Synthesis of alternariol through an intramolecular biaryl coupling reaction using palladium reagent

Article abstract of DOI:10.3987/com-07-s(w)3

The facile synthesis of altemariol was accomplished through an intramolecular biaryl coupling reaction of the phenyl benzoate derivative, which was prepared by the simple esterification of the corresponding phenol and benzoic acid using a palladium reagen

Full text of DOI:10.3987/com-07-s(w)3

HETEROCYCLES, Vol. 74, 2007
265
HETEROCYCLES, Vol. 74, 2007, pp. 265 - 271. © The Japan Institute of Heterocyclic Chemistry
Received, 20th March, 2007, Accepted, 27th April, 2007, Published online, 1st May, 2007. COM-07-S(W)3
SYNTHESIS OF ALTERNARIOL THROUGH AN INTRAMOLECULAR
BIARYL COUPLING REACTION USING PALLADIUM REAGENT
Hitoshi Abe,a* Tomoko Fukumoto,b Yasuo Takeuchi,b and Takashi
Harayamac*
a) Advanced Science Research Center, Okayama University, Okayama 700-8530,
Japan, b) Faculty of Pharmaceutical Sciences, Okayama University, Okayama
700-8530, Japan, c) Faculty of Pharmaceutical Sciences at Kagawa Campus,
Tokushima Bunri University, Sanuki-shi, Kagawa 769-2193, Japan
abe@pharm.okayama-u.ac.jp; harayama@kph.bunri-u.ac.jp
Abstract – The facile synthesis of alternariol was accomplished through an
intramolecular biaryl coupling reaction of the phenyl benzoate derivative, which
was prepared by the simple esterification of the corresponding phenol and benzoic
acid using a palladium reagent. The regioselectivity during the biaryl coupling
reaction was also investigated.
Alternariol (1) is the main metabolic product, which is produced by
Alternaria fungi, and this compound exhibits a significant
mycotoxicity and other biological activities.1 Because of such
Me
OH
interesting properties, several attempts for the total synthesis of
RO
alternariol (1) have been reported.2
In 2005, Podlech et al.
O
OH
O
demonstrated the short-step synthesis of 1 using the Suzuki-Miyaura
coupling reaction as the key step.3 In their synthesis, however, the
final step, which involves a demethylation process, was incomplete so
that a small amount of the 9-methyl ether (2) contaminated the final
product.
1: R = H: alternariol
2: R = Me: alternariol 9-methyl ether
In this report, we demonstrate another strategy for the synthesis of alternariol. A palladiun
mediated-biaryl coupling reaction of phenyl benzoate derivatives is a well known method for the
formation of a dibenzopyran-5-one skeleton.4 Thus, this technique was expected to be useful for the
facile synthesis of 1. The retro-synthetic outline is summarized in Scheme 1, i.e., phenyl benzoate
This paper is dedicated to Prof. Dr. Ekkehard Winterfeldt on the occasion of his 75th birthday.

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HETEROCYCLES, Vol. 74, 2007
would be an appropriate precursor of the biaryl coupling reaction, which could be prepared by a simple
esterification between the corresponding phenol and benzoic acid.
Me
X
OR
Me
OR
RO
RO
X
1
+
O
CO2H
OH
OR
O
OR
Scheme 1 Synthetic outline for alternariol
For the preparation of the phenyl benzoates (4a and 4b), DCC (dicyclohexylcarbodiimide) and DMAP (N,
N-dimethylaminopyridine) combination was effective for the condensation reaction between the benzoic
acid (3) and 3-methoxy- or 3-benzyloxy-5-methylphenol (Scheme 2).5
3-methoxy-5-methylphenol
Me
X
OR
or
3-benzyloxy-5-methylphenol
MeO
I
MeO
O
CO2H
DCC, DMAP, CH2Cl2
OMe
OMe O
Scheme 2 Preparation of phenyl benzoates 4a and 4b
The palladium-catalyzed reaction of 4a and 4b was evaluated under various conditions (Table 1).
