHNO2), 65.80 (CH*NO2), 200.93 (C=O), 202.55 (C=O*).
(1R,6S,7R)-7-Nitro-5,5-diphenylbicyclo[4.1.0]heptan-2-one (11)
Yield: 0.153 g (quant); white solid; mp 65–71 °C; Rf = 0.50
(CH2Cl2); [a]D25 –223.6 (c = 0.7, CHCl3).
HRMS-ESI: m/z calcd for C8H13NO3 + Na [M + Na]+: 194.0787;
found: 194.0793.
1H NMR (400 MHz, CDCl3): d = 1.90–2.01 (m, 1 H, CH2a), 2.29–
2.36 (m, 3 H, CH2b, CH2), 3.22 (dd, J = 9.4, 2.9 Hz, 1 H, CH), 3.29
(dd, J = 9.4, 3.2 Hz, 1 H, CH), 4.81 (t, J = 3.1 Hz, 1 H, CHNO2),
7.24–7.29 (m, 6 Harom), 7.31–7.37 (m, 4 Harom).
13C NMR (100 MHz, CDCl3): d = 29.04 (CH2), 33.96 (CH2), 36.03
(CH), 37.64 (CH), 43.56 (Cq), 60.29 (CHNO2), 126.48, 127.33,
128.88, 128.92 (10 × CHarom), 144.42 (Cqarom), 145.76 (Cqarom),
200.28 (C=O).
1-(2-Nitro-3-propylcyclopropyl)ethanone (15c)
Yield: 0.010 g (11%); colourless oil; Rf = 0.66 (CH2Cl2); [a]D25 –8.0
(c = 0.1, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.97 (t, J = 7.2 Hz, 3 H, CH3),
1.36–1.52 (m, 4 H, 2 × CH2), 2.23–2.29 (m, 1 H, CH), 2.29 (s, 3 H,
CH3CO), 2.54–2.61 (m, 1 H, CH), 4.20 (dd, J = 8.4, 4.8 Hz, 1 H,
CHNO2).
13C NMR (100 MHz, CDCl3): d = 13.42 (CH3), 21.34 (CH2), 28.22
(CH), 30.64 (CH3), 32.04 (CH2), 37.84 (CH), 65.50 (CHNO2),
199.14 (C=O).
HRMS-ESI: m/z calcd for C19H17NO + Na [M + Na]+: 330.1100;
found: 330.1085.
(1R,5S,6R)-1-Methyl-6-nitrobicyclo[3.1.0]hexan-2-one (13)
Yield: 0.009 g (11%); yellow oil; Rf = 0.64 (CH2Cl2); [a]D25 –6.1
(c = 0.6, CHCl3).
HRMS-ESI: m/z calcd for C8H13NO3 [M + Na]+ + Na: 194.0787;
found: 194.0791.
1-(2-Methyl-3-nitrocyclopropyl)ethanone (16) (Mixture of 16a
and 16b)
Yield: 0.039 g (55%); colourless oil; Rf = 0.61 (CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 1.40 (s, 3 H, CH3), 1.99–2.10 (m,
1 H, CH2a), 2.13–2.31 (m, 3 H, CH2b, CH2), 3.00–3.01 (m, 1 H, CH),
4.32 (d, J = 2.2 Hz, 1 H, CHNO2).
1H NMR (400 MHz, CDCl3): d (inseparable mixture of isomers, mi-
nor isomer 16b starred) = 1.19 (d, J = 6.2 Hz, 3 H, CH3), 1.36 (d,
J = 6.6 Hz, 3 H, CH3*), 1.98–2.05 (m, 1 H, CH*), 2.34 (s, 3 H,
CH3CO), 2.36 (s, 3 H, CH3*CO), 2.47–2.54 (m, 1 H, CH), 2.99 (dd,
J = 7.8, 3.3 Hz, 1 H, CH*), 3.17 (dd, J = 11.0, 3.6 Hz, 1 H, CH),
4.58 (dd, J = 4.3, 3.8 Hz, 1 H, CHNO2), 4.64 (dd, J = 8.8, 3.3 Hz, 1
H, CH*NO2).
