Preparation of 6-, 7-, and 8-substituted derivatives of 2-oxa-1,3,4,10-tetraazacyclopenta[b]fluoren-9-one

Article abstract of DOI:10.1002/jhet.5570380514

The preparation of a variety of derivatives of 2-oxa-1,3,4,10-tetraazacyclopenta[b]fluoren-9-one 1 is described. A series of substituted indan-1-ones were prepared and oxidized with N-bromosuccinimide and dimethyl sulfoxide to the corresponding ninhydrin derivatives. Cyclization of the ninhydrins with furazan-3,4-diamine yielded the target tetracycles. Appropiate choice of substituents in ninhydrins led to a preference for one regioisomer in the target tetracycles. This permitted the synthesis of a variety of 8-substituted heterocycles. In those instances where isomer formation was possible, structural assignments were confirmed by X-ray crystallography.

Full text of DOI:10.1002/jhet.5570380514

Sep-Oct 2001
Preparation of 6-, 7-, and 8-Substituted Derivatives of
2-Oxa-1,3,4,10-tetraazacyclopenta[b]fluoren-9-one
1103
Larry D. Bratton*, Paul C. Unangst, J. Ronald Rubin, and Bharat K. Trivedi
Department of Chemistry, Pfizer Global Research and Development, Ann Arbor Laboratories,
2800 Plymouth Road, Ann Arbor, MI 48105
Received November 14, 2000
The preparation of a variety of derivatives of 2-oxa-1,3,4,10-tetraazacyclopenta[b]fluoren-9-one 1 is
described. A series of substituted indan-1-ones were prepared and oxidized with N-bromosuccinimide and
dimethyl sulfoxide to the corresponding ninhydrin derivatives. Cyclization of the ninhydrins with furazan-
3,4-diamine yielded the target tetracycles. Appropiate choice of substituents in ninhydrins led to a preference
for one regioisomer in the target tetracycles. This permitted the synthesis of a variety of 8-substituted hetero-
cycles. In those instances where isomer formation was possible, structural assignments were confirmed by
X-ray crystallography.
J. Heterocyclic Chem., 38, 1103 (2001).
As a part of a screening program to identify new com-
However, a benzoyl ester group was found to be a useful
function for isomer control of certain tetracyclic targets
pounds with pharmacological activity, we became inter-
ested in 2-oxa-1,3,4,10-tetraazacyclopenta[b]fluoren-9-
one 1. The only literature reference to compound 1 [1]
describes the preparation by the reaction of ninhydrin and
furazan-3,4-diamine [2] under acidic conditions. This
reaction is analogous to that of ninhydrin with
o-phenylenediamine and other heterocyclic diamines
[3-5]. We were interested in preparing derivatives of 1 for
biological testing by introducing functionality at positions
6-8 of the tetracycle. We found that electrophilic aromatic
substitution to 1 (bromination, nitration, or Friedel-Crafts
acylation with benzoyl chloride) was unsatisfactory, pre-
sumably due to deactivation of the aromatic ring by the
ketone and fused pyrazine moieties. Ultimately, our
method of choice to synthesize these derivatives was to
incorporate a suitable functional group into an indan-1-one
for conversion to a substituted ninhydrin derivative [6,7]
before cyclization with furazan-3,4-diamine.
Scheme 1).
(
The preparation of 8-substituted derivatives of 1 began
with indanone ester 2 [10]. Electrophilic bromination of 2
with N-bromosuccinimide, followed by oxidation with
dimethyl sulfoxide [7,11], gave the substituted ninhydrin 3
in 61% yield. Condensation of 3 with furazan-3,4-diamine
1
The use of substituted ninhydrins in the cyclization reac-
tion introduces the possibility of regioisomer formation in
the teracyclic products. Therefore, our strategy for prepar-
ing the 8-substituted analogs of 1 was to incorporate a
bulky substituent in the indane-1-one starting material in
order to favor formation of one regioisomer after reaction
of the corresponding ninhydrin derivative [3]. In those
instances where isomer formation was possible, structural
assignments were confirmed by X-ray crystallography.
An initial attempt to use a benzyloxy blocking group
failed due to problems associated with attempted de-ben-
zylation of the final product. Pyrazine and furazan moi-
eties as found in 1 are known to be susceptible to chemical
reduction [8,9] used for removal of the benzyl group.

1104
L. D. Bratton, P. C. Unangst, J. R. Rubin, and B. K. Trivedi
Vol. 38
in a mixture of ethanol and acetic acid afforded the 8-sub-
stituted tetracycle 4, the structure of which was confirmed
by X-ray analysis. Although, concomitant formation of
the 5-substituted regioisomer of 4 was possible, this prod-
uct was not isolated from the reaction mixture.
Ester cleavage of 4 provided a phenolic derivative that
was useful for the introduction of additional functionality.
Reaction of 4 with cesium carbonate in tetrahydrofuran
[12] provided the phenol 5 in 94% yield. An earlier
attempt at preparing 5 by saponification of 4 with sodium
hydroxide in ethanol was unsuccessful. Instead, a small
amount of the diacetal byproduct 6 was isolated.
Similarly, treatment of 4 with lithium hydroxide in aque-
ous tetrahydrofuran did not produce the desired product.
The lack of success, in generating the desired phenol 5 by
the reaction of alkali metal hydroxides with 4, may be
attributed to the sensitivity of the pyrazine and furazan
parts of the molecule to attack by a strong nucleophile.
Alkylation of 5 was accomplished by treating 5 with
cesium carbonate in N,N-dimethylformamide to form the
cesium phenoxide intermediate and then reacting with
methyl bromoacetate to give the alkylated product 7.
Likewise, methyl ether 8 was prepared by reaction of 5 with
sodium hydride in N,N-dimethylformamide, followed by
alkylation with iodomethane (Scheme 2). Mitsunobu reac-
tion conditions were employed for the introduction of a range
of aralkyl groups into the tetracycle. Thus, reactions of phe-
nol 5 with aryl and heteroaryl alcohols in tetrahydrofuran
afforded the alkylated products 9-12 in yields of 24-70%.