Initially, we attempted the reaction of 4a using Pd(OAc)2 (10 mol%), K2CO3, and P(o-tol)3 in DMA
(dimethylacetamide) under reflux conditions. The reaction smoothly proceeded to give the lactones (5a
and 6a) in good yield while the regioselectivity was quite low (5a:6a = 1.5:1) (run 1). Changing the
ligand produced no significant improvement in the regioselectivity (runs 2-4). When we employed the
no-ligand condition, the selectivity was slightly improved (5a:6a = 1.9:1) (run 5). When PdCl2(PPh)3
was used as the catalyst, the chemical yield decreased (run 6). Expecting improvement of the
regioselectivity by the bulkiness of the alkoxy group, we examined the reaction of the benzyloxy
derivative (4b). Since the reaction conditions of run 5 showed the most preferable regioselectivity with
an acceptable yield, we carried out the reaction of 4b under similar conditions (run 7). However, it was
determined that the alkoxy group on that position did not affect the regioselectivity (run 5 vs. run 7).6
For completion of the alternariol synthesis, the obtained lactone (5a) was treated with BBr3 in CH2Cl2 to
remove the three methyl groups,7 so that the objective alternariol was obtained (Scheme 3) in a pure form.
The spectral data of the synthetic material were identical to the reported ones.

HETEROCYCLES, Vol. 74, 2007
267
Table 1 Intramolecular biaryl coupling reaction using palladium reagent
Me
X
OR
RO
Me
Me
OR
Pd [10% mol]
ligand, base
MeO
MeO
MeO
+
O
O
O
DMA
reflux
OMe O
OMe O
OMe O
4a: R = Me
4b: R = Bn
5a: R = Me
5b: R = Bn
6a: R = Me
6b: R = Bn
Ratio b)
Yield
(%, mixture)
Time
(min)
Ligand
[L/Pd] a)
Base
run
R
Pd
5 : 6
1
2
3
Me
Me
Me
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
P(o-tol)3 [2]
K2CO3
K2CO3
K2CO3
40
40
65
71
1.5 : 1
1.0 : 1
PPh3 [2]
nBu3P [2]
71
73
61
1.1 : 1
0.6 : 1
1.9 : 1
40
40
DPPP [1], nBu3P [1]
Pd(OAc)2
Pd(OAc)2
Ag2CO3
K2CO3
4
5
Me
Me
40
6
7
PdCl2(PPh3)2
Pd(OAc)2
NaOAc
K2CO3
60
40
1.5 : 1
1.8 : 1
Me
Bn
35
54
a) The molar ratio of the ligand and Pd. b) Determined by 1H-NMR analysis.
Me
OMe
Me
OH
BBr3 (1M in CH2Cl2)
87%
MeO
HO
O
O
OMe O
OH
O
5a
alternariol (1)
Scheme 3 Removal of three methyl groups for completion of alternariol synthesis
EXPERIMENTAL
General: The melting points were measured using a Yanagimoto micro melting point hot-plate apparatus
and are uncorrected. The IR spectra were recorded by a JASCO FTIR-350 spectrophotometer. The NMR
spectra were taken using a Varian VXR-500 (500 MHz) or MERCURY (300 MHz) instrument. The
chemical shifts are given in δ ppm relative to TMS as the internal standard. The FAB-MS was obtained
using a VG Autospec instrument with m-nitrobenzyl alcohol as the matrix. An elemental analysis was
performed using a Yanaco MT-5 analyzer. Silica gel column chromatography was carried out using
Daisogel 1002W (Daiso) or 9385 Kieselgel 60 (Merck). The TLC analysis was performed on Kieselgel
60 F254 (Merck) plates.

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2-Iodo-4,6-dimethoxybenzoic acid (3)
To a solution of 3,5-dimethoxyiodobenzene8 (6.4 g, 24.3 mmol) in dry DMF (20 mL) was added POCl3
o
o
(7.9 mL, 84.9 mmol) at 0 C. The mixture was stirred for 4 h at 90 C, then poured into ice-water.
