Selenoxanthones via directed metalations in 2-arylselenobenzamide derivatives

Article abstract of DOI:10.1021/jo026635t

The reaction of N, N-diethyl 4-(N′, N′-dimethylamino)-2-phenylselenobenzamide (7a), N, N-diethyl 4-methoxy-2-phenylselenobenzamide (7b), N, N-diethyl 4-(N′, N′-dimethylamino)-2-[(3-(N, N-dimethylamino)phenylseleno]-benzamide (7c), and N, N-diethyl 4-metho

Full text of DOI:10.1021/jo026635t

In several classes of dyes, replacing an O or S atom
with the heavier chalcogen atom Se gives higher quan-
tum yields for the generation of singlet oxygen and longer
wavelengths of absorption.7-9 The higher quantum yields
for the generation of singlet oxygen are a consequence of
increased spin-orbit coupling from Se as a heavy atom
(filled 3d shell), and the longer wavelengths of absorption
are a consequence of less efficient Se4p-C2p orbital
overlap and a smaller HOMO-LUMO gap. Substitution
of Se for the O atom in the rhodamines should also give
dyes with longer wavelengths of absorption and higher
quantum yields for the generation of singlet oxygen.
The most general approaches to selenoxanthones have
been the cyclization of 2-arylseleno benzoyl chloride and
benzoic acid derivatives under Friedel-Crafts acylation
conditions.10 Unfortunately, the amino groups of sele-
noxanthone precursors to rhodamine analogues complex
with the Lewis acids for the Friedel-Crafts acylation and
are protonated under the conditions of acid-catalyzed
cyclization. We sought an alternative route to selenox-
anthones that would permit the facile incorporation of
amino functionality.
Xanthones (1-O) and thioxanthones (1-S) have been
prepared by ring closure of diphenyl ethers (2-O) and
diphenyl sulfides (2-S) bearing a 2-amido substituent as
shown in Scheme 1.11 Long-range directed metalation
gives intermediates 3, which then lose LiNEt2 to give the
chalcogenoxanthones 1. In all examples to date, at-
tempted cyclization of diaryl selenides through directed
metalation has failed.11b The lack of cyclization of 2-Se
to the selenoxanthone 1-Se is presumably due to the lack
of formation of intermediate 3-Se, which has been
unambiguously prepared by the addition of lithium
arylselenide 4 to benzyne (5, Scheme 1).12 Once inter-
mediate 3-Se is formed, selenoxanthone (1-Se) is isolated
in 74% yield. Herein, we describe the first synthesis of
selenoxanthones via long-range directed metalations of
N, N-diethyl 2-phenylselenobenzamide derivatives. Pre-
sumably, derivatives of 3-Se are formed as intermediates.
Attempts to cyclize 2-Se with lithium diisopropylamide
(LDA) failed to give any of the desired product.11b The
lack of cyclization was attributed to the long Se-C bond,
which would disfavor ring closure. However, the pre-
sumed intermediate 3-Se can be formed via the addition
Selen oxa n th on es via Dir ected Meta la tion s
in 2-Ar ylselen oben za m id e Der iva tives
Nancy K. Brennan, David J . Donnelly, and
Michael R. Detty*
Department of Chemistry, University at Buffalo, The State
University of New York, Buffalo, New York 14260
mdetty@acsu.buffalo.edu
Received October 30, 2002
Abstr a ct: The reaction of N, N-diethyl 4-(N′, N′-dimethyl-
amino)-2-phenylselenobenzamide (7a ), N, N-diethyl 4-meth-
oxy-2-phenylselenobenzamide (7b), N, N-diethyl 4-(N′, N′-
dimethylamino)-2-[(3-(N, N-dimethylamino)phenylseleno]-
benzamide (7c), and N, N-diethyl 4-methoxy-2-(3-methoxy-
phenylseleno)-benzamide (7d ) with excess lithium diisopro-
pylamide (LDA) gave 2-N, N-(dimethylamino)-9H-selenox-
anthone (9a ), 2-methoxy-9H-selenoxanthone (9b), 2,7-bis-
N, N-(dimethylamino)-9H-selenoxanthone (9c), and 2,5-
dimethoxy-9H-selenoxanthone (9d ) in 70%, 59%, 23%, and
90% isolated yields, respectively. N, N-Diethyl 2-phenylse-
lenobenzamide (2-Se) gave no reaction with LDA, t-BuLi,
MeLi, or lithium 2,2,6,6-tetramethylpiperidide as base.
