Original TDAE application: synthesis of 2-substituted-4,11-dimethoxy-anthra[2,3-b]furan-5,10-diones via intramolecular Buchwald reaction

Article abstract of DOI:10.1016/j.tetlet.2009.08.096

We report herein an original and rapid synthesis of 2-substituted-4,11-dimethoxy-anthra[2,3-b]furan-5,10-diones by TDAE strategy followed by Palladium-catalyzed cyclo-etherification reaction.

Full text of DOI:10.1016/j.tetlet.2009.08.096

Tetrahedron Letters 50 (2009) 6372–6376
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Tetrahedron Letters
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Original TDAE application: synthesis of 2-substituted-4,11-dimethoxy-anthra-
[2,3-b]furan-5,10-diones via intramolecular Buchwald reaction
*
Omar Khoumeri, Maxime D. Crozet, Thierry Terme, Patrice Vanelle
Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, Universités d’Aix-Marseille I, II et III—CNRS, UMR 6264, Laboratoire Chimie Provence,
27 Bd J. Moulin, 13385 Marseille Cedex 05, France
a r t i c l e i n f o
a b s t r a c t
Article history:
We report herein an original and rapid synthesis of 2-substituted-4,11-dimethoxy-anthra[2,3-b]furan-
5,10-diones by TDAE strategy followed by Palladium-catalyzed cyclo-etherification reaction.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 23 July 2009
Accepted 26 August 2009
Available online 1 September 2009
Anthracycline derivatives such as daunomycin and adriamycin
possess high antitumor activity due to their capability of interca-
lating DNA double helix to result dramatic changes in DNA confor-
mation1 and, furthermore, can also inhibit DNA replication and
transcription.2 Unfortunately, the clinical use is limited by both
dose-related cumulative cardiotoxicity and development of drug-
resistance.3 Several synthesis of heterocyclic anthracycline analogs
were developed by replacing the cyclohexane ring (A) of anthracy-
cline by an heterocycle.4 Interesting activity against drug-resistant
cells is obtained by modification of the 4,11-dihydroxy-naph-
tho[2,3-f]indole-5,10-dione skeleton (Fig. 1).5 On the other hand,
the compounds possessing a furano or pyrano ring fused to
polycyclic, aromatic system such as furanoxanthone,6 benzopyra-
noxanthone,7 and coumarin8 exhibit interesting antitumor9 and
anti-inflammatory properties.10
In connection with our program centered on the synthesis of new
quinonic compounds using the electron transfer methodology
and the preparation of new potentially bioactive compounds as
anticancer agents,15 we report herein an original and efficient syn-
thesis of new 2-substituted-4,11-dimethoxy-anthra[2,3-b]furan-
5,10-diones (6a–f) by an intramolecular Pd-catalyzed C–O bond
forming reaction of halide alcohol derivatives 5a–f prepared by the
TDAE strategy.
The required starting material, 2-bromo-3-bromomethyl-1,4-
dimethoxy-anthracene-9,10-dione (3), was synthesized in two
steps from compound 1 as previously described16 (see Scheme 1).
The aromatic bromination of 1 using Sandmeyer reaction gave the
bromo derivative 2,17 and was followed by a radical bromination
using N-bromosuccinimide (NBS) giving the bromomethyl deriva-
tive 3.18 In contrast to 1,4-dimethoxy-2-methylanthracene-9,10-
dione, whose bromination with an excess of NBS gave the
dibromomethyl derivative,12a the bromination of 2 furnished only
the monobromomethyl derivative 3, even with a large excess of
NBS. This difference of reactivity is probably due to the steric
hindrance.
Since 2003, we have introduced a new program directed toward
the development of original synthetic methods using TDAE meth-
odology in medicinal chemistry.11 We have shown that from o-
and p-nitrobenzyl chloride, Tetrakis(dimethyl-amino)ethylene
(TDAE) could generate a nitrobenzyl carbanion which is able to re-
act with various electrophiles as aromatic aldehydes,
a
-ketoester,
The reaction of 2-bromo-3-bromomethyl-1,4-dimethoxy-
anthracene-9,10-dione (3) with aromatic aldehydes 4a–d and in
the presence of TDAE at À20 °C for 1 h, followed by 8 h at rt led
to the corresponding alcohols 5a–d in moderate to good yields
ketomalonate, and -ketolactam derivatives. We have recently re-
a
ported the extension of this reactivity in anthraquinone series with
aromatic aldehyde and nitro-anthraquinonic with ketomalonate
and a
-keto-ester derivatives.12 Moreover, in order to develop phar-
OH
O
macomodulation studies, our team is interested in the palladium-
catalyzed reactions such as Suzuki–Miyaura and Heck reactions.13
However, Pd-catalyzed coupling of Ar-X with alcohol remains still
not explored in our laboratory despite its potential application in
organic synthesis. Furthermore, aryl ethers, including oxygen het-
erocycles, are prominent in a large number of pharmacologically
important molecules.14
O
C
O
OH
B
O
OR1
B
R2
OH
D
A
D
A
C
O
N
H
O
O
OH
OR1
H3C
O
Adriamycin
H3C
NH2
OH
* Corresponding author. Tel.: +33 4 91 83 55 80; fax: +33 4 91 79 46 77.