After the generating precipitates were washed with water, the crude solid of
2-iodo-4,6-dimethoxybenzaldehyde9 (7.7 g) was obtained. This material was dissolved in a mixture of
CH3CN (70 mL) and H2O (14 mL), and then 33% H2O2 (2.43 mL, 26.3 mmol) and NaH2PO4・2H2O (4.1
g, 26.3 mmol) were added. After a solution of 80% NaClO2 (3.0 g, 26.3 mmol) in H2O (14 mL) was
added to the mixture, the mixture was stirred for 3 h at rt. A NaHSO3 aqueous solution (5%) was added,
and then an extractive work-up with Et2O and evaporation gave 3 (4.0 g, 54%). Recrystallization from
acetone-hexane afforded colorless needles: mp 145-147 oC. IR (KBr) cm–1: 3300, 1729, 1700, 1585, 1146,
1111, 1039, 1027, 1012. 1H-NMR (300 MHz, CDCl3) δ: 3.82 (3H, s, 4-OMe), 3.85 (3H, s, 6-OMe), 6.46
(1H, d, J=2.1 Hz, H-3), 7.00 (1H, d, J=2.1 Hz, H-5). Anal. Calcd for C9H9O4: C, 35.09; H, 2.94. Found: C,
34.97; H, 2.88.
3-Methyoxy-5-methylphenyl 2-iodo-4,6-dimethoxybenzoate (4a)
DCC (73.8 mg, 0.36 mmol) was added to a solution of 3 (100mg, 0.32 mmol) and
3-methoxy-5-methylphenol (44.9 mg, 0.32 mmol) in CH2Cl2 (3 mL). The mixture was stirred for 8 h at
rt, and then DMAP (11.9 mg, 0.10 mmol) was added. After 16 h, the generated precipitates were
collected, dissolved in CH2Cl2, and washed with H2O, a 10% NaOH aqueous solution, and brine. The
CH2Cl2 layer was dried with anhydrous magnesium sulfate and evaporated to give the crude residue.
Purification with silica gel column chromatography (AcOEt : hexane = 1:4) gave 4a (97.0 mg, 70%):
o
1
1
colorless needles, mp 106-108 C (ether). IR (KBr) cm－ : 2875, 1740, 1600, 1250, 1150. H-NMR (300
MHz, CDCl3) δ: 2.36 (3H, d, J=0.6 Hz, Me), 3.81 (3H, s, 3’-OMe), 3.82 (3H, s, 4-OMe), 3.86 (3H, s,
6-OMe), 6.49 (1H, d, J=2.1 Hz, H-5), 6.64 (1H, m, H-4’), 6.67 (1H, dd, J=2.1 Hz, 2.1 Hz, H-2’), 6.73
13
(1H, m, H-6’), 6.96 (1H, d, J=2.1 Hz, H-3). C-NMR (75 MHz, CDCl3) δ: 21.7, 55.4, 55.7, 56.1, 92.8,
99.0, 104.7, 112.6, 114.6, 115.2, 122.5, 140.3, 151.5, 158.1, 160.2, 161.8, 165.8. Anal. Calcd for
C17H17O5I: C, 47.68; H, 4.00. Found: C, 47.84; H, 3.99.
3-Benzyloxy-5-methylphenyl 2-iodo-4,6-dimethoxybenzoate (4b)
DCC (187.9 mg, 0.91 mmol) was added to a solution of 3 (255.1mg, 0.83 mmol) and
3-benzyloxy-5-methylphenol10 (177.4 mg, 0.83 mmol) in CH2Cl2 (5 mL). The mixture was stirred for
17 h at rt, and then DMAP (30.3 mg, 0.25 mmol) was added. After 5 h, the generated precipitates were
collected, dissolved in CH2Cl2, and washed with a cooled 10% aqueous NaOH solution and brine. The
CH2Cl2 layer was dried with anhydrous magnesium sulfate and evaporated to give the crude residue.
Purification with silica gel column chromatography (AcOEt : hexane = 1:4) gave 4b (273.7 mg, 66%) as
1
a colorless oil. IR (neat) cm－ : 2950, 1600, 1250, 1160, 1030. 1H-NMR (300 MHz, CDCl3) δ: 2.36 (3H, s,

HETEROCYCLES, Vol. 74, 2007
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Me), 3.82 (3H, s, 4-OMe), 3.85 (3H, s, 6-OMe), 5.06 (2H, s, Ar-OCH2Ph), 6.48 (1H, d, J=2.1 Hz, H-5),
6.72 (1H, dd, J=1.5 Hz, 0.6 Hz, H-4’), 6.75 (1H, s, H-2’), 6.75 (1H, d, J=1.5 Hz, H-6’), 6.96 (1H, d,
13
J=2.1 Hz, H-3), 7.33—7.46 (5H, m, C6H5). C-NMR (75 MHz, CDCl3) δ: 21.6, 55.7, 56.1, 70.2, 92.8,
99.0, 105.7, 113.4, 114.9, 115.2, 127.6, 128.0, 128.6, 136.7, 140.3, 151.5, 158.1, 159.4, 161.8, 165.8. MS
(FAB, positive ion mode) m/z: 505 [M+1]+.