Electron donation from the 4-substituent of benzamide
derivatives 7a -7d may increase the directing ability of the
carbonyl oxygen to metalate the 2-position of the arylseleno
group.
Selenoxanthone derivatives are precursors to selenox-
anthylium dyes and, in particular, to selenium-containing
analogues of the rhodamines (9-aryl-2,7-diaminoxanthy-
lium dyes). Rhodamine 123 (Rh-123) and related mol-
ecules have properties that make them useful in several
biological applications: as fluorescent stains for mito-
chondria,1 as tumor-selective dyes that accumulate in the
mitochondria of cancer cells relative to normal cells,2 and
as chemotherapeutic agents against certain tumor lines.3
Rh-123 has also shown phototoxicity upon irradiation of
tumor cell lines treated with the dye, but the quantum
yield for generating singlet oxygen, which is presumed
to be the cytotoxic agent, is low and λmax for Rh-123 is at
too short a wavelength to be activated by light that
penetrates tissue effectively.4 Brominated5 and iodinated6
analogues of Rh-123 have been prepared and have higher
quantum yields for the generation of singlet oxygen, but
the have absorption maxima nearly identical to that of
Rh-123.
(7) (a) Cincotta, L.; Foley, J . W.; Cincotta, A. H. Cancer Res. 1993,
53, 2571-2580. (b) Cincotta, L.; Foley, J . W.; MacEachern, T. Lampros,
E.; Cincotta, A. H. Cancer Res. 1994, 54, 1249-1258.
(8) (a) Detty, M. R. Merkel, P. B. J . Am. Chem. Soc. 1990, 112,
3845-3855. (b) Detty, M. R.; Merkel, P. B.; Hilf, R.; Gibson, S. L.;
Powers, S. K. J . Med. Chem. 1990, 33, 1108-1116.
(9) (a) Leonard, K. A.; Nelen, M. I.; Anderson, L. T.; Gibson, S. L.;
Hilf, R.; Detty, M. R. J . Med. Chem. 1999, 42, 3942-3952. (b) Leonard,
K. A.; Nelen, M. I.; Simard, T. P.; Davies, S. R.; Gollnick, S. O.; Oseroff,
A. R.; Gibson, S. L.; Hilf, R.; Chen, L. B.; Detty, M. R. J . Med. Chem.
1999, 42, 3953-3964. (c) Leonard, K. A.; Hall, J . P.; Nelen, M. I.;
Davies, S. R.; Gollnick, S. O.; Camacho, S.; Oseroff, A. R.; Gibson, S.
L.; Hilf, R.; Detty, M. R. J . Med. Chem. 2000, 43, 4488-4498.
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511-521. (b) Sakakibara, M.; Toru, T.; Imai, T.; Watanabe, Y.; Ueno,
Y. Bull. Chem. Soc. J pn. 1992, 65, 1291-1294.
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Biol. 1981, 88, 526-535.
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vukaren, J . J .; Nadakavukaren, K. K.; Shepard, E. L.; Chen, L. B. Proc.
Natl. Acad. Sci. U.S.A. 1982, 79, 5292-5296. (b) Davis, S.; Weiss, M.
J .; Wong, J . R.; Lampidis, T. J .; Chen, L. B. J . Biol. Chem. 1985, 260,
13844-13850. (c) Lampidis, T. J .; Bernal, S. D.; Summerhayes, I. C.;
Chen, L. B. Ann. N.Y. Acad. Sci. 1982, 395, 299-303.
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1986, 222, 169-172.
