Synthesis of enantiopure 2-C-glycosyl-3-nitrochromenes

Article abstract of DOI:10.1021/jo4021634

A novel methodology has been developed to obtain enantiopure 2-C-glycosyl-3-nitrochromenes. First, (Z)-1-bromo-1-nitroalkenes were prepared from the corresponding sugar aldehydes through a sodium iodide-catalyzed Henry reaction with bromonitromethane followed by elimination of the resulting 1-bromo-1-nitroalkan-2-ols. In the next step, reaction of the sugar-derived (Z)-1-bromo-1-nitroalkenes with o-hydroxybenzaldehydes afforded enantiopure (2S,3S,4S)-3-bromo-3,4-dihydro-4-hydroxy-3-nitro-2H-1-benzopyrans, which, upon SmI₂-promoted β-elimination, yielded chiral enantiopure 2-C-glycosyl-3-nitrochromenes.

Full text of DOI:10.1021/jo4021634

Note
pubs.acs.org/joc
Synthesis of Enantiopure 2‑C‑Glycosyl-3-nitrochromenes
Raquel G. Soengas,*,† Humberto Rodríguez-Solla,*,‡ Artur M. S. Silva,*,† Ricardo Llavona,‡
and Filipe A. Almeida Paz§
†Department of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal
‡Departamento de Química Organ
Spain
́ ́ ́
ica e Inorganica, Facultad de Química, Universidad de Oviedo, Julian Clavería 8, 33006 Oviedo,
§Department of Chemistry, CICECO, University of Aveiro, 3810-193 Aveiro, Portugal
S
* Supporting Information
ABSTRACT: A novel methodology has been developed to obtain
enantiopure 2-C-glycosyl-3-nitrochromenes. First, (Z)-1-bromo-1-
nitroalkenes were prepared from the corresponding sugar
aldehydes through a sodium iodide-catalyzed Henry reaction with
bromonitromethane followed by elimination of the resulting 1-
bromo-1-nitroalkan-2-ols. In the next step, reaction of the sugar-
derived (Z)-1-bromo-1-nitroalkenes with o-hydroxybenzaldehydes
afforded enantiopure (2S,3S,4S)-3-bromo-3,4-dihydro-4-hydroxy-3-
nitro-2H-1-benzopyrans, which, upon SmI2-promoted β-elimina-
tion, yielded chiral enantiopure 2-C-glycosyl-3-nitrochromenes.
wide variety of secondary metabolites isolated from plants
scope. Moreover, the basic conditions required are not suitable
Aare glycosidic in nature. Over the last 2 decades, a great for the preparation of enantiopure chromene derivatives
because of problems with isomerization.9
We describe here a methodology for the preparation of 2-C-
deal of effort has been devoted to the study of the largest group
of glycosides (i.e, O-glycosides).1 Less effort has been focused
glycosyl-3-nitro-2H-chromenes that features a reaction between
sugar-derived gem-bromonitroalkenes and o-hydroxybenzalde-
hydes followed by a samarium-promoted β-elimination
reaction. The starting sugar-derived bromonitroalkenes were
obtained by a novel tandem Henry reaction with bromonitro-
methane/dehydration. Our proposed synthetic procedure is
based on the use of sugar-derived gem-bromonitroalkenes as
starting materials. Accordingly, a short, reliable, and high-
yielding synthetic procedure for these derivatives was needed.
The general synthetic method for the preparation of gem-
bromonitroalkenes is based on the bromination−debromina-
tion of nitroalkenes.10 However, because the starting nitro-
alkene is prepared from the sugar aldehyde and nitromethane
by a Henry reaction followed by elimination, it is clear that the
preparation of the sugar-derived gem-bromonitroalkenes
involves a complex multistep sequence.
on C-glycosyl compounds because their synthesis is more
complex. C-Glycosides are a class of glycosides in which
carbohydrates are directly attached to the aglycone through a
C−C bond rather than the usual hemiacetal C−O linkage.2 The
main feature of C-glycosides is their resistance toward
hydrolysis: the C−C bond linking the sugar residue to the
aglycone is stable even upon acid treatment, and it is only
cleaved under harsh conditions.3 Because of their enhanced
stability toward enzymatic and chemical hydrolysis when
compared to the O-glycosides, C-glycosides are of great value
in medicinal chemistry. C-Glycosides are relatively rare in the
literature, probably because of the difficulties encountered in
their preparation. Several aromatic ring systems are known to
be C-glycosylated,4 and on account of their biological relevance,
we became interested in the preparation of chiral enantiopure
C-glycosylated chromene derivatives.
A direct procedure involving the nitroaldol condensation of
aldehydes with bromonitromethane in the presence of tri-n-
butylarsine was described some years ago.11 However, the
method appears to work with aromatic aldehydes only.
However, a fully heterogeneous synthetic approach for the
preparation of gem-bromonitroalkenes was described recently.12
Nevertheless, the procedure has proven to be problematic in
our hands for the preparation of some carbohydrate-based
Chromenes and their derivatives belong to an important
family of heterocycles that are widespread in plants5 and
possess a wide range of biological properties.6 Of particular
relevance are the 3-nitro-2H-chromenes because of their
potential uses as pesticides, endothelin-A (ETA)-selective
receptor antagonists, inhibitors of the proliferation of cancer
cells, highly potent antihypertensive drugs, and important
intermediates in the synthesis of medicinally active 2H-
benzopyrans.7 3-Nitro-2H-chromenes can be readily prepared
from 2-hydroxybenzaldehydes and 2-nitroethylene,8 but these
procedures are somewhat limited in terms of yield and substrate
Received: October 13, 2013
Published: November 26, 2013
© 2013 American Chemical Society
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Note
Scheme 1. Synthesis of Sugar-Based gem-Bromonitroalkenes 3 through a NaI-Catalyzed Bromonitromethane Addition/
Dehydration Protocol
derivatives, probably because of the incompatibility between the
acidic conditions used for the dehydration step and the
protective groups of the common carbohydrate building blocks.
