Oxidative ring-opening of ferrocenylcyclopropylamines to N-ferrocenylmethyl β-hydroxyamides

Article abstract of DOI:10.1039/c5ob02577j

The in situ reduction of ferrocenyl cyclopropylimines to the corresponding amines triggers a facile oxidative ring-opening to yield the formal four-electron oxidation products: N-ferrocenylmethyl β-hydroxyamides. This process is believed to proceed via generation of a ferrocinium ion in the presence of air, leading to facile formation of a distonic radical cation that is ultimately trapped by oxygen.

Full text of DOI:10.1039/c5ob02577j

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Oxidative ring-opening of
ferrocenylcyclopropylamines to
Cite this: DOI: 10.1039/c5ob02577j
N-ferrocenylmethyl β-hydroxyamides†
Yi Sing Gee,‡a Neils J. M. Goertz,‡a Michael G. Gardinerb and
Christopher J. T. Hyland*a
Received 16th December 2015,
Accepted 20th January 2016
The in situ reduction of ferrocenyl cyclopropylimines to the corresponding amines triggers a facile oxi-
dative ring-opening to yield the formal four-electron oxidation products: N-ferrocenylmethyl β-hydro-
xyamides. This process is believed to proceed via generation of a ferrocinium ion in the presence of air,
leading to facile formation of a distonic radical cation that is ultimately trapped by oxygen.
DOI: 10.1039/c5ob02577j
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Introduction
Cyclopropylamines 1 are found in a broad variety of biologi-
cally active compounds, such as the antibiotics Ciprofloxacin,
Moxifloxacin,
Trovafloxacin
and
the
antidepressant
2-phenylcyclopropylamine (2-PCPA).1,2 Therefore, much atten-
tion has been paid to understanding the reactivity of these
important structures.3,4 Cyclopropylamines 1 can undergo
characteristic, irreversible ring-opening reactions via a single-
electron transfer mechanism to yield a distonic radical cation
2 (Scheme 1). This process is particularly important in biologi-
cal systems; for example, 2-PCPA inhibits monoamine oxidase
by flavin adenine dinucleotide (FAD) oxidation of the cyclo-
propylamine nitrogen and subsequent ring-opening to a
distonic radical cation similar to 2.5 The ability of cyclopropyl-
amines to undergo this ring-opening process has also seen
them used as tools for studying biological amine-oxidation.6,7
Given this widespread importance, several groups have studied
the ring-opening of cyclopropylamines initiated by single elec-
tron oxidation and subsequent reaction with oxygen
(Scheme 1). Endoperoxides 3 derived from aminocyclopro-
panes 1 have been prepared by aerobic electrochemical oxi-
dation8 as well as autocatalytic radical ring-opening under
aerobic conditions using an oxidising agent [(phen)3Fe(PF6)3]
or hydrogen-abstracting agents ((RO)2/UV) (Scheme 1).9 In the
latter case, excess peroxide can convert the endoperoxide into
Scheme 1 Previous work on ring-opening of cyclopropylamines
1
initiated by oxidation of amine nitrogen and subsequent reaction with
oxygen. Current study on the internal oxidation of ferrocenyl-amino-
cyclopropanes. Fc = ferrocene.
a simple β-hydroxyamide 4. Epoxy-ketones can also be formed
by CuCl2-catalysed oxygenation of 1-pyrrolidino[n,1,0]-bicy-
cloalkanes.10 It has also been shown that N-cyclopropylanilines
can undergo slow air oxidation under ambient conditions to
yield simple β-hydroxyamides 4.11 However, to date we are
unaware of any studies into the reactivity of organometallic
derivatives of cyclopropylamines.
aSchool of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia.
E-mail: chris_hyland@uow.edu.au
bSchool of Physical Sciences - Chemistry, University of Tasmania, Hobart, TAS 7001,
Australia
†Electronic supplementary information (ESI) available. CCDC 1434659. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c5ob02577j
Ferrocene (Fc) can undergo reversible oxidation and this
has rendered it important in bioorganometallic drugs, such as
‡These authors contributed equally to this paper.
