An efficient, asymmetric organocatalyst-mediated conjugate addition of nitroalkanes to unsaturated cyclic and acyclic ketones

Article abstract of DOI:10.1039/b601877g

5-Pyrrolidin-2-yltetrazole is a versatile organocatalyst for the asymmetric conjugate addition of nitroalkanes to enones. Using this catalyst, this transformation requires short reaction times, tolerates a broad substrate scope, and possibly proceeds via

Full text of DOI:10.1039/b601877g

View Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
An efficient, asymmetric organocatalyst-mediated conjugate addition of
nitroalkanes to unsaturated cyclic and acyclic ketones
Claire E. T. Mitchell, Stacey E. Brenner, Jorge Garc´ıa-Fortanet and Steven V. Ley*
Received 7th February 2006, Accepted 13th March 2006
First published as an Advance Article on the web 20th April 2006
DOI: 10.1039/b601877g
5-Pyrrolidin-2-yltetrazole is a versatile organocatalyst for the asymmetric conjugate addition of
nitroalkanes to enones. Using this catalyst, this transformation requires short reaction times, tolerates a
broad substrate scope, and possibly proceeds via generation of an iminium species.
Introduction
Nitroalkanes are a particularly useful source of stabilised car-
banions for asymmetric addition to electron-poor alkenes. The
strongly electron-withdrawing nature of the nitro group (pKa
MeNO2 = 10) facilitates generation of the nitronate anion under
mild conditions.1 In addition, nitroalkanes can be easily prepared
and the nitro group is a versatile functionality that can be readily
modified, enabling access to a range of products.
There are numerous examples of substrate-controlled asym-
metric conjugate additions of nitroalkanes to a,b-unsaturated
Fig. 1 Proline and related organocatalysts.
carbonyls, in which the chirality resides in either the donor or
the acceptor.2 Additionally, a variety of catalyst systems have been
developed for the asymmetric conjugate addition of nitroalkanes,
and in particular nitromethane, to chalcones. These include chiral
crown ethers,3 chiral Lewis acids,4 phase-transfer catalysts derived
from cinchona alkaloids5 and cinchona alkaloid-derived thiourea
catalysts.6 Recently, the use of an aluminium-salen catalyst with
substrates other than chalcones was reported.7
catalyst again performed best for acyclic enones relative to cyclic
precursors.
Although a range of methods have been developed for the
addition of nitroalkanes to enones, none are both broadly
applicable and amenable to large-scale organic synthesis. The
tetrazole analogue of proline (4) had been demonstrated to be
a more soluble and effective catalyst than proline itself in a
variety of transformations,12 thus its application in the addition of
nitroalkanes to enones was investigated.13
Proline (1, Fig. 1) has been used as its rubidium salt in the
addition of nitroalkanes to both acyclic and cyclic enones with
moderate to good enantioselectivities (41–84%).8 The use of
proline with amine additives for additions to cyclic enones was
extensively investigated by Hanessian and Pham. The best results
were obtained with piperazine bases.9 Specifically, trans-2,5-
dimethylpiperazine gave moderate to excellent enantioselectivities
(61–93%), the lower enantioselectivities arising from the addition
of the less bulky nitromethane and nitroethane nucleophiles. The
use of proline for acyclic systems has yet to be reported.
Imidazoline catalyst 2 has been found to give good enantios-
electivities (34–86%) for the conjugate addition of nitroalkanes
to acyclic a,b-unsaturated enones.10 However, only a moderate
enantioselectivity (49%) was obtained using cyclohexenone as
the acceptor. Reaction times were typically between 4.5 and
12.5 days. In addition, the nitroalkanes were employed as the
reaction solvent, and thus were used in approximately 20-fold
excess. Very recently, the tetrazole analogue 3 was reported,
and led to improved enantioselectivities and rates (3–8 days).11
Nitroalkanes were still employed as the reaction solvent and the
Results and discussion
Catalyst screen
Initial investigations into the addition of 2-nitropropane to
cyclohexenone (6) employed achiral meso base trans-2,5-
dimethylpiperazine (7), according to the conditions developed
by Hanessian and Pham for the corresponding proline-catalysed
transformation.9 These results were promising, as tetrazole cata-
lyst 4 outperformed proline in chloroform in terms of both product
yield and ee (Table 1, entries 1, 2). Reducing the reaction time
resulted in a corresponding drop in yield (entry 3). There was only
minimal background reaction observed in the absence of base
(entry 4), and no background reaction in the absence of catalyst
(entry 5).
While homologated tetrazole 5 effectively catalysed the asym-
metric Michael addition of ketones to nitro-olefins,14 in the
Michael addition of nitroalkanes to enones it provided the product
in only poor yield and enantioselectivity (entry 6). Two of the chiral
imidazolidinone catalysts developed by MacMillan and Austin15
were also screened, but gave none of the expected product under
these particular reaction conditions (entries 7, 8).
Department of Chemistry, University of Cambridge, Lensfield Rd, Cam-
bridge, UK CB2 1EW. E-mail: svl1000@cam.ac.uk; Fax: +44 (0) 1223
336442
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 2039–2049 | 2039
©

View Online
Table 1 Catalyst screen
Table 2 Solvent screen
Entry
Solvent
CHCl3
CHCl3
CH2Cl2
ClH2CCH2Cl
THF
Dioxane
THF–CH2Cl2 (1 : 1)
MeCN
MeOH
DMSO
Yield (%)b
Ee (%)c
Entry Catalyst
Base equiv. Yield (%)b
Ee (%)c
1
2
3
4
5
6
7
8
9
27
49
65
33
10
5
28
38
58
39
76
58
72
84
84
76
71
66
7
d
1
2
3
4
5
6
7
1
1
1
1
—
1
64
70
58
4
89
98
99
53
—
28
—
4
4 d
4
—
5
0
1
1
17
—
10
−4
a Conditions: 9 (0.5 mmol), 2-nitropropane (1.0 mmol), 4 (15 mol%), 7
(0.5 mmol), solvent (2 mL), oven-dried glassware, rt, 2.5 d. b Isolated yield.
c Determined by chiral GC. d Using proline (1, 15 mol%).
8
1
—
—
Table 3 Further optimisation
a Conditions: 6 (0.5 mmol), 2-nitropropane (1.0 mmol), catalyst (15 mol%),
7 (0.5 mmol), CHCl3 (2 mL), oven-dried glassware, rt, 2 d. b Isolated yield.
c Determined by chiral GC. d 1 d.
Solvent screen
With proline tetrazole 4 identified as an effective catalyst for ad-
dition to cyclic enones, optimisation of reaction conditions using
less reactive acyclic enones ensued. 4-Phenyl-3-buten-2-one (9)
was chosen as a representative substrate. Using chloroform as the
reaction solvent, the product was generated in good ee; however,
the isolated yield was low (Table 2, entry 1). Proline gave the
product in higher yield but only moderate enantioselectivity (entry
2). An enhanced rate of reaction was observed in dichloromethane,
with a 65% isolated yield after 2.5 days (entry 3). Use of 1,2-
dichloroethane, THF or dioxane as reaction solvent afforded the
product in very good ee, but only poor yield, presumably due to
low solubility of the catalyst in these solvents (entries 4–6). Efforts
to improve the solubility of 4 in THF by using dichloromethane as
a cosolvent led to an improved, but still poor, product yield. Both
polar protic and polar aprotic solvents led to almost complete
erosion of the enantioselectivity, suggesting that these solvents
disrupt interactions necessary for stereocontrol (entries 8–10).
Entry
Conditionsa
Time/d
Yield (%)b
Ee (%)c
1
2
3
4
5
6
7
5 mol% 4
2
2
4
1
2
1
3
55
57
30
68
20
48
34
72
71
79
46
78
67
75
1.1 equiv. 2-nitropropane
0 ◦
C
C
40 ◦
0.5 equiv. 7
2 equiv. 7
0.13 M
a 9 (0.5 mmol), 2-nitropropane (1.0 mmol), 4 (15 mol%), 7 (0.5 mmol),
CH2Cl2 (2 mL, 0.25 M), oven-dried glassware, rt, unless otherwise
indicated. b Isolated yield. c Determined by chiral GC.
over 4 d showed that the reaction did not progress significantly
after 3 d.
Effect of amine bases
The relative effectiveness of a variety of amine bases in this
transformation was examined. The choice of base was found
to have an impact not only on the product yield, but also on
the enantioselectivity. Use of the tertiary triethylamine generated
the desired product in low yield and ee (Table 4, entry 2). Use
of the secondary diethylamine provided the product in higher
yield, but lower enantioselectivity relative to 7 (entries 1, 3).
Whereas substoichiometric amounts of diethylamine resulted in
improved enantioselectivities but diminished yields (entry 4),
excess diethylamine resulted in enhanced yields but decreased
enantioselectivities (entry 5). Other piperazines were not found
to be as effective as 2,5-dimethyl piperazine. Piperazine itself gave
the product in a slightly higher ee, but significantly lower yield
(entry 6). The latter effect might be due to the low solubility of
piperazine under the reaction conditions. However, other more
Further optimisation
Reducing the catalyst loading to 5 mol% slowed the reaction but
had no detrimental effect on the enantioselectivity (Table 3, entry
1). Similarly, using only 1.1 equiv. of nitroalkane reduced the
reaction rate, without decreasing the enantioselectivity (entry 2).