We previously reported the use of bromonitromethane and
sugar aldimines for the synthesis of sugar-derived bromonitro-
amines.13 On the basis of these results, we performed a new
synthesis of sugar-derived gem-bromonitroalkenes through a
sodium iodide-catalyzed reaction of bromonitromethane and
sugar aldehydes14 followed by dehydration of the resulting 2-
bromo-2-nitroalkanols.
Table 1. Synthesis of Sugar-Based gem-Bromonitroalkenes 3
The initial reactions were performed on the sugar aldehyde
derived from galactose 1a. Treatment of a solution of
bromonitromethane (1.0 equiv) and the galactose-derived
aldehyde 1a (1.0 equiv) in THF with a catalytic amount NaI
(0.15 equiv) at room temperature afforded the corresponding
gem-bromonitrosugar 2a in an 83:17:0:0 diastereomeric ratio.
Crude reaction product 2a was reasonably pure after aqueous
workup and was used in the following elimination step without
the need for purification by column chromatography. We
assessed several reagents (such as Ac2O/DMAP,15 DCC,16 and
MsCl/NEt317) for the dehydration reaction on 2a. The best
results in terms of yield and cleanliness of the crude product
were obtained upon treating a solution of bromonitroalkanol 2a
(1.0 mmol) in CH2Cl2 (1.0 mL) and NEt3 (4.0 equiv) at 0 °C
with MsCl (3.0 equiv) and stirring the resulting mixture at
room temperature for 1 h. Under these conditions, (Z)-1-
bromo-1-nitroalkene 3a was obtained as a single stereoisomer
in 98% yield (Scheme 1). The (Z) configuration could be
inferred from the low field observed for the resonance of the
ethylenic protons (7.67 ppm) and is in agreement with
previous results on the synthesis of sugar-derived gem-
bromonitroalkenes.10d,e
a
The isolated yield of pure compounds 3 after column chromatog-
raphy is based on sugar aldehydes 1a−d.
dihydro-4-hydroxy-3-nitro-2H-1-benzopyran 5a in good yield
and with excellent diastereoselectivity; of the four possible
diastereomers, only the one with the relative (2S*,3S*,4S*)
configuration was obtained (Table 2, entry 1). The scope of the
process was investigated with a series of substituted o-
hydroxybenzaldehydes 4b−d, and these afforded 3-bromo-3,4-
dihydro-4-hydroxy-3-nitro-2H-1-benzopyrans 5b−d in good
yields and with >99% de (Table 2, entries 2−4). Reaction of
(Z)-4-(2-bromo-2-nitrovinyl)-1,2-dimethoxybenzene 3g and
salicylaldehyde 4a also yielded the corresponding 2H-1-
benzopyran 5e, albeit in a lower yield (Table 2, entry 5).
Taking into account these satisfactory results, the methodology
was extended to the reaction of sugar-derived bromonitroal-
kenes and o-hydroxybenzaldehydes with enantiopure
(2S,3S,4S)-3-bromo-3,4-dihydro-4-hydroxy-3-nitro-2H-1-ben-
zopyrans 5f−i obtained in good yields in all cases (Table 2,
entries 6−9).
The structures of 2H-benzopyrans 5 were established on the
basis of 1H and 13C NMR spectroscopic analysis and confirmed
by X-ray crystallography by examining 5i as a representative of
this class of compounds. (Figure S1−S3 in the Supporting
Information).19
The formation of enantiopure sugar (2S,3S,4S)-2H-1-
benzopyrans as single isomers can be explained on the basis
of a Felkin−Ahn/Michael addition of the alkoxide derived from
the o-hydroxybenzaldehyde to the nitroalkene. This step is
followed by an intramolecular Henry addition of the
bromonitronate to the aldehyde group to give the more
These reaction conditions were used to explore the scope of
this new stereoselective synthesis of gem-bromonitroalkenes 3
(Table 1).
Analysis of the results compiled in Table 1 (entries 1−4)
indicates the following: (a) the synthesis of gem-bromoni-
troalkenes 3 took place efficiently (87−92% yield) and with
total stereoselectivity (Z/E > 98:2), (b) this process tolerates a
broad scope of sugar-based aldehydes 1a−d bearing different
hydroxyl protecting groups, and (c) all reactions occurred
without epimerization of any stereogenic atom on the sugar
moiety.
Once we had achieved easy access to sugar-derived gem-
bromonitroalkenes, we pursued a tandem Michael/Henry
reaction between these molecules and o-hydroxybenzaldehydes
and gem-bromonitroalkenes to afford the corresponding 2H-
benzopyrans.18 To identify the optimal conditions, we first
investigated the reaction of (Z)-(2-bromo-2-nitrovinyl)benzene
3f with salicylaldehyde 4a. Thus, the reaction of alkene 3f (1
equiv) with an excess of salicylaldehyde 4a (5.0 equiv) and
catalytic NEt3 (0.5 equiv) in THF afforded 3-bromo-3,4-
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Note
Table 2. Reactions of (Z)-gem-Bromonitroalkenes 3 and
o‑Hydroxybenzaldehydes 4
Table 3. SmI2-Mediated β-Elimination Reaction of
Benzopyrans 5 to Afford 3-Nitro-2H-chromenes 6
a
Isolated yield after column chromatography.
a
Aromatic gem-bromonitroalkenes 3f and 3g were synthesized
We hypothesize that the generation of 3-nitrochromenes 6
proceeds through a β-elimination process controlled by
chelation (Scheme 2).22 Thus, metalation and removal of the
according to a literature procedure.10 The isolated yield after column
b
chromatography is based on bromonitroalkanes 3.
Scheme 2. Mechanistic Proposal
thermodynamically favored product (Figure S4 in Supporting
Information).