13C NMR (100 MHz, CDCl3): d (inseparable mixture of isomers,
minor isomer 16b starred) = 9.18 (CH3), 10.08 (CH3*), 27.34
(CH*), 28.29 (CH), 31.19 (CH3*), 31.67 (CH3), 36.81 (CH*), 37.03
(CH), 64.92 (CHNO2), 66.25 (CH*NO2), 200.85 (C=O), 202.50
(C=O*).
13C NMR (100 MHz, CDCl3): d = 7.55 (CH3), 20.92 (CH2), 31.93
(CH2), 33.88 (CH), 41.62 (Cq), 65.99 (CHNO2), 209.65 (C=O).
HRMS-ESI: m/z calcd for C7H9NO3 + Na [M + Na]+: 178.0474;
found: 178.0482.
5-Methyl-6-nitrobicyclo[3.1.0]hexan-2-one (14a) (Major Dia-
stereomer)
Yield: 0.012 g (16%); light yellow oil; Rf = 0.42 (CH2Cl2); [a]D
–1.6 (c = 0.4, CHCl3).
25
1H NMR (400 MHz, CDCl3): d = 1.52 (s, 3 H, CH3), 1.98–2.39 (m,
4 H, 2 × CH2), 2.88 (br, 1 H, CH), 4.44 (d, J = 1.6 Hz, 1 H, CHNO2).
13C NMR (100 MHz, CDCl3): d = 14.15 (CH3), 30.23 (CH2), 33.58
(CH2), 37.56 (Cq), 41.80 (CH), 67.05 (CHNO2), 207.53 (C=O).
HRMS-ESI: m/z calcd for C7H9NO3 + Na [M + Na]+: 178.0474;
found: 178.0477.
HRMS-ESI: m/z calcd for C6H9NO3 + Na [M + Na]+: 166.0474;
found: 166.0483.
1-(2-Methyl-3-nitrocyclopropyl)ethanone (16c)
Yield: 0.006 g (8%); colourless oil; Rf = 0.46 (CH2Cl2); [a]D25 –31.0
(c = 0.15, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.24 (d, J = 6.3 Hz, 3 H, CH3),
2.24–2.31 (m, 1 H, CH), 2.29 (s, 3 H, CH3CO), 2.56–2.64 (m, 1 H,
CH), 4.23 (dd, J = 8.4, 4.3 Hz, 1 H, CHNO2).
5-Methyl-6-nitrobicyclo[3.1.0]hexan-2-one (14b) (Minor Dia-
stereomer)
Yield: 0.006 g (8%); light yellow oil; Rf = 0.35 (CH2Cl2); [a]D
–93.0 (c = 0.1, CHCl3).
25
1H NMR (400 MHz, CDCl3): d = 1.50 (s, 3 H, CH3), 2.21–2.25 (m,
2 H, CH2), 2.37–2.53 (m, 3 H, CH, CH2), 4.55 (d, J = 8.4 Hz, 1 H,
CHNO2).
13C NMR (100 MHz, CDCl3): d = 21.76 (CH3), 26.29 (CH2), 38.44
(CH2), 42.02 (Cq), 43.30 (CH), 72.74 (CHNO2), 208.22 (C=O).
13C NMR (100 MHz, CDCl3): d = 15.18 (CH3), 22.93 (CH), 30.86
(CH3), 38.92 (CH), 66.30 (CHNO2), 199.08 (C=O).
HRMS-ESI: m/z calcd for C6H9NO3 + Na [M + Na]+: 166.0474;
found: 166.0479.
Synthesis 2008, No. 8, 1269–1275 © Thieme Stuttgart · New York

1274
V. Wascholowski et al.
PAPER
1-(2-Isopropyl-3-nitrocyclopropyl)ethanone (18) (Mixture of
18a and 18b)
Yield: 0.050 g (59%); colourless oil; Rf = 0.68 (CH2Cl2).