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ferroquine12 and ferrocifens.13 In ferrocifens it is likely that
the active quinone methide form of the drug is only formed
following oxidation of the ferrocene to the ferrocinium ion. As
such, we postulated that cyclopropylamine-ferrocene conju-
gates could harness the redox ability of ferrocene to initiate
oxidative ring-opening processes in the presence of air.
Given the importance of both the ferrocene moiety and
cyclopropylamines in biological systems, understanding of
these ring-opening processes could provide important infor-
mation for the utilisation of organometallic derivatives of
cyclopropylamines in biological applications. Herein, we
describe the NaBH4 initiated oxidative ring-opening of ferroce-
nyl cyclopropylimines
5 to N-ferrocenylmethyl β-hydroxy-
amides 7 (Scheme 1). This is the first process where ferrocene
initiates an oxidative cyclopropane ring-opening, allowing syn-
thesis of a series of novel organometallic β-hydroxyamides.
Results and discussion
Scheme 3 Syntheses of 2-PCPA derivatives.
Work commenced with commercially available 2-PCPA, which
was transformed to imine 5a by condensation with ferrocene-
carboxyaldehyde. Upon reduction of this imine with stoichio-
metric sodium borohydride none of the amine 8a was
observed – instead the ring-opened and oxidised N-ferrocenyl-
methyl β-hydroxyamide product 7a was observed to form
rapidly (Scheme 2). The same product was formed when
Bu3SnH on silica gel was used as the reducing agent.
It is of note that unlike the previously reported electroche-
mical and autocatalytic ring-opening reactions no dioxolane
products were observed under these present conditions.
Following this intriguing result, a series of 2-PCPA ana-
logues were prepared (Scheme 3). The procedure originated
with cinnamic esters 9b–g, which were subjected to Corey–
Chaykovsky cyclopropanation to yield cyclopropanes 10b–g.
After basic hydrolysis, the carboxylic acids were converted to
2-PCPA analogues 11b–g by a Curtius rearrangement and de-
protection. These 2-PCPA analogues 11b–g were then subjected
to condensation with ferrocenecarboxaldehyde to yield imines
5b–g (Scheme 4). In all cases, treatment of these cyclopropyl-
amines with sodium borohydride, gave the ring-opened N-fer-
Scheme 4 Reductive amination of ferrocenecarboxaldehyde and
2-PCPA analogues 11a–g to yield N-ferrocenylmethyl β-hydroxyamides
7a–g. Molecular structure of 7d. Thermal ellipsoids are shown at the
50% probability level. All methine, methylene and aromatic-ring hydro-
gen atoms are omitted for clarity. Intra-/intermolecular H-bonding is
also not shown for clarity. The asymmetric unit contains another similar
molecule of 7d, featuring
a 120° rotation of the C(methylene)–
C(methine) bond to allow intramolecular H-bonding to the carbonyl
carbon (CvO⋯H–O).
rocenylmethyl β-hydroxyamides 7b–g (22–58% yield over two
steps from the amine salt). A range of differently substituted
aromatic groups, including ortho, meta and para substituents
could be tolerated. The structure of 7d was confirmed un-
ambiguously by X-ray crystallography (Scheme 4).
Scheme 2 Oxidative ring-opening of 5a initiated by treatment with
NaBH4.