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1997, 1081-1083. (b) Storm, J . P.; Ionescu, R. D.; Martinsson, D.;
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10.1021/jo026635t CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/18/2003
3344
J . Org. Chem. 2003, 68, 3344-3347

SCHEME 1
SCHEME 3
SCHEME 2
benzamide was observed in the absence of TMEDA.
Benzamide derivative 7b gave 2,6-di(N, N-dimethyl-
amino)anthraquinone 8 and unreacted PhSeSePh as the
only isolable products after treatment with either s-BuLI
or t-BuLi in THF at -78 °C followed by the addition of
PhSeSePh.
The 2-arylselenobenzamide derivatives were treated
with 4 equiv of LDA for 1 h at 0 °C and then the reaction
mixture was warmed to ambient temperature. 2-(N, N-
Dimethylamino)-9H-selenoxanthone (9a ) was isolated in
70% yield and 2-methoxy-9H-selenoxanthone (9b)12 was
isolated in 59% yield following workup. The cyclization
of 7c and 7d to 9c and 9d , respectively, was sluggish at
0 °C with 4 equiv of LDA. Stirring 7c with 8 equiv of
LDA for 15 h at ambient temperature gave 9c17 in 23%
yield (70% recovered 7c) as a single isomer. Similarly,
stirring 7d with 4 equiv of LDA for 4 h at ambient
temperature gave 9d as a single isomer in 90% isolated
yield.
of LiSePh to benzyne and cyclization is observed to give
selenoxanthone (1-Se).12 Obviously, the Se-C bond length
is not the primary reason for the lack of cyclization of
2-Se in the presence of LDA. We thought that decreased
acidity of the 2-proton of the phenylseleno substituent
was more likely. Selenium is electropositive relative to
O and S, which would increase electron density toward
the C atom of the Se-C bond relative to O-C and S-C
bonds. Inductive effects would decrease acidity at the
2-position of the phenylseleno group.
2-Phenylselenobenzamide derivatives substituted in
the 4-position with heteroatoms capable of back-donation
of a pair of electrons should increase the directing effect
of the amide carbonyl as shown in Scheme 2. To this end
we prepared analogues of 2 bearing 4-dimethylamino and
4-methoxy substituents.
The symmetry of 9c was reflected in the 8-line 13C
NMR spectrum (1 carbonyl signal, 6 signals for aromatic
C’s, one aliphatic signal) and the 4-pattern 1H NMR
spectrum (a 3-proton 1,2,4-trisubstituted aromatic pat-
tern, one 6-proton aliphatic singlet). While we expected
to see a mixture of 2,7- and 2,5-isomers (9, X ) Y ) NMe2,
Z ) H), we saw only the bis-2,7-(dimethylamino)selenox-
anthone 9c. The steric bulk of the dimethylamino sub-
stituent might hinder formation of the 2,5-isomer.
In contrast, the methoxy derivative 7d gave only the
2,5-isomer 9d and none of the 2,7-isomer (9, X ) Z )
OMe, Y ) H) was detected by 1H NMR spectroscopy.
Selenoxanthone 9d displayed a 15-line 13C NMR spec-
trum (1 carbonyl signal, 12 signals for aromatic C’s, two
aliphatic C’s) and an 8-pattern 1H NMR spectrum (a
3-proton 1,2,4-trisubstituted aromatic pattern, a 3-proton
1,2,3-trisubstituted aromatic pattern, two 3-proton ali-
phatic singlets). The directing effect of the methoxy
substituent and its smaller steric bulk relative to the
dimethylamino substituent would favor formation of 9d .
N, N-Diethyl 4-(N′, N′-dimethylamino)benzamide (6a )13
and N, N-diethyl 4-methoxybenzamide (6b)14 are lithi-
ated at the 2-position upon treatment with t-BuLi and
N, N, N, N-tetramethylethylenediamine (TMEDA) in THF
at -78 °C.11 The addition of PhSeSePh to the 2-lithiated
benzamide gave diarylselenides 7a and 7b in 74% and
70% isolated yields, respectively (Scheme 3). Similarly,
the addition of di-3-(N, N-dimethylamino)phenyl dis-
elenide15 and di-3-methoxyphenyl diselenide16 gave diaryl
selenides 7c and 7d in 57% and 9% isolated yields,
respectively. The yield of 7c was unchanged using s-BuLi
as base. However, the yield of 7d improved to 47% upon
using s-BuLi instead of t-BuLi.