We subsequently envisioned the synthesis of 3-nitro-
chromenes by SmI2-mediated β-elimination on the intermedi-
ate benzopyrans 5. SmI2 has been widely employed to promote
β-elimination reactions with high or total stereoselectivity.20
We previously described the synthesis of nitroalkenes from 1-
bromo-1-nitroalkan-2-ols under mild conditions by means of a
samarium-promoted elimination,21 but this procedure has not
been applied to either sugar derivatives or cyclic systems. The
synthetic possibility of preparing 3-nitrochromenes by means of
a SmI2-promoted β-elimination reaction was investigated by
attempting the elimination of racemic benzopyrans 5a−e to the
corresponding 3-nitrochromenes. Accordingly, treatment of a
solution of the corresponding benzopyran 5 (1.0 equiv) in
THF with a 0.1 M solution of SmI2 in THF (2.5 equiv) at room
temperature for 2 h gave rise to 3-nitrochromenes 6a−d in
yields of 88−91% (Table 3, entries 1−4). Crude reaction
products were obtained with high purity after an aqueous
workup.
The satisfactory results obtained in the synthesis of racemic
3-nitrochromenes 6a−d prompted us to assess the utility of this
methodology for the synthesis of optically active sugar-derived
3-nitrochromenes. These studies were carried out on
benzopyrans 5f−i, which reacted with SmI2 in THF (2.5
equiv, 0.1 M) to provide the corresponding enantiopure 3-
nitrochromenes 6e−g (Table 3, entries 5−7). Compounds 6e
and 6g were isolated in high yield and with high purity (Table
3, entries 5 and 7), whereas compound 6f, arising from nitro-
substituted benzopyran 5g, was isolated in moderate yield
(Table 3, entry 6).
bromine atom by samarium diiodide would generate nitronate
intermediate 7. Chelation of the oxophilic SmIII center with the
oxygen atom of the alcohol group23 would produce six-
membered ring 8 in which the ability of the hydroxyl group to
function as a leaving group would be increased. Consequently, a
β-elimination process from 8 would afford 3-nitrochromenes 6.
In conclusion, we have developed a procedure for the
synthesis of carbohydrate-based (Z)-1-bromo-1-nitroalkenes 3
in good yields and with excellent selectivity. Compounds 3
were reacted with o-hydroxybenzaldehydes to yield selectively
(2S,3S,4S)-3-bromo-3,4-dihydro-4-hydroxy-3-nitro-2H-1-ben-
zopyrans 5. A SmI2-promoted β-elimination reaction of the
corresponding 3-bromo-3,4-dihydro-4-hydroxy-3-nitro-2H-1-
benzopyrans 5 allowed novel access to enantiopure 2-C-
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Note
salicylaldehyde 4a (0.7 mL) in THF (1 mL). After stirring the
reaction mixture at room temperature for 16 h, the solvents were
removed under reduced pressure (0.7 Torr, 45 °C). The residue was
purified by flash column chromatography in mixtures of ethyl acetate/
hexane or dichloromethane/hexane affording products 5a, 5e, 5f, and
5i.
3-Bromo-3,4-dihydro-4-hydroxy-3-nitro-2-phenyl-2H-1-benzo-
pyran (5a). Yellow oil, yield 88% (0.15 g). 1H NMR (300 MHz,
CDCl3): δ 7.58−7.54 (m, 1H), 7.49−7.31 (m, 6H), 7.15−7.10 (m,
1H), 7.01 (dd, J = 1.0, 8.2 Hz, 1H), 5.88 (d, J = 12.1 Hz, 1H), 5.63 (s,
1H), 2.58 (d, J = 12.1 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 152.3,
132.0, 130.8, 130.5, 128.8, 128.2, 127.2, 123.1, 123.0, 117.1, 109.0,
80.7, 74.5. MS (ESI+-TOF, m/z, %): 350 ([M + H]+, 70). HRMS
(ESI+-TOF) calcd for C15H13BrNO4 [M + H]+, 350.0022; found,
350.0045. Rf = 0.61 (CH2Cl2).
glycosyl-3-nitrochromenes 6. To the best of our knowledge,
this strategy constitutes the first approach to this type of 3-
nitrochromene and also involves a series of novel processes that
are of broad interest to synthetic organic chemists.
EXPERIMENTAL SECTION
■
General Procedure for the Preparation of (Z)-gem-Bromoni-
troalkenes 3. NaI (0.12 mmol, 0.15 equiv) was added to a stirred
solution of bromonitromethane (0.8 mmol, 1 equiv) and the
corresponding aldehyde 1 (0.8 mmol, 1 equiv) in THF (10 mL).
The reaction mixture was stirred at room temperature for 5 h. After
this period, the mixture was quenched with aqueous HCl (10 mL, 0.1
M) before the organic material was extracted with diethyl ether. The
combined extracts were washed with an aqueous saturated solution of
Na2S2O3 and dried over Na2SO4, and the solvent was removed under
reduced pressure, affording crude 1-bromo-1-nitroalkan-2-ols. MsCl
(0.05 mL, 0.6 mmol) was added dropwise to a stirred solution of the
1-bromo-1-nitroalkan-2-ol (0.2 mmol) and Et3N (0.12 mL, 0.8 mmol)
in THF (1 mL). After stirring the reaction mixture at room
temperature for 1 h, it was filtered (Celite), and the filtrate was
evaporated in vacuo. The residue was dissolved in CH2Cl2 and washed
with aqueous saturated solution of NaHCO3, water, and brine. The
organic material was then dried over Na2SO4, and the solvent was
removed under reduced pressure. The residue was purified by column
chromatography in mixtures of ethyl acetate/hexane, affording
products 3a−d.