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Mechanistically, it is proposed that the ferrocene moiety would appear more likely as no clear mechanism for gen-
plays a key role in the reaction, especially as the corresponding eration of RO• is apparent and our conditions are intrinsically
benzyl-derivatives have been reported to be air stable.14 Air- basic due to the presence of NaBH4.
generated ferrocinium ions have been recently utilised as the
The analogue 18 of 2-PCPA, where the phenyl ring is
terminal oxidant in asymmetric dehydrogenative Heck reac- replaced with ferrocene, also displays a strong propensity to
tions.15 Therefore, it is proposed the ferrocinium ion 12, gen- undergo these ferrocene-mediated ring-opening processes
erated in situ by air that acts as an internal oxidant to generate (Scheme 5). When carboxylic acid 17 was subjected to a
aminium radical 6 from cyclopropylamines 8, which are the Curtius rearrangement, enal 21 was observed instead of cyclo-
initial NaBH4 reduction products (Fig. 1). Cyclopropane ring- propylamine 18. The analogous cinnamaldehyde product has
opening of 6 then occurs exclusively by cleavage of the C1–C2 been reported to be obtained from the oxidation of 2-PCPA by
bond as this pathway gives the more stable benzylic carbon- horseradish peroxidase.18 Similarly to the 2-PCPA analogues 8,
centred radical. This is consistent with Wimalasena et al. who it is thought that amine 18 is intrinsically unstable in the pres-
suggest the carbon-centered radical is a discrete intermediate ence of air and likely undergoes a similar oxidation/ring-
in radical ring-opening of cyclopropylamines and therefore, opening sequence. Interestingly, the distonic radical cation 19
ring-opening and molecular oxygen insertion are not con- does not appear to be trapped by molecular oxygen, prefering
certed.9 The resulting distonic radical cation 13 is able to be to undergo a second oxidation, then elimination and hydro-
trapped with dioxygen to give adduct 14 which can undergo lysis to the enal. The preference for oxidation to an α-ferroce-
5-exo-trig cyclisation to radical cation 15. The catalytic cycle is nylcarbenium ion 20, rather than trapping with molecular
propagated by abstraction of an electron from 8 by radical oxygen, may be related to the well-established stabilisation of
cation 15, which yields dioxolane 16 as an intermediate.
Dioxolane 16 is not observed for the current reaction, as it
is likely isomerisation with concomitant O–O bond cleavage to
yield N-ferrocenylmethyl β-hydroxyamides 7 is a facile process
under basic conditions. This isomerisation step to the hydro-
xyamide could occur via several pathways. While it has been
reported that 1,2-dioxolanes can undergo conversion to
β-ketoalcohols in the presence of silica gel,16 in our case this is
unlikely as signals corresponding to the hydroxyamide were
observed in the 1H NMR of the crude reaction material prior to
contact with silica gel. Therefore, it is more likely that the iso-
merisation occurs via base-mediated17 or radical abstraction9
of H. Of these two possibilities the base-mediated mechanism
Scheme 5 Attempted Curtius rearrangement of 17 to yield enal 21.
Fig. 1 Proposed mechanism of NaBH4-initiated ring-opening-oxidation of cyclopropylimines 5.
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1
α-carbocations by ferrocene. Such systems show fulvene solvent (7.26 ppm for H NMR and 77.16 ppm for 13C NMR).
character and direct iron–α-carbon bonding.19
The following abbreviations are used to assign the multiplicity
of the 1H NMR signal: s = singlet; bs = broad singlet; d =
doublet; t = triplet; q = quartet; quin = quintet; dd = doublet of
doublets; m = multiplet. For mass spectroscopy analytes were
dissolved in HPLC grade methanol. Spectra of low-resolution
Conclusion
In conclusion, we have unveiled a novel ring-opening process mass spectrometry were obtained from
a
Shimadzu
of cyclopropylamine facilitated by the redox ability of ferrocene LC-2010 mass spectrometer (ESI) or a Shimadzu QP5050 mass
in air. This process yields novel N-ferrocenylmethyl β-hydroxy- spectrometer (EI). High-resolution mass spectra were collected
amides and provides information about the reactivity of organo- from a Waters Xevo G1 QTOF mass spectrophotometer (ESI or
metallic cyclopropylamine derivatives. The increased reactivity ASAP) or Thermo Scientific LTQ Orbitrap XL (ESI). Infrared
of the ferrocenyl derivatives of 2-PCPA towards oxidation with spectra were obtained from a Shimadzu IRAffinity-1 Fourier
molecular oxygen and ring-opening suggests the possibility of transform infrared spectrophotometer with ATR attachment.