+
93% yield. Reaction of 14 with benzoyl chloride in ace-
tone under basic conditions gave the benzoyl ester 15,
which was oxidized by the previous method to give ninhy-
drin 16. In addition to 16, the gem-dibromo indanone 17
was isolated as a side product. Condensation of 16 with
furazan-3,4-diamine under acidic conditions afforded the
tetracycle 18 as a single regioisomer (the structure of 18
was confirmed by X-ray analysis). Ammonia in methanol
was used for conversion of 18 to the phenol 19 in 97%
yield. Unlike the cleavage of ester 4, reaction of 18 with
cesium carbonate did not result in a complete conversion
to the desired phenol product. Alkylation of 19 with
methyl bromoacetate and cesium carbonate gave the target
ester tetracycle 20 (Scheme 4).
Cyclization reactions of ninhydrin derivatives without a
suitable blocking function invariably led to mixtures of
tetracyclic isomers. This was realized in the preparation of
tetracycle ester 24 (Scheme 5). The indanone 21 [15] was
alkylated with methyl bromoacetate, and the ester product
22 was oxidized to yield the ninhydrin derivative 23.
Cyclization of 23 with furazan-3,4-diamine gave a mixture
of the 6- and 7-substituted ester tetracycles. However,
Several analogs were prepared with functionality
attached at the 6-position of the tetracycle (Scheme 3). A
4-methyl substituent in the starting indan-1-one 13 served
as a viable blocking group [13] to ensure a single regioiso-
mer in the target tetracycles.
Trisubstituted indanone 13 [14] was demethylated with
aluminum chloride in toluene to afford the phenol 14 in

Sep-Oct 2001
Preparation of 6-, 7-, and 8-Substituted Derivatives
1105
Table 1
Crystal and Refinement Data for 4
H N O
8 8 4
formula
C
18
formula weight
crystal system
space group
a, Å
344.3
triclinic
P-1
5.40(5)
b, Å
c, Å
V, Å
16.64(5)
18.36(5)
1541.260(1)
4; 1.62
0.2 x 0.2 x 0.2
10.85
3
3
Z; density (calc), g/cm
crystal size, mm
absorption coef., mm
2q (max), deg.
-1
100.28
5357
reflections collected
independent reflections
parameters refined
final R indices
2346
249
R1 = 0.089, wR2 = 0.050
0.48
3
largest diff. Peak, e/Å
Table 2
Fractional Atomic Coordinates and Equivalent Isotropic Displacement
2
Parameters (Å ) for 4 [a,b]
Atom
x
y
z
U(eq)
O1
O2
C3
N4
N6
O7
-0.240(4)
-0.351(4)
-0.729(5)
-0.561(4)
-0.254(4)
-0.550(4)
-0.399(7)
-0.197(4)
-0.598(5)
-0.045(3)
0.287(4)
-0.385(6)
-0.400(5)
-0.133(5)
-0.628(5)
0.100(5)
-0.693(4)
0.112(5)
-0.439(5)
-0.536(5)
-0.652(6)
0.244(4)
-0.434(6)
0.069(5)
0.182(5)
-0.037(5)
-0.062(4)
-0.321(6)
0.094(6)
-0.865(6)
-0.487(5)
0.235(7)
-0.366(5)
-0.175(5)
-0.984(5)
-0.097(5)
0.504(6)
0.475(9)
0.342(8)
-0.929(6)
0.201(1)
0.161(1)
0.073(2)
0.116(2)
0.191(1)
0.127(1)
0.089(2)
0.416(1)
0.109(2)
0.371(1)
0.304(2)
0.163(2)
0.158(2)
0.396(2)
0.101(2)
0.344(2)
0.083(1)
0.338(2)
0.483(2)
0.121(2)
0.087(2)
0.309(1)
0.003(2)
0.494(2)
0.332(2)
0.384(2)
0.386(2)
0.172(2)
0.421(2)
0.035(2)
0.504(2)
0.278(2)
0.470(2)
0.410(2)
0.001(2)
0.394(2)
0.268(2)
0.345(3)
0.404(3)
0.017(2)
-0.132(1)
0.201(1)
-0.108(1)
0.161(1)
0.026(1)
-0.273(1)
-0.343(2)
-0.030(1)
-0.154(1)
0.276(1)
-0.159(1)
-0.108(1)
-0.030(1)
0.030(1)
-0.033(1)
0.030(1)
0.029(1)
0.110(1)
0.139(1)
0.092(1)
-0.232(2)
-0.029(1)
-0.368(1)
0.367(1)
-0.090(1)
-0.091(1)
-0.161(1)
0.087(1)
0.339(1)
-0.261(1)
0.215(1)
0.340(2)
0.265(1)
0.231(1)
-0.214(1)
0.161(1)
0.437(2)
0.470(2)
0.445(2)
-0.138(1)
0.072(5)
0.076(5)
0.053(6)
0.077(6)
0.053(5)
0.083(5)
0.088(9)
0.059(5)
0.054(6)
0.076(5)
0.070(6)
0.060(7)
0.052(6)
0.055(6)
0.051(5)
0.052(6)
0.056(5)
0.059(6)
0.065(7)
0.049(6)
0.075(7)
0.061(5)
0.123(7)
0.108(7)
0.059(6)
0.057(6)
0.072(6)
0.062(6)
0.064(7)
0.072(7)
0.063(6)
0.083(8)
0.072(7)
0.067(7)
0.073(7)
0.061(6)
0.083(8)
0.140(1)
0.130(1)
0.076(7)
C10
N11
C13
O14
N15
C16
C17
C18
C19
C20
N21
C22
C23
C24
C25
N26
O27
O28
C29
C30
N31
C32
C33
C34
C36
C37
C38
C39
C40
C41
C48
C49
C50
C63
recrystallization of the isomeric mixture from aqueous
acetonitrile afforded the pure 6-substituted isomer 24,
which was structurally confirmed by X-ray analysis.