3-Bromo-3,4-dihydro-4-hydroxy-3-nitro-2-(3,4-dimethoxyphen-
1
yl)-2H-1-benzopyran (5e). Yellow oil, yield 43% (0.09 g). H NMR
(300 MHz, CDCl3): δ 7.58−7.55 (m, 1H), 7.36−7.33 (m, 1H), 7.13−
6.96 (m, 4H), 6.84 (d, J = 8.4 Hz, 1H), 5.87 (d, J = 11.2 Hz, 1H), 5.29
(s, 1H), 3.90 (s, 3H), 3.88 (s, 3H). 13C NMR (75 MHz, CDCl3): δ
152.5, 148.9, 147.1, 131.9, 131.0, 130.3, 128.6, 127.8, 127.4, 124.0,
123.5, 115.9, 109.4, 80.8, 75.6. MS (ESI+-TOF, m/z, %): 410 ([M +
H]+, 90). HRMS (ESI+-TOF) calcd for C17H17BrNO6 [M + H]+,
410.0234; found, 410.0250. Rf = 0.32 (CH2Cl2).
3-Bromo-3,4-dihydro-4-hydroxy-3-nitro-2-[1,2:3,4-di-O-isopropy-
liden-β-L-arabinopyranosid-5-yl]-2H-1-benzopyran (5f). Clear oil,
[α]2D0 −4.9° (c 1.5, CHCl3), yield 95% (0.24 g). H NMR (300 MHz,
1
(Z)-7-Bromo-6,7-dideoxy-1,2:3,4-di-O-isopropyliden-7-nitro-β-D-
galacto-hept-6-enopyranose (3a). White solid, mp 148−150 °C
(Et2O/Hex), [α]2D0 −8.3° (c 1.2, CHCl3), yield 92% (0.28 g). 1H NMR
(300 MHz, CDCl3): δ 7.67 (d, J = 7.7 Hz, 1H), 5.55 (d, J = 5.0 Hz,
1H, H-1), 4.71−4.66 (m, 2H), 4.41−4.35 (m, 2H) 1.60 (s, 3H), 1.49
(s, 3H), 1.36 (s, 3H), 1.34 (s, 3H). 13C NMR (75 MHz, CDCl3): δ
137.0, 130.6, 110.1, 109.2, 96.1, 71.4, 70.6, 69.9, 68.3, 26.0, 25.8, 24.8,
24.2. MS (ESI+-TOF, m/z, %): 402 ([M + Na]+, 92), 380 ([M + H]+,
29). HRMS (ESI+-TOF) calcd for C13H18BrNaNO7 [M + Na]+,
402.01674; found, 402.01589. Rf 0.35 (hexane/EtOAc 6:1).
CDCl3): δ 7.49 (d, J = 7.7 Hz, 1H), 7.31−7.25 (m, 1H), 7.08−7.03
(m, 1H), 6.90 (dd, J = 0.8, 8.3 Hz, 1H), 5.59 (d, J = 11.4 Hz, 1H), 5.40
(d, J = 5.0 Hz, 1H), 5.09 (d, J = 8.7 Hz, 1H), 4.70 (dd, J = 2.7, 7.8 Hz,
1H), 4.56 (dd, J = 1.9, 7.8 Hz, 1H), 4.33 (dd, J = 2.7, 5.0 Hz, 1H), 4.22
(dd, J = 1.9, 8.7 Hz, 1H), 2.96 (d, J = 11.4 Hz, 1H), 1.63 (s, 3H), 1.44
(s, 3H), 1.38 (s, 3H), 1.33 (s, 3H). 13C NMR (75 MHz, CDCl3): δ
155.5, 145.2, 125.6, 123.8, 123.2, 117.1, 110.1, 109.5, 102.7, 95.8, 76.4,
73.1, 70.4, 70.2, 70.0, 68.1, 60.6, 25.8, 25.8, 24.7, 24.6. MS (ESI+-TOF,
m/z, %): 503 ([M + 2H]+, 28). HRMS (ESI+-TOF) calcd for
C20H25BrNO9 [M + 2H]+, 503.07936; found, 503.07855. Rf = 0.41
(hexane/EtOAc 5:1).
(Z)-3-O-Benzyl-6-bromo-5,6-dideoxy-1,2-O-isopropyliden-6-
nitro-α-D-xylo-hex-5-enofuranose (3b). White solid, mp 75−77 °C
3-Bromo-3,4-dihydro-4-hydroxy-8-methoxy-3-nitro-2-[3-O-
methyl-1,2-O-isopropyliden-β-L-threofuranosid-4-yl]-2H-1-benzo-
pyran (5i). Colorless oil, [α]2D0 −2.9° (c 0.9, CHCl3), yield 87% (0.19
(Et2O/Hex), [α]2D0 −10.7° (c 1.1, CHCl3), yield 91% (0.29 g). H
1
NMR (300 MHz, CDCl3): δ 7.75 (d, J = 6.9 Hz, 1H), 7.33−7.21 (m,
5H), 6.05 (d, J = 3.4 Hz, 1H), 4.88 (dd, J = 3.4, 6.9 Hz, 1H), 4.68−
4.65 (m, 2H), 4.42 (d, J = 12.1 Hz, 1H), 4.20 (d, J = 3.4 Hz, 1H), 1.52
(s, 3H), 1.35 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 137.0, 130.0,