modulating aminocyclopropane reactivity with less-readily oxi- Melting point measurements were taken on a Buchi M-560.
dised metallocene fragments. It may also be possible to employ The 2-PCPA derivatives (11a–g) were prepared according to lit-
ferrocene as a catalytic additive to enhance the oxidative ring- erature procedures; their syntheses and characterisation are
opening of aminocyclopropanes. It is worth noting that distonic provided in the ESI.†
radical cations can participate in useful reactions like [3 + 2]
Typical procedure for the synthesis of N-ferrocenylmethyl
β-hydroxyamides
cycloadditions with olefins.20 As such, the current method of
generating such species under environmentally friendly con-
ditions could lead to reaction with species other than molecular Triethylamine (0.93 mmol, 1.9 equiv.) was added to a suspen-
oxygen to obtain more complex organometallic compounds.
sion of 2-PCPA derivative hydrochloride salt (0.48 mmol, 1
It is also the first report of a very facile conversion to the equiv.) and magnesium sulphate (1.82 mmol, 3.8 equiv.) in dry
hydroxyamide skeleton by internal redox. As β-hydroxyamide dichloromethane (4 mL). This mixture was stirred for
products feature in bioactive compounds, such as Cruentaren 10 minutes before ferrocenecarboxaldehyde (0.58 mmol, 1.2
A (antifungal)21 and Octreotide (growth hormone inhibitor),22 equiv.) was added. After 3 hours of stirring, another portion of
organometallic derivatives of this moiety are of potential inter- ferrocenecarboxaldehyde (93.4 μmol, 0.2 equiv.) and one
est to medicinal chemists.23
spatula of magnesium sulphate were added. The mixture was
allowed to stir overnight, after which another portion of ferro-
cenecarboxaldehyde (67.3 μmol, 0.1 equiv.) and a spatula of
magnesium sulphate were added. After 2 hours of stirring, dry
toluene (8 mL) was added to precipitate triethylamine hydro-
chloride and the mixture was filtered. After removal of solvents
Experimental
General information
Unless stated specifically, all chemicals were purchased from under reduced pressure, more triethylamine hydrochloride
commercial suppliers and used without purification. All reac- precipitated out, therefore dry toluene (10 mL) was added and
tions were conducted in oven-dried glassware under nitrogen the mixture was filtered again. After removal of solvents,
atmosphere. Reaction solvents were dried by passing through sodium borohydride (2.07 mmol, 4.3 equiv.) was added to the
a column of activated alumina and then stored over 4 Å mole- solution of crude imine mixture in dry methanol (5 mL) at
cular sieves. Progress of reactions was tracked by TLC and was −10 °C. After stirring for 15 minutes at −10 °C, the reaction
performed on aluminium backed silica gel sheets (Grace was left stirring at room temperature. Another portion of
Davison, UV254). TLC plates were visualised under UV lamp at sodium borohydride (0.78 mmol, 1.6 equiv.) was added after
254 nm and/or by treatment with one of the following TLC 45 min at −10 °C. After stirring for 15 minutes at −10 °C, the
stains: Phosphomolybdic acid (PMA) stain: PMA (10 g), absol- reaction solution was left stirring overnight at room tempera-
ute EtOH (100 mL); Potassium permanganate stain: KMnO4 ture. The reaction was quenched with water (5 mL) and metha-
(1.5 g), 10% NaOH (1.25 mL), water (200 mL); Vanillin stain: nol was evaporated under reduced pressure. After the aqueous
Vanillin (15 g), concentrated H2SO4 (2.5 mL), EtOH (250 mL). layer was extracted with ethyl acetate (3 × 10 mL), the com-
Preparative TLC was carried out on glass backed TLC plates bined organic extracts were washed with brine (10 mL) and
with silica matrix. Column chromatography was performed dried over magnesium sulphate. This crude mixture was sub-
using silica gel (40–75 μm) as the solid phase. For NMR spec- jected to column chromatography (typically 40–80% ethyl
troscopy analytes were dissolved in deuterated chloroform or acetate in hexane), which yielded the N-ferrocenylmethyl
stated otherwise. NMR spectra for each compound were col- β-hydroxyamides.