E-mail address: patrice.vanelle@pharmacie.univ-mrs.fr (P. Vanelle).
Figure 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.096

O. Khoumeri et al. / Tetrahedron Letters 50 (2009) 6372–6376
6373
O
O
OMe
OMe
O
O
OMe
OMe
O
OMe
1) NaNO2, HBr
H2O
NH2
Me
Br
Br
NBS
Br
hν, CCl4
2) CuBr, HBr
H2O
Me
O
OMe
3
2
1
84%
60%
Scheme 1. Synthesis of the 2-bromo-3-bromomethyl-1,4-dimethoxy-anthracene-9,10-dione 3.
O
O
OMe
OMe
O
O
OMe
OMe
Br
Br
O
OH
R1
TDAE
THF
+
Br
R1
R2
R2
3
4a-f
5a-f
Scheme 2. Reaction of 3 with carbonyl derivatives in the presence of TDAE.
O
O
OMe
O
OMe
Pd(OAc)2,
p-tol-BINAP, K2CO3
Br
O
R1
R2
OH
R1
toluene
R2
OMe
O
OMe
5a-f
6a-f
Scheme 3. Pd-catalyzed cyclization reaction of alcohols 5a–f.
(53–70%).19 Under the same conditions, we have studied the reac-
tion of 3 with
-keto-esters 4e,f19 in the presence of TDAE which
gives the corresponding -hydroxy-ester derivatives 5e,f in respec-
p-tol-BINAP as supporting ligand, 10 mol % of Pd(OAc)2 as palla-
dium source, and 1.4 equiv of K2CO3 as base in toluene at 100 °C
for 5–8 h.20 From derivatives 5a–f, this method furnished the
corresponding 2-substituted-4,11-dimethoxy-anthra[2,3-b] furan-
5,10-dione derivatives (6a–f) in good yields (70–84%)21 as shown
in Scheme 3, Table 2.
a
a
tively, 67% and 46% yield (see Scheme 2, Table 1).
Compounds 5a–f constitute promising candidates to effect an
intramolecular Pd-catalyzed ipso substitution of an aryl halide with
an alcohol. The first method which was tested to carry out palla-
dium-catalyzed C–O bond forming reaction, used 15 mol % of
In conclusion, we developed the reaction of 2-bromo-3-bromo-
methyl-1,4-dimethoxy-anthracene-9,10-dione (3) with various
Table 1
Reaction of 2-bromo-3-bromomethyl-1,4-dimethoxy-anthracene-9,10-dione 3 and carbonyl derivatives using TDAEa
Entry
R1
R2
Product
Yieldb (%)
O
OMe
Br
Br
Br
OH
OH
OH
1
4-Nitrophenyl
H
64
5a
O
O
OMe
OMe
NO2
CF3
CN
2
4-(Trifluoromethyl)phenyl
H
53
5b
5c
O
O
OMe
OMe
3
4-Cyanophenyl
H
56
O
OMe
(continued on next page)

6374
O. Khoumeri et al. / Tetrahedron Letters 50 (2009) 6372–6376
Table 1 (continued)
Entry
R1
R2
Product
Yieldb (%)
O
OMe
Br
OH
4
5-Nitrofuran-2-yl
H
70
5d
O
NO2
O
O
OMe
OMe
Br
OH
CO2Et
5
CO2Et
H
67
5e
5f
O
O
OMe
OMe
Br
OH
CO2Et
6
CO2Et
Me
46
Me
O
OMe
a
All the reactions are performed using 3 equiv of carbonyl derivatives, 1 equiv of bromide 3, and 1 equiv of TDAE in anhydrous THF stirred at À20 °C for 1 h and then
warmed up to rt for 2 h.
b
All yields refer to chromatographically isolated pure products and are relative to bromide 3.