128.4, 128.2, 127.8, 112.2, 105.4, 82.3, 82.1, 79.2, 72.2, 26.7, 26.0. MS
(ESI+-TOF, m/z, %): 424 (100), 422 ([M + Na]+, 96). HRMS (ESI+-
TOF) calcd for C16H18BrNO6 [M + Na]+, 422.02166; found,
422.02097. Rf 0.28 (hexane/EtOAc 7:1).
1
g). H NMR (300 MHz, CDCl3): δ 7.32−6.82 (m, 8H), 5.85 (d, J =
3.0 Hz, 1H), 5.64 (d, J = 11.5 Hz, 1H), 5.00 (d, J = 8.6 Hz, 1H), 4.70−
4.64 (m, 3H), 4.51−4.50 (m, 1H), 4.35−4.32 (m, 1H), 3.83 (s, 3H),
2.89 (bs, 1H), 1.42 (s, 3H), 1.26 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 147.7, 140.2, 137.5, 128.4, 127.9, 127.8 2, 123.6, 122.5,
117.9, 112.4, 112.1, 105.7, 105.6, 82.2, 81.8, 79.2, 75.6, 73.8, 73.1, 55.9,
27.0, 26.5. MS (ESI+-TOF, m/z, %): 552 ([M + H]+, 100). HRMS
(ESI+-TOF) calcd for C24H27BrNO9 [M + H]+, 552.08700; found,
552.08637. Rf = 0.28 (hexane/EtOAc 3:1).
(Z)-6-Bromo-1-O-tert-butyldimethylsilyl-5,6-dideoxy-2,3-O-iso-
propyliden-6-nitro-α-D-xylo-hex-5-enofuranose (3c). Colorless oil,
[α]2D0 −1.9° (c 0.7, CHCl3), yield 87% (0.29 g). H NMR (300 MHz,
1
Method B, for o-Hydroxybenzaldehydes 4b−d. The correspond-
ing gem-bromonitroalkene 3 (0.5 mmol) and o-hydroxybenzaldehyde
4b−d (2.75 mmol) were dissolved in THF (1 mL). Et3N (0.04 mL)
was added, and the resulting solution was stirred at room temperature
for 16 h. Removal of the solvents (0.7 Torr, 45 °C) left a residue,
which was taken up with a lukewarm (50 °C) solution of Girard
reagent T (prepared by dissolving 0.45 g of the reagent in 4 mL of a
mixture of EtOH/H2O/AcOH 8:1:1). This mixture was stirred for 2 h,
diluted with H2O (40 mL), and extracted with CH2Cl2 (2 × 80 mL).
The combined organic extracts were dried over Na2SO4, filtered, and
concentrated in vacuo to give a residue that was purified by flash
column chromatography in mixtures of ethyl acetate/hexane or
dichloromethane/hexane affording products 5b−d and 5g−h.
3-Bromo-3,4-dihydro-4-hydroxy-3,5-dinitro-2-phenyl-2H-1-ben-
zopyran (5b). White solid, mp 161−165 °C (CHCl3), yield 72% (0.14
g). 1H NMR (300 MHz, CDCl3): δ 8.54 (dd, J = 2.7 and 1.1 Hz, 1H),
8.27−8.23 (m, 1H), 7.49−7.42 (m, 5H), 7.15 (d, J = 9.0 Hz, 1H), 5.94
(d, J = 11.7 Hz, 1H), 5.80 (s, 1H), 2.73 (d, J = 11.7 Hz, 1H). 13C
NMR (75 MHz, acetone-d6): δ 158.1, 143.4, 132.7, 131.0, 129.1,
128.9, 126.4, 126.2, 124.2, 118.1, 107.2, 81.5, 74.1, 56.1. MS (ESI+-
CDCl3): δ 7.69 (d, J = 7.3 Hz, 1H), 5.40 (s, 1H), 4.97−4.94 (m, 1H),
4.82−4.79 (m, 2H), 4.60 (d, J = 5.6 Hz, 1H), 1.46 (s, 3H), 1.29 (s,
3H), 0.89 (s, 9H), 0.13 (s, 3H), 0.11 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 136.3, 131.0, 113.2, 102.0, 86.8, 80.7, 78.6, 26.0, 25.6, 24.7,
17.7, −4.5, −5.4. MS (ESI+-TOF, m/z, %): 424 ([M + H]+, 100).
HRMS (ESI+-TOF) calcd for C15H27BrNO6Si [M + H]+, 424.07876;
found, 424.07855. Rf = 0.26 (hexane/EtOAc 2:19).
(Z)-1-Bromo-1-nitro-1,2-dideoxy-3,4:5,6-di-O-isopropylidene-L-
xylo-hex-1-enitol (3d). [α]D20 −1.1° (c 1.2, CHCl3), yield 92% (0.26
g). 1H NMR (300 MHz, CDCl3): δ 7.56 (d, J = 8.7 Hz, 1H); 4.69 (dd,
J = 7.1, 8.7 Hz, 1H), 4.17−4.10 (m, 2H), 3.99−3.86 (m, 2H), 1.45 (s,
6H), 1.33 (s, 3H), 1.32 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 136.1,
133.2, 111.7, 110.6, 109.9, 81.0, 77.8, 76.1, 67.3, 27.0, 26.8, 26.7, 25.0.
MS (ESI+-TOF, m/z, %): 352 ([M + H]+, 100). HRMS (ESI+-TOF)
calcd for C12H19BrNO6 [M + H]+, 352.03879; found, 352.03903. Rf =
0.31 (hexane/EtOAc 8:1).
General Procedure for the Preparation of 3-Bromo-3,4-
dihydro-4-hydroxy-3-nitro-2H-1-benzopyrans 5. Method A, for
Salicylaldehyde 4a. Et3N (0.04 mL) was added to a stirred solution of
the corresponding gem-bromonitroalkene 3 (0.5 mmol) and
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The Journal of Organic Chemistry
Note
TOF, m/z, %): 395 ([M + H]+, 100). HRMS (ESI+-TOF) calcd for
C15H12BrN2O6 [M + H]+, 394.98809; found, 394.98809. Rf = 0.32
(CH2Cl2).
133.7, 129.6, 129.3, 128.9, 127.9, 126.9, 119.1, 118.6, 74.3. MS (ESI+-
TOF, m/z, %): 288 ([M + H]+, 100). HRMS (ESI+-TOF) calcd for
C15H11ClNO3 [M + H]+, 288.04220; found, 288.04248. Rf = 0.31
(hexane/EtOAc 5:1).