The presence of TMEDA was critical to the success of
the reaction since only dimerization of the lithiated
(13) Braun, D.; Rettig, W.; Delmond, S.; Le´tard, J . F.; Lapouyade,
R. J . Phys. Chem. 1997, 101, 6836-6841.
(14) Badjic, J . D.; Kostic, N. M. J . Mater. Chem. 2001, 11, 408-
418.
(15) Waschulzik, G.; Schuldes, H.; Oelschlaeger, H. Ger. Offen. DE
3125296 A1 19830113, 1983; Chem. Abstr. 1983, 98:215600.
(16) Evers, M.; Christiaens, L. Tetrahedron Lett. 1983, 24, 377-
380.
(17) Nealey, R. H.; Driscoll, J . S. J . Heterocycl. Chem. 1966, 3, 228-
230.
J . Org. Chem, Vol. 68, No. 8, 2003 3345

washed with brine, dried over MgSO4, and concentrated. The
crude product was purified via chromatography on SiO2 eluted
with 10% ether/CH2Cl2 to give 0.50 g (74%) of 7a as white
crystals, mp 90-91 °C: 1H NMR (CD2Cl2) δ 7.56 (m, 2 H), 7.30
(m, 3 H), 7.09 (d, 1 H, J ) 8.9 Hz), 6.59 (m, 2 H), 3.35 (br s, 4
H), 2.81 (s, 6 H), 1.13 (br s, 6 H); 13C NMR (CD2Cl2) δ 170.4,
151.1, 134.6, 131.1, 130.8, 129.5, 127.9, 127.6, 127.5, 116.5, 110.9,
40.2, 13.7; IR (KBr) 1619 cm-1; HRMS (ES) m/z 377.1143 (calcd
for C19H24N2O80Se + H, 377.1132). Anal. Calcd for C19H24N2-
OSe: C, 60.79; H, 6.44; N, 7.46. Found: C, 60.53; H, 6.45; N,
7.43.
We re-examined the cyclization of N, N-diethyl 2-phen-
ylselenobenzamide (2-Se) with several different bases.
As reported previously, LDA11b did not give cyclization
but returned only unreacted 2-Se. Similar results were
obtained with lithium 2,2,6,6-tetramethylpiperidide. Both
t-BuLi and MeLi consumed starting material. However,
neither base gave detectable amounts of selenoxanthone
1-Se from amide 2-Se.
In summary, we have successfully prepared selenox-
anthone derivatives via long-range directed metalations
of N, N-diethyl 2-arylselenobenzamides bearing dimethyl-
amino or methoxy substituents at the 4-position of the
benzamide ring. The heteroatoms at these positions are
critical to the success of the ring closure, perhaps by
increasing the directing ability of the carbonyl oxygen
as shown in Scheme 2. The approach also tolerates
substituents in the arylseleno ring and allows the prepa-
ration of selenoxanthone 9c, which is an immediate
precursor to selenium-containing analogues of the rhod-
amines.
P r ep a r a tion of 2,7-Di(N,N-d im eth yla m in o)a n th r a qu in o-
n e (8). tert-Butyllithium (1.7 M in pentane, 1.2 mL, 2.0 mmol)
or s-BuLi (1.3 M in pentane, 1.5 mL, 2.0 mmol) was added
dropwise to a stirred solution of 6a (0.40 g, 1.8 mmol) in 10 mL
of THF at -78 °C. After 0.5 h at -78 °C, diphenyldiselenide
(0.57 g, 1.8 mmol) in 5 mL of THF was added dropwise. After
0.5 h at -78 °C, the reaction mixture was warmed to ambient
temperature. Ten milliliters of saturated NH4Cl was added, and
the products were extracted with CH2Cl2 (3 × 25 mL). The
combined organic extracts were washed with brine, dried over
MgSO4, and concentrated. The crude product was purified via
chromatography on SiO2 eluted with 10% ether/CH2Cl2 to give
0.15 g (80%) of PhSeSePh and 0.20 g (75%) of 8 as an orange
powder, mp 270-274 °C: 1H NMR (CD2Cl2) δ 8.08 (d, 2 H, J )
8.7 Hz), 7.44 (d, 2 H, J ) 2.7 Hz), 6.91 (dxd, 2 H, J ) 2.7, 8.7
Hz), 3.16 (s, 12 H); IR (KBr) 2361, 1655, 1577 cm-1; EIMS m/z
294 (calcd for C18H18N2O2, 294). Anal. Calcd for C18H18N2O2: C,
73.45; H, 6.16; N, 9.52. Found: C, 73.35; H, 6.22; N, 9.43.