Table 2
Pd-catalyzed C–O bond forming reactiona
Entry
Substrate
Time (h)
Product
Yieldb (%)
O
OMe
O
1
5a
8
83
NO2
6a
O
O
OMe
OMe
O
2
3
4
5b
5c
5d
8
7
7
70
81
83
CF3
6b
6c
6d
O
O
OMe
OMe
O
CN
O
O
OMe
OMe
NO2
O
O
O
OMe

O. Khoumeri et al. / Tetrahedron Letters 50 (2009) 6372–6376
6375
Table 2 (continued)
Entry
Substrate
Time (h)
Product
Yieldb (%)
O
OMe
O
5
5e
5
70
CO2Et
6e
O
O
OMe
OMe
O
CO2Et
Me
6
5f
6
84
6f
O
OMe
a
All the reactions are performed using 10 mol % Pd(OAc)2, 15 mol % p-tol-BINAP, 1.4 equiv of K2CO3 in toluene at 80 °C.
All yields refer to chromatographically isolated pure products and are relative to substrate 5a–f.
b
Vanelle, P. Tetrahedron Lett. 2006, 47, 6573–6576; (f) Montana, M.; Crozet, M.
D.; Castera-Ducros, C.; Terme, T.; Vanelle, P. Heterocycles 2008, 75, 925–932;
(g) Since, M.; Terme, T.; Vanelle, P. Tetrahedron 2009, 65, 6128–6134; (h)
Juspin, T.; Terme, T.; Vanelle, P. Synlett 2009, 1485–1489.
aromatic aldehydes and
a-keto-esters using TDAE, leading to the
corresponding alcohols. The products obtained were good candi-
dates for intramolecular palladium-catalyzed cyclo-etherification
reaction, to synthesize 2-substituted-4,11-dimethoxy-anthra[2,3-
b] furan-5,10-dione compounds. These last results constitute the
first example of intramolecular Pd-catalyzed C–O bond forming
reaction in anthraquinone series. The pharmacological evaluation
of these compounds is under active investigation.
12. (a) Khoumeri, O.; Montana, M.; Terme, T.; Vanelle, P. Tetrahedron 2008, 64,
11237–11242; (b) Khoumeri, O.; Terme, T.; Vanelle, P. Synthesis 2009, in press,
doi:10.1055/s-0029-1217001.
13. (a) Castera, C.; Crozet, M. D.; Vanelle, P. Heterocycles 2005, 65, 2979–2989; (b)
Castera-Ducros, C.; Crozet, M. D.; Vanelle, P. Synthesis 2006, 2777–2783; (c)
Crozet, M. D.; Castera-Ducros, C.; Vanelle, P. Tetrahedron Lett. 2006, 47, 7061–
7065; (d) Verhaeghe, P.; Azas, N.; Gasquet, M.; Hutter, S.; Ducros, C.; Laget, M.;
Rault, S.; Rathelot, P.; Vanelle, P. Bioorg. Med. Chem. Lett. 2008, 18, 396–401;
Kabri, Y.; Gellis, A.; Vanelle, P. Eur. J. Org. Chem. 2009. doi:10.1002/
ejoc.200900421; Crozet, M. D.; Zink, L.; Remusat, V.; Curti, C.; Vanelle, P.
Synthesis 2009. doi:10.1055/s-0029-1216905.
14. Mustafa, A.. In The Chemistry of Heterocyclic Compounds; Weissberger, A.,
Taylor, E. C., Eds.; John Wiley & Sons: New York, 1974; Vol. 29 Ellis, G. P.. In The
Chemistry of Heterocyclic Compounds; Weissberger, A., Taylor, E. C., Eds.; John
Wiley & Sons: New York, 1977; Vol. 31.
Acknowledgments
This work supported by the Centre National de la Recherche Sci-
entifique and the Université de la Méditerranée. We express our
thanks to Dr. V. Remusat for NMR spectra recording.
15. (a) Crozet, M. P.; Jentzer, O.; Vanelle, P. Tetrahedron Lett. 1987, 28, 5531–5534;
(b) Crozet, M. P.; Giraud, L.; Sabuco, J. F.; Vanelle, P.; Barreau, M. Tetrahedron
Lett. 1991, 32, 4125–4128; (c) Crozet, M. P.; Vanelle, P.; Jentzer, O.; Donini, S.;
Maldonado, J. Tetrahedron 1993, 49, 11253–11262; (d) Vanelle, P.; Donini, S.;
Terme, T.; Maldonado, J.; Roubaud, C.; Crozet, M. P. Tetrahedron Lett. 1996, 37,
3323–3324; (e) Vanelle, P.; Terme, T.; Crozet, M. P. Tetrahedron Lett. 2000, 41,
6383–6385; (f) Beziane, A.; Khoumeri, O.; Terme, T.; Vanelle, P. Lett. Org. Chem.