lected from one of the following instrument: Mercury 2000
N-(Ferrocenylmethyl)-3-hydroxy-3-phenylpropanamide (7a).
spectrometer operates at 500 and 125 MHz for 1H and 13C Obtained as a yellowish orange solid (77.8 mg, 0.21 mmol) in a
1
NMR respectively, or Varian spectrometer operates at 300 and 44% overall yield. H NMR (500 MHz, CDCl3): δ 7.36–7.25 (m,
75 MHz for 1H and 13C NMR respectively. NMR data are 5H), 6.08 (s, 1H), 5.09 (dd, J = 8.75, 3.5 Hz, 1H), 4.14–4.12 (m,
expressed in parts per million (ppm) and referenced to the 11H), 2.59–2.50 (m, 2H) ppm. 13C NMR (125 MHz, CDCl3):
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δ 171.1, 143.1, 128.5, 127.7, 125.6, 84.4, 70.9, 68.6, 68.2, 68.1,
N-(Ferrocenylmethyl)-3-hydroxy-3-(p-bromophenyl) propana-
44.7, 38.8 ppm. IR (Neat): 3300, 1646 cm−1. HRMS (ASAP) mide (7g). Obtained as a yellowish orange solid (82.5 mg,
1
Found: M, 363.0914. C20H21FeNO2 requires M, 363.0922. 0.19 mmol) in a 44% overall yield. H NMR (500 MHz, CDCl3):
Melting point: 114.7–116.9 °C.
δ 7.44 (d, J = 8 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H), 6.13 (bs, 1H),
N-(Ferrocenylmethyl)-3-hydroxy-3-(o-methylphenyl) propana- 5.03–5.00 (m, 1H), 4.14–4.09 (m, 11H), 2.48–2.47 (m, 2H) ppm.
mide (7b). Obtained as brownish orange solid (46.1 mg, 13C NMR (125 MHz, CDCl3): δ 170.9, 142.2, 131.7, 127.4, 121.5,
1
0.12 mmol) in a 22% overall yield. H NMR (500 MHz, CDCl3): 84.2, 70.3, 68.7, 68.4, 68.3, 68.3, 44.5, 38.9 ppm. IR (Neat):
δ 7.47 (d, J = 7.5 Hz, 1H), 7.21–7.14 (m, 2H), 7.10–7.09 (m, 1H), 3302, 1636 cm−1. HRMS (ESI) Found: (M + Na)+, 463.9934.
6.29 (bs, 1H), 5.27 (d, J = 9 Hz, 1H), 4.14–4.12 (m, 11H), C20H20BrFeNO2 requires (M + Na)+, 463.9925. Melting point:
2.50–2.40 (m, 2H), 2.29 (s, 3H) ppm. 13C NMR (125 MHz, 113.6–115.1 °C.
CDCl3): δ 171.3, 141.1, 134.1, 130.5, 127.5, 126.5, 125.3, 84.5,
68.7, 68.3, 68.3, 67.5, 43.4, 38.9, 19.1 ppm. IR (Neat): 3305,
1636 cm−1. HRMS (ESI) Found: M+, 377.10726. C21H23FeNO2
requires M+, 317.10782. Melting point: 103.2–107.3 °C.
Acknowledgements
N-(Ferrocenylmethyl)-3-hydroxy-3-(m-methoxyphenyl) propa- The University of Wollongong is gratefully acknowledged for
namide (7c). Obtained as a brownish orange solid (111.5 mg, the financial support of this research.