Typical procedure for the coupling reaction of 4a and 4b (Table 1)
A mixture of 4a (100 mg, 0.23 mmol) and Pd(OAc)2 (5.25 mg, 0.02 mmol), K2CO3 (32.3 mg, 0.23 mmol),
o
P(o-tol)3 (14.0 mg, 0.05 mmol), and DMA (3 mL) was heated for 40 min at 190 C. After cooling, the
mixture was diluted with AcOEt and the solid material was filtered off. The filtrate was poured into
H2O and extracted with AcOEt. The organic layer was washed with brine, dried over MgSO4, and
evaporated to give a crude residue. Purification with silica gel column chromatography (AcOEt :
hexane = 1:1) gave both 5a and 6a in the pure form.
3,7,9-Trimethoxy-1-methyl-6H-dibenzo[b,d]pyran-6-one (5a)
o
o
1
Colorless needles, 155-157 C (Et2O-CH2Cl2) [lit.,1a 162.5-164 C]. IR (KBr) cm－ : 1710, 1610, 1590,
1
1360, 1240, 1160. H-NMR (300 MHz, CDCl3) δ: 2.81 (3H, s, Me), 3.84 (3H, s, 3-OMe), 3.95 (3H, s,
9-OMe), 4.01 (3H, s, 7-OMe), 6.54 (1H, d, J=2.1 Hz, H-8), 6.69 (1H, d, J=2.7 Hz, H-2 or H-4), 6.72 (1H,
d, J=2.7 Hz, H-2 or H-4), 7.29 (1H, d, J=2.1 Hz, H-10). 13C-NMR (75 MHz, CDCl3) δ: 25.6, 55.4, 55.5,
56.3, 97.0, 99.2, 102.3, 103.4, 110.9, 116.2, 137.3, 140.6, 154.0, 158.0, 160.0, 164.0, 164.7. Anal. Calcd
for C17H16O5: C, 67.99; H, 5.37. Found: C, 67.86; H, 5.40. MS (FAB, positive ion mode) m/z: 301
[M+1]+.
1,7,9-Trimethoxy-3-methyl-6H-dibenzo[b,d]pyran-6-one (6a)
o
1
Colorless needles, 210.5-211.5 C (Et2O-CH2Cl2). IR (KBr) cm－ : 1725, 1620, 1240, 1220, 1210, 1160,
1150, 1070. 1H-NMR (300 MHz, CDCl3) δ: 2.40 (3H, s, Me), 3.40 (3H, s, 1-OMe), 4.00 (3H, s, 9-OMe),
4.01 (3H, s, 7-OMe), 6.55 (1H, d, J=2.4 Hz, H-8), 6.62 (1H, d, J=1.5 Hz, H-2 or H-4), 6.78 (1H, dd,
J=1.5 Hz, 0.6 Hz, H-2 or H-4), 8.21 (1H, d, J=2.4 Hz, H-10). 13C-NMR (75 MHz, CDCl3) δ: 21.7, 55.3,
56.0, 56.3, 97.9, 103.0, 103.2, 105.6, 107.6, 110.3, 139.0, 141.0, 153.0, 156.0, 158.0, 163.5, 165.0. Anal.
Calcd for C17H16O5・1/4 H2O: C, 66.98; H, 5.46. Found: C, 66.80; H, 5.38. MS (FAB, positive ion mode)
m/z: 301 [M+1]+.
