Oxidative dearomatization of resorcinol derivatives: Useful conditions leading to valuable cyclohexa-2,5-dienones

Article abstract of DOI:10.1016/S0040-4039(03)01118-3

The oxidative dearomatization of resorcinol derivatives with various oxidants is examined, as is the reactivity of cyclohexa-2,5-dienone that emerged. The results of these studies are presented herein.

Full text of DOI:10.1016/S0040-4039(03)01118-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5109–5113
Oxidative dearomatization of resorcinol derivatives:
useful conditions leading to valuable cyclohexa-2,5-dienones
Ryan W. Van De Water, Christophe Hoarau and Thomas R. R. Pettus*
Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106-9510, USA
Received 7 April 2003; revised 29 April 2003; accepted 30 April 2003
Abstract—The oxidative dearomatization of resorcinol derivatives with various oxidants is examined, as is the reactivity of
cyclohexa-2,5-dienone that emerged. The results of these studies are presented herein. © 2003 Published by Elsevier Science Ltd.
Cyclohexadienones,1 in principle, should be very useful
tions? Herein we report our first round of observations
intermediates for preparing a myriad of complex natu-
ral products. Despite their implicit malleability, a ten-
dency toward rearomatization2 and the absence of
general enantioselective methods for preparing these
structures3 have prevented their widespread use in total
synthesis. For example, cyclohexa-2,4-dienones4 readily
undergo [4+2] dimerization,5 while cross-conjugated
in regards to these questions.
After a bit of experimentation,11 we postulated that if
an amide moiety was tethered to the resorcinol nucleus
by a methylene linker, such as shown in 2, then forma-
tion of the phenoxycation C would result in an
intramolecular cyclization between the amide carbonyl
oxygen atom and the phenoxycation. Such a transfor-
mation might address many of our concerns regarding
the stability of the cyclohexa-2,5-dienone nucleus and
lead to a recoverable fragment that could serve at a
later stage as a chiral auxiliary Xc. The type of ortho-
lactonization that we envisioned, however, was
unprecedented in the chemical literature. Oxidative
dearomatizations resulting in lactonization usually
result in ipso substitution and lead to a spiroadduct.12
cyclohexa-2,5-dienones
undergo
acid-catalyzed
rearrangements2a or reductive eliminations2b resulting
in rearomatization. However, there are several elegant
examples of efficient syntheses using cyclohexadienones
in a variety of 1,2-additions,6 1,4-additions,7 rearrange-
ments,8 and cycloadditions9 in spite of these shortcom-
ings. With an appreciation of the unrealized utility of
cyclohexadienones as synthons, we set out to devise a
general method for preparing them with the hope that
such a method might one day be amenable to enan-
tioselective natural product synthesis.
Many questions had to be addressed to realize this
goal. Figure 1 shows our general plan designed to
address our first round of questions. First, what frag-
ment could be attached to the resorcinol nucleus A that
might eventually serve as a chiral auxiliary? Clearly,
general applicability hinged upon easy access to both
the Xc-fragment and A,10 as well as a high yielding
procedure to anneal these together. The second ques-
tion, what oxidative conditions afford the phenoxyca-
tion C and induce formation of the chiral center in D in
an efficient manner? Third, how might the Xc-fragment
be recovered from D? Lastly, could the resulting cyclo-
hexadienone D undergo useful diastereoselective reac-
* Corresponding author. Fax: +1-805-893-5690; e-mail: pettus@
chem.ucsb.edu
Figure 1. The initial plan.
0040-4039/03/$ - see front matter © 2003 Published by Elsevier Science Ltd.
doi:10.1016/S0040-4039(03)01118-3

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R. W. Van De Water et al. / Tetrahedron Letters 44 (2003) 5109–5113
Table 1. Survey of oxidants for efficacy in the production
of 3 from 2
Scheme 1.
Nevertheless, we believed that in our intended transfor-
mation the remnants of the methylene amide template,
a [1,4]-dioxan-2-one fused at the 3,4-positions with the
cyclohexa-2,5-dienone (cf. D), would discourage
rearomatization in subsequent synthetic manipulations
and assert diastereocontrol.