1
0.28 mmol) in a 56% overall yield. H NMR (500 MHz, CDCl3):
δ 7.26–7.23 (m, 1H), 6.94–6.91 (m, 2H), 6.81 (d, J = 8 Hz, 1H),
6.05 (bs, 1H), 5.08–5.07 (m, 1H), 4.15–4.13 (m, 11H), 3.80 (s,
Notes and references
3H), 2.56–2.54 (m, 2H) ppm. 13C NMR (125 MHz, CDCl3): δ
171.2, 160.0, 145.0, 129.8, 118.0, 113.5, 111.3, 84.6, 71.1, 68.8,
68.4, 68.4, 68.4, 55.5, 44.9, 39.0 ppm. IR (Neat): 3310,
. HRMS (ESI) Found: (M + Na)+, 416.0918.
C21H23NO3Fe requires (M + Na)+, 416.0925. Melting point:
83.2–86.8 °C.
1 A. de Meijere, Chem. Rev., 2003, 103, 931.
2 C. Binda, M. Li, F. Hubálek, N. Restelli, D. E. Edmondson
and A. Mattevi, Proc. Natl. Acad. Sci. U. S. A., 2003, 100,
9750.
3 B. Cao, D. Xiao and M. M. Joullié, Org. Lett., 1999, 1, 1799.
4 B. Denolf, S. Mangelinckx, K. W. Törnroos and N. De
Kimpe, Org. Lett., 2007, 9, 187.
5 R. B. Silverman, J. Biol. Chem., 1983, 258, 14766.
6 M. A. Cerny and R. P. Hanzlik, J. Am. Chem. Soc., 2006, 128,
3346.
7 Q. Sun, R. Zhu, F. W. Foss and T. L. Macdonald, Chem. Res.
Toxicol., 2008, 21, 711.
8 C. Madelaine, Y. Six and O. Buriez, Angew. Chem., Int. Ed.,
2007, 46, 8046.
9 K. Wimalasena, H. B. Wickman and M. P. D. Mahindaratne,
Eur. J. Org. Chem., 2001, 3811.
10 T. Itoh, K. Kaneda and S. Teranishi, Tetrahedron Lett., 1975,
16, 2801.
1647 cm−1
N-(Ferrocenylmethyl)-3-hydroxy-3-(m-fluorophenyl) propana-
mide (7d). Obtained as a brown solid (35.2 mg, 0.09 mmol) in
a 49% overall yield. 1H NMR (300 MHz, CDCl3): δ 7.33–7.26
(m, 1H), 7.13–7.10 (m, 2H), 6.99–6.93 (m, 1H), 5.93 (bs, 1H),
5.11 (t, J = 6.3 Hz, 1H), 4.15–4.14 (m, 11H), 2.53 (d, J = 6 Hz,
2H) ppm. 13C NMR (125 MHz, CDCl3): δ 171.0, 163.0 (d, J = 245
Hz), 145.9 (d, J = 7.5 Hz), 130.1 (d, J = 8.75 Hz), 121.2 (d, J =
3.75 Hz), 114.5 (d, J = 21.25 Hz), 112.7 (d, J = 22.5 Hz), 84.3,
70.3, 68.7, 68.3, 68.3, 68.3, 44.5, 38.9 ppm. IR (Neat): 3238,
1650 cm−1
.
HRMS (ESI) Found: (M
+
Na)+, 404.0710.
C20H20NO2FFe requires (M + Na)+, 404.0725. Melting point:
112.3–116.3 °C.
N-(Ferrocenylmethyl)-3-hydroxy-3-(p-methylphenyl) propana-
mide (7e). Obtained as a yellow oil (118.8 mg, 0.32 mmol) in 11 A. Blackburn, D. M. Bowles, T. T. Curran and H. Kim,
1
58% overall yield. H NMR (500 MHz, CDCl3): δ 7.25 (d, J = 7.5
Synth. Commun., 2012, 42, 1855.
