A catalytic highly enantioselective direct synthesis of 2-bromo-2-nitroalkan-1-ols through a Henry reaction

Article abstract of DOI:10.1039/b809739a

Highly enantiomerically enriched 2-bromo-2-nitroalkan-1-ols are prepared by direct condensation of aliphatic and aromatic aldehydes with bromonitromethane in the presence of a catalytic amount of copper(ii) acetate and a C ₁-symmetric camphor-d

Full text of DOI:10.1039/b809739a

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A catalytic highly enantioselective direct synthesis of
2-bromo-2-nitroalkan-1-ols through a Henry reactionw
´ ´
Gonzalo Blay,* Victor Hernandez-Olmos and Jose R. Pedro*
Received (in Cambridge, UK) 10th June 2008, Accepted 10th July 2008
First published as an Advance Article on the web 29th August 2008
DOI: 10.1039/b809739a
Highly enantiomerically enriched 2-bromo-2-nitroalkan-1-ols
are prepared by direct condensation of aliphatic and aromatic
aldehydes with bromonitromethane in the presence of a catalytic
amount of copper(II) acetate and a C1-symmetric camphor-
derived amino pyridine ligand.
The reaction between a nitroalkane and a carbonyl com-
pound, the so called Henry or nitro-aldol reaction, provides
Scheme 1 Nitro-aldol reaction between nitroalkanes and aldehydes
catalyzed by copper(II) acetate and amino pyridine ligand 1.
b-hydroxy nitroalkanes that are valuable intermediates for the
synthesis of polyfunctionalized molecules and biologically
active compounds.1 In the last years, a number of catalytic
enantioselective procedures for this reaction have been
developed, most of them involving aldehydes and nitro-
methane2 or, to a lesser extent, other unfunctionalized
nitroalkanes.3 However, the use of functionalized nitroalkanes
has been little studied. The addition of bromonitromethane to
a carbonyl compound appears as an attractive method to
prepare 2-bromo-2-nitroalkan-1-ols. This kind of compound
shows activity against bacteria4 and other microorganisms,
such as algae and fungi, and hence they are used as industrial
microbicides5 in oil and gas wells,6 paper manufacture,7
fertilizers,8 and are included in a number of patented formula-
tions for photographic and printing materials.9
Recently our group has developed new ligands for the
asymmetric metal-catalyzed Henry (or nitro-aldol) reaction.14
We have found that the catalytic system formed by copper(II)
acetate and a camphor-derived C1-symmetric amino pyridine
ligand 1 catalyzes the addition of nitromethane and other
nitroalkanes to aliphatic and aromatic aldehydes with very high
enantioselectivity, up to 98% ee, under very advantageous
experimental conditions (Scheme 1).15 From these results, we
envisioned that the reaction between bromonitromethane and
aldehydes using this catalytic system could provide the expected
2-bromo-2-nitroalkan-1-ols in highly enantioenriched form.