P r ep a r a tion of N, N-Dieth yl 4-Meth oxy-2-(p h en ylsele-
n o)ben za m id e (7b). Amide 6b (2.00 g, 9.65 mmol) in 25 mL of
dry THF was treated with TMEDA (1.35 g, 11.6 mmol), 1.5 M
t-BuLi in pentane (7.7 mL, 12 mmol), and PhSeSePh (3.01 g,
9.65 mmol) as described for 7a . Product yield was 2.45 g (70%)
of 7b as a pale yellow oil: 1H NMR (CD2Cl2) δ 7.63-7.58 (m, 2
H), 7.38-7.32 (m, 3, H), 7.19 (d, 1 H, J ) 8 Hz), 6.81 (dxd, 1 H,
J ) 2, 8 Hz), 6.79 (d, 1 H, J ) 2 Hz), 3.74 (s, 3 H), 3.55 (br s, 2
H), 3.25 (br s, 2 H), 1.26 (br s, 3 H), 1.10 (br s, 3 H); 13C NMR
(CD2Cl2) δ 169.6, 160.2, 135.0, 132.1, 131.7, 130.0, 129.7, 128.4,
127.7, 118.2, 112.5, 55.45, 43.35 (br), 39.3 (br), 14.3 (br), 12.9
(br); IR (NaCl plates) 1627 cm-1; HRMS (ES) m/z 386.0629 (calcd
for C18H21NO280Se + Na, 386.0630).
P r ep a r a tion of N, N-Dieth yl 4-N,N-Dim eth yla m in o-2-[3-
(N,N-d im eth yla m in o)p h en ylselen o]ben za m id e (7c). Amide
6a (0.79 g, 3.6 mmol) in 25 mL of dry THF was treated with
TMEDA (0.43 g, 3.6 mmol), t-BuLi (1.7 M in pentane, 2.1 mL,
3.6 mmol) or s-BuLi (1.3 M in pentane, 2.8 mL, 3.6 mmol), and
di-3-(N, N-dimethylamino)phenyl diselenide15 (1.43 g, 3.6 mmol)
as described for 7a . Product yield was 0.83 g (57%) of 7c as a
pale yellow oil: 1H NMR (CD2Cl2) δ 7.14 (t, 1 H, J ) 8 Hz), 7.07
(d, 1 H, J ) 8.5 Hz), 6.97 (t, 1 H, J ) 2 Hz), 6.87 (d, 1 H, J ) 8
Hz), 6.67 (dxd, 1 H, J ) 2, 8.5 Hz), 6.64 (d, 1 H, J ) 2 Hz), 6.57
(dxd, 1 H, J ) 2, 8.5 Hz), 3.35 (br s, 4 H), 2.92 (s, 6 H), 2.82 (s,
6 H), 1.16 (br s, 6 H); 13C NMR (CD2Cl2) δ 170.5, 151.6, 151.1,
131.3, 131.1, 129.9, 127.45, 127.43, 122.6, 118.6, 116.2, 112.2,
110.7, 43.0 (br), 40.6, 40.3, 13.8 (br); IR (NaCl plates) 1622, 1595
cm-1; HRMS (EI) m/z 420.1551 (calcd for C21H29N3O80Se + H,
420.1554).