3-Bromo-5-chloro-3,4-dihydro-4-hydroxy-3-nitro-2-phenyl-2H-1-
benzopyran (5c). White solid, mp 163−166 °C (CHCl3), yield 75%
8-Methoxy-3-nitro-2-phenyl-2H-chromene (6c). Orange solid, mp
123−126 °C (CHCl3), yield 91% (0.13 g). 1H NMR (300 MHz,
CDCl3): δ 8.00 (s, 1H), 7.40−7.37 (m, 2H), 7.30−7.27 (m, 3H),
6.92−6.91 (m, 3H), 6.65 (s, 1H), 3.76 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 148.4, 142.5, 141.2, 136.5, 129.3, 129.2, 128.6, 126.8, 122.1,
122.0, 118.6, 116.6, 74.0, 56.1. MS (ESI+-TOF, m/z, %): 285 ([M +
H]+, 100). HRMS (ESI+-TOF) calcd for C16H14NO4 [M + H]+,
284.09272; found, 284.09173. Rf = 0.32 (hexane/EtOAc 5:1).
3-Nitro-2-(3,4-dimethoxyphenyl)-2H-chromene (6d). Orange oil,
1
(0.14 g). H NMR (300 MHz, CDCl3): δ 7.56 (dd, J = 1.1, 2.5 Hz,
1H), 7.48−7.38 (m, 5H), 7.29 (ddd, J = = 0.7, 2.5, 8.8, Hz, 1H), 6.96
(d, J = 8.8 Hz, 1H), 5.86 (d, J = 12.1 Hz, 1H), 5.64 (s, 1H), 2.54 (d, J
= 12.1 Hz, 1H). 13C NMR (75 MHz, acetone-d6): δ 151.8, 133.3,
130.8, 130.3, 129.0, 128.9, 127.6, 127.4, 126.8, 118.7, 108.2, 81.1, 74.4.
MS (ESI+-TOF, m/z, %): 241 (100), 405 ([M + Na]+, 31). HRMS
(ESI+-TOF) calcd for C15H11BrClNaNO4 [M + H]+, 405.94534;
found, 405.94522. Rf = 0.47 (CH2Cl2).
1
yield 88% (0.14 g). H NMR (300 MHz, CDCl3): δ 8.05 (s, 1H),
3-Bromo-3,4-dihydro-4-hydroxy-8-methoxy-3-nitro-2-phenyl-
2H-1-benzopyran (5d). White solid, mp 145−148 °C (CHCl3), yield
7.34−7.26 (m, 2H), 7.02−6.97 (m, 1H), 6.93 (d, J = 2.1 Hz, 1H),
6.88−6.84 (m, 2H), 6.75 (d, J = 8.3 Hz, 1H), 6.52 (s, 1H), 3.82 (s,
6H). 13C NMR (75 MHz, CDCl3): δ 153.4, 149.9, 149.1, 141.2, 134.2,
130.3, 129.1, 129.1, 122.4, 119.3, 118.0, 117.3, 110.8, 110.4, 74.1, 55.8,
55.8. MS (ESI+-TOF, m/z, %): 314 ([M + H]+, 100). HRMS (ESI+-
TOF) calcd for C17H16NO5 [M + H]+, 314.10181; found, 314.10230.
Rf = 0.42 (hexane/EtOAc 3:1).
3-Nitro-2-[1,2:3,4-di-O-isopropyliden-β-L-arabinopyranosid-5-yl]-
2H-chromene (6e). Yellow oil, [α]2D0 −0.6° (c 0.9, CHCl3), yield 82%
(0.16 g). 1H NMR (300 MHz, CDCl3): δ 7.84 (s, 1H), 7.38−7.27 (m,
2H), 7.06−7.00 (m, 2H), 6.05 (d, J = 9.2 Hz, 1H), 5.39 (d, J = 5.0 Hz,
1H), 4.61 (dd, J = 2.8,7.8 Hz, 1H), 4.36 (dd, J = 2.0, 7.8 Hz, 1H), 4.27
(dd, J = 2.8, 5.0 Hz, 1H), 4.01 (dd, J = 2.0, 9.2 Hz, 1H), 1.54 (s, 3H),
1.41 (s, 3H), 1.21 (s, 3H), 1.03 (s, 3H). 13C NMR (75 MHz, CDCl3):
δ 153.0, 141.5, 133.5, 130.1, 127.1, 122.9, 118.5, 117.0, 110.3, 108.8,
96.4, 70.6, 70.5, 70.1, 68.8, 66.5, 26.0, 25.2, 25.0, 24.9. MS (ESI+-TOF,
m/z, %): 406 ([M + H]+, 100). HRMS (ESI+-TOF) calcd for
C20H24NO8 [M + H]+, 406.14915; found, 406.14964. Rf = 0.28
(hexane/EtOAc 5:1).
1
63% (0.12 g). H NMR (300 MHz, CDCl3): δ 7.36−7.53 (m, 5H),
7.15−7.19 (m, 1H), 7.08 (t, J = 8.0 Hz, 1H), 6.94 (dd, J = 1.2, 8.0 Hz,
1H), 5.80 (d, J = 12.3 Hz, 1H), 5.66 (s, 1H), 3.88 (s, 3H), 2.45 (d, J =
12.3 Hz, 1H). 13C NMR (75 MHz, acetone-d6): δ 148.9, 142.5, 133.7,
130.6, 129.0, 128.9, 125.6, 126.5, 119.1, 112.8, 109.0, 80.9, 74.9, 56.2.
MS (ESI+-TOF, m/z, %): 380 ([M + H]+, 65). HRMS (ESI+-TOF)
calcd for C16H15BrNO5 [M + H]+, 380.01307; found, 380.01281. Rf =
0.55 (CH2Cl2).