Unsurprisingly, lowering the temperature decreased the reaction
rate, but improved the product ee (entry 3). In contrast, increasing
the temperature led to a large drop in enantioselectivity (entry
4). Varying the loading of 7 revealed that the optimal level
of base additive was one equivalent (entries 5, 6). Decreasing
the concentration had an effect similar to that of lowering the
temperature; the product was generated in lower yield but higher
ee (entry 7). Additionally, monitoring the reaction by HPLC
2040 | Org. Biomol. Chem., 2006, 4, 2039–2049
This journal is
The Royal Society of Chemistry 2006
©

View Online
Table 4 Effect of amine basea
lower yield and higher enantioselectivities than those run under
anhydrous conditions (Table 5, entries 1 and 2; 3 and 4). These
variations were due to the presence or absence of water, rather than
the presence or absence of argon, as there was not a substantial
difference between reactions run in oven-dried glassware under
standard atmosphere or under inert atmosphere (entries 2 and 5).
As further verification, the addition of small amounts of water to
the reaction again generated the product in lower yield and higher
enantioselectivity (entries 6, 7). The addition of large amounts
of water, however, did not result in further enhancement of the
product ee, but instead substantially eroded the yield (entry 8).
Finally, the reaction did proceed in the presence of molecular
sieves, albeit in very poor ee. Although the mechanism for these
reactions has not been rigorously established, it is plausible that
they proceed via the formation of an iminium species, which would
necessitate the involvement of water in the catalytic cycle.
Entry
1
Base
Equiv.
1
Yield (%)b
65
Ee (%)c
72
2
3
4
5
6
Et3N
2
1
0.5
2
1
28
72
8
84
30
29
62
80
60
76
Et2NH
Et2NH
Et2NH
7
8
1
1
1
2
1
27
44
63
7
68
67
47
60
—
Reaction scope: donor
9
The addition of a variety of nitroalkanes to both cyclic and acyclic
enones was examined. Generally, reactions with cyclohexenone
provided products in good yield and excellent enantioselectively
(Table 6) and did not exhibit the sensitivity to water that those
with trans-4-phenyl-3-buten-2-one did. Reactions proceeded more
quickly in dichloromethane relative to chloroform, but with
slightly lower enantioselectivity (Conditions A vs. B). The lower
yield obtained with nitromethane may be due to further reactions
of the product, which contains a reactive primary nitroalkane
(entry 4).16 To circumvent this, the addition of a higher excess of
nitromethane was investigated, but led to similar ratios of product
10
11
0
12
1
86
53
13
14
15
16
2
1
1
1
93
36
14
30
52
28
67
50
DBU
i-Pr2NH
1
to side products as indicated by H NMR. Using nitroethane,
the high stereoselectivity at the b-position was maintained;
however, almost no stereocontrol was observed at the exocyclic
stereocentre of the nitroalkyl side chain (entries 6, 7). The high
enantioselectivities observed for nitromethane and nitroethane
using the tetrazole catalyst are an improvement over the results
reported using proline, where poorer selectivity was observed
for the addition of these less sterically hindered nucleophiles.9
Using 1-nitropentane, a mixture of diastereomers again resulted,
although pleasingly the products were obtained in good yield
and excellent enantioselectivity (entry 8). It should be noted that
the poor selectivities generally observed at the acidic c-position
have been proposed to arise from epimerisation under the basic
conditions typically required for these reactions.1 Finally, although
the addition of the more hindered nitrocyclohexane nucleophile
proceeded more slowly, the products were obtained in good yield
and excellent ee (entries 9, 10).
As mentioned above, 4-phenyl-3-buten-2-one (9) was less reac-
tive compared to cyclohexenone, and reactions with this substrate
did not proceed to completion. Moderate to good yields and
good enantioselectivities were obtained in all cases (Table 7). As
discussed previously, higher yields but lower enantioselectivities
were observed with oven-dried glassware (Conditions A vs. B). The
addition of 2-nitropropane was also run over 4 d on a 15 mmol
scale using 5 mol% catalyst 4, and product yields and ee values
were comparable to those in entry 1. As with cyclohexenone,
very good enantioselectivities but poor yields were obtained with
nitromethane (entry 3). In this case, however, the addition of
10 equiv. of nitromethane afforded the product in good yield
17
2
—
—
a Conditions: 9 (0.5 mmol), 2-nitropropane (1.0 mmol), 4 (15 mol%), base,
CH2Cl2 (2 mL), oven-dried glassware, rt. b Isolated yield. c Determined by
chiral GC.
soluble piperazines also gave the product in low yield (entries
7, 8). Using an acyclic diamine, the product was obtained in
comparable yield, but appreciably lower ee (entry 9), suggesting
that the ring structure of the piperazines was crucial. Generally,
the use of weaker bases resulted in lower yields (entries 10 and
11), whereas stronger bases, such as piperidine, resulted in higher
yields (entries 12, 13). An exception was the use of DBU, which
afforded the product in poor yield (entry 14). Hindered amines
performed poorly in this reaction (entries 15, 16). Finally, the use
of pyrrolidine resulted only in significant formation of unidentified
side products (entry 17). Thus, the original base choice (7) was
found to be optimal.
Effect of water
The reaction of certain substrates demonstrated an unexpected
sensitivity to water. For example, reactions of 9 that were not
run under anhydrous conditions provided the product 10, in
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 2039–2049 | 2041
©

View Online
Table 5 Effect of water
Entry
Conditionsa
Yield (%)b
Ee (%)c
1
2
3
4
5
6
7
8
9
Non-oven-dried glassware
Oven-dried glassware, cooled under argon
Non-oven-dried glassware, dried 7
Oven-dried glassware, dried 7
Oven-dried glassware, reaction run under Ar
0.25 equiv. H2O
50
65
54
63
67
46
38
25
59
74
72
74
72
71
74
76
72
12
0.5 equiv. H2O
2 equiv. H2O
˚
4 A MS
a 9 (0.5 mmol), 2-nitropropane (1.0 mmol), 4 (15 mol%), 7 (0.5 mmol), CH2Cl2 (2 mL), 3 d, rt. b Isolated yield. c Determined by chiral GC.
Table 6 Varying the nitroalkane with cyclohexenone
Entry
R1, R2
Conditionsa
Yield (%)b
Ee (%)c
1
2
3
4
5
6
7
8
9
R1 = R2 = Me
A
Ad
B
A
B
A
B
A
A
B
84
84
70
47
49
84
74
73
63
53
96
96
98
94
R1 = R2 = Me
R1 = R2 = Me
R1 = R2 = H
R1 = R2 = H
95
R1 = H, R2 = Me
R1 = H, R2 = Me
R1 = H, R2 = (CH2)3CH3
R1 = R2 = –(CH2)5–
R1 = R2 = –(CH2)5–
95/94, dr 1.1 : 1
95, dr 1.2 : 1
94, dr 1.3 : 1
94
10
97
a Conditions A: 6 (0.5 mmol), nitroalkane (1.0 mmol), 4 (15 mol%), 7 (0.5 mmol), CH2Cl2 (2 mL), oven-dried glassware, rt, 1 d. Conditions B: as A,
except CHCl3 (2 mL), 2 d. b Isolated yield. c Determined by chiral GC, ee major/minor diastereomer. d Non-oven-dried glassware.
Table 7 Varying the nitroalkane with trans-4-phenyl-3-buten-2-one
Entry
R1, R2
Conditionsa
Yield (%)b
Ee (%)c
1
2
3
4
5
6
7
8
9
R1 = R2 = Me
A
B
A
Ad
A
B
A
A
B
65
50
45
76
67
40
80
80
59
72
74
89
77
R1 = R2 = Me
R1 = R2 = H
R1 = R2 = H
R1 = H, R2 = Me
R1 = H, R2 = Me
R1 = H, R2 = (CH2)3CH3
R1 = R2 = –(CH2)5–
R1 = R2 = –(CH2)5–
80, dr 1.3 : 1
82/80, dr 1.3 : 1
84, dr 1.9 : 1
73
77
a Conditions A: 9 (0.5 mmol), nitroalkane (1.0 mmol), 4 (15 mol%), 7 (0.5 mmol), CH2Cl2 (2 mL), oven-dried glassware, rt, 3 d. Conditions B: as A,
except non-oven-dried glassware. b Isolated yield. c Determined by chiral GC, ee major/minor diastereomer. d Nitroalkane (5.0 mmol) used.
2042 | Org. Biomol. Chem., 2006, 4, 2039–2049
This journal is
The Royal Society of Chemistry 2006
©

View Online
Table 9 Addition of nitroalkanes to various enones
(entry 4). Using nitroethane, good stereoselectivity was obtained
at the b-position, but the product was, again, a mixture of diastere-
omers at the c-position (entries 5, 6). The relative stereochemistry
of the minor diastereoisomer was determined by X-ray crystal-
lography. 1-Nitropentane underwent addition in good yield and
enantioselectively, and gave a higher 1.9 : 1 diastereomeric ratio
(entry 7). The relative configuration of the minor diastereomer
was assigned by analogy to the product of nitroethane addition.
The addition of the hindered nitrocyclohexane nucleophile also
proceeded in good ee (entries 8, 9).
Entry
Product
Conditionsa Yield (%)b
Ee (%)c
1
2
A
21
78
83
78
Ad
3
4
Ae
B
62
63
80
75
Reaction scope: acceptor
The addition of 2-nitropropane to a variety of linear, aromatic
enones was investigated (Table 8). None of the aromatic enones
examined demonstrated the sensitivity to water that trans-4-
phenyl-3-buten-2-one did. The reaction tolerated incorporation
of both electron-donating and electron-withdrawing substituents
on the phenyl ring of this substrate (entries 1–4). The use
of heterocyclic enones provided products in moderate yields
and good enantioselectivities (entries 5–10). Pyridine 15 was
inseparable from the starting enone, but was generated in excellent
conversion and moderate ee (entries 9, 10).