Exp er im en ta l Section
P r ep a r a tion of N, N-Dieth yl 4-(N′, N′-Dim eth yla m in o)-
ben za m id e (6a ).13 Thionyl chloride (2.2 mL. 30 mmol) was
added to a stirred solution of 4-(N, N-dimethylamino)benzoic acid
(5.0 g, 30 mmol) in 20 mL of CH2Cl2 at 0 °C, and the resulting
solution was stirred for 3 h at 0 °C. Diethylamine (6.8 mL, 66
mmol) was added dropwise. The resulting solution was stirred
for 0.5 h at 0 °C and was then warmed to ambient temperature,
where stirring was maintained for 1 h. Saturated aqueous
NaHCO3 (100 mL) was added slowly, and the product was
extracted with CH2Cl2 (3 × 25 mL). The combined organic
extracts were washed with brine, dried over MgSO4, and
concentrated. The crude product was purified via chromatogra-
phy on SiO2 eluted with ether to give a crystalline solid, which
was recrystallized from 10% ether-hexanes to give 5.7 g (86%)
of 6a as white needles, mp 72-73 °C (lit.13 mp 71-72 °C): 1H
NMR (CD2Cl2) δ 7.26 (AA′BB′, 2 H, J ) 8.9 Hz), 6.68 (AA′BB′,
2 H, J ) 8.9 Hz), 3.39 (br s, 4 H), 2.97 (s, 6 H), 1.16 (br t, 6 H,
J ) 7.0 Hz); 13C NMR (CD2Cl2) δ 171.8, 151.5, 128.4, 124.9,
111.5, 40.4, 13.8.
P r epar ation of N, N-Dieth yl 4-Meth oxyben zam ide (6b).14
Thionyl chloride (10.5 mL, 17.2 g, 0.145 mol) was added to a
stirred solution of 4-methoxybenzoic acid (10.0 g, 65.7 mmol) in
50 mL of benzene containing a drop of N, N-dimethylformamide
at reflux, and the resulting solution was stirred for 2 h at reflux.
The reaction mixture was concentrated, and the residue was
dissolved in 60 mL of ether. Diethylamine (13.2 g, 197 mmol) in
30 mL of ether was added dropwise, and the resulting solution
was stirred for 1 h at ambient temperature. The reaction mixture
was poured into water, and the products were extracted with
ether. The combined ether extracts were washed with cold 10%
HCl, saturated NaHCO3, and brine, dried over MgSO4, and
concentrated. The crude product was purified via chromatogra-
phy on SiO2 eluted with ether and was then recrystallized from
MeOH to give 11.3 g (83%) of amide 6b as a white, crystalline
solid, mp 42-43 °C (lit.14 mp: 42-43 °C): 1H NMR (CDCl3) δ
7.27 (AA′BB′, 2 H, J ) 8.7 Hz), 6.82 (AA′BB′, 2 H, J ) 8.7 Hz),
3.74 (s, 3 H), 3.38 (br s, 4 H), 1.11 (br s, 6 H).