2008, 5, 38–41.
References and notes
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N.; Suvorov, N. N. Chem. Heterocycl. Compd. 2002, 38, 543–546.
17. For procedure see: Huszthy, P.; Kontos, Z.; Vermes, B.; Pinter, A. Tetrahedron
2001, 57, 4967–4975. Compound 2: yellow solid; mp 195 °C, 1H NMR (CDCl3,
200 MHz): d 3.53 (s, 3H); 3.91 (s, 3H); 3.99 (s, 3H); 7.72–7.76 (m, 2H); 8.15–
8.20 (m, 2H). 13C NMR (CDCl3, 50 MHz): d 17.5 (CH3); 61.7 (OCH3); 61.8
(OCH3); 125.6 (C); 125.7 (C); 126.4 (CH); 126.5 (CH); 131.0 (C); 133.6 (2CH);
133.7 (C); 133.9 (C); 142.9 (C); 153.7 (C); 155.3 (C); 182.0 (CO); 182.5 (CO).
Anal. Calcd for C17H13BrO4: C, 56.53; H, 3.63. Found: C, 56.16; H, 3.62.
18. For procedure see: Shchekotikhin, A. E.; Luzikov, Y. N.; Buyanov, V. N.;
Preobrazhenskaya, M. N. Chem. Heterocycl. Compd. 2006, 42, 1236–1241.
Compound 3: yellow solid; mp 168 °C. 1H NMR (CDCl3, 200 MHz): d 4.02 (s,
3H); 4.09 (s, 3H); 4.82 (s, 2H); 7.75–7.79 (m, 2H); 8.17–8.22 (m, 2H). 13C NMR
(50 MHz, CDCl3): d 27.0 (CH2Br); 61.9 (OCH3); 63.3 (OCH3); 128.8 (C); 126.6
(2CH); 127.8 (C); 130.9 (C); 133.5 (C); 133.6 (C); 133.8 (2CH); 140.9 (C); 153.8
(C); 155.9 (C); 181.7 (2CO). Anal. Calcd for C17H12Br2O4: C, 46.40; H, 2.75.
Found: C, 46.36; H, 2.80.
19. General procedure for TDAE reaction: Into a two-necked flask equipped with a
drying tube (silica gel) and a nitrogen inlet was added 10 mL of anhydrous THF
solution of 2-bromo-3-bromomethyl-1,4-dimethoxy-anthracene-9,10-dione
(3) (0.3 g, 0.68 mmol) and corresponding carbonyl derivatives (3 equiv). The
solution was stirred and maintained at this temperature for 30 min and then
was added dropwise (via a syringe) the TDAE (0.15 g, 0.75 mmol). A red color
immediately developed with the formation of a fine white precipitate. The
solution was vigorously stirred at À20 °C for 1 h and then warmed up to rt for
8 h. After this time, TLC analysis (CH2Cl2) clearly showed that compound (3)
was totally consumed. The solution was filtered (to remove the octamethyl-
oxamidinium dibromide) and hydrolyzed with 70 mL of H2O. The aqueous
solution was extracted with chloroform (3 Â 40 mL), the combined organic
layers washed with H2O (2 Â 40 mL), and dried over MgSO4. Evaporation of the
solvent yield to an orange viscous liquid as a crude product. Purification by
silica gel chromatography (CH2Cl2/diethyl ether: 95/5) and recrystallization
3. Menna, P.; Salvatorelli, E.; Gianni, L.; Minotti, G. Top. Curr. Chem. 2008, 283, 21–
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V. N.; Preobrazhenskaya, M. N. Bioorg. Med. Chem. 2005, 13, 2285–2291; (b)
Shchekotikhin, A. E.; Dezhenkova, L. G.; Susova, O. Y.; Glazunova, V. A.; Luzikov,
Y. N.; Sinkevich, Y. B.; Buyanov, V. N.; Shtil, A. A.; Preobrazhenskaya, M. N.
Bioorg. Med. Chem. 2007, 15, 2651–2659.
6. (a) Habib, A. M.; Ho, D. K.; Masuda, S.; McCloud, T.; Reddy, K. S.; Aboushoer, M.;
McKenzie, A.; Byrn, S. R.; Chang, C. J.; Cassady, J. M. J. Org. Chem. 1987, 52, 412–
418; (b) Hansen, M.; Lee, S. J.; Cassady, J. M.; Hurley, L. M. J. Am. Chem. Soc.