5
6
A
C
64
59
91
91
7
8
A
C
88
96
82
82
9
10
A
23
44
54
58
Af
The tetrazole catalyst was also effective for the addition of
various nitroalkanes to all other substrates examined, which in-
11
12
Ae
Ce
40
39
42
46
13
Ae
67
0
Table 8 Addition of 2-nitropropane to linear, aromatic enones
a Conditions A: enone (0.5 mmol), nitroalkane (1.0 mmol), 4 (15 mol%),
7 (0.5 mmol), CH2Cl2 (2 mL), oven-dried glassware, rt, 3 d. Conditions B:
as A, except CHCl3 (2 mL). Conditions C: as A, except non-oven-dried
glassware. b Isolated yield. c Determined by chiral GC. d Reaction time 12
d. e Reaction time 21 h. f 7 (1.0 mmol) used.
Entry
Product
Conditionsa
Yield (%)b Ee (%)c
1
2
A
B
72
70
61
62
3
4
A
B
73
66
66
68
cluded a,b-unsaturated ethyl ketones, cyclic enones, non-aromatic
enones, and enal substrates (Table 9). Ethyl ketone 16 was
formed considerably more slowly than the corresponding methyl
ketone and thus required longer reaction times (entries 1, 2).
The addition of 2-nitropropane to cyclopentenone gave the
product in moderate yield and good enantioselectivity (entries
3, 4). While the addition of bulky 2-nitropropane to sterically
congested enone substrates, such as 3-methylcyclohexenone, does
not readily occur, excellent ee values were obtained for the addition
of nitromethane to this substrate (entries 5, 6). The reaction
of (E)-methyl-4-oxopent-2-enoate afforded the product 19 in
excellent regioselectivity, and good yield and enantioselectivity
(entries 7, 8). The aliphatic enone, nonenone, was found to be
less reactive, and also gave poorer enantioselectivity (entry 9).
The use of 2 equiv. of base, however, gave improved results
(entry 10). Reactions of aldehydes proceeded in, at best, modest
enantioselectivities and yields: 21 was obtained in 46% ee and
cinnamaldehyde gave racemic product 22 (entries 11–13). Further
studies on cinnamaldehyde showed significant levels of back-
ground reaction with the base additive but no catalyst (data not
shown).
5
6
A
B
61
63
72
72
7
8
A
B
53
51
66
66
9
10
A
B
96d
97d
64
65
a Conditions A: enone (0.5 mmol), 2-nitropropane (1.0 mmol),
(15 mol%), 7 (0.5 mmol), CH2Cl2 (2 mL), oven-dried glassware, rt, 3
d. Conditions B: as A, except non-oven-dried glassware. b Isolated yield.
c Determined by chiral GC/HPLC. d Conversion as measured by 1H NMR.
4
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 2039–2049 | 2043
©

View Online
Effect of chiral bases
and 1750 cm−1 more closely, it was possible to observe the
disappearance of the enone (peak under 1700 cm−1) and formation
of the product (peak over 1700 cm−1); however, there was no
evidence confirming the formation of intermediates (data not
shown). The reactions of both enone 9 and cyclohexenone with
one equivalent of catalyst were also investigated in methanol.
Again, however, no changes in absorption were observed which
could be assigned to the formation of a carbon–nitrogen bond.
The reaction was followed by HPLC over 4 d with React ArrayTM
SK233 equipment using stilbene as an internal standard. The data
showed that 14% of the starting material was consumed within
the first 15 min of the reaction, although only 0.3% of the product
had been formed (data not shown). This is consistent with rapid
reaction of the catalyst (15 mol% used) with the enone, presumably
to form an iminium species, followed by slower reaction with the
nitroalkane.
Although the reaction of 9 with nitroethane in the presence of
trans-2,5-dimethylpiperazine was a highly enantioselective pro-
cess, the diastereoselectivity was poor. As the base employed was
found to influence product enantioselectivity, it was thought that
the use of chiral bases might improve the diastereoselectivity of
this transformation. A range of chiral non-racemic bases were in-
vestigated in this reaction (Table 10). The use of either enantiomer
of 27 gave a slightly improved diastereomeric ratio compared to
trans-2,5-dimethylpiperazine. In both cases, however, the major
diastereomer generated was the same (entries 4, 5). Similarly, both
enantiomers of 28 favoured formation of the same diastereomer
in an improved 1.6 : 1 ratio (entries 6, 7). Interestingly, the major
diastereomer was formed with a higher enantioselectivity than the
minor diastereomer. As opposite enantiomers of base pairs gave
the same diastereoselectivity, the use of asymmetric bases was not
investigated further.
Conclusions
Kinetic investigations
As an improvement over other catalyst systems, tetrazole catalyst
4 is a versatile catalyst for the asymmetric addition of a variety
of nitroalkanes to both cyclic and acyclic enones using trans-
2,5-dimethylpiperazine as a stoichiometric base additive. Using
4, this reaction is scalable, providing enantiomeric excesses of
up to 98% in relatively short reaction times of 1–3 d, and using
only 2 equiv. of the coupling nitroalkane. The use of chiral amine
base additives to improve the diastereoselectivites arising from the
conjugate addition of prochiral nitroalkanes was examined, but
was unproductive. Finally, kinetic investigations combined with
the observed sensitivity of certain substrates to water support a
possible mechanism in which this transformation proceeds via
reaction of the catalyst with the enone to form an iminium species
and liberate water.
The reaction of nitroethane with enone 9 was monitored every
20 min using ReactIR. Examining the region between 1600
Table 10 Effect of chiral amines
Entry
1
Base
Conv. (%)b Dr b
Ee (%)c
66/46
16
1.1 : 1
Experimental
2
3
4
5
6
1.3 : 1
1.3 : 1
1.5 : 1
1.4 : 1
58/44
76/74
62
All reactions were carried out in oven-dried test tubes cooled
under an atmosphere of argon or non-oven-dried test tubes unless
otherwise stated. Dichloromethane, methanol and acetonitrile
were distilled from calcium hydride. Tetrahydrofuran was pre-
dried over sodium wire and distilled from calcium hydride.
Other reagents and solvents were used as received. Flash column
chromatography was performed using Merck 60 Kieselgel (230–
400 mesh) under pressure. Analytical thin layer chromatography
(TLC) was performed on glass plates pre-coated with Merck
Kieselgel 60 F254, and visualised by ultra-violet irradiation
(254 nm) or by staining with aqueous acidic ammonium hexa-
molybdate, aqueous acidic potassium permanganate, acidic 2,4-
dinitrophenol, cerium ammonium nitrate solutions or iodine,
and developed with appropriate heating. Melting points were
recorded on a Reichert hot-stage apparatus, and are uncorrected.
Optical rotations were acquired on a Perkin-Elmer 343 digital
polarimeter using a sodium lamp (589 nm) as the light source.
Infra-red spectra were obtained on a Spectrum One FT-IR ATR
(Attenuated Total Reflectance) spectrometer, from a thin film
deposited on the ATR. Mass spectra were obtained on a Kratos
MS890MS, a Kratos Q-TOF or an LCT Premier spectrometer
by Waters using Micromass MS software, by electron impact,
96
21
11
46
6
7
41
38
1.6 : 1
1.6 : 1
88/76
88/78
a Conditions: 9 (0.5 mmol), nitroethane (1.0 mmol), 4 (15 mol%), base
(0.5 mmol), CH2Cl2 (1 mL), oven-dried glassware, rt. b Conversion,
measured by 1H NMR. c Determined by chiral GC, ee major/minor
diastereomer.
2044 | Org. Biomol. Chem., 2006, 4, 2039–2049
This journal is
The Royal Society of Chemistry 2006
©

View Online
fast atom bombardment or electrospray ionisation techniques
at the Department of Chemistry, Lensfield Road, Cambridge.
1H NMR spectra were recorded at ambient temperature on
Bruker DPX-400 or Bruker DRX-600 spectrometers at 400 or
600 MHz with residual protic solvent CHCl3 as the internal
reference (dH = 7.26 ppm); chemical shifts (d) are given in parts
per million (ppm) and coupling constants (J) are given in Hertz
(Hz). The proton spectra are reported as follows d/ppm (number
of protons, multiplicity, coupling constant J/Hz, assignment).
13C NMR spectra were recorded at ambient temperature on the
same spectrometers at 100 or 150 MHz, with the central peak of
CHCl3 as the internal reference (dC = 77.0 ppm). DEPT135 and
two-dimensional (COSY, HMQC, HMBC) NMR spectroscopy
were used, where appropriate, to aid the assignments of signals
(R)-3-(Nitromethyl)cyclohexanone9. Purification using flash
column chromatography (EtOAc–petroleum ether 40/60, 1 :
2) to give the title compound as a clear oil (40 mg, 49%).
mmax (film)/cm−1: 1709, 1543, 1384; [a]2D5 = +8.8 (c = 0.635,
1
CHCl3, 96% ee). H NMR (600 MHz, CDCl3): d = 4.36 (1H,
dd, J = 7.3, 12.1 Hz, CHHꢀNO2), 4.33 (1H, dd, J = 6.6,
12.1 Hz, CHHꢀNO2), 2.67–2.60 (1H, m, CHCH2NO2), 2.48
ꢀ
=
[1H, ddd, J = 2.1, 4.2, 14.2 Hz, C( O)CHH CH], 2.42 [1H,
ꢀ
=
dd, J = 11.4, 14.8 Hz, C( O)CHH CH2], 2.31–2.26 [1H, m,
ꢀ
ꢀ
=
=
C( O)CHH CH2], 2.18–2.14 [1H, m, C( O)CHH CH], 2.13–2.09
ꢀ
ꢀ
=
[1H, m, C( O)CH2CHH ], 1.99–1.97 (1H, m, CHRCHH ), 1.77–
ꢀ
ꢀ
=
1.69 [1H, m, C( O)CH2CHH ], 1.54–1.47 (1H, m, CHRCHH ).