The observed X-ray structure of 4, which exists as a
stacked dimer, is illustrated as an ORTEP diagram in
Figure 1 and confirms the attachment of the benzoyloxy
substituent at the 8-position of the tetracycle. Crystal and
refinement parameters for compound 4 as well as posi-
tional parameters and their estimated standard deviations
are shown in Tables 1 and 2. Bond distances and angles
for 4 are listed in Tables 3 and 4. Similarly, an X-ray
analysis of compound 24 confirmed the attachment of the
ester substituent at the 6-position of the tetracycle, and its
ORTEP diagram and X-ray data are represented in Figure
2 and Tables 5-8, respectively.
We have described the preparation of a variety of deriv-
atives of 2-oxa-1,3,4,10-tetraazacyclopenta[b]fluoren-9-
one. A series of substituted indan-1-ones were prepared
and oxidized with N-bromosuccinimide and dimethyl sul-
foxide to ninhydrin derivatives. Cyclization of the ninhy-
drins with furazan-3,4-diamine yielded the target tetracy-
cles. Isomeric control at the tetracyclic products was made

1106
L. D. Bratton, P. C. Unangst, J. R. Rubin, and B. K. Trivedi
Vol. 38
Table 4 (continued)
Table 2 (continued)
Atom
x
y
z
U(eq)
Atom 1 Atom 2 Atom 3
Angle
Atom 1 Atom 2 Atom 3
Angle
C64
N65
C66
C67
C68
C69
C70
C71
0.203(7)
-0.219(5)
-0.272(9)
-0.130(1)
-0.298(7)
-0.140(1)
-0.060(1)
0.014(9)
0.359(2)
0.195(2)
0.227(3)
0.280(3)
0.136(3)
0.103(3)
0.143(4)
0.241(4)
0.373(2)
0.156(1)
-0.338(2)
-0.370(3)
-0.373(2)
-0.444(3)
-0.475(3)
-0.433(3)
0.081(8)
0.076(6)
0.120(1)
0.150(2)
0.084(9)
0.150(2)
0.150(2)
0.160(1)
C20
N15
N11
C29
N6
C24
C25
C42
O14
C38
C39
C18
C23
C48
C3
N26
C29
C30
C30
C32
C32
C34
C37
C39
C39
C41
C47
C47
C49
C63
C64
C66
C68
C69
C29
C30
C29
N31
C24
N65
C40
C64
C38
C41
C47
C23
C41
C50
C40
C50
C68
C69
C70
112.0(22)
110.4(22)
124.0(22)
108.5(22)
126.2(24)
104.7(23)
118.5(25)
126.4(32)
120.9(22)
122.1(27)
120.5(26)
130.2(25)
117.3(22)
129.2(39)
115.8(27)
118.4(35)
124.9(38)
122.6(40)
124.7(53)
N15
N26
N11
O8
C29
C29
C30
N31
C32
C33
C36
C38
C39
C40
C42
C47
C48
C50
N65
C67
C68
C68
N26
C30
N31
C30
N65
O28
C38
C39
C41
C63
C48
C41
C49
C64
C32
C71
C66
C69
126.2(25)
123.1(22)
127.3(24)
104.5(21)
129.1(28)
122.5(28)
125.4(26)
116.2(23)
116.7(25)
125.4(29)
116.2(34)
112.6(24)
118.7(37)
110.5(37)
109.1(24)
118.4(48)
125.8(34)
110.5(37)
N6
O14
C23
C36
O14
C34
C37
C18
C42
C49
O2
[a] Numbers in parentheses are estimated standard deviations in the least
significant digits; [b] U = (1/3)∑ ∑ U a* a* a .a .
eq
i
j
ij
i
j
i
j
Table 3
Bond Distances (Å) for 4 [a]
C37
C67
C10
C68
C66
C10
C66
Atom 1
Atom 2
Distance
Atom 1
Atom 2 Distance
O1
O2
C3
N4
N6
O8
O9
C16
N65
C19
C24
C32
N15
C22
C68
C30
C33
C29
C47
N26
C36
C32
C29
N65
C38
C64
C41
C47
C49
C64
C71
C69
1.18(4)
1.35(4)
1.40(4)
1.32(4)
1.31(4)
1.40(3)
1.21(4)
1.24(6)
1.37(4)
1.39(4)
1.31(4)
1.43(4)
1.29(3)
1.33(4)
1.45(5)
1.35(4)
1.32(4)
1.39(4)
1.26(6)
1.29(4)
1.47(4)
1.21(7)
1.47(6)
1.35(7)
1.47(6)
O2
C3
C3
N6
O7
O8
N4
1.42(4)
1.39(4)
1.40(5)
1.26(4)
1.30(4)
1.39(3)
1.35(5)
1.30(3)
1.38(4)
1.40(4)
1.46(4)
1.31(3)
1.39(4)
1.44(5)
1.42(5)
1.14(5)
1.35(5)
1.37(6)
1.42(5)
1.36(4)
1.39(5)
1.42(7)
1.44(7)
1.43(7)
1.13(8)
C13
C63
C17
C25
N31
O27
C18
C25
C39
C17
N21
C24
C47
C34
C33
C40
C42
C39
C63
C48
C50
C66
C68
C70
[a] Numbers in parentheses are estimated standard deviations in the least signifi-
cant digits.
C10
N11
C13
O14
C16
C19
N21
C23
C25
O28
C34
C37
C38
C40
C42
C49
C67
C66
C69
C10
N11
O14
N15
C18
C20
C23
C24
N26
C32
C36
C37
C39
C41
C48
C50
C67
C68
Figure 1. ORTEP Plot of compound 4.
[a] Numbers in parentheses are estimated standard deviations in the
least significant digits.
possible by introduction of a suitable blocking group in the
starting indan-1-ones.
Table 4
Bond Angles (deg) for 4 [a]
EXPERIMENTAL
Atom 1 Atom 2 Atom 3
Angle
Atom 1 Atom 2 Atom 3
Angle
Melting points were determined on a Mel-Temp or
Electrothermal apparatus and are uncorrected. Elemental Analysis
was performed by Quantitative Technologies, Inc. (Whitehouse, N.