The reaction between bromonitromethane (3) and benzalde-
hyde (2a) was used for the optimization process (Scheme 2,
R = Ph). Initially, the reaction was carried out under similar
conditions to those used in our previous work with nitro-
methane, which involved the use of 1 eq. of diisopropylethyl-
amine (DIPEA) in ethanol at ꢀ40 1C. We were very pleased to
observe that, after 7 h, the reaction was almost completed
affording compound 4a as an anti : syn 1 : 1 diastereomeric
mixture with 67 and 74% ee, respectively. The enantioselectivity
of the reaction was lower than that obtained in the reaction of
nitromethane with benzaldehyde (98% ee) under identical
conditions.15 We hypothesized that this lower enantioselectivity
may be due to the competitive uncatalyzed addition of the
bromonitromethane nitronate which should be present in high-
er concentration than in the case of nitromethane. As antici-
pated, a reduction in the amount of base minimized this side
reaction and the expected product 4a was obtained with
increased enantioselectivity (Table 1, entries 2–4). The amount
Bromonitroalkanols are normally obtained by bromina-
tion of the corresponding nitroalkanols with bromine,10 in a
procedure that may lead to double bromination giving
2,2-dibromo-2-nitroalkanols as by-products. 2-Bromo-2-
nitroalkan-1,3-diols have been prepared by double nitro-
aldol addition of bromonitromethane to aldehydes under
pH-controlled conditions.11 On the other hand, controlled
mono-addition of bromonitromethane to aldehydes has been
achieved under heterogeneous acidic (one example) or basic
(two examples) catalysis,12 and very recently by NaI catalysis
under very mild conditions.13 However, despite the effect of
the absolute stereochemistry on the biological activity of chiral
compounds, a procedure for the synthesis of 2-bromo-
2-nitroalkan-1-ols in enantiomerically enriched form has not
been reported to date, with the only exception of one example
of diastereoselective addition of bromonitromethane to a
chiral 2-amino aldehyde.13
Departament de Quı´mica Orga`nica, Facultat de Quı´mica, Universitat
`
de Valencia, Dr Moliner 50, Burjassot (Valencia), E-46100, Spain.
E-mail: jose.r.pedro@uv.es; gonzalo.blay@uv.es;
`
Fax: +34 963544328; Tel: +34 963544336
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data and copies of NMR spectra and
chromatograms for compounds 4a–t. See DOI: 10.1039/b809739a
Scheme
nitroalkan-1-ols by addition of bromonitromethane to aldehydes.
2
Catalytic enantioselective synthesis of 2-bromo-2-
ꢁc
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Table 1 Asymmetric addition of bromonitromethane to benzalde-
hyde (R = Ph) catalyzed by copper(II) acetate and ligand 1 according
to Scheme 2. Optimizationa
Table 2 Asymmetric addition of bromonitromethane to aldehydes
catalyzed by copper(II) acetate and ligand 1. Substrate scopea
Yield
ee
T/1C t/h (%)b anti : sync (%)d
Conv.
T/1C t/h (%)b
Entry Aldehyde
Entry Additive
Anti : synb ee (%)c
1
2
3
Benzaldehyde (2a)
2-Methylbenzaldehyde (2b) ꢀ40 40
ꢀ40 40
99 60 : 40
99 16 : 84
95 21 : 79
95/93
98/96
94/95
1
2
3
4
5
6
7
8
DIPEA (1 eq)
ꢀ40
DIPEA (60 mol%) ꢀ40
DIPEA (20 mol%) ꢀ40
DIPEA (10 mol%) ꢀ40
7
7
7
7
499
499
499
499
52 : 48
64 : 36
52 : 48
42 : 58
31 : 69
31 : 69
60 : 40
59 : 41
67/74
73/70
77/77
86/93
89/90
79/81
95/93
84/78
2-Methoxybenzaldehyde ꢀ40
4
(2c)
2-Chlorobenzaldehyde (2d) ꢀ40 45
2-Chlorobenzaldehyde (2d) 24
4
80 13 : 87
92 15 : 85
86 15 : 85
99 32 : 68
98 61 : 39
94/97
93/88
88/96
94/97
94/94
5e
6
0
NaI (10 mol%)
CsF (10 mol%)
—
—
ꢀ20 40 499
ꢀ20 490
ꢀ40 40 499
499
6
2-Nitrobenzaldehyde (2e) ꢀ40 45
3-Methylbenzaldehyde (2f) ꢀ40 45
3-Methoxybenzaldehyde ꢀ40 45
(2g)
3-Chlorobenzaldehyde (2h) ꢀ40 45
3-Nitrobenzaldehyde (2i) ꢀ40 45
4-Methylbenzaldehyde (2j) ꢀ40 40
4-Methoxybenzaldehyde ꢀ40 45
(2k)
7
8
0
2
a
All experiments were carried out under nitrogen: 0.5 mmol of 2,
0.025 mmol of Cu(OAc)2ꢂH2O, 0.025 mmol of 1, 5.0 mmol of 3 and
9
97 41 : 59
72 40 : 60
83 70 : 30
95 63 : 37
94/nd
87/94
89/92
93/94
10
11
12
b
1
c
additive in 2 mL of EtOH. Determined by H NMR. Determined
by HPLC.