13C NMR (150 MHz, CDCl3): d = 208.1, 80.0, 44.4, 40.8, 37.2,
◦
28.2, 24.2. Chiral GC: Chiradex G-TA, 150 C, 25 psi, 12.9 min
1
in the H and 13C NMR spectra. Where a compound has been
(321.5 pA s, R), 14.3 min (8.5 pA s, S) gave 95% ee.
characterised as an inseparable mixture of diastereoisomers, the
NMR data for the major (maj) and minor (min) isomers have
been reported as far as was discernable from the spectrum of the
mixture. Where coincident coupling constants have been observed
in the 1H NMR spectrum, the apparent multiplicity of the proton
resonance concerned has been reported.
(1ꢀR,3R)-3-(1ꢀ-Nitroethyl)cyclohexanone9 and (1ꢀS,3R)-3-(1ꢀ-
nitroethyl)cyclohexanone9. Filtration through a silica pad using
dichloromethane as eluent to give the title compounds as a clear
oil (74 mg, 84%), as an inseparable 1.1 : 1 mixture of diastereomers.
mmax (film)/cm−1: 1710, 1542, 1358; [a]D25 = +5.4 (c = 0.765, CHCl3,
1
dr 1.1 : 1, 95/94% ee). H NMR (400 MHz, CDCl3): d = 4.50–
4.42 [1Hmaj and 1Hmin, m, CHC(NO2)], 2.44–2.04 [6Hmaj and 6Hmin
,
General procedure for the addition of nitroalkanes to enones
=
=
m, 2 × C( O)CH2CHR, 2 × C( O)CH2CH2, 2 × CHC(NO2),
ꢀ
=
2 × C( O)CH2CHH ], 1.94–1.81 (1Hmaj and 1Hmin, m, 2 ×
The enone (0.5 mmol), tetrazole 4 (15 mol%), base 7 (0.5 mmol)
and nitroalkane (1 mmol) were stirred in dichloromethane (2 mL)
under air at room temperature for the specified time period
(unless otherwise indicated). The crude reaction mixture was
diluted with dichloromethane (30 mL), and washed with aqueous
ammonium chloride (30 mL). The aqueous layer was extracted
with dichloromethane (30 mL) and the combined organic fractions
were dried (MgSO4) and the solvent removed under reduced
pressure. When isolated yields are reported, the products were
further purified either by filtration through a pad of silica (eluting
with dichloromethane) or by flash column chromatography.
CHCHHꢀ), 1.69–1.57 (1Hmaj and 1Hmin, m, 2 × COCH2CHHꢀ),
1.52 [3Hmaj, d, J = 6.7 Hz, C(NO2)CH3], 1.49 [3Hmin, d, J = 6.7 Hz,
C(NO2)CH3], 1.47–1.38 (1Hmaj and 1Hmin, m, 2 × CHCHHꢀ). 13
C
NMR (100 MHz, CDCl3): d = 208.5 (maj), 208.3 (min), 86.9,
43.6 (min), 43.3 (maj), 42.4 (min), 42.3 (maj), 40.8, 27.5 (maj),
26.9 (min), 24.5 (min), 24.2 (maj), 16.3 (min), 16.1 (maj). Chiral
GC: Chiradex G-TA, 160 ◦C, 25 psi, 7.6 min (189.5 pA s, R),
9.0 min (5.3 s pA s, S) gave 95% ee for the major diastereomer,
11.4 min (5.9 pA s, S), 12.6 min (175.5 pA s, R) gave 94% ee for
the minor diastereomer.
(1ꢀR,3R)-3-(1ꢀ-Nitropentyl)cyclohexanone17 and (1ꢀS,3R)-3-(1ꢀ-
nitropentyl)cyclohexanone17. Purification using flash column
chromatography (EtOAc–petroleum ether 40/60, 1 : 4) to give
the title compounds as a clear oil (81 mg, 73%), as an inseparable
1.3 : 1 mixture of diastereomers. mmax (film)/cm−1: 2959, 2932,
2873, 1713, 1544, 1362; [a]2D5 = +1.1 (c = 0.515, CHCl3, dr 1.3 :
1, 94% ee). 1H NMR (400 MHz, CDCl3): d 4.41–4.31 (1Hmaj
and 1Hmin, m, 2 × CHNO2), 2.49–2.32 [2Hmaj and 2Hmin, m,
(R)-3-(2-Nitropropan-2-yl)cyclohexanone9 8. Filtration through
a silica pad using dichloromethane as eluent to give the title
compound as white prisms (80 mg, 84%). Mp = 61–63 ◦C;
mmax (film)/cm−1: 3003, 2967, 2916, 2878, 1710, 1530, 1348;
1
[a]2D5 = +23.3 (c = 0.525, CHCl3, 96% ee). H NMR (400 MHz,
ꢀ
=
CDCl3): d 2.42–2.29 [3H, m, CHC(NO2), C( O)CHH CH,
=
=
C( O)CHHCH2], 2.26–2.17 [1H, m, C( O)CHHCH2], 2.13–2.06
[2H, m, C( O)CHH CH, C( O)CH2CHH ], 1.80–1.75 (1H, m,
CHCHH ), 1.62–1.57 [1H, m, C( O)CH2CHH ], 1.55 [3H, s,
C(CH3)(CHꢀ3)], 1.53 [3H, s, C(CH3)(CHꢀ3)], 1.44–1.37 (1H, m,
CHCHHꢀ). Chiral GC: Chirasil Dex-CB, 140 ◦C, 25 psi, 17.8 min
(4.0 pA s, S), 18.1 min (187.6 pA s, R) gave 96% ee.
ꢀ
ꢀ
=
=
ꢀ
ꢀ
=
=
2 × C( O)CHH CHR, 2 × C( O)CHH CH2], 2.30–2.03 [4Hmaj
ꢀ
ꢀ
=
ꢀ
=
=
and 4Hmin, m, 2 × C( O)CHH CHR, 2 × C( O)CH2CHR, 2 ×
ꢀ
ꢀ
=
COCH2CHH , 2 × C( O)CHH CH2], 2.01–1.75 [2Hmaj and 2Hmin
,
ꢀ
ꢀ
=
2 × C( O)(CH2)2CHH , 2 × CHH CHNO2], 1.72–1.57 (2Hmaj
and 2Hmin, m, 2 × COCH2CHHꢀ, 2 × CHHꢀCHNO2), 1.51–1.20
ꢀ
(R)-5-methyl-5-nitro-4-phenylhexan-2-one10 10. Purification
using flash column chromatography (EtOAc–petroleum ether
40/60, 1 : 4) to give the title compound as white prisms (74 mg,
[5Hmaj and 5Hmin, m, 2 × C( O)(CH2)2CHH , 2 × CH2CH2CH3,
=
2 × CH2CH3], 0.87 and 0.86 (3Hmaj and 3Hmin, t, J = 7.0 Hz, 2 ×
CH3). 13C NMR (100 MHz, CDCl3): d 208.5, 92.6, 43.8 (maj),
43.3 (min), 41.7 (maj), 41.4 (min), 40.8, 30.3, 27.9 (min), 27.7
(maj), 27.6 (min), 27.3 (maj), 24.3 (min), 24.1 (maj), 22.0 (min),
21.9 (maj), 13.6. m/z (ESI): found, 214.1441; [MH]+ C11H20NO3
requires, 214.1443. Chiral GC: Chiradex G-TA, 160 ◦C, 25 psi,
12.9 min (4402.1 pA s, R), 14.9 min (125.5 s pA s, S) gave 94%
ee for the major diastereomer, 15.5 min (165.0 pA s, S), 17.8 min
(5658.7 pA s, R) gave 94% ee for the minor diastereomer, and a
diastereomeric ratio of 1 : 1.3.
61%). Mp = 51–52 ◦C; mmax (film)/cm−1: 1703, 1530, 1353; [a]2D5
=
1
−34.1 (c = 1, EtOH, 99% ee). H NMR (400 MHz, CDCl3):
d = 7.32–7.26 (3H, m, ArH), 7.20–7.18 (2H, m, ArH), 3.92 (1H,
dd, J = 3.5, 10.6 Hz, PhCH), 3.08 [1H, dd, J = 10.6, 16.9 Hz,
ꢀ
ꢀ
=
=
C( O)CHH ], 2.72 [1H, dd, J = 3.5, 16.9 Hz, C( O)CHH ],
ꢀ
=
2.02 [3H, s, C( O)CH3], 1.55 [3H, s, C(CH3)(CH 3)], 1.45 [3H, s,
C(CH3)(CHꢀ3)]. Chiral GC: Chirasil Dex-CB, 140 ◦C, 25 psi,
27.3 min (area 504.4 pA s, R), 28.1 min (51.3 pA s, S) gave 82% ee.
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 2039–2049 | 2045
©

View Online
(R)-3-(1-Nitrocyclohexyl)cyclohexanone9. Purification using
flash column chromatography (EtOAc–petroleum ether 40/60,
1 : 4) to give the title compound as white prisms (60 mg, 53%).
on a Nonius Kappa CCD diffractometer (Rint = 0.0273) using
˚
Mo-Ka radiation (k = 0.71073 A). Refinement using full-matrix
least-squares on F2. Final residues were R1 = 0.0312, wR2 = 0.0752
[for reflections with I > 2r(I)], R1 = 0.0341, wR2 = 0.0770 for all
reflections.