J.). The Proton Nuclear Magnetic Resonance spectra were recorded
on a Varian Unity 400 NMR spectrometer with chemical shifts
reported in ppm relative to internal tetramethylsilane. Mass spectra
were recorded on a Micromass Platform LC Mass spectrometer
operating at atmospheric pressure. Infrared spectra were recorded
as potassium bromide disks on a Mattson NU 30,000 FT IR or a
Biorad FTS 45 IR spectrometer. Reactions were usually run under
N4
C13
O2
N15
C18
C33
O1
N11
C19
N4
O2
C3
N4
O8
N11
O14
C16
C18
N21
C24
C24
C25
N65
C63
C24
N31
C30
C39
C17
C47
C24
N21
C32
C34
111.3(19)
121.6(23)
102.3(21)
113.8(17)
112.8(22)
119.4(22)
128.1(26)
128.9(25)
112.2(21)
124.9(25)
122.7(21)
119.5(25)
C13
C19
C17
O27
C3
O8
N6
C3
C36
N4
C3
C3
N6
C19
C63
C32
C68
C25
C29
C16
N21
C47
C32
C13
C34
109.5(24)
129.0(25)
111.1(24)
132.6(33)
120.3(26)
102.9(21)
127.7(26)
130.4(25)
117.6(25)
112.5(22)
120.8(28)
C10
C13
N15
C17
C19
C23
C24
C25
C25
N21
O7
O7
C13
118.0(27) a nitrogen atmosphere, and solutions were concentrated at reduced

Sep-Oct 2001
Preparation of 6-, 7-, and 8-Substituted Derivatives
1107
Table 5
Crystal and Refinement Data for 24
Table 7
Bond Distances (Å) for 24 [a]
Atom 1 Atom 2 Distance Atom 1 Atom 2 Distance
formula
C H N O
14 8 4 5
formula weight
crystal system
space group
a, Å
312.2
monoclinic
O1
O2
O3
O5
N6
N8
N9
C10
C11
C13
C14
C18
C16
C19
N9
1.304(5) O2
1.420(5) O3
1.390(6) O4
1.177(6) N6
1.376(6) N7
1.300(6) N8
1.312(6) C10
1.474(6) C11
1.398(6) C11
1.410(6) C13
1.411(7) C17
1.378(7)
C13
N7
1.358(6)
1.392(6)
1.201(6)
1.293(6)
1.320(6)
1.386(6)
1.464(7)
1.480(7)
1.388(7)
1.404(7)
1.383(7)
P2 /c
1
C15
C12
C14
C14
C12
C15
C20
C22
C20
22.26(5)
5.28(5)
24.87(6)
1281.190(1)
4; 1.48
0.2 x 0.2 x 0.2
9.16
100.0
C16
C21
C10
C21
C20
C18
C17
C21
C22
b, Å
c, Å
V, Å
3
3
Z; density (calc), g/cm
crystal size, mm
absorption coef., mm
2q (max), deg.
reflections collected
independent reflections
parameters refined
final R indices
-1
4401
1924
209
[a] Numbers in parentheses are estimated standard deviations in
the least significant digits.
R1 = 0.058, wR2 = 0.033
0.23
3
largest diff. Peak, e/Å
and evaporated. The residue was purified by flash chromatogra-
phy (eluting with 50 and 70% ethyl acetate in hexane, gradient
elution) to yield 1.4 g (61%) of 3. A sample recrystallized from
water had mp 133-136°; ir: 3491, 3412, 3353, 1755, 1742, 1719
Table 6
Fractional Atomic Coordinates and Equivalent Isotropic Displacement
2
Parameters (Å ) for 24 [a,b]
-1
1
cm ; H nmr (DMSO-d ): δ 7.55 (s, 2H), 7.63 (t, J = 7.7 Hz, 2H),
6
Atom
x
y
z
U(eq)
7.77 (t, J = 7.5 Hz, 1H), 7.89-7.98 (m, 2H), 8.07-8.19 (m, 3H);
-
ms: m/z 280 M -H O.
2
O1
O2
O3
O4
O5
N6
N9
C10
C11
C12
C13
C14
C15
C16
C17
C18
C19
C20
C21
C22
C23
1.3094(3)
1.1408(3)
0.3456(3)
0.7973(3)
1.1867(3)
0.5744(3)
0.3839(4)
0.7152(4)
0.8908(4)
0.6806(4)
1.0517(4)
0.5283(4)
0.7919(4)
1.2070(4)
0.9265(4)
1.0141(4)
1.1108(4)
0.8481(4)
0.4970(4)
1.0933(4)
1.4002(4)
-1.0600(6)
-0.7042(6)
0.0588(7)
0.2299(6)
-1.1876(7)
0.1823(7)
0.2065(8)
-0.1790(9)
-0.1351(9)
0.0384(9)
-0.5232(9)
-0.1132(9)
0.069(1)
-1.050(1)
-0.4682(9)
-0.193(1)
-0.8325(9)
-0.2755(9)
0.1004(9)
-0.387(1)
-1.276(1)
1.3267(3)
1.2172(2)
0.4950(3)
1.0441(3)
1.1580(3)
0.7832(3)
0.5696(3)
0.8682(4)
1.0729(4)
0.8743(4)
1.1624(4)
0.6714(4)
1.0056(4)
1.2107(4)
1.0359(4)
1.1979(4)
1.1443(4)
0.9945(4)
0.6780(4)
1.2414(4)
1.3935(4)
0.104(2)
0.094(2)
0.118(2)
0.137(2)
0.130(2)
0.106(2)
0.115(3)
0.093(3)
0.101(3)
0.097(3)
0.094(3)
0.093(3)
0.108(3)
0.087(3)
0.087(3)
0.105(3)
0.100(3)
0.082(3)
0.098(3)
0.096(3)
0.112(3)
Anal. Calcd. for C
H O : C, 64.43; H, 3.38. Found: C,
16 10 6
64.11; H, 3.57.