1996, 118, 5553–5561; (c) Iinuma, M.; Tosa, H.; Tanaka, T.; Riswan, S.
Phytochemistry 1996, 42, 245–247.
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P.; Pierré, A.; Atassi, G. Chem. Pharm. Bull. 2001, 49, 675–679.
8. Magiatis, P.; Melliou, E.; Skaltsounis, A.-L.; Mitaku, S.; Léonce, S.; Renard, P.;
Pierré, A.; Atassi, G. J. Nat. Prod. 1998, 61, 982–986.
9. (a) Fellows, I. M.; Schwaebe, M.; Dexheimer, T. S.; Vankayalapati, H.; Gleason-
Guzman, M.; Whitten, J. P.; Hurley, L. H. Mol. Cancer. Ther. 2005, 4, 1729–1739;
(b) Nguyen, H. T.; Lallemand, M.-. C.; Boutefnouchet, S.; Michel, S.; Tillequin, F.
J. Nat. Prod. 2009, 72, 527–539.
10. (a) Ghate, M.; Kusanur, R. A.; Kulkarni, M. V. Eur. J. Med. Chem. 2005, 40, 882–
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2003, 44, 6433–6435; (b) Giuglio-Tonolo, G.; Terme, T.; Médebielle, M.;
Vanelle, P. Tetrahedron Lett. 2004, 45, 5121–5124; (c) Amiri-Attou, O.; Terme,
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O. Khoumeri et al. / Tetrahedron Letters 50 (2009) 6372–6376
from isopropanol gave corresponding alcohol derivatives (5a–f). New
(1.4 equiv) were added. Then the alcohol (0.15 g, 1 equiv) dissolved in toluene
(6 mL) was added to the flask. The resulting mixture was heated at 100 °C until
the disappearance of the starting material as monitored by TLC. The solution
was cooled to rt, diluted with chloroform, filtered through Celite, and
concentrated. The crude product was purified by silica gel chromatography
(CH2Cl2/diethyl ether: 95/5) and recrystallized from isopropanol. New
products: 6a: yellow solid; mp 204 °C. 1H NMR (CDCl3, 200 MHz): d 3.32 (dd,
J = 16.6 Hz, J = 9.5 Hz, 1H); 3.88 (dd, J = 16.6 Hz, J = 8.1 Hz, 1H); 3.94 (s, 3H);
4.08 (s, 3H); 6.09 (dd, J = 9.5 Hz, J = 8.1 Hz, 1H); 7.57 (d, J = 8.6 Hz, 2H); 7.70–
7.75 (m, 2H); 8.14–8.20 (m, 2H); 8.27 (d, J = 8.6 Hz, 2H). 13C NMR (CDCl3,
50 MHz): d 36.3 (CH2); 61.2 (OCH3); 61.3 (OCH3); 84.7 (CH); 121.4 (C); 124.2
(2 Â CH); 126.3 (2 Â CH); 126.4 (CH); 126.5 (CH); 126.9 (C); 129.0 (C); 133.3
(CH); 133.6 (CH); 134.1 (C); 141.5 (C); 145.4 (C); 147.4 (C); 147.9 (C); 154.3
(C); 157.9 (C); 181.9 (CO); 183.3(CO). Anal. Calcd for C24H17NO7: C, 66.82; H,
3.97; N, 3.25. Found: C, 66.63; H, 4.01; N, 3.22. Compound 6b: yellow solid; mp
147 °C. 1H NMR (CDCl3, 200 MHz): d 3.33 (dd, J = 16.6 Hz, J = 8.9 Hz, 1H); 3.90
(dd, J = 16.6 Hz, J = 7.9 Hz, 1H); 3.94 (s, 3H); 4.07 (s, 3H); 6.05 (dd, J = 8.9 Hz,
J = 7.9 Hz, 1H); 7.53 (d, J = 8.2 Hz, 2H); 7.67 (d, J = 8.2 Hz, 2H);7.69–7.74 (m,
2H); 8.14–8.21 (m, 2H). 13C NMR (CDCl3, 50 MHz): d 36.3 (CH2); 61.1 (OCH3);
61.2 (OCH3); 85.3 (CH); 121.2 (C); 123.8 (q, J = 271.0, CF3); 125.9 (2 Â CH);
126.0 (q, J = 3.7, 2 Â CH); 126.4 (CH); 126.5 (CH); 127.3 (C); 128.9 (C); 130.8 (q,
J = 32.5 2 Â CH C); 131.2 (C); 133.3 (CH); 133.6 (CH); 134.2 (C); 141.5 (C);
144.4 (C); 154.3 (C); 158.2 (C); 182.0 (CO); 183.4 (CO). Anal. Calcd for