To test our thoughts, the mono-protected resorcinol
derivative 2 was constructed as shown in Scheme 1. The
resorcinol derivative 1 can be produced readily from
2,4-dihydroxy acetophenone.10 Compound 1 smoothly
couples with 2-chloro-1-pyrrolidin-1-ylethanone (cat.
TBAI, 0.5 M in acetone, 1.5 equiv. K2CO3). Subsequent
cleavage of the -OBOC phenolic carbonate with H3O+
affords the etherificated resorcinol 2 in a 80–90% over-
all yield.
Next, a variety of reagents were examined to determine
their efficacy in producing lactone 3 from the phenol 2
(Table 1). Addition of a mixture of PhIO and BF3·Et2O
(1 equiv.) left the starting material 2 unchanged (entry
1). This suggests to us that this reagent combination
lacks the necessary oxidation potential to effect a
dearomatization. Addition of DDQ to 2 produces a
complex mixture of unidentified products (entry 2).13
Similarly dissatisfying results are obtained with Ag2O
and MnO2 in entries 3 and 4.14 We speculate that the
decomposition observed with these one electron oxi-
dants results from the formation of unstable para-qui-
none methide intermediates. Treatment of 2 with
Tl(NO3)3·3H2O15 afforded the nitrated aromatic 4
(35%) along with the cyclohexadienone 5 (53%) (entry
5). Similarily, treatment of 2 with PhI+OH(−OTs)
resulted in the corresponding tosylate 6 (56%) (entry
6).16 Addition of Pb(OAc)4 to 2 provided the 2,4-cyclo-
hexadienone 7 (24%) and the 2,5 cyclohexadione 8
(21%) as the two major products in low yields (entry 7).
IBX results in the ortho functionalization of 2 produc-
ing 9 in 69% yield (entry 8).17 Thus, it would appear
that the oxidants Tl(NO3)3·3H2O, PhI+OH(−OTs), and
Pb(OAc)4 exhibit a competition between ortho and para
functionalization of phenols. IBX, however, displays a
penchant for exclusive ortho oxidation suggesting that
this oxidant proceeds through a concerted rearrange-
ment rather than the formation of a discreet cation
intermediate.
However, cation intermediates are alleged in reactions
that employ various PhI(OR)2 hypervalent iodide oxi-
dants.18 Treatment of 2 with PhI(OAc)2 afforded the
acetate 8 (46%) (entry 9). We surmised that the cation
and counteranion must be closely associated in a tight
ion pair such that addition of the ligand occurred with
greater ease than lactonization. If true, then increasing

R. W. Van De Water et al. / Tetrahedron Letters 44 (2003) 5109–5113
5111
the solvent polarity and decreasing the reaction concen-
tration and ligand nucleophilicity ought to facilitate
formation of the desired lactone. Trifluoroacetic acid
should be significantly less nucleophilic than acetic acid,
thus, we examined PhI(OCOCF3)2 in THF (entry 10).
However, use of THF as a solvent led to the ester 10
(72%), produced by the addition of THF to the result-
ing cation followed by nucleophilic opening of the
oxonium ring with trifluoroacetate. The relatively non-
nucleophilic protic solvent, (CF3)2CHOH, often
employed in hypervalent iodine oxidations,18 proved
problematic as well (entry 11). This solvent led to a
complex mixture of products involving both amide
closure (3 and 13) as well as ortho functionalization (12
and 13) and the solvent adduct (11). Upon switching to
acetonitrile as the solvent, a similar yield of the desired
lactone 3 was produced along with the alcohol 1419 and
the cyclohexadienone 15; the latter two presumably
result from trifluoroacetate addition (entry 12). The use
of methylene chloride results in a cleaner reaction with
fewer unidentified side products, however, trifluoroac-
etate addition to the phenoxycation is the principle
reaction pathway (entry 13). Gratifyingly, CH3NO2
reduced the addition of the trifluoroacetate ligand and
improved the overall conversion of 2 into 3 (35–42%)
(entry 14).
stereochemistry of 16, determined by long-range NOE
effects, indicates that the ethyl group effectively shields
one face of the molecule, overcoming dipole directive
effects observed in other cyclohexa-2,5-dienone sys-
tems.20 Treatment of 3 with the potassium enolate of
dimethyl malonate afforded 17, again as a single
diastereomer. A Diels–Alder reaction between Dan-
ishefsky’s diene and 3, although sluggish, affords 18 as
a single diastereomer indicating a diastereoselective
process. The vinylogous ester of 3 can be cleanly con-
verted to the ketal by treatment with NBS and MeOH
followed by subsequent treatment with Zn° and
aqueous NH4Cl providing 19. Hydrogenation of 3 with
Wilkinson’s catalyst affords either the masked diol 20
or the vinylogous ester 21 depending on duration of the
reaction. Clearly, the cyclohexa-2,5-dienone 3 is a
highly malleable intermediate, undergoes a myriad of
diastereoselective reactions, and is well worth pursuing
from the persectives of higher yields and optical
enrichment.