Hz, 2H), 7.15 (d, J = 8 Hz, 2H), 5.99 (bs, 1H), 5.08 (d, J = 8.5 Hz, 12 C. Biot, G. Glorian, L. A. Maciejewski, J. S. Brocard,
1H), 4.15–4.13 (m, 11H), 3.92 (bs, 1H), 2.61–2.50 (m, 2H), 2.34
(s, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ 171.1, 140.1, 137.4,
O. Domarle, G. Blampain, P. Millet, A. J. Georges, H. Abessolo,
D. Dive and J. Lebibi, J. Med. Chem., 1997, 40, 3715.
129.2, 125.5, 84.4, 70.9, 68.6, 68.2, 68.2, 44.8, 38.8, 21.1 ppm. 13 M. Görmen, P. Pigeon, S. Top, E. A. Hillard, M. Huché,
IR (Neat): 3299, 1636 cm−1. HRMS (ESI) Found: (M + Na)+,
400.0979. C21H23NO2Fe requires (M + Na)+, 400.0976.
C. G. Hartinger, F. de Montigny, M.-A. Plamont,
A. Vessières and G. Jaouen, ChemMedChem, 2010, 5, 2039.
N-(Ferrocenylmethyl)-3-hydroxy-3-(p-methoxyphenyl) propa- 14 S. J. Cho, N. H. Jensen, T. Kurome, S. Kadari,
namide (7f). Obtained as a yellowish orange solid in 25%
yield. 1H NMR (300 MHz, CDCl3): δ 7.27 (d, J = 8.1 Hz, 2H),
M. L. Manzano, J. E. Malberg, B. Caldarone, B. L. Roth and
A. P. Kozikowski, J. Med. Chem., 2009, 52, 1885.
6.86 (d, J = 8.4 Hz, 2H), 6.13 (bs, 1H), 5.04 (d, J = 8.4 Hz, 1H), 15 C. Pi, Y. Li, X. Cui, H. Zhang, Y. Han and Y. Wu, Chem. Sci.,
4.15–4.14 (m, 11H), 3.79 (s, 3H), 2.61–2.46 (m, 2H) ppm. 13C
2013, 4, 2675.
NMR (75 MHz, CDCl3): δ 171.3, 159.2, 135.4, 127.0, 114.0, 84.5, 16 (a) K. S. Feldman and R. E. Simpson, Tetrahedron Lett., 1989,
70.7, 68.8, 68.7, 68.3, 55.4, 44.9, 38.9 ppm. IR (Neat): 3301,
1636 cm−1
HRMS (ESI) Found: (M Na)+, 416.0937.
30, 6985–6988; (b) T. Iwama, H. Matsumoto, T. Ito,
H. Shimizu and T. Kataoka, Chem. Pharm. Bull., 1998, 46, 913.
.
+
C21H23FeNO3 requires (M + Na)+, 416.0925. Melting point: 17 M. G. Zagorski and R. G. Salomon, J. Am. Chem. Soc., 1980,
80.5–83.8 °C.
102, 2501.
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18 L. M. Sayre, R. T. Naismith, M. A. Bada, W. S. Li, 21 B. Kunze, H. Steinmetz, G. Höfle, M. Huss,
M. E. Klein and M. D. Tennant, Biochim. Biophys. Acta,
1996, 1296, 250.
H. Wieczorek and H. Reichenbach, J. Antibiot., 2006, 59,
664.
19 K. Müther, R. Fröhlich, C. Mück-Lichtenfeld, S. Grimme 22 R. Cozzi and R. Attanasio, Expert Rev. Clin. Pharmacol.,
and M. Oestreich, J. Am. Chem. Soc., 2011, 133, 12442. 2012, 5, 125.
20 S. Maity, M. Zhu, R. S. Shinabery and N. Zheng, Angew. 23 H. Kakei, T. Nemoto, T. Ohshima and M. Shibasaki, Angew.
Chem., Int. Ed., 2011, 51, 222.
Chem., Int. Ed., 2004, 43, 317.
Org. Biomol. Chem.
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