66.56 (CHNO2*), 128.32, 128.38, 128.89, 133.94, 134.00
(5 × CHarom and 5 × CHarom*), 136.18 (Cq*), 136.74 (Cq), 192.52
(C=O), 194.2 (C=O*).
1H NMR (400 MHz, CDCl3): d (inseparable mixture of isomers, mi-
nor isomer 18b starred) = 0.88 (d, J = 6.5 Hz, 3 H, CH3), 0.94 (d,
J = 6.1 Hz, 3 H, CH3*), 1.06 (d, J = 6.5 Hz, 3 H, CH3), 1.11 (d,
J = 6.6 Hz, 3 H, CH3*), 1.58–1.88 [m, 1 H, CH* and 1 H, CH(CH3)2
and 1 H, CH*(CH3)2], 2.19–2.26 (m, 1 H, CH), 2.35 (s, 3 H,
CH3*CO), 2.37 (s, 3 H, CH3CO), 3.03 (dd, J = 6.8, 3.2 Hz, 1 H,
CH*), 3.18 (dd, J = 11.0, 3.3 Hz, 1 H, CH), 4.65 (dd, J = 4.8, 3.3
Hz, 1 H, CHNO2), 4.70 (dd, J = 8.5, 3.3 Hz, 1 H, CH*NO2).
13C NMR (100 MHz, CDCl3): d (inseparable mixture of isomers,
minor isomer 18b starred) = 21.29 (CH3*), 21.71 (CH3), 21.86
(CH3), 22.40 (CH3*), 23.99 [CH(CH3)2], 25.67 [CH*(CH3)2], 30.92
(CH3), 31.75 (CH3), 35.86 (CH*), 37.35 (CH), 40.73 (CH*), 42.08
(CH), 64.19 (CHNO2), 65.99 (CH*NO2), 200.95 (C=O), 202.44
(C=O*).
HRMS-ESI: m/z calcd for C11H11NO3 + Na [M + Na]+: 228.0631;
found: 228.0641.
Acknowledgment
We thank the Deutsche Forschungsgemeinschaft (V.W.), the Da-
nish University of Pharmaceutical Sciences and the Danish Medical
Research Council (H.M.H.), the EPSRC and Trinity College
(D.A.L.), and Novartis (through a Research Fellowship to S.V.L.)
for financial support. In addition, we thank V. Aureggi and Dr. G.
Sedelmeier at Novartis Pharma AG, Werk Klybeck, Postfach, CH-
4002 Basel, Switzerland, for a generous gift of (R)-5-pyrrolidin-2-
yl-1H-tetrazole (1).
HRMS-ESI: m/z calcd for C8H10NO3 + Na [M + Na]+: 194.0787;
found: 194.0794.
References
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1-(2-Isopropyl-3-nitrocyclopropyl)ethanone (18c)
Yield: 0.009 g (10%); colourless oil; Rf = 0.53 (CH2Cl2); [a]D
–31.0 (c = 0.1, CHCl3).
(2) (a) Corey, E. J.; Achiwa, K.; Katzenellenbogen, J. A. J. Am.
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25
1H NMR (400 MHz, CDCl3): d = 1.01 (d, J = 6.7 Hz, 3 H, CH3),
1.05 (d, J = 7.1 Hz, 3 H, CH3), 1.30–1.41 [m, 1 H, CH(CH3)2], 2.28–
2.33 (m, 1 H, CH), 2.30 (s, 3 H, CH3CO), 2.41–2.47 (m, 1 H, CH),
4.28 (dd, J = 8.4, 4.9 Hz, 1 H, CHNO2).
13C NMR (100 MHz, CDCl3): d = 21.06 (CH3), 21.27 (CH3), 29.85
[CH(CH3)2], 30.99 (CH3), 36.02 (CH), 37.25 (CH), 65.01
(CHNO2), 199.58 (C=O).
HRMS-ESI: m/z calcd for C8H10NO3 + Na [M + Na]+: 194.0787;
found: 194.0797.
1-(2-Me thyl-3-nitrocyclopropyl)propan-1-one (20) (Mixture of
20a and 20b)
Yield: 0.037 g (47%); colourless oil; Rf = 0.78 (CH2Cl2).