13
14
15
4-Chlorobenzaldehyde (2l) ꢀ40 45
4-Nitrobenzaldehyde (2m) ꢀ40 45
Thiophene-2-carbaldehyde ꢀ40 45
(2n)
95 69 : 31
85 64 : 36
99 36 : 64
90/90
44/38
89/95
of DIPEA could be decreased to 10 mol% with respect to the
aldehyde without any noticeable decrease of the reaction rate,
the addition product 4a being obtained in 86 and 93% ee for the
anti and syn isomers, respectively (entry 4). When NaI was used
in place of DIPEA, compound 4a was obtained with similar
enantiomeric excesses but with higher diastereoselectivity,
although the reaction required more time (entry 5). Similar
results were obtained when CsF, with the more basic fluoride
ion, was used as the base. Finally, it was observed that the
acetate ion of the copper salt was able to promote the reaction
without the need for an external base. Under these conditions,
compound 4a was obtained as a 6 : 4 anti : syn mixture in
95/93% ee, respectively (entries 7 and 8). Note that the reac-
tions without base and with NaI gave different major
diastereomers (entries 5 and 7); however, this was not a general
trend (vide infra).
16
Thiophene-3-carbaldehyde ꢀ40 45
99 32 : 68
91/95
(2o)
Decanal (2p)
Dihydrocinnamaldehyde
(2q)
17
18
0
0
24
24
95 54 : 46
99 54 : 46
83/91
87/87
19
20
Isovaleraldehyde (2r)
Cyclohexanecarbaldehyde
(2s)
0
0
16
16
97 57 : 43
99 66 : 34
86/92
90/91
21
Cinnamaldehyde (2t)
ꢀ40 40
All experiments were carried out under nitrogen: 0.5 mmol of 2,
99 32 : 68
81/96
a
0.025 mmol of Cu(OAc)2ꢂH2O, 0.025 mmol of 1, 5.0 mmol of 3, in
2 mL of EtOH. Isolated yield of 4. Determined by 1H NMR.
b
c
d
e
Determined by HPLC. 10 mol% NaI, conditions as in Table 1,
entry 5.
Substrate scope was studied under ‘‘base-free’’ conditions.z A
variety of aromatic and heteroaromatic aldehydes were found to
be suitable substrates,16 with the reaction providing the expected
bromonitroalkanols 4 in high to quantitative yields (Tables 1 and
2, entries 1–16). 2-Methoxybenzaldehyde reacted especially fast,
indicating a possible chelating effect of the substrate with the
catalyst. The reaction products 4 were obtained as mixtures of anti
and syn diastereomers with moderate to good diastereoselectivities
and very high enantiomeric excesses (near or above 90% ee) for
both diastereomers. Only 4-nitrobenzaldehyde (entry 14) gave the
condensation product 4m with low ee. A substituent at the ortho-
or meta-position favored the syn products (with the exception of
3-methoxybenzaldehyde, entry 8), while para-substituted benzal-
dehydes gave the anti isomers as the major products. The reaction
with 2-chlorobenzaldehyde was also tested with the addition of
10 mol% NaI (entry 5); however an inversion of the diastereo-
selectivity with respect to the reaction in absence of additives was
not observed in this case. Remarkably, the reaction could also be
performed with unbranched and even branched or sterically
hindered aliphatic aldehydes (entries 17–20). In these cases, the
reaction needed to be carried out at higher temperature (0 1C) and
the resulting products were obtained in high yield and good
enantiomeric excesses, only slightly below the ee values obtained
with aromatic aldehydes. Finally, the reaction with the
a,b-unsaturated aldehyde, cinnamaldehyde (2t), afforded
exclusively the 1,2-addition product 4t in almost quantitative
yield, good diastereoselectivity and high ee for both diastereomers
(entry 21). It should be noted that although a 90% pure technical
bromonitromethane containing 10% nitromethane was used in all
the reactions, no products arising from the addition of nitro-
methane were observed in the reaction mixtures.