1
Supporting information: H NMR data for compounds
2–21 are reported in Ref. 21.
Acknowledgements
Having established a process leading to 3 in moderate
yields we set out to ascertain its potential as a synthetic
intermediate (Scheme 2). For example, treatment of 3
with PhMgBr at −78°C afforded the 1,2-carbonyl addi-
tion product 16 as a single diastereomer. The relative
Research Grants from Research Corporation (R10296),
the UC Committee on Cancer Research (19990641) and
(SB010064), the National Science Foundation (CHE-
9971211) and (Career-0135031), NIH (GM-64831), the
Petroleum Research Fund (PRF34986-G1) and UC-
AIDS (K00-SB-039) are greatly appreciated. R.W.V.
acknowledges fellowship funds provided by the John H.
Tokuyama Memorial Graduate Fellowship, the 2001–
2002 American Chemical Society Division of Organic
Chemistry Graduate Fellowship sponsored by Organic
Synthesis, and the DOD Breast Cancer Research Pro-
gram, DAMD17-02-1-0334.
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Scheme 2. Diastereoselective reactions of 3. Reagents and
conditions: (a) CH2Cl2/PhMgBr (3 equiv.)/−78°C; H2O/−78°C
to rt (50%); (b) KHMDS/dimethyl malonate/THF/−50°C
(70%); (c) Danishefsky’s diene (1.5 equiv.)/benzene/reflux
(32%, 87% BORSM); (d) MeOH/NBS/CH2Cl2, 0°C“rt; Zn/
NH4Cl/MeCN (63%); (e) Rh(PPh3)3Cl/H2/CH2Cl2, 10
(72%); (f) Rh(PPh3)3Cl/H2/CH2Cl2, 2 h (61%, 22% 20).
h

5112
R. W. Van De Water et al. / Tetrahedron Letters 44 (2003) 5109–5113
7. (a) Solomon, M.; Jamison, W. C. L.; McCormick, M.;
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11. Additional studies detailing (a) the selection of this par-
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aromatic ring, and (c) enantioselective lactonizations are
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upon chromatography significant amounts of 14 are
isolated.
20. Wipf, P.; Kim, Y. J. Am. Chem. Soc. 1994, 116, 11678–
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21. Experimental data:
1
Compound 2: H NMR (CDCl3, 400 MHz) l 7.36–7.28
(br s, 1-OH), 6.98 (d, J=8.0 Hz, 1H), 6.54 (d, J=2.4 Hz,
1H), 6.44 (dd, J=8.0, 2.4 Hz, 1H), 4.63 (s, 2H), 3.55 (q,
J=7.2 Hz, 4H), 2.58 (q, J=7.5 Hz, 2H), 1.98–1.90 (m,
2H), 1.88–1.80 (m, 2H), 1.16 (t, J=7.5 Hz, 3H) ppm.
Compound 3: 1H NMR (CDCl3, 400 MHz) l 6.66 (d,
J=10.1 Hz, 1H), 6.27 (dd, J=10.1, 1.4 Hz, 1H), 5.87 (d,
J=1.4 Hz, 1H), 4.93 (d, J=17.9 Hz, 1H), 4.81 (d,
J=17.9 Hz, 1H), 2.20–2.00 (m, 2H), 0.93 (t, J=7.5 Hz,
3H) ppm.
Compound 4: 1H NMR (CDCl3, 400 MHz) l 6.65 (d,
J=10.1 Hz, 1H), 6.38 (dd, J=10.1, 1.7 Hz, 1H), 5.57 (d,
J=1.7 Hz, 1H), 4.65 (d, J=14.5 Hz, 1H), 4.55 (d,
J=14.5 Hz, 1H), 3.52 (t, J=6.9 Hz, 2H), 3.40–3.35 (m,
2H), 2.22–2.15 (m, 1H), 2.05–1.85 (m, 5H), 1.25 (br s,
1-OH), 0.95 (t, J=7.5 Hz, 3H) ppm.