P r ep a r a tion of N,N-Dieth yl 4-Meth oxy-2-(3-m eth oxy-
p h en ylselen o)ben za m id e (7d ). Amide 6b (1.10 g, 5.37 mmol)
in 25 mL of dry THF was treated with TMEDA (0.62 g, 5.37
mmol), 1.3 M s-BuLi in pentane (4.13 mL, 5.37 mmol), and di-
3-methoxyphenyl diselenide16 (2.00 g, 5.37 mmol) as described
for 7a . Product yield was 0.99 g (47%) of 7d as a yellow oil: 1H
NMR (CD2Cl2) δ 7.38 (t, 1 H, J ) 8.5 Hz), 7.10-7.18 (m, 3 H),
6.88 (dxdxd, 1 H, J ) 1.8, 2.4, 8.5 Hz), 6.79 (m, 2 H), 3.79 (s, 3
H), 3.69 (s, 3 H), 3.52 (br s, 2 H), 3.20 (br s, 2 H), 1.22 (br s, 3
H), 1.08 (br s, 3 H); 13C NMR (CDCl3) δ 170.1, 160.3, 160.2, 131.9,
131.7, 130.7, 130.5, 127.7, 127.2, 118.3, 114.3, 112.7, 55.6, 55.5,
43.4 (br), 39.3 (br), 14.4 (br), 13.1 (br); HRMS (EI) m/z 394.0924
(calcd for C19H24O3N80Se + H, 394.0921)
P r epar ation of N, N-Dieth yl 4-(Dim eth ylam in o)-2-(ph en -
ylselen o)ben za m id e (7a ). tert-Butyllithium (1.7 M in pentane,
1.2 mL, 2.0 mmol) was added dropwise to a stirred solution of
6a (0.40 g, 1.8 mmol) and N, N, N, N-tetramethylethylenedi-
amine (TMEDA, 0.31 mL, 2.0 mmol) in 10 mL of THF at -78
°C. After 0.5 h at -78 °C, PhSeSePh (0.57 g, 1.8 mmol) in 5 mL
of THF was added dropwise. After 0.5 h at -78 °C, the reaction
mixture was warmed to ambient temperature. Ten milliliters
of saturated NH4Cl was added, and the products were extracted
with CH2Cl2 (3 × 25 mL). The combined organic extracts were
P r ep a r a tion of 2-(N, N-Dim eth yla m in o)-9H-selen oxa n -
th on e (9a ). To a solution of 7a (0.50 g, 1.3 mmol) in 10 mL of
THF at 0 °C was added LDA (1.8 M in hexanes, 3.0 mL, 5.4
3346 J . Org. Chem., Vol. 68, No. 8, 2003

mmol). Upon completion of the addition, the reaction mixture
was stirred 1 h at 0 °C and then warmed to ambient tempera-
ture, where stirring was maintained for 0.5 h. The reaction was
quenched by the addition of 20 mL of saturated NH4Cl. The
products were extracted with CH2Cl2 (3 × 10 mL), washed with
brine, dried over Na2SO4, and concentrated. The crude product
was purified by sonication with ether followed by recrystalliza-
tion from CH3CN to give 0.28 g (70%) of 9a as a yellow powder,
mp 187-188 °C: 1H NMR (CD2Cl2) δ 8.55 (d, 1 H, J ) 7.9 Hz),
8.43 (d, 1 H, J ) 9.2 Hz), 7.59 (d, 1 H, J ) 7.9 Hz), 7.48 (t, 1 H,
J ) 7.0 Hz), 7.42 (t, 1 H, J ) 8.0 Hz), 6.82 (dxd, 1 H, J ) 2, 9.2
Hz), 6.75 (d, 1 H, J ) 2 Hz); 13C NMR (CD2Cl2) δ 180.4, 152.5,
137.4, 134.8, 132.7, 131.8, 131.7, 130.9, 128.4, 126.6, 119.9, 112.1,
107.9, 40.1; IR (KBr) 1586 cm-1; HRMS (ES) m/z 304.0238 (calcd
for C15H13NO80Se + H, 304.0241). Anal. Calcd for C15H13NOSe:
C, 59.61; H, 4.34; N, 4.63. Found: C, 59.53; H, 4.33; N, 4.59.
P r epar ation of 2-Meth oxy-9H-selen oxan th on e (9b). Amide
7b (0.500 g, 1.46 mmol) in 10 mL of dry THF at 0 °C was treated
with LDA (1.8 M in hexanes, 3.2 mL, 5.8 mmol) as described
for the preparation of selenoxanthone 9a . Product yield was
0.236 g (59%) of selenoxanthone 9b as an yellow powder, mp
125-126 °C: 1H NMR (CD2Cl2) δ 8.58 (dxd, 1 H, J ) 1.5, 8 Hz),
8.55 (d, 1 H, J ) 9 Hz), 7.64 (dxd, 1 H, J ) 1.5, 7.5 Hz), 7.54
(dxt, 1 H, J ) 1.5, 7.5 Hz), 7.47 (dxt, 1 H, J ) 1.5, 7.5 Hz), 7.11
(d, 1 H, J ) 2.5 Hz), 7.03 (dxd, 1 H, J ) 2.5, 9 Hz), 3.92 (s, 3 H);
13C NMR (CD2Cl2) δ 162.1, 137.1, 135.3, 134.3, 132.8, 131.6,
130.7, 129.6, 127.9, 126.4, 124.2, 114.7, 110.6, 55.5; IR (KBr)
1592 cm-1; HRMS (ES) m/z 290.9921 (calcd for C13H10O280Se +
H, 290.9924). Anal. Calcd for C14H10O2Se: C, 58.15; H, 3.49.