3-Bromo-3,4-dihydro-4-hydroxy-3,5-dinitro-2-[1,2:3,4-di-O-iso-
propyliden-β-L-arabinopyranosid-5-yl]-2H-1-benzopyran (5g). Yel-
low oil, yield 91% (0.25 g). 1H NMR (300 MHz, CDCl3): δ 8.45 (dd, J
= 1.0, 2.7 Hz, 1H), 8.17 (dd, J = 2.4, 8.7 Hz, 1H), 7.04 (d, J = 9.1 Hz,
1H), 5.66 (d, J = 9.3 Hz, 1H), 5.41 (d, J = 4.9 Hz, 1H), 5.24 (d, J = 8.7
Hz, 1H), 4.73 (dd, J = 2.7, 7.8 Hz, 1H), 4.55 (dd, J = 1.9, 7.8 Hz, 1H),
4.36 (dd, J = 2.7, 4.9 Hz, 1H), 4.25 (dd, J = 1.9, 8.7 Hz, 1H), 3.87 (s,
3H), 1.63 (s, 3H), 1.45 (s, 3H), 1.39 (s, 3H), 1.34 (s, 3H). 13C NMR
(75 MHz, CDCl3): δ 155.5, 145.2, 125.6, 123.8, 123.2, 117.1, 110.1,
109.5, 102.7, 95.8, 76.4, 73.1, 70.4, 70.2, 70.0, 68.1, 60.6, 25.8, 25.8,
24.7, 24.6. MS (ESI+-TOF, m/z, %): 547 ([M + H]+, 60). HRMS
(ESI+-TOF) calcd for C20H24BrN2O11 [M + H]+, 547.0558; found,
547.0564. Rf = 0.35 (hexane/EtOAc 3:1).
3,5-Dinitro-2-[1,2:3,4-di-O-isopropyliden-β-L-arabinopyranosid-
5-yl]-2H-chromene (6f). Yellow oil, [α]2D0 −3.3° (c 0.8, CHCl3), yield
1
45% (0.10 g). H NMR (300 MHz, CDCl3): δ 8.26−8.23 (m, 2H),
7.82 (s, 1H), 7.10 (d, J = 10.0 Hz, 1H), 6.17 (d, J = 7.8 Hz, 1H), 5.37
(d, J = 4.9 Hz, 1H), 4.61 (dd, J = 2.6, 7.8 Hz, 1H), 4.32 (dd, J = 1.8,
7.7 Hz, 1H), 4.28−4.26 (m, 1H), 4.01 (dd, J = 1.8, 7.7 Hz, 1H), 1.48
(s, 3H), 1.36 (s, 3H), 1.23 (s, 3H), 1.18 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 158.2, 142.7, 142.5, 128.5, 125.2, 118.7, 117.3, 110.4, 109.0,
96.3, 70.8, 70.7, 70.5, 69.9, 68.2, 29.7, 25.8, 25.7, 24.8. MS (ESI+-TOF,
m/z, %): 451 ([M + H]+, 100). HRMS (ESI+-TOF) calcd for
C20H23N2O10 451.1347 [M + H]+, 451.13454; found, 451.13472. Rf =
0.28 (hexane/EtOAc 5:1).
3-Nitro-2-[3-O-methyl-1,2-O-isopropyliden-β-L-threofuranosid-4-
yl]-2H-chromene (6g). Yellow oil, [α]2D0 −5.7° (c 1.4, CHCl3), yield
85% (0.15 g). 1H NMR (300 MHz, CDCl3): δ 7.83 (s, 1H), 7.39−7.27
(m, 2H), 7.05−7.00 (m, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.12 (d, J = 8.8
Hz, 1H), 5.83 (d, J = 3.7 Hz, 1H), 4.57 (d, J = 3.7 Hz, 1H), 4.42 (dd, J
= 3.3, 8.8 Hz, 1H), 3.80 (d, J = 3.3 Hz, 1H), 3.52 (s, 3H), 1.33 (s, 3H),
1.26 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 153.1, 140.4, 133.7,
130.5, 128.4, 122.8, 118.1, 116.6, 118.8, 105.0, 82.9, 81.4, 78.6, 67.9,
58.2, 26.6, 25.9. MS (ESI+-TOF, m/z, %): 350 ([M + H]+, 100).
HRMS (ESI+-TOF) calcd for C17H20NO7 [M + H]+, 350.12427;
found, 350.12343. Rf 0.30 (hexane/EtOAc 5:1).
3-Bromo-3,4-dihydro-4-hydroxy-3-nitro-2-[3-O-methyl-1,2-O-iso-
propyliden-β-L-threofuranosid-4-yl]-2H-1-benzopyran (5h). White
solid, mp 219−222 °C (Et2O/Hex), [α]2D0 −5.0° (c 0.8, CHCl3),
1
yield 74% (0.20 g). H NMR (300 MHz, CDCl3): δ 7.52 (d, J = 7.7
Hz, 1H), 7.33−7.29 (m, 1H), 7.11−7.06 (m, 1H), 5.83 (d, J = 3.6 Hz,
1H), 5.62 (d, J = 12.1 Hz, 1H), 5.04 (d, J = 8.7 Hz, 1H), 4.56−4.54
(m, 1H), 4.51 (d, J = 3.0 Hz, 1H), 4.00 (d, J = 3.0 Hz, 1H), 2.42 (d, J
= 12.1 Hz, 1H), 3.47 (s, 3H), 1.51 (s, 3H), 1.32 (s, 3H). 13C NMR (75
MHz, CDCl3): δ 150.6, 130.3, 126.5, 122.5, 122.5, 116.0, 112.4, 105.6,
83.5, 80.9, 79.0, 74.9, 73.8, 58.4, 27.0, 26.4. MS (ESI+-TOF, m/z, %):
468 ([M + Na]+, 100). HRMS (ESI+-TOF) calcd for C17H20BrNaNO8
[M + Na]+, 468.02603; found, 468.02645. Rf = 0.30 (hexane/EtOAc
2:1).