Compound 5: 1H NMR (CDCl3, 400 MHz) l 10.98 (s,
1-OH), 7.89 (s, 1H), 6.43 (s, 1H), 4.73 (s, 2H), 3.55 (t,
J=6.9 Hz, 2H), 3.48 (t, J=6.8 Hz, 2H), 2.65 (dq, J=7.5,
0.6 Hz, 2H), 2.05–2.00 (m, 2H), 1.95–1.87 (m, 2H), 1.23
(t, J=7.5 Hz, 3H) ppm.
Compound 6: 1H NMR (CDCl3, 400 MHz) l 7.74 (d,
J=8.3 Hz, 2H), 7.33 (d, J=8.3 Hz, 2H), 6.45 (s, 1H),
6.42 (s, 1H), 6.35 (br s, 1-OH), 4.55 (s, 2H), 3.55–3.45 (m,
4H), 2.48–2.42 (m, 2H), 2.45 (s, 3H), 2.04–1.85 (m, 4H),
0.97 (t, J=7.5 Hz, 3H) ppm.
12. (a) Tamura, Y.; Yakura, T.; Haruta, J.; Kita, Y. J. Org.
Chem. 1987, 52, 3927–3930; (b) Wipf, P.; Kim, Y.; Fritch,
P. C. J. Org. Chem. 1993, 58, 7195–7203.
13. Jurd, L. Tetrahedron 1977, 33, 163–168.
14. (a) Angle, S. R.; Arnaiz, D. O.; Boyce, J. P.; Frutos, R.
P.; Louie, M. S.; Mattson-Arnaiz, H. L.; Rainier, J. D.;
Turnbull, K. D.; Yang, W. J. Org. Chem. 1994, 59,
6322–6337; (b) Hyatt, J. A. J. Org. Chem. 1983, 48,
129–131.
15. For a review of thallium oxidants, see: Ferraz, H. M. C.;
Silva, L. F., Jr.; Vieira, T. O. Synthesis 1999, 2001–2023.
16. In the crude reaction mixture compound 6 was found to
be the minor product, formed in a 1:2 ratio with a
cyclohexadienone which we were unable to isolate. How-
ever, due to the relatively high yield of 6, we believe the
cylcohexadienone to be compound i which can undergo a
[3,3]-sigmatropic rearrangement and tautomerization
thereby producing 6 upon chromatography.
Compound 7: 1H NMR (CDCl3, 400 MHz) l 6.38 (t,
J=1.7 Hz, 1H), 5.52 (s, 1H), 4.57 (s, 2H), 3.55 (t, J=6.9
Hz, 2H), 3.42 (t, J=6.8 Hz, 2H), 2.45 (dq, J=7.3, 1.7
Hz, 2H), 2.11 (s, 6H), 2.03–1.85 (m, 4H), 1.13 (t, J=7.3
Hz, 3H) ppm.
Compound 8: 1H NMR (CDCl3, 400 MHz) l 6.53 (d,
J=10.1 Hz, 1H), 6.27 (dd, J=10.1, 1.6 Hz, 1H), 5.50 (d,
1.7 Hz, 1H), 4.55 (d, J=14.0 Hz), 4.50 (d, J=14.0 Hz,
1H), 3.54–3.51 (m, 2H), 3.40–3.35 (m, 2H), 2.15–1.87 (m,
6H), 2.09 (s, 3H), 0.90 (t, J=7.5 Hz, 3H) ppm.
Compound 9: 1H NMR (CDCl3, 400 MHz) l 6.27 (t,
J=1.6 Hz, 1H), 5.64 (s, 1H), 4.67 (s, 2H), 3.55 (t, J=6.9
Hz, 2H), 3.42 (t, J=6.7 Hz, 2H), 2.60 (dq, J=7.3, 1.8
Hz, 2H), 2.08–2.04 (m, 2H), 1.23 (t, J=7.2 Hz, 3H) ppm.