CCDC reference number 287832. For crystallographic data in
CIF or other electronic format see DOI: 10.1039/b601877g
Mp = 60–61 ◦C; mmax (film)/cm−1: 1709, 1524, 1346; [a]2D5
=
1
+2.1 (c = 0.515, CHCl3, 97% ee). H NMR (600 MHz, CDCl3):
ꢀ
ꢀ
=
d 2.52–2.41 [3H, m, CHH CNO2CH2, CH2CNO2CHH , C( O)-
ꢀ
ꢀ
=
CHH CHR], 2.40–2.33 [1H, m, C( O)CHH CH2], 2.24–2.19
ꢀ
ꢀ
=
=
[1H, m, C( O)CHH CH2], 2.17–2.02 [3H, m, C( O)CH2CHH ,
ꢀ
=
=
C( O)CH2CHR, C( O)CHH CHR], 1.96–1.89 [1H, m, 2 ×
(4R,5R)-5-Nitro-4-phenylnonan-2-one and (4R,5S)-5-nitro-4-
phenylnonan-2-one. Purification using flash column chromatog-
raphy (CH2Cl2–toluene, 1 : 2) and repurification using flash
column chromatography (Et2O–petroleum ether 40/60, 1 : 9 → 1 :
4) to give the major diastereomer of the title compound as an oil
(47 mg, 36%). mmax (film)/cm−1: 1719, 1548, 1366; [a]2D5 = +4.2 (c =
0.515, CHCl3, 84% ee). 1H NMR (600 MHz, CDCl3): d 7.32 (2H,
t, J = 7.5 Hz, ArorthoH), 7.26 (1H, t, J = 7.2 Hz, ArparaH), 7.19
(2H, d, J = 7.4 Hz, ArmetaH), 4.65 (1H, m, CHNO2), 3.68 (1H,
app td, J = 3.5, 10.0 Hz, PhCH), 2.96 [1H, dd, J = 10.0, 16.7 Hz,
ꢀ
ꢀ
=
C( O)(CH2)2CHH ], 1.71–1.62 [3H, m, CHH CH2CNO2CH2-
CH2, CH2CH2CNO2CHHꢀCH2, CHHꢀ(CH2)2CNO2], 1.61–1.48
ꢀ
[3H, CHHꢀCNO2CH2, CH2CNO2CHHꢀ, C( O)CH2CHH ],
=
1.39–1.28 [3H, m, CHHꢀCH2CNO2CH2CH2, CH2CH2CNO2-
ꢀ
ꢀ
ꢀ
=
CHH CH2, C( O)(CH2)2CHH ], 1.27–0.81 [1H, m, CHH (CH2)2-
CNO2]. 13C NMR (125 MHz, CDCl3): d 209.5, 93.9, 47.0, 42.5,
40.9, 32.1, 31.4, 25.7, 24.7, 24.5, 22.3, 22.2. Chiral GC: Chiradex
◦
G-TA, 170 C, 25 psi, 21.0 min (19.3 pA s, S), 22.1 min (1219.3
pA s, R) gave 97% ee.
ꢀ
ꢀ
=
=
C( O)CHH ], 2.67 [1H, dd, J = 3.5, 16.7 Hz, C( O)CHH ], 1.98
(R)-5-Nitro-4-phenylpentan-2-one10. Purification using flash
column chromatography (CH2Cl2–petroleum ether 40/60, 2 : 1) to
give the title compound as white prisms (52 mg, 48%). Mp = 116–
ꢀ
=
[3H, s, C( O)CH3], 1.85–1.80 [1H, m, CH(NO2)CHH ], 1.39–
1.36 [1H, m, CH(NO2)CHHꢀ], 1.24–1.16 [4H, m, (CH2)2CH3],
0.77 (3H, t, J = 6.6 Hz, CH3). 13C NMR (150 MHz, CDCl3): d
204.9, 138.6, 129.0, 128.0, 127.8, 92.7, 46.3, 44.7, 31.6, 30.4, 27.8,
21.8, 13.6. m/z (ESI): found, 286.1416; [M + Na]+ C15H21NaNO3
117 ◦C; mmax (film)/cm−1: 1712, 1546, 1383; [a]25 = −2.8 (c = 0.53,
D
1
CHCl3, 82% ee). H NMR (400 MHz, CDCl3): d 7.35–7.24 (3H,
m, ArH), 7.22–7.19 (2H, m, ArH), 4.68 [1H, dd, J = 6.9, 12.4 Hz,
CHHꢀ(NO2)], 4.59 (1H, dd, J = 7.7, 12.4 Hz, CHHꢀNO2), 4.00
(1H, apparent qn, J = 7.1 Hz, PhCH), 2.91 [2H, d, J = 7.0 Hz,
◦
requires, 286.1419. Chiral GC: Chirasil Dex-CB, 130 C, 25 psi,
89.6 min (area 830.6 pA s, R), 91.5 min (70.3 pA s, S) gave 84% ee.
Purification using flash column chromatography (CH2Cl2–
toluene, 1 : 2) and repurification using flash column chromatogra-
phy (Et2O–petroleum ether 40/60, 1 : 9 → 1 : 4) to give the minor
diastereomer of the title compound as white needles (28 mg, 21%).
=
=
C( O)CH2], 2.11 [3H, s, C( O)CH3]. Chiral GC: Chiradex G-
TA, 150 ◦C, 25 psi, 23.1 min (area 27.7 pA s, S), 23.8 min (278.2
pA s, R) gave 82% ee.
◦
Mp = 71–73 C; mmax (film)/cm−1: 2957, 2929, 2862, 1719, 1544,
(4R,5R)-5-Nitro-4-phenylhexan-2-one18 (23) and (4R,5S)-5-
nitro-4-phenylhexan-2-one18 (23ꢀ). Purification using flash col-
umn chromatography (EtOAc–petroleum ether 30/40, 1 : 9 →
2 : 3) to give the title compound, 23, as an oil (41 mg, 36%). mmax
(film)/cm−1: 1717, 1543, 1357; [a]D25 = −10.9 (c = 0.54, CHCl3,
80% ee). 1H NMR (400 MHz, CDCl3): d 7.35–7.24 (3H, m, ArH),
7.20–7.17 (2H, m, ArH), 4.92 (1H, qd, J = 6.6, 9.9 Hz, CHNO2)
1370; [a]2D5 = −8.6 (c = 0.565, CHCl3, 84% ee). 1H NMR (600 MHz,
CDCl3): d 7.31–7.24 (3H, m, ArH), 7.13 (2H, d, J = 7.2 Hz,
ArmetaH), 4.75 (1H, ddd, J = 3.5, 6.8, 10.5 Hz, CHNO2), 3.72 (1H,
apparent q, J = 7.0 Hz, PhCH), 3.02 [1H, dd, J = 6.6, 17.5 Hz,
ꢀ
ꢀ
=
=
C( O)CHH ], 2.86 [1H, dd, J = 7.4, 17.5 Hz, C( O)CHH ], 2.10
ꢀ
=
[3H, s, C( O)CH3], 1.92–1.88 [1H, m, CH(NO2)CHH ], 1.72–
1.67 [1H, m, CH(NO2)CHHꢀ], 1.35–1.25 [4H, m, (CH2)2CH3],
0.87 (3H, t, J = 7.0 Hz, CH3). 13C NMR (150 MHz, CDCl3): d
205.7, 138.0, 128.7, 128.2, 127.9, 91.5, 45.2, 43.9, 30.8, 30.6, 28.0,
22.1, 13.7. m/z (ESI): found, 286.1416; [M + Na]+ C15H21NaNO3
3.71 (1H, apparent td, J = 4.3, 9.6 Hz, PhCH), 2.96 [1H, dd,
ꢀ
=
J = 9.5, 16.9 Hz, C( O)CHH ], 2.74 [1H, dd, J = 4.3, 17.0 Hz,
ꢀ
=
=
C( O)CHH ], 2.00 [3H, s, C( O)CH3], 1.32 [3H, d, J = 6.6 Hz,
CH(NO2)(CH3)]. Chiral GC: Chirasil Dex-CB, 130 ◦C, 25 psi,
36.5 min (area 29.6 pA s, R), 37.4 min (269.5 pA s, S) gave 80% ee.
Purification using flash column chromatography (EtOAc–
petroleum ether 30/40, 1 : 9 → 2 : 3) to give the title compound,
23ꢀ, as white needles (34 mg, 31%). mmax (film)/cm−1: 1713, 1541,
1357; [a]2D5 = −1.4 (c = 0.485, CHCl3, 80% ee). 1H NMR (400 MHz,
CDCl3): d 7.33–7.24 (3H, m, ArH), 7.15–7.13 (2H, m, ArH), 4.88
◦
requires, 286.1419. Chiral GC: Chirasil Dex-CB, 130 C, 25 psi,
113.8 min (area 45.6 pA s, S), 116.2 min (389.7 pA s, S) gave
approximately (due to incomplete resolution) 80% ee.
(S)-4-(1-Nitrocyclohexyl)-4-phenylbutan-2-one10. Purification
using flash column chromatography (CH2Cl2–toluene, 1 : 3)
and repurification using preparative TLC (Et2O–CH2Cl2, 1 :
9) to give the title compound as white prisms (112 mg, 80%).
(1H, qn, J = 6.6 Hz CHNO2), 3.73 (1H, apparent q, J = 6.9 Hz,
ꢀ
=
PhCH), 3.04 [1H, dd, J = 6.6, 17.5 Hz, C( O)CHH ], 2.89 [1H,
◦
Mp = 68–69 C; mmax (film)/cm−1: 2935, 2856, 1706, 1527, 1336;
ꢀ
=
=
dd, J = 7.6, 17.5 Hz, C( O)CHH ], 2.11 [3H, s, C( O)CH3], 1.48
[3H, d, J = 6.7 Hz, CH(NO2)(CH3)]. Chiral GC: Chirasil Dex-CB,
130 ◦C, 25 psi, 40.9 min (area 228.3 pA s, R), 42.6 min (25.0 pA s,
S) gave 80% ee.