Benzoic Acid 9-Oxo-9H-2-oxa-1,3,4,10-tetraazacyclopenta-
[b]fluoren-8-yl Ester (4).
A mixture of 3 (1.2 g, 4.0 mmoles) and furazan-3,4-diamine (0.40
g, 3.9 mmoles) in 12 mL of ethanol and 12 mL of glacial acetic acid
was stirred at room temperature for 18 hours and then heated at
reflux for 6 hours. The precipitated solid was filtered and washed
with water to yield 0.62 g (46%) of 4, mp 215-217°; ir: 1741, 1597,
-1
1
1264, 1229, 1208, 1063 cm ; H nmr (TFA-d): δ 7.67 (t, J = 7.8 Hz,
2H), 7.81-7.88 (m, 2H), 8.22 (t, J = 7.9 Hz, 1H), 8.36 (d, J = 7.9 Hz,
-
2H), 8.44 (d, J = 7.7 Hz, 1H); ms: m/z 344 M .
Anal. Calcd. for C H N O : C, 62.80; H, 2.34; N, 16.27.
18
8 4 4
Found: C, 62.62; H, 2.19; N, 16.07.
8-Hydroxy-2-oxa-1,3,4,10-tetraazacyclopenta[b]fluoren-9-one
(5).
A mixture of 4 (0.87 g, 2.5 mmoles) and cesium carbonate (1.7
g, 5.3 mmoles) in 50 mL of tetrahydrofuran was stirred at room
temperature for 5 days. The precipitated solid was filtered,
washed with fresh tetrahydrofuran, and dissolved in 100 mL of
water. The aqueous mixture was acidified with 1.0 M hydrochlo-
ric acid to pH 2-3. The precipitated solid was filtered and rinsed
with water to yield 0.57 g (94%) of 5. A sample recrystallized
from methanol had mp 305°; ir: 3431, 1711, 1601, 1443, 1306,
[a] Numbers in parentheses are estimated standard deviations in the least
significant digits; [b] U = (1/3)∑ ∑ U a* a* a .a .
eq
i
j
ij
i
j i j
pressure on a rotary evaporator. Flash chromatography was per-
formed with EM Science silica gel 60, 230-400 mesh ASTM.
Benzoic Acid 2,2-Dihydroxy-1,3-dioxo-indan-4-yl Ester (3).
-1
1
1256 cm ; H nmr (THF-d ): δ 7.22 (d, J = 8.2 Hz, 1H), 7.69-
8
-
7.85 (m, 2H), 9.94 (bs, 1H); ms: m/z 240 M .
To a solution of 2 [10] (2.0 g, 7.9 mmol) in 40 mL of dimethyl
sulfoxide was added N-bromosuccinimide (2.9 g, 16 mmol). The
reaction mixture was stirred at 60° for 3 hours and then at 80° for
4 hours with a vacuum line attached to the top of the reaction flask
condenser. The reaction mixture was cooled to room temperature
and then poured into 200 mL of water. The product was extracted
Anal. Calcd. for C H N O : C, 55.01; H, 1.68; N, 23.33.
11
4 4 3
Found: C, 55.09; H, 1.99; N, 23.03.
9,9-Diethoxy-9H-2-oxa-1,3,4,10-tetraazacyclopenta[b]fluoren-
8-ol (6).
with three portions of 100 mL of dichloromethane, and then the
combined organic extracts were dried (sodium sulfate), filtered
To a mixture of 4 (0.21 g, 0.60 mmoles) in 10 mL of ethanol was
added 0.60 mL of an aqueous solution of 1.0 M sodium hydroxide

1108
L. D. Bratton, P. C. Unangst, J. R. Rubin, and B. K. Trivedi
Vol. 38
Table 8
Bond Angles (deg) for 24 [a]
Atom 1
Atom 2
Atom 3
Angle
Atom 1
Atom 2
Atom3
Angle
C13
C12
C10
N8
C12
C15
N6
O2
N7
N8
O1
O2
N6
N8
C19
C21
C14
C12
C20
C20
C10
C22
N8
C21
O5
C22
C17
N9
117.8(4)
110.4
N7
O3
O3
N8
C15
C18
O2
C17
N7
O3
N7
N9
N9
112.3(3)
103.5(4)
104.3(4)
127.4(5)
128.8(5)
120.4(5)
124.0(4)
120.8(5)
110.3(4)
129.1(5)
117.0(4)
109.8(4)
122.3(4)
124.5(4)
120.9(4)
C14
C21
C20
C18
C20
C17
C22
C21
C11
C20
C11
C17
C14
C18
109.0(4)
126.1(4)
106.5(4)
110.8(4)
125.5(4)
115.2(4)
124.9(5)
124.8(4)
126.7(5)
118.5(4)
127.8(4)
125.8(5)
109.7(4)
C10
C10
C11
C12
C13
C14
C14
C16
C18
C20
C21
C21
C10
C11
C11
C13
C13
C14
C15
C17
C20
C20
C21
C22
O4
C13
C10
C11
N6
C11
C10
N6
N9
C14
C13
[a] Numbers in parentheses are estimated standard deviations in the least significant digits.
Figure 2. ORTEP Plot of compound 24.