General Procedure for the Preparation of 3-Nitrochromenes
6. A solution of SmI2 in 0.1 M in THF (1 mmol) was added to a
stirred solution of the 2H-benzopyran 5a−g or 5i (0.4 mmol) in THF
(4 mL), and the reaction mixture was stirred at room temperature for
2 h. An aqueous solution of 0.1 M HCl was then added, and the
resulting mixture was extracted with CH2Cl2 (3 × 5 mL). The
combined organic extracts were dried over Na2SO4, filtered, and
concentrated in vacuo to give a residue that was purified by flash
column chromatography in mixtures of ethyl acetate/hexane, affording
products 6a−h.
ASSOCIATED CONTENT
* Supporting Information
■
S
1H and 13C NMR spectra for compounds 3, 5, and 6. Single-
crystal structure solution and refinement details for compound
5i. Supramolecular contacts present in the crystal structure of
compound 5i. This material is available free of charge via the
Internet at http://pubs.acs.org.
3-Nitro-2-phenyl-2H-chromene (6a). Yellow oil, yield 88% (0.11
g). 1H NMR (300 MHz, CDCl3): δ 8.04 (s, 1H), 7.38−7.24 (m, 7H),
7.00−6.95 (m, 1H), 6.86−6.83 (m, 1H), 6.57 (s 1H). 13C NMR (75
MHz, CDCl3): δ 153.5, 141.1, 136.7, 134.2, 130.4, 129.4, 129.2, 128.7,
127.0, 122.5, 117.8, 117.2, 74.2. MS (ESI+-TOF, m/z, %): 254 ([M +
H]+, 100). Rf = 0.31 (hexane/EtOAc 5:1).
5-Chloro-3-nitro-2-phenyl-2H-chromene (6b). Yellow solid, mp
115−119 °C (CHCl3), yield 90% (0.13 g). 1H NMR (300 MHz,
CDCl3): δ 7.94 (s, 1H), 7.35−7.29 (m, 4H), 7.27 (d, J = 2.7 Hz, 1H),
7.24−7.23 (m, 1H), 7.21 (d, J = 2.5 Hz, 1H), 6.78 (d, J = 8.7 Hz, 1H),
6.56 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 151.8, 141.9, 136.1,
AUTHOR INFORMATION
Corresponding Authors
*E-mail: rsoengas@ua.pt (R.G.S.).
*E-mail: hrsolla@uniovi.es (H.R.-S.).
■
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The Journal of Organic Chemistry
Note
(12) Palmieri, A.; Gabrielli, S.; Ballini, R. Synlett 2013, 24, 114−116.
*E-mail: artur.silva@ua.pt (A.M.S.S.).
́
(13) Rodríguez-Solla, H.; Concellon, C.; Alvaredo, N.; Soengas, R. G.
Notes
Tetrahedron 2012, 68, 1736−1744.
́
(14) Concellon, J. M.; Rodríguez-Solla, H.; Concellon, C.; García-
The authors declare no competing financial interest.
́
Granda, S.; Díaz, M. R. Org. Lett. 2006, 8, 5979−5982.
(15) Dunny, E.; Evans, P. J. Org. Chem. 2010, 75, 5334−5336.
(16) Knochel, P.; Seebach, D. Synthesis 1982, 1017−1018.
ACKNOWLEDGMENTS
■
We thank the University of Aveiro, the Portuguese “Fundaca
̧
o
̃
(17) Melton, J.; McMurry, J. E. J. Org. Chem. 1975, 40, 2138−2139.
(18) Dauzonne, D.; Demerseman, P. Synthesis 1990, 66−70.
(19) C17H20BrNO8: Mw = 446.25 g mol−1, pink needle (0.18 × 0.08
× 0.02 mm3), orthorhombic, space group P212121, a = 9.8090(10) Å, b
= 10.7205(9) Å, c = 17.2919(16) Å, V = 1818.4(3) Å3, Z = 4,
Dc=1.630 g cm−3, μ (Mo Kα) = 2.307 mm−1, 45 489 reflections were
collected in the range 3.67° ≤ θ ≤ 29.12°, index ranges −13 ≤ h ≤ 13,
para a Cien
̂
cia e a Tecnologia” (FCT), the European Union
cia Estrategico Nacional” (QREN),
“Fundo Europeu de Desenvolvimento Regional” (FEDER), and
“Programa Operacional Tematico Factores de Competitivi-
(EU), “Quadro de Referen
̂
́
́
dade” (COMPETE), for funding the Organic Chemistry
Research Unit (project PEst-C/QUI/UI0062/2013), the
Associated Laboratory CICECO (Pest-C/CTM/LA0011/
−14 ≤ k ≤ 13, −23 ≤ l ≤ 23, of which 4876 were independent (Rint
=
0.0399), completeness to θ = 29.12° = 99.7%, final R1 ([I > 2σ(I)]) =
0.0269, wR2 ([I > 2σ(I)]) = 0.0606, R1 (all data) = 0.0316, wR2 (all
data) = 0.0624. Flack parameter = −0.008(6). CCDC 962788.
(20) Procter, D. J.; Flowers, R. A.; Skrysdtrup, T. Organic Synthesis
Using Samarium Diiodide: A Practical Guide; Royal Society of
Chemistry: Cambridge, UK, 2010.
́
2013), the Spanish Ministerio de Economıa y Competitividad
(CTQ2010-14959), and the Portuguese National NMR
Network (RNRMN). R.S. thanks the FCT for an “Investigador
Auxiliar” position. We further thank CICECO for specific
funding toward the purchase of the single-crystal X-ray
diffractometer.
(21) Concellon
C. J. Org. Chem. 2007, 72, 5421−5423.
(22) Concellon, J. M.; Rodríguez-Solla, H. Chem. Soc. Rev. 2004, 33,
599−609.
́ ́
, J. M.; Bernad, P. L.; Rodríguez-Solla, H.; Concellon,
́
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