1
[a]2D5 = +3.7 (c = 0.505, CHCl3, 73% ee). H NMR (400 MHz,
CDCl3): d 7.31–7.25 (3H, m, ArH), 7.11 (2H, dd, J = 2.0, 5.9 Hz,
ArH), 3.65 (1H, dd, J = 4.3, 9.6 Hz, PhCH), 3.02 [1H, dd, J =
ꢀ
=
9.6, 17.3 Hz, C( O)CHH ], 2.92 [1H, dd, J = 4.3, 17.3 Hz,
Crystal data: compound 23ꢀ. C12H15NO3, M = 221.25, or-
C( O)CHH ], 2.52 (1H, dd, J = 2.3, 14.1 Hz, CHH CNO2CH2),
ꢀ
ꢀ
=
thorhombic, space group P212121, a = 5.6440(10), b = 8.4770(2),
2.32 (1H, dd, J = 2.4, 14.2 Hz, CH2CNO2CHHꢀ), 2.01 [3H, s,
3
ꢀ
c = 25.1210(5) A, V = 1201.89(4) A , Z = 4, Dcalc = 1.223 Mg
m−3, F(000) = 472, l(Mo-Ka) = 0.088 mm−1, T = 180(2) K, 9256
total reflections measured, 1600 independent reflections measured
C( O)CH3], 1.68–1.08 [8H, m, CHH (CH2)3 CHHꢀ]. HPLC:
˚
˚
=
R
Daicel Chiralpakꢀ AD-H. Hexane–i-PrOH, 90 : 10, 215 nm: tR
(major) = 7.9 min; tR (minor) = 13.2 min.
2046 | Org. Biomol. Chem., 2006, 4, 2039–2049
This journal is
The Royal Society of Chemistry 2006
©

View Online
(R)-4-(4-Hydroxy-phenyl)-5-methyl-5-nitro-hexan-2-one10 11.
Purification using flash column chromatography (Et2O–CH2Cl2,
1 : 49) to give the title compound as a white solid (90 mg, 72%).
mmax (film)/cm−1: 3272, 1699, 1612, 1594, 1532, 1517, 1451, 1410,
1397, 1370, 1354, 1305, 1274, 1232, 1200, 1179, 1140, 1111, 1067,
1029, 965, 851, 805; [a]D25 = +26.8 (c = 4.50, CH3CN, 62% ee).
1H NMR (400 MHz, CDCl3): d 7.02, 2H, d, J = 8.5 Hz, ArH),
6.68 (2H, d, J = 8.5 Hz, ArH), 5.78 (1H, br s, OH), 3.85 (1H, dd,
J = 11.1, 3.4 Hz, CHArOH), 3.04 (1H, dd, J = 16.6, 11.1 Hz,
CHHꢀCOCH3), 2.67 (1H, dd, J = 16.6, 3.4 Hz, CHHꢀCOCH3),
2.04 (3H, s, COCH3), 1.54 [3H, s, CH3C(CHꢀ3)NO2], 1.47 [3H, s,
CH3C(CHꢀ3)NO2]. 13C NMR [100 MHz, (CD3)2SO]: d 205.7,
156.6, 130.1, 127.9, 114.9, 91.6, 47.7, 43.0, 30.2, 23.5, 23.0.
m/z (ES+): found, 274.1074; [MNa]+ C13H17NO4Na requires,
274.1055. HPLC: Daicel Chiralpak AD-H. Hexane–i-PrOH, 95 :
5, 1 mL min−1, 280 nM: tR (major) = 52 min; tR (minor) = 47 min.
(R)-5-Methyl-5-nitro-4-(pyridin-4-yl)hexan-2-one 15. Purifica-
tion using flash column chromatography (petroleum ether 40/60–
EtOAc, 1 : 4) to give the title compound. mmax (film)/cm−1: 2920,
1717, 1537, 1345, 850, 703; [a]2D5 = +21.2 (c = 0.51, CHCl3, 65%
1
ee). H NMR (400 MHz, CDCl3): d 8.56 (2H, d, J = 5.8 Hz,
ArH), 7.12 (2H, d, J = 5.9 Hz, ArH), 3.91 [1H, dd, J = 10.5,
3.2 Hz, CHC(CH3)2NO2], 3.07 [1H, dd, J = 17.7, 10.5 Hz,
ꢀ
ꢀ
=
=
C( O)CHH ], 2.80 [1H, dd, J = 17.7, 3.3 Hz, C( O)CHH ], 2.07
ꢀ
=
[3H, s, C( O)CH3], 1.56 [3H, s, (CH3)(CH 3)CNO2], 1.40 [3H, s,
(CH3)(CHꢀ3)CNO2]. 13C NMR (100 MHz, CDCl3): d 204.1, 150.0,
147.0, 124.3, 90.1, 48.0, 43.5, 30.3, 35.7, 22.9. m/z (ES): found,
237.1237; [MH]+ C12H17N2O3 requires, 237.1239. HPLC: Daicel
Chiralcel OD-H. Hexane–i-PrOH, 80 : 20, 1 mL min−1, 254 nM:
tR (minor) = 14 min; tR (major) = 16 min.
(R)-6-Methyl-6-nitro-5-phenylheptan-3-one10 16. Purification
using flash column chromatography (EtOAc–petroleum ether
40/60, 1 : 24) to give the title compound as a colorless oil
(67 mg, 78%). mmax (film)/cm−1: 2980, 1717, 1536, 1456, 1397,
1373, 1344, 1112, 849; [a]2D5 = +6.81 (c = 3.34, CHCl3, 78% ee).
1H NMR (400 MHz, CDCl3): d 7.18–7.32 (5H, m, ArH), 3.95
(1H, dd, J = 10.6, 3.4 Hz, CHAr), 3.07 (1H, dd, J = 16.8,
10.6 Hz, CHHꢀCOCH2CH3), 2.69 (1H, dd, J = 16.8, 3.4 Hz,
CHHꢀCOCH2CH3), 2.32–2.42 (1H, m, COCHHꢀCH3), 2.18–2.28
(1H, m, COCHHꢀCH3), 1.55 [3H, s, CH3C(CHꢀ3)NO2], 1.49 [3H, s,
CH3C(CHꢀ3)NO2], 0.91 (3H, t, J = 7.3 Hz, COCH2CH3). 13C
NMR (100 MHz, CDCl3): d 207.8, 137.8, 129.1, 128.5, 127.8,
91.1, 48.9, 42.9, 36.4, 25.9, 22.5, 7.5. m/z (ES+): found, 272.2195;
[MNa]+ C14H19NO3Na requires, 272.1263. Chiral GC: Chirasil
Dex-CB, 150 ◦C, 25 psi, 22.9 min (173.8 pA s, R), 23.6 min (21.5
pA s, S) gave 78% ee.
(R)-5-Methyl-5-nitro-4-(4-trifluoromethylphenyl)hexan-2-one
12. Purification using flash column chromatography (EtOAc–
hexane, 3 : 17) to give the title compound (101 mg, 66%). mmax
(film)/cm−1: 2989, 2348, 1720, 1621, 1538, 1460, 1425, 1399,
1375, 1347, 1324, 1163, 1114, 1070, 1017, 959, 912, 850, 803;
1
[a]2D5 = +23.2 (c = 5.03, CHCl3, 68% ee). H NMR (400 MHz,
CDCl3): d 7.57 (2H, d, J = 8.2 Hz, ArH), 7.32 (2H, d, J =
8.1 Hz, ArH), 3.99 (1H, dd, J = 10.5, 3.3 Hz, CHArCF3),
3.09 (1H, dd, J = 17.5, 10.6 Hz, CHHꢀCOCH3), 2.80 (1H, dd,
J = 17.5, 3.4 Hz, CHHꢀCOCH3), 2.05 (3H, s, COCH3), 1.55
[3H, s, CH3C(CHꢀ3)NO2], 1.50 [3H, s, CH3C(CHꢀ3)NO2]. 13C
NMR (100 MHz, CDCl3): d 204.4, 142.0 (d, J = 1.3 Hz), 130.1
(q, J = 32.5 Hz), 129.5, 125.4 (q, J = 3.8 Hz), 125.2, 90.5,
48.4, 43.8, 30.2, 25.5, 22.8. m/z (ES+): found, 326.0981; [MNa]+
C14H16F3NO3Na requires, 326.0974. Chiral GC: Chirasil Dex-CB,
150◦, 25 psi, 18.4 min (417.0 pA s, R), 19.1 min (78.8 pA s, S) gave
68% ee.
(R)-3-(2-Nitropropan-2-yl)cyclopentanone9
17. Purification
using flash column chromatography (EtOAc–petroleum ether
40/60, 1 : 9) to give the title compound as a colorless oil (53 mg,
62%). mmax (film)/cm−1: 2986, 1738, 1528, 1473, 1400, 1374,
1338, 1281, 1252, 1241, 1225, 1208, 1191, 1164, 1120, 1079,
1000, 980, 946, 918, 900, 853, 839, 819; [a]2D5 = +80.8 (c = 2.64,
(S)-5-Methyl-5-nitro-4-(thiophen-2-yl)hexan-2-one10 13. Pu-
rification using flash column chromatography (EtOAc–petroleum
ether 40/60, 1 : 9) to give the title compound. mmax (film)/cm−1:
2920, 1717, 1537, 1345, 850, 703; [a]2D5 = +26.4 (c = 1.242,
1
CHCl3, 80% ee). H NMR (400 MHz, CDCl3): d 2.85 [1H, m,
1
CHCl3, 66% ee). H NMR (400 MHz, CDCl3): d 7.19 (1H, d,
CHC(CHꢀ3)2NO2], 2.19–2.44 (3H, m, CH2COCHHꢀ), 2.02–2.14
(2H, m, CH2COCHHꢀ and cpent-H), 1.64–1.73 (1H, m, cpent-H),
J = 4.6 Hz, ArH), 6.90–6.93 (2H, m, ArH), 4.29 [1H, dd, J =
10.8, 2.9 Hz, CHC(CH3)2NO2], 3.01 [1H, dd, J = 16.9, 10.9 Hz,
1.62 [3H, s, CH3C(CHꢀ3)NO2], 1.61 [3H, s, CH3C(CHꢀ3)NO2]. 13
C
ꢀ
ꢀ
=
=
C( O)CHH ], 2.65 [1H, dd, J = 16.9, 3.0 Hz, C( O)CHH ], 2.05
NMR (100 MHz, CDCl3): d 215.4, 89.4, 45.6, 40.1, 38.5, 24.4,
ꢀ
=
[3H, s, C( O)CH3], 1.62 [3H, s, (CH3)(CH 3)CNO2], 1.52 [3H, s,
◦
23.6, 23.3. Chiral GC: Chiradex G-TA, 150 C, 25 psi, 10.4 min
(CH3)(CHꢀ3)CNO2]. 13C NMR (100 MHz, CDCl3): d 204.4, 140.3,
(43.0 pA s, S), 10.8 min (392.9 pA s, R) gave 80% ee.