(0.60 mmoles). The reaction mixture was heated at reflux for 18
hours. The reaction was monitored by thin layer chromatography,
and additional aqueous sodium hydroxide was added as needed until
all of the starting material 4 was consumed. The reaction mixture
was evaporated to give a residue, which was diluted with 10 mL of
water and then acidified with aqueous 1.0 M hydrochloric acid to pH
2-3. The resulting precipitate was isolated by filtration and purified
by flash chromatography (eluting with 30% ethyl acetate in hexane)
to give 0.12 g (6%) of 6; ir: 3285, 1598, 1441, 1309, 1095, 1025
solid was filtered to give 0.48 g of the cesium salt of the starting phe-
nol. The salt was combined with an additional 0.13 mL (0.21 g, 1.4
mmol) of methyl bromoacetate in 10 mL of N,N-dimethylfor-
mamide. The reaction mixture was heated at 60° for 4 hours, stirred
at room temperature for 18 hours, and added to a mixture of ice and
water. The precipitated solid was filtered and purified by flash chro-
matography (eluting with 30% ethyl acetate in hexane) to yield 0.11
g (27%) of 7. A sample recrystallized from aqueous acetonitrile had
-1
1
mp 205-206°; ir: 1753, 1727, 1592, 1486, 1313, 1213 cm ; H nmr
-1
1
cm ; H nmr (THF-d ): δ 1.08 (t, J = 7.0 Hz, 6H), 3.69-3.81 (m,
(TFA-d): δ 4.05 (s, 3H), 5.18 (s, 2H), 7.34-7.46 (m, 1H), 8.03-8.16
8
-
2H), 3.82-3.95 (m, 2H), 7.03 (d, J = 7.6 Hz, 1H), 7.37-7.46 (m, 1H),
(m, 2H); ms: m/z 312 M .
-
7.57 (d, J = 7.6 Hz, 1H), 8.60 (s, 1H); ms: m/z 314 M .
Anal. Calcd. for C H N O : C, 53.85; H, 2.58; N, 17.94.
14
8 4 5
Anal. Calcd. for C
H N O : C, 57.32; H, 4.49; N, 17.83.
Found: C, 53.80; H, 2.56; N, 17.83.
15 14 4 4
Found: C, 57.39; H, 4.52; N, 17.64.
8-Methoxy-2-oxa-1,3,4,10-tetraazacyclopenta[b]fluoren-9-one (8).
(9-Oxo-9H-2-oxa-1,3,4,10-tetraaza-cyclopenta[b]fluoren-
8-yloxy) Acetic Acid Methyl Ester (7).
To a solution of 5 (0.50 g, 2.1 mmol) in 50 mL of N,N-dimethyl-
formamide was added sodium hydride (0.09 g, 2.3 mmol of 60%
dispersion in mineral oil), followed by 0.21 mL of iodomethane (2.3
mmol). The reaction mixture was stirred at 60° for 2 hours, and the
solvent was evaporated to give a residue, which was dissolved in
A mixture of 5 (0.25 g, 1.0 mmol), cesium carbonate (0.37 g, 1.1
mmol) and 0.10 mL of methyl bromoacetate (0.17 g, 1.1 mmol) in
10 mL of acetone was heated at reflux for 18 hours. The precipitated

Sep-Oct 2001
Preparation of 6-, 7-, and 8-Substituted Derivatives
1109
ethyl acetate and washed with three 100 mL portions of water. The
organic layer was dried (magnesium sulfate), filtered and evapo-
rated. The residue was purified by flash chromatography (eluting
with 20% ethyl acetate in dichloromethane) and recrystallized from
acetonitrile/hexane to yield 0.12 g (22%) of 8, mp 291-293°; ir:
for the preparation of 10 to yield 0.38 g (27%) of 12. The crude
product was purified by flash chromatography (eluting with chlo-
roform). A sample recrystallized from acetonitrile had mp 198-
-1
1
200°; ir: 1723, 1588, 1483, 1438, 1300, 1275 cm ; H nmr
(THF-d ): δ 5.59 (s, 2H), 6.97-7.01 (m, 1H), 7.22-7.27 (m, 1H),
8
-1 1
1716, 1588, 1485, 1434, 1308, 1284 cm ; H nmr (TFA-d): δ 4.49
7.40-7.45 (m, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.79-8.00 (m, 2H);
-
(s, 3H), 7.83 (d, J = 8.4 Hz, 1H), 8.31 (d, J = 7.5 Hz, 1H), 8.41 (t, J =
ms: m/z 336 M .
-
8.4 Hz, 1H); ms: m/z 254 M .
Anal. Calcd. for C H N O S: C, 57.14; H, 2.40; N, 16.66.
16
8 4 3
Anal. Calcd. for C H N O : C, 56.34; H, 2.48; N, 21.68.
Found: C, 56.94; H, 2.32; N, 16.78.
12
6 4 3
Found: C, 56.70; H, 2.38; N, 22.04.
6-Hydroxy-4,5-dimethylindan-1-one (14).
8-Benzyloxy-2-oxa-1,3,4,10-tetraazacyclopenta[b]fluoren-9-one
(9).
A suspension of aluminum chloride (33.2 g, 249 mmol) in 300
mL of toluene was treated with 13 [14] (22.7 g, 119 mmol). The
mixture was stirred at reflux for 1 hour, then added to 2.75 kg of
ice and water. The solid was filtered, stirred in 1.5 L of 20%
methanol in water, and filtered again to give 19.6 g (93%) of 14.
A sample recrystallized from aqueous 2-propanol had mp 245°
A mixture of 5 (1.0 g, 4.2 mmol), 0.47 mL of phenyl methanol
(0.50 g, 4.6 mmol), triphenylphosphine (1.3 g, 5.0 mmol), 0.58 mL
of triethylamine (0.42 g, 4.2 mmol) and 0.79 mL of diethyl azodi-
carboxylate (0.87 g, 5.0 mmol) in 30 mL of tetrahydrofuran was
stirred at room temperature for 18 hours. The precipitated solid was
filtered and washed with tetrahydrofuran. The crude product was
purified by flash chromatography (eluting with chloroform) to yield
0.38 g (27%) of 9. A sample recrystallized from acetonitrile had mp
-1
1
(dec); ir: 3309, 1674, 1600, 1437, 1324, 1298 cm ; H nmr
(DMSO-d ): δ 2.10 (s, 3H), 2.15 (s, 3H), 2.49-2.52 (m, 2H),
6
+
2.82-2.85 (m, 2H), 6.82 (s, 1H), 9.60 (s, 1H); ms: m/z 177 M +1.
Anal. Calcd. for C
H O : C, 74.98; H, 6.86. Found: C,
11 12 2
-1
1
236-237°; ir: 1723, 1588, 1487, 1438, 1307, 1029 cm ; H nmr
74.85; H, 6.78.