3-Benzyloxy-7,9-dimethoxy-1-methyl-6H-dibenzo[b,d]pyran-6-one (5b)
o
1
Colorless needles, 210-212 C (CH2Cl2). IR (KBr) cm－ : 1730, 1600, 1580, 1560, 1240, 1210, 1160,
1
1140. H-NMR (300 MHz, CDCl3) δ: 2.81 (3H, s, Me), 3.95 (3H, s, 9-OMe), 4.01 (3H, s, 7-OMe), 5.10
(2H, s, Ar-OCH2Ph), 6.54 (1H, d, J=2.1 Hz, H-8), 6.78 (2H, bs, H-2, H-4), 7.31 (1H, d, J=2.1 Hz, H-10),
7.34—7.46 (5H, m, C6H5). 13C-NMR (75 MHz, CDCl3) δ: 25.5, 55.5, 56.3, 70.1, 97.1, 100.3, 102.4,

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103.5, 111.1, 116.9, 127.4, 128.2, 128.7, 136.2, 137.3, 140.5, 154.0, 157.9, 159.1, 164.0, 164.7. Anal.
Calcd for C23H20O5・1/4 H2O: C, 72.52; H, 5.43. Found: C, 72.77; H, 5.45. MS (FAB, positive ion mode)
m/z: 377 [M+1]+.
1-Benzyloxy-7,9-dimethoxy-3-methyl-6H-dibenzo[b,d]pyran-6-one (6b)
o
1
Colorless needles, 246-248 C (CH2Cl2). IR (KBr) cm－ : 1720, 1620, 1600, 1580, 1560, 1460, 1250,
1
1240, 1210, 1160, 1100, 1070. H-NMR (300 MHz, CDCl3) δ: 2.42 (3H, s, Me), 3.21 (3H, s, 9-OMe),
3.94 (3H, s, 7-OMe), 5.15 (2H, s, Ar-OCH2Ph), 6.46 (1H, d, J=2.4 Hz, H-8), 6.75 (1H, d, J=1.5 Hz, H-2
or H-4), 6.82 (1H, dd, J=1.5 Hz, 0.9 Hz, H-2 or H-4), 7.39—7.56 (5H, m, C6H5), 8.07 (1H, d, J=2.4 Hz,
H-10). 13C-NMR (75 MHz, CDCl3) δ: 21.8, 54.8, 56.3, 71.6, 99.2, 101.8, 103.3, 105.7, 108.2, 110.6,
128.8, 128.8, 135.8, 139.2, 141.1, 153.1, 157.3, 158.0, 163.2, 165.0. Anal. Calcd for C23H20O5・1/4 H2O:
C, 72.52; H, 5.43. Found: C, 72.25; H, 5.51. MS (FAB, positive ion mode) m/z: 377 [M+1]+.
Alternariol (1)
BBr3 (1 mol/L in CH2Cl2)11 (3.9 mL, 3.9 mmol) was added to 4a (59 mg, 0.20 mmol), and the mixture
was stirred for 9h at rt. The mixture was slowly poured into MeOH while cooling. The volatile
materials were removed under reduced pressure to give the crude solid. Purification with silica gel
column chromatography (MeOH : CH2Cl2 = 1:50 to 1:10) gave 1 (44.0 mg, 87%) as colorless needles, mp
o
o
1
320-325 C (decomp.) [lit.1a 350 C (decomp.)]. IR (KBr) cm－ : 3445, 3190, 2975, 2560, 2380, 2370,
1660, 1615, 1580, 1515, 1460, 1354, 1290, 1263, 1250, 1200, 1160, 1127, 1107, 1056, 1030, 992, 965,
1
935, 850, 796, 748, 710, 660. H-NMR (300 MHz, CD3OD) δ: 2.73 (3H, s, Me), 6.34 (1H, d, J=2.0 Hz,
H-8), 6.58 (1H, d, J=2.6 Hz, H-2 or H-4), 6.67 (1H, d, J=2.6 Hz, H-2 or H-4), 7.23 (1H, d, J=2.0 Hz,
13
H-10). C-NMR (150 MHz, CD3OD) δ: 25.8 (Me), 99.1(Ar-C), 102.0 (Ar-C-H), 102.8 (Ar-C-H), 105.5
(Ar-C-H), 110.9 (Ar-C), 118.6 (Ar-C-H), 139.8 (Ar-C), 140.1 (Ar-C), 154.5 (Ar-C), 159.9, 166.2, 166.9,
166.9 (4×Ar-C-OH, CO). MS (FAB, positive ion mode) m/z: 259 [M+1]+. HRMS (FAB) calcd for
+
C14H11O5 : 259.0606, found 259.0607.