C25H17F3O5: C, 66.08; H, 3.77. Found: C, 65.64; H, 3.91. Compound 6c: yellow
solid; mp 175 °C. 1H NMR (CDCl3, 200 MHz): d 3.30 (dd, J = 16.6 Hz, J = 9.5 Hz,
1H); 3.90 (dd, J = 16.6 Hz, J = 7.8 Hz, 1H); 3.94 (s, 3H); 4.07 (s, 3H); 6.05 (dd,
J = 9.5 Hz, J = 7.8 Hz, 1H); 7.53 (d, J = 8.3 Hz, 2H); 7.71 (d, J = 8.3 Hz, 2H); 7.73–
7.75 (m, 2H); 8.14–8.20 (m, 2H). 13C NMR (CDCl3, 50 MHz): d 36.2 (CH2); 61.2
(OCH3); 61.3 (OCH3); 84.9 (CH); 112.5 (C); 118.3 (C); 121.3 (C); 126.2 (2 Â CH);
126.4 (CH); 126.5 (CH); 127.0 (C); 129.0 (C); 132.8 (2 Â CH); 133.3 (CH); 133.6
(CH); 134.1 (C); 141.4 (C); 145.6 (2 Â C); 154.3 (C); 158.0 (C); 181.9 (CO); 183.3
(CO). Anal. Calcd for C25H17NO5: C, 72.99; H, 4.16; N, 3.40. Found: C, 72.81; H,
4.24; N, 3.40. Compound 6d: yellow solid; mp 205 °C. 1H NMR (CDCl3,
products: 5a: yellow solid; mp 209 °C. 1H NMR (CDCl3, 200 MHz): d 3.39 (dd,
J = 13.3 Hz, J = 9.0 Hz, 1H); 3.48 (dd, J = 13.3 Hz, J = 5.2 Hz, 1H); 3.99 (s, 6H);
5.20 (dd, J = 9.0 Hz, J = 5.2 Hz, 1H); 7.64 (d, J = 8.5 Hz, 2H); 7.76–7.81 (m, 2H);
8.18–8.23 (m, 2H); 8.21 (d, J = 8.5 Hz, 2H). 13C NMR (DMSO-d6, 50 MHz): d 41.2
(CH2); 61.8 (OCH3); 62.8 (OCH3); 71.0 (CH); 123.8 (2 Â CH); 125.8 (C); 126.6
(2 Â CH); 126.8 (C), 127.3 (2 Â CH), 131.0 (C), 133.8 (C), 134.1 (C), 134.5 (CH),
134.6 (CH), 142.3 (C); 147.1 (C); 153.2 (C); 153.5 (C); 156.4 (C); 181.9 (CO);
182.2 (CO). Anal. Calcd for C24H18BrNO7: C, 56.27; H, 3.54; N, 2.73. Found: C,
56.41; H, 3.72; N, 2.69. Compound 5b: yellow solid; mp 168 °C. 1H NMR (CDCl3,
200 MHz):
d 3.33 (dd, J = 13.5 Hz, J = 9.4 Hz, 1H); 3.49 (dd, J = 13.5 Hz,
J = 3.8 Hz, 1H); 3.98 (s, 3H); 4.00 (s, 3H); 5.16 (dd, J = 9.4 Hz, J = 3.8 Hz, 1H);
7.60 (d, J = 8.7 Hz, 2H); 7.65 (d, J = 8.7 Hz, 2H); 7.75–7.80 (m, 2H); 8.17–8.21
(m, 2H). 13C NMR (CDCl3, 50 MHz): d 41.3 (CH2); 62.0 (OCH3); 62.7 (OCH3);
72.9 (CH); 124.1 (q, J = 271.0 Hz, CF3); 125.5 (q, J = 32.2 Hz, 2 Â CH); 125.8
(C);125.9 (2 Â CH); 126.7 (2 Â CH); 127.0 (C); 129.9 (q, J = 3.7 Hz, C); 131.4 (C);
133.7 (C); 133.8 (C); 133.9 (CH); 134.0 (CH); 141.9 (C); 148.1 (C); 154.2 (C);
155.9 (C); 182.0 (CO); 182.3 (CO). Anal. Calcd for C25H18BrF3O5: C, 56.09; H,
3.39. Found: C, 55.49; H, 3.86. Compound 5c: yellow solid; mp 173 °C. 1H NMR
(CDCl3, 200 MHz): d 3.35 (dd, J = 13.5 Hz, J = 9.0 Hz, 1H); 3.46 (dd, J = 13.5 Hz,
J = 4.0 Hz, 1H); 3.99 (s, 3H); 4.00 (s, 3H); 5.17 (dd, J = 9.0 Hz, J = 4.0 Hz, 1H);
7.59 (d, J = 8.3 Hz, 2H); 7.68 (d, J = 8.3 Hz, 2H); 7.76–7.81 (m, 2H); 8.18–8.23
(m, 2H). 13C NMR (CDCl3, 50 MHz): d 41.3 (CH2), 61.8 (OCH3); 62.8 (OCH3); 71.2
(CH); 110.2 (C); 119.4 (C); 125.8 (C); 126.6 (2 Â CH); 126.7 (C); 127.1 (2 Â CH);
131.1 (C); 132.6 (2 Â CH); 133.8 (C); 134.1 (C); 134.5 (CH); 134.6 (CH); 142.4
(C); 151.3 (C); 153.2 (C); 156.4 (C); 181.8 (CO); 182.2 (CO). Anal. Calcd for
C25H18BrNO5: C, 60.99; H, 3.69; N, 2.85. Found: C, 61.02; H, 3.78; N, 2.79.