The anti : syn diastereomeric ratio was determined from the
integration of the 1H NMR signals for the protons adjacent to
the OH and NO2 groups corresponding to each diastereomer.
The coupling constants (J) between these protons appear in
the 7.5–9.0 Hz range for the anti isomer and in the 2.1–5.4 Hz
range for the syn isomer. These J values are in good agreement
with those calculated from the dihedral angles (B1801 for the
anti and B451 for the syn isomers) between H1 and H2 in the
lower-energy conformation,17 and with those observed for
related 2-alky-2-nitroalkan-1-ols.3,15
The absolute stereochemistry of bromonitroalkanol 4a was
determined by chemical conversion into the known compound
(S)-5, via reductive dehalogenation (Scheme 3). Treatment of a
65 : 35 anti : syn mixture of 4a (79% ee for the anti isomer,
80% ee for the syn isomer) with Bu3SnH in the presence of
AIBN18 afforded (S)-5 in almost quantitative yield and 80%
ee,19 showing that the configuration of the carbon atom
bearing the hydroxyl group was S in both the anti and syn
diastereomers. Similar results were obtained with compounds
4b,f,j,s indicating the existence of a common stereochemical
ꢁc
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Scheme
compound 4a.
3
Determination of the absolute stereochemistry of
pathway regardless of the location of the substituent on the
aromatic ring or the aromatic/aliphatic nature of the aldehyde.
The stereochemistry for the rest of compounds 4 was assigned
as 1S on the assumption of this uniform reaction mechanism.
The absolute stereochemistry of compounds 4 is in agreement
with the preferential approach of the nitronate from the Re
face of the aldehyde carbonyl group according to our pre-
viously proposed mechanism.15
In summary, we have developed the first general procedure for
the enantioselective synthesis of 2-bromo-2-nitroalkan-1-ols,
which are compounds with important practical applications.
The procedure involves the Henry reaction between bromonitro-
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methane and aldehydes in the presence of
a low load
(5 mol%) of a catalytic system, recently developed in our labora-
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derived amino pyridine ligand. The reaction is general in scope
providing the expected products with high to quantitative yields
and good to excellent enantioselectivities with a broad range of
aromatic, heteroaromatic, aliphatic and unsaturated aldehydes.
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The authors thank the Ministerio de Educacion y Ciencia
´
and FEDER (Grant CTQ 2006-14199/BQU) for financial
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Notes and references
z A solution of amino pyridine 1 (6.7 mg, 0.025 mmol) in absolute
ethanol (2 mL) was added to Cu(OAc)2ꢂH2O (5.0 mg, 0.025 mmol)
contained in a Schlenk tube under nitrogen. The mixture was stirred
for 1 h at room temperature until the formation of a deep blue
solution. Benzaldehyde (2a, 53 mL, 0.5 mmol) was added and the
reaction flask introduced in a bath at ꢀ40 1C. After 5 min, 90% pure
technical bromonitromethane (3, 0.39 mL, 5 mmol) was added and the
reaction mixture was stirred for 40 h. The mixture was treated
with 1 M aqueous HCl (15 mL) and extracted with dichloromethane
(3 ꢃ 15 mL). The organic layer was washed with brine (20 mL), dried
over MgSO4 and concentrated under reduced pressure to give 4a
(121 mg, 99%).
14 G. Blay, E. Climent, I. Ferna
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´ ´
´
´
´
´
16 Ketones such as acetophenone do not react under this experimental
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1 M. Shibasaki and H. Goger, in Comprehensive Asymmetric Cata-
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ꢁc
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4842 | Chem. Commun., 2008, 4840–4842