Compound 10: 1H NMR (CDCl3, 400 MHz) l 6.50 (d,
J=10.1 Hz, 1H), 6.31 (dd, J=10.1, 1.8 Hz, 1H), 5.51 (d,
J=1.8 Hz, 1H), 4.62 (d, J=14.5 Hz, 1H), 4.57 (d,
J=14.5 Hz, 1H), 4.41 (t, J=6.6 Hz, 2H), 3.58–3.49 (m,
3H), 3.45–3.39 (m, 2H), 3.38–3.32 (m, 1H), 2.12–2.00 (m,
3H), 1.94–1.79 (m, 5H), 1.70–1.62 (m, 2H), 0.79 (t, J=7.7
Hz, 3H) ppm.
17. Magdziak, D.; Rodriguez, A. A.; Van De Water, R. W.;
Pettus, T. R. R. Org. Lett. 2002, 4, 285–288.
1
Compound 11: H NMR (CDCl3, 400 MHz) l 6.53 (dd,
18. (a) Kita, Y.; Takada, T.; Ibaraki, M.; Gyoten, M.;
Mihara, S.; Fujita, S.; Tohma, H. J. Org. Chem. 1996, 61,
223–227; (b) Kita, Y.; Arisawa, M.; Gyoten, M.; Naka-
jima, M.; Hamada, R.; Tohma, H.; Takada, T. J. Org.
Chem. 1998, 63, 6623–6625.
J=10.1, 1.4 Hz, 1H), 6.39 (dd, J=10.1, 1.7 Hz, 1H), 5.53
(d, J=1.7 Hz, 1H), 4.62 (d, J=14.7 Hz, 1H), 4.50 (d,
J=14.7 Hz, 1H), 4.39 (septet, J=5.9 Hz, 1H), 3.53 (t,
J=7.0 Hz, 2H), 3.42 (t, J=7.1 Hz, 2H), 2.39–2.28 (m,
1H), 2.09–1.86 (m, 5H), 0.91 (t, J=7.6, 3H) ppm.
1
19. The alcohol 14 is thought to result from the hydrolysis of
the trifluoroacetate ester of 15 during chromatography.
In entries 12–14, the trifluoroacetate ester 15 is present in
Compound 12: H NMR (CDCl3, 400 MHz) l 7.99 (dd,
J=8.0, 1.1 Hz, 1H), 7.43 (td, J=7.5, 1.1 Hz, 1H), 7.33
(dd, J=7.5, 1.8 Hz, 1H), 7.08 (ddd, J=8.0, 7.5, 1.8 Hz,
1H), 6.88 (s, 1H), 6.51 (s, 1H), 4.90 (br s, 1-OH), 4.66 (s,
1
significant quantities in the crude H NMR spectra with

R. W. Van De Water et al. / Tetrahedron Letters 44 (2003) 5109–5113
5113
2H), 3.57 (t, J=7.0 Hz, 4H), 2.66 (q, J=7.5 Hz, 2H),
2.05–1.94 (m, 2H), 1.93–1.84 (m, 2H), 1.21 (t, J=7.5 Hz,
3H) ppm.
1H), 4.81 (d, J=17.5 Hz, 1H), 4.71 (d, J=17.5 Hz, 1H),
3.81 (d, J=6.3 Hz, 1H), 3.76 (s, 3H), 3.66 (s, 3H),
3.52–3.47 (m, 1H), 2.77 (dd, J=18.7, 0.8 Hz, 1H), 2.65
(dd, J=18.7, 5.8 Hz, 1H), 2.20–2.09 (m, 2H), 1.16 (t,
J=7.4 Hz, 3H) ppm.
1
Compound 13: H NMR (CDCl3, 400 MHz) l 7.90 (dd,
J=8.0, 1.0 Hz, 1H), 7.39 (td, J=7.5, 1.0 Hz, 1H), 7.15
(dd, J=7.5, 1.7 Hz), 7.09 (td, J=8.0, 1.7 Hz, 1H), 6.64 (s,
1H), 6.01 (s, 1H), 4.97 (d, J=17.8 Hz, 1H), 4.88 (d,
J=17.8 Hz, 1H), 2.34–2.25 (m, 1H), 2.24–2.14 (m 1H),
1.14 (t, J=7.5 Hz, 3H) ppm.