Compound 5d: yellow solid; mp 80 °C. 1H NMR (CDCl3, 200 MHz): d 3.55 (dd,
J = 13.4 Hz, J = 7.8 Hz, 1H); 3.61 (dd, J = 13.4 Hz, J = 5.4 Hz, 1H); 3.97 (s, 3H),
3.98 (s, 3H); 5.17 (dd, J = 7.8 Hz, J = 5.4 Hz, 1H); 6.63 (d, J = 3.7 Hz, 2H); 7.28 (d,
J = 3.7 Hz, 2H); 7.74–7.79 (m, 2H); 8.15–8.19 (m, 2H). 13C NMR (CDCl3,
50 MHz): d 37.7 (CH2); 62.1 (OCH3); 62.8 (OCH3); 67.2 (CH); 109.6 (CH); 112.4
(CH); 125.8 (C); 126.7 (2 Â CH); 127.3 (C); 131.4 (C); 133.6 (C); 133.8 (C); 134.0
(CH); 134.1 (CH); 140.1 (C); 151.8 (C); 154.2 (C); 155.8 (C); 159.2 (C); 181.9
(CO); 182.2 (CO). HRMS (EI): m/z calcd for [M+H]+: 502.0132. found: 502.0143.
Compound 5e: yellow solid; mp 132 °C. 1H NMR (CDCl3, 200 MHz): d 1.20 (t,
J = 7.1 Hz, 3H); 3.31 (dd, J = 13.2 Hz, J = 8.1 Hz, 1H); 3.41 (dd, J = 13.2 Hz,
J = 6.5 Hz, 1H); 3.92 (s, 3H), 3.96(s, 3H); 4.20 (q, J = 7.1 Hz, 2H); 4.54 (dd,
J = 8.1 Hz, J = 6.5 Hz, 1H); 7.70–7.75 (m, 2H); 8.12–8.17 (m, 2H). 13C NMR
(CDCl3, 50 MHz): d 14.0 (CH3); 36.4 (CH2); 61.8 (OCH3); 62.0 (OCH2); 62.6
(OCH3); 69.0 (CH); 125.4 (C); 126.6 (2 Â CH); 126.8 (C); 131.3 (C); 133.6 (C);
133.8 (2 Â CH); 141.0 (2 Â C); 153.7 (C); 156.3 (C); 174.0 (C); 181.9 (CO); 182.2
(CO). Anal. Calcd for C21H19BrO7: C, 54.44; H, 4.13. Found: C, 54.43; H, 4.23.
Compound 5f: yellow solid; mp 101 °C. 1H NMR (CDCl3, 200 MHz): d 1.25 (t,
J = 7.1 Hz, 3H); 1.50 (s, 3H); 3.50 (s, 2H); 3.87 (s, 3H); 3.96 (s, 3H); 4.24 (q,
J = 7.1 Hz, 2H); 7.73–7.78 (m, 2H); 8.15–8.21 (m, 2H). 13C NMR (CDCl3,
50 MHz): d 14.0 (CH3); 25.4 (CH3); 41.2 (CH2); 61.8 (OCH3); 62.2 (OCH2); 62.2
(OCH3); 74.8 (C); 125.2 (C); 126.5 (CH); 126.6 (CH); 126.8 (C); 132.8 (C); 133.6
(C); 133.8 (2 Â CH); 140.6 (2 Â C); 153.8 (C); 156.3 (C); 175.8 (C); 181.9 (CO);
182.0 (CO). Anal. Calcd for C22H21BrO7: C, 55.36; H, 4.43. Found: C, 55.67; H,
4.58.