Found: C, 58.13; H, 3.45.
recovered (0.13 g, 70%) as well as 0.033 g (23%) of 9c, as a
yellow-green, crystalline powder, mp 224-225 °C (lit. mp17 261-
262 °C): 1H NMR (CD2Cl2) δ 8.42 (d, 2 H, J ) 9.2 Hz), 6.81
(dxd, 2 H, J ) 2.4, 9.2 Hz), 6.74 (d, 2 H, J ) 2.4 Hz), 3.11 (s, 12
H), 13C NMR (CD2Cl2) δ 179.1, 151.6, 136.1, 131.6, 119.9, 111.0,
107.5, 39.53; IR (KBr) 1589 cm-1; λmax (EtOH) 388 nm; HRMS
(ES) m/z 347.0669 (calcd for C17H18ON280Se + H, 347.0663).
Anal. Calcd for C17H18ON2Se: C, 59.13; H, 5.25; N, 8.11.
Found: C, 59.22; H, 5.23; N, 8.07.
P r ep a r a tion of 2,5-Dim eth oxy-9H-selen oxa n th on e (9d ).
Amide 7d (0.20 g, 0.51 mmol) in 5 mL of dry THF at ambient
temperature was treated with LDA (1.8 M in hexanes, 2.2 mL,
4.0 mmol) as described for the preparation of selenoxanthone
9a except that stirring was continued for 8 h at ambient
temperature. Product yield was 0.145 g (90%) of 9d , as a yellow-
green, crystalline powder, mp 121-122 °C: 1H NMR (CD2Cl2) δ
8.22 (d, 1 H, J ) 8.5 Hz), 7.39 (t, 1 H, J ) 8 Hz), 2.28 (dxd, 1 H,
J ) 1, 8 Hz),7.02 (d, 1 H, J ) 2.5 Hz), 6.96 (dxd, 2 H, J ) 2.5,
8.5 Hz), 6.94 (d, 1 H, J ) 8 Hz), 3.93 (s, 6 H), 3.88 (s, 6 H); 13C
NMR (CD2Cl2) δ 182.1, 161.9, 161.5, 135.8, 134.1, 132.1, 132.0,
128.0, 121.3, 120.0, 114.2, 110.2, 110.0, 55.9, 55.5; IR (KBr) 1630,
1596 cm-1; λmax (CH2Cl2) 373, 302 (sh), 274 nm; HRMS (ES) m/z
321.0033 (calcd for C15H12O380Se + H, 321.0030). Anal. Calcd
for C15H12O3Se: C, 56.44; H, 3.79. Found: C, 56.59; H, 3.45.
Ack n ow led gm en t. The authors thank the National
Institutes of Health (grant CA69155 to M.R.D.) for
partial support of this work.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
N, N-diethyl 2-arylselenobenzamide derivatives 7a -d and
selenoxanthones 9a -d and 13C NMR spectra for 7b-d . This
material is available free of charge via the Internet at
http://pubs.acs.org.
P r ep a r a t ion of 2,7-Bis-N,N-(d im et h yla m in o)-9H-sele-
n oxa n th on e (9c).17 Amide 7c (0.19 g, 0.42 mmol) in 10 mL of
dry THF at ambient temperature was treated with LDA (1.8 M
in hexanes, 1.0 mL, 1.8 mmol) as described for the preparation
of selenoxanthone 9a except that stirring was continued for 15
h at ambient temperature. Unreacted starting material was
J O026635T
J . Org. Chem, Vol. 68, No. 8, 2003 3347