(THF-d ): δ 5.42 (s, 2H), 7.29 (t, J = 7.3 Hz, 1H), 7.38 (t, J = 7.3 Hz,
8
-
Benzoic Acid 6,7-Dimethyl-3-oxo-indan-5-yl Ester (15).
2H), 7.50-7.60 (m, 3H), 7.83 (d, J = 7.3 Hz, 2H); ms: m/z 330 M .
Anal. Calcd. for C
Found: C, 65.22; H, 2.84; N, 17.01.
H N O : C, 65.45; H, 3.05; N, 16.96.
18 10 4 3
A suspension of 14 (21.0 g, 119 mmol) and cesium carbonate
(42.9 g, 132 mmol) in 600 mL of acetone was treated dropwise
with 14.9 mL of benzoyl chloride (18.0 g, 128 mmol). The mix-
ture was stirred for 24 hours and added to 3.0 kg of ice and water.
The solid was filtered, stirred in 1.0 L of 20% methanol in water,
and filtered again to give 31.5 g (94%) of 15. A sample recrys-
tallized from aqueous acetonitrile had mp 125-127°; ir: 1736,
8-(Furan-2-ylmethoxy)-2-oxa-1,3,4,10-tetraazacyclopenta[b]flu-
oren-9-one (10).
A mixture of 5 (2.0 g, 8.3 mmol), 0.79 mL of furan-2-yl-methanol
(0.90 g, 9.2 mmol), triphenylphosphine (2.6 g, 10 mmol), 1.2 mL of
triethylamine (0.84 g, 8.3 mmol) and diethyl azodicarboxylate (1.7
g, 10 mmol) in 60 mL of tetrahydrofuran was stirred at room tem-
perature for 18 hours. The solvent was evaporated, and the residue
was purified by flash chromatography (eluting with 30-50% ethyl
acetate in hexane, gradient elution). The chromatographed material
was triturated in water to give 0.64 g (24%) of 10, 184-185°; ir:
-1
1
1703, 1601, 1442, 1249, 1088 cm ; H nmr (DMSO-d ): δ 2.13
6
(s, 3H), 2.26 (s, 3H), 2.62-2.65 (m, 2H), 2.99-3.02 (m, 2H), 7.29
(s, 1H), 7.57-7.61 (m, 2H), 7.71-7.76 (m, 1H), 8.12-8.14 (m, 2H);
-
ms: m/z 279 M .
Anal. Calcd. for C
H O : C, 77.12; H, 5.75. Found: C,
18 16 3
77.02; H, 5.76.
-1
1
1719, 1588, 1484, 1429, 1299, 1276 cm ; H nmr (THF-d ): δ 5.36
8
(s, 2H), 6.38-6.42 (m, 1H), 6.59 (d, J = 3.2 Hz, 1H), 7.52-7.55 (m,
1H), 7.62 (d, J = 8.3 Hz, 1H), 7.80-7.95 (m, 2H); ms: m/z 320 M .
Benzoic Acid 7,8-Dimethyl-9-oxo-9H-2-oxa-1,3,4,10-tetraaza-
cyclopenta[b]-fluoren-6-yl Ester (18).
-
Anal. Calcd. for C H N O : C, 60.01; H, 2.52; N, 17.49.
16
8 4 4
A mixture of 15 (16.3 g, 58.1 mmol) and N-bromosuccinimide
(20.9 g, 117 mmol) in 150 mL of dimethyl sulfoxide was heated at
40° for 3 hours. A vacuum line was attached to the top of the reac-
tion flask condenser, and the mixture was heated at 80° for 4 hours.
The cooled reaction mixture was added to 1.5 L of brine and
extracted with four 350 mL portions of dichloromethane. The com-
bined extracts were washed with three 500 mL portions of 5%
aqueous sodium bicarbonate solution and two 500 mL portions of
brine. The organic layer was dried (sodium sulfate) and evapo-
rated. The residue was purified by flash chromatography (eluting
with 50% ethyl acetate in hexane) to yield 11.4 g (64%) of benzoic
Found: C, 59.71; H, 2.67; N, 17.27.
8-(Pyridin-4-ylmethoxy)-2-oxa-1,3,4,10-tetraazacyclopenta-
[b]fluoren-9-one (11).
A mixture of 5 (2.0 g, 8.3 mmol), pyridin-4-yl-methanol (1.0 g,
9.2 mmol), triphenylphosphine (2.6 g, 10 mmol), 1.2 mL of tri-
ethylamine (0.84 g, 8.3 mmol) and diethyl azodicarboxylate (1.7 g,
10 mmol) in 60 mL of tetrahydrofuran was stirred at room temper-
ature for 18 hours. The precipitated solid was filtered and washed
with tetrahydrofuran to yield 1.9 g (70%) of 11, mp 200-201°; ir:
1731, 1589, 1439, 1304, 1279, 1027 cm ; H nmr (TFA-d): δ 6.07
(s, 2H), 7.89 (d, J = 7.4 Hz, 1H), 8.39-8.47 (m, 2H), 8.89 (d, J = 6.4
Hz, 2H), 9.24 (d, J = 6.5 Hz, 2H); ms: m/z 331 M .
-1
1
1
acid 6,7-dimethyl-1,2,3-trioxoindan-5-yl ester 16 as an oil; H nmr
-
(DMSO-d ): δ 2.24 (s, 3H), 2.69 (s, 3H), 7.46 (s, 1H), 7.57-7.64
6
-
(m, 2H), 7.73-7.81 (m, 1H), 8.12-8.19 (m, 2H); ms: m/z 308 M .
Anal. Calcd. for C H N O : C, 61.63; H, 2.74; N, 21.14.
17
9 5 3
An additional chromatography product (0.60 g, 8%) was identi-
fied as benzoic acid 2,2-dibromo-6,7-dimethyl-3-oxo-indan-5-yl
ester 17. A sample recrystallized from ethyl acetate/hexane had mp
Found: C, 61.49; H, 3.05; N, 21.34.
8-(Thiophen-2-ylmethoxy)-2-oxa-1,3,4,10-tetraazacyclopenta-
[b]fluoren-9-one (12).