ACKNOWLEDGEMENTS
Part of this study was financially supported by the Japan Society for the Promotion of Science for H. A.
(Grant No. 18590005). We thank the SC-NMR Laboratory of Okayama University for performing all
the NMR experiments.
REFERENCES AND NOTES
1. a) H. Raistrick, C. E. Stickings, and R. Thomas, Bicchem. J., 1953, 55, 421. b) F. Li and T.
Yoshizawa, J. Agric. Food Chem., 2000, 48, 2920. c) G. F. Griffin and F. S. Chu, Appl. Environ.

HETEROCYCLES, Vol. 74, 2007
271
Microbiol., 1983, 46, 1420. d) G. G. Freeman, Phytochemistry, 1965, 5, 719. e) R. J. Cole and R. H.
Cox, ‘Handbook of Toxic Fungal Metabolites,’ Academic Press, 1981, pp. 614-645.
2. a) C. C. Kanakam, N. S. Mani, and G. S. R. Subba Rao, J. Chem. Soc., Perkin Trans. 1, 1990, 2233.
b) T. M. Harris and J. V. Hay, J. Am. Chem. Soc., 1997, 99, 1631.
3. K. Koch, J. Podlech, E. Pfeiffer, and M. Metzler, J. Org. Chem., 2005, 70, 3275.
4. a) D. Alberico, M. E. Scott, and M. Lautens, Chem. Rev., 2007, 107, 174. b) T. Harayama, Yakugaku
Zasshi, 2006, 126, 543. c) G. Bringmann, M. Breuning, and S. Tasler, Synthesis, 1999, 525. d) G.
Bringmann and D. Menche, Acc. Chem. Res., 2001, 34, 615. e) T. Harayama and H. Yasuda,
Heterocycles, 1997, 46, 61. f) T. Harayama, H. Yasuda, T. Akiyama, Y. Takeuchi, and H. Abe,
Chem. Pharm. Bull., 2000, 48, 861. g) S. Takeda, H. Abe, Y. Takeuchi, and T. Harayama,
Tetrahedron, 2007, 63, 396. h) H. Abe, S. Takeda, T. Fujita, K. Nishioka, Y. Takeuchi, and T.
Harayama, Tetrahedron Lett., 2004, 45, 2327. i) H. Abe, K. Nishioka, S. Takeda, M. Arai, Y.
Takeuchi, and T. Harayama, Tetrahedron Lett., 2005, 46, 3197. j) T. Matsumoto, T. Hosoya, and K.
Suzuki, J. Am. Chem. Soc., 1992, 114, 3568. k) T. Hosoya, E. Takashiro, T. Matsumoto, and K.
Suzuki, J. Am. Chem. Soc., 1994, 116, 1004.
5. 3-Methoxy-5-methylphenol is commercially available, while 3-benzyloxy-5-methylphenol was
prepared by the reported method.10
6. We have reported the effect of alkoxy groups on the regioselectivity in the Pd-mediated
intramolecular biaryl coupling reactions of benzanilides; a) T. Harayama, Y. Kawata, C. Nagura, T.
Sato, T. Miyagoe, H. Abe, and Y. Takeuchi, Tetrahedron Lett., 2005, 46, 6091. b) T. Harayama, A.
Hori, H. Abe, and Y. Takeuchi, Heterocycles, 2006, 67, 385. c) H. Nishioka, C. Nagura, H. Abe, Y.
Takeuchi, and T. Harayama, Heterocycles, 2006, 70, 549.
7. M. V. Bhatt and S. U. Kulkarni, Synthesis, 1983, 249.
8. T. Jeffery and B. Ferber, Tetrahedron Lett., 2003, 44, 193.
9. M. Pailer, H. Berner, and S. Makleit, Monatsh. Chem., 1967, 98, 1603.
10. J. R. Cannon, T. M. Cresp, B. W. Metcalf, and M. V. Sargent, J. Chem. Soc., Perkin Trans. 1, 1972,
1200.
11. Concentration of the reagent was crucial. When a lower concentration of BBr3 was employed, only
the partially demethylated products were detected.