1H NMR (400 MHz, CDCl3): d (inseparable mixture of isomers, mi-
nor isomer 20b starred) = 1.05–1.25 (m, 3 H, CH3 and 3 H, CH3*),
1.17 (d, J = 6.7 Hz, 3 H, CH3), 1.35 (d, J = 6.5 Hz, 3 H, CH3*),
1.99–2.04 (m, 1 H, CH*), 2.41–2.79 (m, 2 H, CH2 and 2 H, CH2*
and 1 H, CH), 2.90–2.96 (m, 1 H, CH*), 3.15 (dd, J = 10.9, 3.2 Hz,
1 H, CH), 4.60 (dd, J = 4.4, 3.3 Hz, 1 H, CHNO2), 4.64 (dd, J = 8.7,
3.3 Hz, 1 H, CH*NO2).
13C NMR (100 MHz, CDCl3): d (inseparable mixture of isomers,
minor isomer 20b starred) = 9.32 (CH3), 10.11 (CH3*), 27.23
(CH3*), 28.28 (CH3), 36.10 (CH*), 36.41 (CH), 36.46 (CH*), 36.66
(CH), 37.57 (CH2*), 37.86 (CH2), 64.84 (CHNO2), 66.17
(CH*NO2), 203.79 (C=O), 205.41 (C=O*).
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(6) de Meijere, A.; Wessjohann, L. Synlett 1990, 20.
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HRMS-ESI: m/z calcd for C7H11NO3 + Na [M + Na]+: 180.0631;
found: 180.0631.
(f) Johansson, C. C. C.; Bremeyer, N.; Ley, S. V.; Owen, D.
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1-(2-Methyl-3-nitrocyclopropyl)-1¢phenylmethanone (21) (Mix-
ture of 21a and 21b)
Yield: 0.043 g (42%); colourless oil; Rf = 0.73 (CH2Cl2).
1H NMR (400 MHz, CDCl3): d (inseparable mixture of isomers, mi-
nor isomer 21b starred) = 1.20 (d, J = 6.7 Hz, 3 H, CH3), 1.46 (d,
J = 6.6 Hz, 3 H, CH3*), 2.18–2.27 (m, 1 H, CH*), 2.64–2.75 (m, 1
H, CH), 3.70 (dd, J = 6.9, 3.3 Hz, 1 H, CH*), 3.82 (dd, J = 11.3, 3.6
Hz, 1 H, CH), 4.82–4.86 (m, 1 H, CHNO2 and 1 H, CH*NO2), 7.49–
7.54 (m, 2 Harom and 2 Harom*), 7.61–7.65 (m, 1 Harom and 1 Harom*),
8.00–8.03 (m, 2 Harom and 2 Harom*).
13C NMR (100 MHz, CDCl3): d = 9.06 (CH3), 10.27 (CH3*), 27.73
(CH*), 28.78 (CH), 33.44 (CH*), 34.78 (CH), 64.69 (CHNO2),
(8) Dolbier, W. R. Jr.; Battiste, M. A. Chem. Rev. 2003, 103,
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Synthesis 2008, No. 8, 1269–1275 © Thieme Stuttgart · New York

PAPER
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Ikonnokov, N. S.; Kozhushkov, S. I.; Yufit, D. S.; Howard,
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(20) The reaction between bromonitromethane (3) and
morpholine (4) may lead to the formation of the product 22
(Figure 2), which is confirmed by 1H and 13C NMR
spectroscopy. MS analysis was unsuccessful.
O
N
O2N
NO2
(15) Hartikka, A.; Arvidsson, P. I. Tetrahedron: Asymmetry
2004, 15, 1831.
22
(16) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H.
Angew. Chem. Int. Ed. 2004, 43, 1983.
Figure 2 Product formed from the reaction of bromonitromethane
(3) and morpholine (4)
(21) One recrystallisation gives material of ≥ 99% ee.
Synthesis 2008, No. 8, 1269–1275 © Thieme Stuttgart · New York