127.5, 126.9, 126.3, 91.0, 45.6, 44.3, 30.3, 25.6, 22.5.
(S)-4-(Furan-2-yl)-5-methyl-5-nitrohexan-2-one10 14. Purifica-
tion using flash column chromatography (EtOAc–petroleum ether
40/60, 1 : 9) to give the title compound. mmax (film)/cm−1: 1719,
1538, 1346, 1014, 746; [a]2D5 = +22.4 (c = 0.905, CHCl3, 72%
(R)-3-Methyl-3-(2-nitropropan-2-yl)cyclohexanone 18. Purifi-
cation using flash column chromatography (EtOAc–hexane, 1 :
4) to give the title compound as a colorless oil (55 mg,
64%). mmax (film)/cm−1: 2953, 1708, 1544, 1462, 1430, 1378,
1297, 1229, 1193, 1146, 1080, 1051, 932, 886; [a]2D5 = +1.5
(c = 2.73, CHCl3, 91% ee). 1H NMR (400 MHz, CDCl3): d
4.29 (2H, dd, J = 19.7, 10.7 Hz, CH2NO2), 2.24–2.44 (4H,
m, CH2COCCH2), 1.58–2.03 (4H, m, chex-H), 1.12 (3H, s,
CH3CCHꢀ2NO2). 13C NMR (100 MHz, CDCl3): d 208.7, 84.9, 50.8,
40.5, 39.8, 33.5, 23.2, 21.3. m/z (ES+): found, 194.0435; [MNa]+
C8H13NO3Na requires, 194.0793. Chiral GC: Chirasil Dex-CB,
150 ◦C, 25 psi, 8.8 min (286.6 pA s, R), 9.3 min (13.6 pA s, S) gave
91% ee.
1
ee). H NMR (400 MHz, CDCl3): d 7.30 (1, s, ArH), 6.27 (1H,
m, ArH), 6.15 (1H, d, J = 3.1 Hz, ArH), 4.09 [1H, dd, J =
10.9, 3.0 Hz, CHC(CH3)2NO2], 3.06 [1H, dd, J = 16.9, 10.9 Hz,
ꢀ
ꢀ
=
=
C( O)CHH ], 2.51 [1H, dd, J = 16.9, 3.30 Hz, C( O)CHH ], 2.04
ꢀ
=
[3H, s, C( O)CH3], 1.55 [3H, s, (CH3)(CH 3)CNO2], 1.48 [3H, s,
(CH3)(CHꢀ3)CNO2]. 13C NMR (100 MHz, CDCl3): d 204.6, 151.3,
142.2, 110.5, 109.1, 90.5, 42.5, 42.1, 30.0, 25.6, 22.4. Chiral GC:
Chiraldex G-TA, 130◦, 25 psi, 23.4 min (S), 24.2 min (R) gave
66% ee.
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 2039–2049 | 2047
©

View Online
(S)-Methyl 2-(2-nitropropan-2-yl)-4-oxopentanoate10 19. Pu-
rification using flash column chromatography (EtOAc–hexane,
1 : 4) to give the title compound as a white solid (105 mg,
96%). mmax (film)/cm−1: 2959, 1736, 1715, 1541, 1438, 1401, 1372,
1346, 1288, 1221, 1198, 1178, 1163, 1133, 1095, 1047, 977, 956,
Kinetic investigations using ReactIR
Reactions were run using a Mettler Toledo ReactIR 4000 in-
strument with a SiComp probe. (E)-4-Phenyl-3-buten-2-one (9)
(72 mg, 0.49 mmol), trans-2,5-dimethylpiperazine (7) (67 mg,
0.50 mmol), and tetrazole 4 (10 mg, 0.074 mmol) were dissolved
in dichloromethane (0.75 mL). Nitroethane (70 lL, 74 mg,
0.98 mmol) was added and the reaction monitored every 20 min
for 50 h.
Tetrazole 4 (35 mg, 0.26 mmol) was dissolved in methanol
(4 mL) in a test tube. The ReactIR side arm was fitted, and
five spectra were acquired (1 spectrum min−1). Cyclohexenone (6)
(25 mL, 25 mg, 0.26 mmol) was added and the reaction monitored
every minute for 2 h. No changes were observed in the region
1600–1800 cm−1.
Tetrazole 4 (75 mg, 0.55 mmol) was dissolved in methanol
(4 mL) in a 10 mL round-bottomed flask under argon. The
ReactIR side arm was fitted, and two spectra were acquired (2
spectra min−1). (E)-4-Phenyl-3-buten-2-one (9) (80 mg, 0.55 mmol)
was added and the reaction monitored every 2 min for 5 h. No
changes were observed in the region 1600–1800 cm−1.
1
907, 851; [a]2D5 = +38.1 (c = 3.81, CHCl3, 82% ee). H NMR
(400 MHz, CDCl3): d = 3.71 (3H, s, OCH3), 3.67 (1H, dd, J =
11.1, 2.9 Hz, CHCO2CH3), 3.04 (1H, dd, J = 17.8, 11.1 Hz,
CHHꢀCOCH3), 2.43 (1H, dd, J = 17.8, 2.8 Hz, CHHꢀCOCH3),
2.16 (3H, s, COCH3), 1.61 [3H, s, CH3C(CHꢀ3)NO2], 1.59 [3H, s,
CH3C(CHꢀ3)NO2]. 13C NMR (100 MHz, CDCl3): d 204.8, 171.3,
88.2, 52.3, 48.2, 41.3, 29.7, 25.4, 23.0. m/z (ES+): found, 240.0828;
[MNa]+ C9H15NO5Na requires, 240.0848. Chiral GC: Chirasil
Dex-CB, 130 ◦C, 25 psi, 10.9 min (257.2 pA s, S), 11.3 min (26.2
pA s, R) gave 82% ee.
(S)-4-(2-Nitropropan-2-yl)nonan-2-one 20. Purification using
flash column chromatography (Et2O–petroleum ether 40/60, 1 :
9 → 3 : 7) to give the title compound as a clear oil (49 mg,
44%). mmax (film)/cm−1: 1718, 1535, 1348; [a]2D5 = +12.6 (c =
1
0.495, CHCl3, 58% ee). H NMR (600 MHz, CDCl3): d 2.75–
2.71 [1H, m, C(NO2)CH], 2.50 [1H, dd, J = 4.4, 18.0 Hz,
ꢀ
ꢀ
=
=
C( O)CHH ], 2.32 [1H, dd, J = 6.2, 18.0 Hz, C( O)CHH ], 2.15
Kinetic investigations using a React ArrayTM
ꢀ
=
[3H, s, C( O)CH3], 1.50 [3H, s, C(NO2)(CH3)(CH 3)], 1.49 [3H, s,
Reactions were performed using a React ArrayTM SK233 au-
tomated workstation subjected to in-line HPLC analysis on
a Hewlett Packard HP1100 instrument. Column: SupercosilTM
ABZ+ 3.3 cm × 4.6 mm, 3 lm. Eluent: A: water, 0.1% TFA;
B: 95% acetonitrile, 5% water, 0.05% TFA. Flow rate: 1 mL min−1.
Method: gradient 10–95% B in A over 7 min, run time 10 min.
All reactions were performed in air in 5 mL vessels. 50 lL
aliquots were sampled at specified intervals. The aliquots were
dispensed into 1.5 mL vials, quenched with acetonitrile (1 mL) and
mixed [75% by volume (aspirated and dispensed at 10 mL min−1)].
100 lL of these solutions were transferred to clean 1.5 mL
vials, diluted with acetonitrile (1 mL) and mixed as described
previously to give analytical samples ready for HPLC analysis
(20 lL injected).
(E)-4-Phenyl-3-buten-2-one (9) (148 mg, 1.01 mmol), trans-2,5-
dimethylpiperazine (7) (114 mg, 1.00 mmol), the internal standard
trans-stilbene (16 mg, 0.09 mmol) and 2-nitropropane (200 lL,
198 mg, 2.22 mmol) were dissolved in dichloromethane (4 mL).
The SK233 was initiated, the tetrazole 4 (19 mg, 0.14 mmol) added
and the timer started. The reactions were sampled at t = 0.25, 0.5,
0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26,
28, 30, 32, 34, 36, 38, 40, 42, 44, 48, 54, 60, 66, 72, 78 and 84 h.
The HPLC trace areas were normalised with respect to the
internal standard (trans-stilbene). The HPLC trace areas were
then extrapolated back to their respective concentrations using the
calibration curves. Percentages of (E)-4-phenyl-3-buten-2-one (9)
remaining in solution and (R)-5-methyl-5-nitro-4-phenylhexan-2-
one (10) formed were calculated and plotted against the reaction
time.