200 MHz):
d 3.68 (dd, J = 16.7 Hz, J = 9.5 Hz, 1H); 3.71 (dd, J = 16.7 Hz,
J = 7.7 Hz, 1H); 3.98 (s, 3H); 4.01 (s, 3H); 6.00 (dd, J = 9.5 Hz, J = 7.7 Hz, 1H);
6.71 (d, J = 3.7 Hz, 1H); 7.31 (d, J = 3.7 Hz, 1H); 7.70–7.74 (m, 2H); 8.13–8.20
(m, 2H). 13C NMR (CDCl3, 50 MHz): d 32.7 (CH2); 61.3 (2 Â OCH3); 78.2 (CH);
111.8 (CH); 112.0 (CH); 121.6 (C); 126.4 (C); 126.5 (CH); 126.6 (CH); 129.1 (C);
133.3 (CH); 133.6 (CH); 134.0 (C); 134.1 (C); 141.6 (C); 154.2 (C); 154.4 (C);
157.2 (C); 159.9(C); 181.9 (CO); 183.2 (CO). HRMS (EI): m/z calcd for [M+H]+:
422.0870. found: 422.0877. Compound 6e: yellow solid; mp 128 °C. 1H NMR
(CDCl3, 200 MHz): d 1.31 (t, J = 7.1 Hz, 3H); 3.48 (dd, J = 16.9 Hz, J = 10.5 Hz,
1H); 3.71 (dd, J = 16.9 Hz, J = 6.0 Hz, 1H); 3.95 (s, 3H); 4.07 (s, 3H); 4.26 (q,
J = 7.1 Hz, 2H); 5.38 (dd, J = 10.5 Hz, J = 6.0 Hz, 1H); 7.68–7.75 (m, 2H); 8.12–
8.18 (m, 2H). 13C NMR (CDCl3, 50 MHz): d 14.1 (CH3); 32.1 (CH2); 61.1 (OCH3);
61.2 (OCH3); 62.1 (OCH2); 80.5 (CH); 121.3 (C); 126.3 (C); 126.4 (CH); 126.5
(CH); 128.8 (C); 133.2 (CH); 133.5 (CH); 134.0 (C); 134.1 (C); 141.6 (C); 154.0
(C); 157.9 (C); 169.8 (C); 181.9 (CO); 183.2 (CO). Anal. Calcd for C21H18O7: C,
65.96; H, 4.74. Found: C, 66.06; H, 4.84. Compound 6f: yellow solid; mp °C. 1H
NMR (CDCl3, 200 MHz):
d 1.29 (t, J = 7.1 Hz, 3H); 1.82 (s, 3H); 3.24 (d,
J = 17.0 Hz, 1H); 3.75 (d, J = 17.0 Hz, 1H); 3.94 (s, 3H); 4.06 (s, 3H); 4.23 (q,
J = 7.1 Hz, 2H); 7.68–7.73 (m, 2H), 8.12–8.19 (m, 2H). 13C NMR (CDCl3,
50 MHz): d 14.0 (CH3); 24.4 (CH3); 38.8 (CH2); 61.1 (2OCH3); 62.1 (OCH2);
89.4 (CIV); 121.0 (C); 126.3 (CH); 126.4 (CH); 126.8 (C); 128.7 (C); 133.2 (CH);
133.4 (CH); 134.1 (C); 134.2 (C); 141.5 (C); 154.0 (C); 157.6 (C); 171.8 (C);
181.9 (CO); 183.3 (CO). Anal. Calcd for C22H20O7: C, 66.66; H, 5.09. Found: C,
66.81; H, 5.24.
20. (a) Palucki, M.; Wolfe, J.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 10333–
10334; (b) Torraca, K. E.; Kuwabe, S.-. I.; Buchwald, S. L. J. Org. Chem. 2000, 122,
12907–12908; (c) Kuwabe, S. I.; Torraca, K. E.; Buchwald, S. J. Am. Chem. Soc.
2001, 123, 12202–12206; (d) Parrish, C. A.; Buchwald, S. L. J. Org. Chem. 2001,
66, 2498–2500.
21. General procedure for Buchwald reaction: Into a two-necked flask equipped
with an argon inlet, Pd(OAc)2 (10 mol %), p-tol-BINAP (15 mol %), and K2CO3