Compound 18: 1H NMR (CDCl3, 400 MHz) l 5.73 (s,
1H), 4.80 (d, J=17.6 Hz, 1H), 4.72 (d, J=17.6 Hz, 1H),
3.77–3.73 (m, 1H), 3.39 (s, 3H), 3.14–3.12 (m, 1H),
2.86–2.77 (m, 2H), 2.72–2.64 (m, 2H), 2.39 (dd, J=15.9,
13.6 Hz, 1H), 2.17 (q, J=7.5 Hz, 2H), 1.16 (t, J=7.5 Hz,
3H) ppm.
Compound 14: 1H NMR (CDCl3, 400 MHz) l 6.66 (d,
J=10.0 Hz, 1H), 6.16 (dd, J=10.0, 1.4 Hz, 1H), 5.49 (d,
J=1.4 Hz, 1H), 4.66 (d, J=14.9 Hz, 1H), 4.58 (d,
J=14.9 Hz, 1H), 3.52 (t, J=6.9 Hz, 2H), 3.39 (t, J=6.7
Hz, 2H), 2.12–1.96 (m, 3H), 1.92–1.82 (m, 3H), 0.79 (t,
J=7.6, 3H) ppm.
Compound 19: 1H NMR (CDCl3, 400 MHz) l 6.98 (d,
J=10.3 Hz, 1H), 6.04 (dd, J=10.3, 0.9 Hz, 1H), 4.44 (d,
J=17.7 Hz, 1H), 4.29 (d, J=17.7 Hz, 1H), 3.30 (s, 3H),
3.14 (dd, J=18.1, 0.9 Hz, 1H), 2.70 (d, J=18.1 Hz, 1H),
2.20–2.12 (m, 1H), 2.00–1.88 (m, 1H), 1.14 (t, J=7.5 Hz,
3H) ppm.
Compound 15: 1H NMR (CDCl3, 400 MHz) l 6.55 (d,
J=10.1 Hz, 1H), 6.35 (dd, J=10.1, 1.6 Hz, 1H), 5.55 (d,
J=1.6 Hz, 1H), 4.61 (d, J=14.5 Hz, 1H), 4.48 (d,
J=14.5 Hz, 1H), 3.52 (t, J=6.9 Hz, 2H), 3.42–3.32 (m,
2H), 2.35–2.25 (m, 1H), 2.28–2.09 (m, 1H), 2.08–1.98 (m,
2H), 1.95–1.85 (m, 2H), 0.96 (t, J=7.5 Hz, 3H) ppm.
Compound 20: 1H NMR (CDCl3, 400 MHz) l 4.51 (d,
J=18.1 Hz, 1H), 4.41 (d, J=18.1Hz, 1H), 3.87 (dd,
J=12.8, 5.8 Hz, 1H), 2.81 (ddd, J=16.0, 5.7, 2.2 Hz,
1H), 2.54–2.46 (m, 2H), 2.35–2.23 (m, 2H), 2.11–2.04 (m,
1H), 1.96–1.88 (m, 1H), 1.80–1.73 (m, 1H), 1.13 (t, J=7.4
Hz, 3H) ppm.
1
Compound 16: H NMR (CDCl3, 400 MHz) l 7.94–7.90
(m, 2H), 7.70–7.65 (m, 1H), 7.57–7.51 (m, 2H), 6.66 (d,
J=10.1 Hz, 1H), 6.19 (dd, J=10.1, 1.6 Hz, 1H), 5.45 (d,
J=1.6 Hz, 1H), 5.35 (d, J=16.5 Hz, 1H), 5.28 (d,
J=16.5 Hz, 1H), 2.18–2.08 (m, 1H), 1.96–1.86 (m, 1H),
0.83 (t, J=7.5 Hz, 3H) ppm.
Compound 21: 1H NMR (CDCl3, 400 MHz) l 5.61 (d,
J=0.8 Hz, 1H), 4.83 (d, J=17.4 Hz, 1H), 4.74 (d,
J=17.5 Hz, 1H), 2.62–2.55 (m, 1H), 2.54–2.48 (m, 1H),
2.42–2.32 (m, 1H), 2.29–2.19 (m, 1H), 2.09–2.01 (m, 2H),
1.14 (t, J=7.5 Hz, 3H) ppm.
Compound 17: 1H NMR (CDCl3, 400 MHz) l 5.59 (s,