C(NO2)(CH3)(CHꢀ3)], 1.41–1.34 (1H, m, CHRCHHꢀ), 1.24–1.16
[6H, m, –(CH2)3–], 1.08–1.03 (1H, m, CHRCHHꢀ), 0.84 (3H, t,
J = 7.1 Hz, CH2CH3). 13C NMR (600 MHz, CDCl3): d 206.1,
91.6, 45.0, 41.3, 31.8, 31.2, 30.0, 27.5, 23.9, 23.7, 22.4, 13.9. m/z
(ESI): found, 252.1573; [MNa]+ C12H23NO3Na requires, 252.1576.
Chiral GC: Chirasil Dex-CB, 130 ◦C, 25 psi, 19.9 min (148.5. pA s,
S), 20.7 min (39.5 pA s, R) gave 58% ee.
(S)-3,4-Dimethyl-4-nitropentanal 21. Purification using flash
column chromatography (CH2Cl2–petroleum ether 40/60, 2 : 3 →
3 : 2) to give the title compound as a clear oil of approximately
90% purity (30 mg, 39%). mmax (film)/cm−1: 1723, 1533, 1349; [a]D25 =
+1.0 (c = 0.355, CHCl3, 46% ee). 1H NMR (600 MHz, CDCl3): d
9.73 (1H, m, CHO), 2.90–2.82 [1H, m, C(NO2)CH], 2.46 [1H, ddd,
ꢀ
=
J = 0.7, 2.9, 17.1 Hz, C( O)CHH ], 2.28 [1H, ddd, J = 2.3, 10.2,
ꢀ
ꢀ
=
17.2 Hz, C( O)CHH ], 1.56 [3H, s, C(CH3)(CH 3)], 1.54 [3H, s,
C(CH3)(CHꢀ3)], 0.98 (3H, d, J = 6.3 Hz, CHRCH3). 13C NMR
(150 MHz, CDCl3): d 199.7, 91.2, 46.2, 35.9, 23.9, 22.5, 15.3. m/z
(ESI): found, 182.0791; [MNa]+ C7H13NO3Na requires, 182.0793.
Chiral GC: Chirasil Dex-CB, 130 ◦C, 25 psi, 5.6 min (100.1 pA s,
S), 5.9 min (37.3 pA s, R) gave 46% ee.
(R)-4-Methyl-4-nitro-3-phenylpentanal 22. Purification using
flash column chromatography (EtOAc–petroleum ether 40/60, 1 :
23) to give the title compound as a white solid. mmax (film)/cm−1:
2998, 2836, 2732, 1723, 1532, 1495, 1455, 1397, 1374, 1344, 1292,
1218, 1134, 1092, 1060, 1019, 910, 846. 1H NMR (400 MHz,
CDCl3): d 9.53 (1H, d, J = 1.8 Hz, COCH), 7.20–7.35 (5H, m,
ArH), 4.00 (1H, dd, J = 11.1, 3.7 Hz, CHAr), 3.06 (1H, ddd,
J = 17.2, 11.1, 2.3 Hz, CHHꢀCOH), 2.71 (1H, dd, J = 17.2, 3.6
Hz), 1.58 [3H, s, CH3C(CHꢀ3)NO2], 1.49 [3H, s, CH3C(CHꢀ3)NO2].
13C NMR (100 MHz, CDCl3): d 199.0, 136.8, 129.3, 128.7, 128.1,
91.0, 47.6, 43.9, 25.5, 22.2. m/z (ES+): found, 244.1225; [MNa]+
C12H15NO3Na requires, 244.0950. Chiral GC: Chiradex G-TA,
130 ◦C, 25 psi, 56.8 min (256.9 pA s), 59.5 min (253.7 pA s) gave
0% ee
Acknowledgements
We thank Avecia (to C. E. T. M.), the EPSRC (to C. E. T. M.),
the Spanish Ministry of Science and Technology (to J. G. F.), and
Novartis (through a Research Fellowship to S. V. L.) for financial
2048 | Org. Biomol. Chem., 2006, 4, 2039–2049
This journal is
The Royal Society of Chemistry 2006
©

View Online
support. We also thank Dr Marike Herold-Dublin for assistance
with ReactIR experiments, Dr John Davies for acquisition of
crystallographic data, and Dr A. J. A. Cobb and Professor
W. Motherwell for helpful discussions.
6 B. Vakulya, S. Varga, A. Csa´mpai and T. Soo´s, Org. Lett., 2005, 7, 1967.
7 M. S. Taylor, D. N. Zalatan, A. M. Lerchner and E. N. Jacobsen, J. Am.
Chem. Soc., 2005, 127, 1313.
8 M. Yamaguchi, Y. Igarashi, R. S. Reddy, T. Shiraishi and M. Hirama,
Tetrahedron, 1997, 53, 11 223; M. Yamaguchi, T. Shiraishi, Y. Igarashi
and M. Hirama, Tetrahedron Lett., 1994, 35, 8233.
9 S. Hanessian and V. Pham, Org. Lett., 2000, 2, 2975.
10 N. Halland, R. G. Hazell and K. A. Jørgensen, J. Org. Chem., 2002, 67,
8331.
References
1 R. Ballini, G. Bosica, D. Fiorini, A. Palmieri and M. Petrini, Chem.
Rev., 2005, 105, 933.
11 A. Prieto, N. Halland and K. A. Jørgensen, Org. Lett., 2005, 7, 3897.
12 A. J. A. Cobb, D. M. Shaw and S. V. Ley, Synlett, 2004, 558; Y.
Yamamoto, N. Momiyama and H. Yamamoto, J. Am. Chem. Soc.,
2004, 126, 5962; N. Momiyama, H. Torii, S. Saito and H. Yamamoto,
Proc. Natl. Acad. Sci. U. S. A., 2004, 101, 5374; H. Torii, M. Nakadai,
K. Ishihara, S. Saito and H. Yamamoto, Angew. Chem., Int. Ed., 2004,
43, 1983; A. Hartikka and P. I. Arvidsson, Tetrahedron: Asymmetry,
2004, 15, 1831; A. J. A. Cobb, D. A. Longbottom, D. M. Shaw and
S. V. Ley, Chem. Commun., 2004, 1808; A. J. A. Cobb, D. M. Shaw,
D. A. Longbottom, J. B. Gold and S. V. Ley, Org. Biomol. Chem., 2005,
3, 84; D. B. Ramachary and C. F. Barbas, Org. Lett., 2005, 7, 1577; S.
Kumarn, D. M. Shaw, D. A. Longbottom and S. V. Ley, Org. Lett.,
2005, 7, 4189.
2 J. S. Costa, A. G. Dias, A. L. Anholeto, M. D. Monteiro, V. L. Patrocinio
and P. R. R. Costa, J. Org. Chem., 1997, 62, 4002; V. L. Patrocinio,
P. R. R. Costa and C. R. D. Correia, Synthesis, 1994, 474; A. C. Pinto,
C. B. L. Freitas, A. G. Dias, V. L. P. Pereira, B. Tinant, J. P. Declercq and
P. R. R. Costa, Tetrahedron: Asymmetry, 2002, 13, 1025; A. Thomas,
S. G. Manjunatha and S. Rajappa, Helv. Chim. Acta, 1992, 75, 715.
3 P. Bako´, Z. Bajor and L. To˜ke, J. Chem. Soc., Perkin Trans. 1, 1999,
3651; P. Bako´, T. Kiss and L. To˜ke, Tetrahedron Lett., 1997, 38, 7259;
P. Bak o´, T. Nova´k, K. Luda´nyi, B. Pete, L. To˜ke and G. Keglevich,
Tetrahedron: Asymmetry, 1999, 10, 2373; P. Bako´, A. Szo¨llo˜sy, P.
Bombicz and L. To˜ke, Synlett, 1997, 291; T. Bako´, P. Bako´, G.
Keglevich, N. Ba´thori, M. Czugler, J. Tatai, T. Nova´k, G. Parlagh
and L. To˜ke, Tetrahedron: Asymmetry, 2003, 14, 1917; T. Bako´, P.
Bako´, A. Szo¨llo˜sy, M. Czugler, G. Keglevich and L. To˜ke, Tetrahedron:
Asymmetry, 2002, 13, 203.
13 C. E. T. Mitchell, S. E. Brenner and S. V. Ley, Chem. Commun., 2005,
5346.
14 C. E. T. Mitchell, A. J. A. Cobb and S. V. Ley, Synlett, 2005, 611.
15 J. F. Austin and D. W. C. MacMillan, J. Am. Chem. Soc., 2002, 124,
1172.
16 R. G. Coombes, in Comprehensive Organic Chemistry, D. H. R. Barton
and W. D. Ollis, eds., Pergamon Press: Oxford, 1979, vol. 2, p. 323.
17 R. Ballini and G. Bosica, Tetrahedron Lett., 1996, 37, 8027.
18 J. M. Betancort, K. Sakthivel, R. Thayumanavan, F. Tanaka and C. F.
Barbas, Synthesis, 2004, 1509.
4 K. Funabashi, Y. Saida, M. Kanai, T. Arai, H. Sasai and M. Shibasaki,
Tetrahedron Lett., 1998, 39, 7557.
5 E. J. Corey and F.-Y. Zhang, Org. Lett., 2000, 2, 4257; S. Colonna, H.
Hiemstra and H. Wynberg, J. Chem. Soc., Chem. Commun., 1978, 238;
S. Colonna, A. Re and H. Wynberg, J. Chem. Soc., Perkin Trans. 1,
1981, 547.
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 2039–2049 | 2049
©