-1
1
180-182°; ir: 1723, 1598, 1253, 1243, 1221, 1120 cm ; H nmr
Prepared from 5 (1.0 g, 4.2 mmoles) and 0.43 mL of thiophen-
2-yl-methanol (0.52 g, 4.6 mmoles) by the procedure described
(DMSO-d ): δ 2.18 (s, 3H), 2.23 (s, 3H), 4.31 (s, 2H), 7.55-7.66 (m,
3H), 7.70-7.78 (m, 1H), 8.11-8.17 (m, 2H); ms: m/z 439 M +1.
6
+

1110
L. D. Bratton, P. C. Unangst, J. R. Rubin, and B. K. Trivedi
Vol. 38
Anal. Calcd. for C
49.47; H, 3.22.
H
Br O : C, 49.35; H, 3.22. Found: C,
(9-Oxo-9H-2-oxa-1,3,4,10-tetraazacyclopenta[b]fluoren-6-
yloxy) Acetic Acid Methyl Ester (24).
18 14
2 3
A mixture of intermediate 16 (11.4 g, 37 mmol) and furazan-
3,4-diamine (3.8 g, 38 mmol) in 25 mL of ethanol and 25 mL of
glacial acetic acid was stirred at reflux for 4 hours. The precipi-
tated solid was filtered, stirred in 150 mL of 50% methanol in
water, and filtered again. Recrystallization of the final solid from
aqueous acetonitrile gave 4.5 g (33%) of 18, mp 245° (dec); ir:
Intermediate 23 was prepared from 22 (6.0 g, 27.2 mmol) by
the procedure described for the preparation of 16 to yield 0.70 g
(10%) of (1,2,3-trioxo-indan-5-yloxy)-acetic acid methyl ester as
an oil. The crude product was purified by flash chromatography
1
(eluting with 3% methanol in dichloromethane); H nmr (deute-
rochloroform): δ 3.78 (s, 3H), 4.75 (s, 2H), 7.22 (s, 1H), 7.43 (d,
-1
1
1719, 1584, 1241, 1199, 1086, 1020 cm ; H nmr (TFA-d): δ
-
J = 8.5 Hz, 1H), 7.92 (d, J = 8.5 Hz, 1H); ms: m/z 248 M .
2.56 (s, 3H), 3.00 (s, 3H), 7.71 (t, J = 7.7 Hz, 2H), 7.88 (t, J = 7.5
A mixture of 23 (0.65 g, 3.0 mmol) and furazan-3,4-diamine
(0.31 g, 3.1 mmol) in 4.0 mL of ethanol and 4.0 mL of glacial
acetic acid was stirred at reflux for 4 hours. The cooled reaction
mixture was added to 100 g of ice and water and extracted with
four 50 mL portions of ethyl acetate. The combined extracts
were washed with three 150 mL portions of 5% aqueous sodium
bicarbonate solution and one 150 mL portion of brine. The
organic layer was dried (sodium sulfate) and evaporated. The
residue was purified by flash chromatography (eluting with 40%
ethyl acetate in hexane) to yield 0.26 g (19%) of 24. A sample
recrystallized from aqueous acetonitrile had mp 203-205°; ir:
-
Hz, 1H), 8.23 (s, 1H), 8.41 (d, J = 7.5 Hz, 2H); ms: m/z 372 M .
Anal. Calcd. for C
H N O : C, 64.52; H, 3.25; N, 15.05.
20 12 4 4
Found: C, 64.38; H, 3.42; N, 14.94.
6-Hydroxy-7,8-dimethyl-2-oxa-1,3,4,10-tetraazacyclopenta-
[b]fluoren-9-one (19).
A suspension 18 (5.0 g, 13.4 mmol) in 100 mL of methanol
was treated with a solution of 50 mL of 2.0 M ammonia in
methanol. The mixture was stirred at room temperature for 18
hours, then added to 500 mL of water. The mixture was filtered,
and the filtrate was adjusted to pH 2 by the addition of 4.0 M
hydrochloric acid. The precipitated solid was filtered, stirred in
100 mL of 20% methanol in water, and filtered again to yield 3.5
g (97%) of 19. A sample recrystallized from aqueous acetonitrile
had mp 280° (dec.); ir: 3237, 1716, 1591, 1548, 1318, 1291
-1
1
1723, 1615, 1591, 1301, 1270, 1251 cm ; H nmr (TFA-d): δ
4.09 (s, 3H), 5.16 (s, 2H), 7.61 (d, J = 8.6 Hz, 1H), 7.95 (s, 1H),
-
8.27 (d, J = 8.6 Hz, 1H); ms: m/z 312 M .
Anal. Calcd. for C H N O : C, 53.85; H, 2.58; N, 17.94.
14
8 4 5
Found: C, 53.65; H, 2.31; N, 17.70.
-1
1
cm ; H nmr (THF-d ): δ 2.26 (s, 3H), 2.72 (s, 3H), 7.35 (s,
8
-
X-ray Structure Determination of 4.
1H), 10.82 (bs, 1H); ms: m/z 267 M -1.
Anal. Calcd. for C H N O : C, 58.21; H, 3.01; N, 20.89.
Found: C, 58.28; H, 3.13; N, 20.63.
13
8 4 3
Compound 4 crystallized as yellow needles from ethanol solu-
tions. X-ray data were collected on an Enraf-Nonius CAD-4 dif-
fractometer using CuK radiation (λ = 1.54184 Å). The cell con-
stants and the orientation matrix for data collection were deter-
mined from centered angles of 25 reflections. X-ray diffraction
data were collected at 23° C using the omega scan technique with
a variable omega scan rate from 2° to 20° per minute. The data
were collected to a maximum 2θ of 100.28°. A total of 5357
reflections were collected, of which 2346 were unique and not
systematically absent. Lorentz and polarization corrections were
applied to the data as well as an empirical absorption correction
based on a series of psi scans. The crystal structure was deter-
mined by direct methods using SIR-92. A total of 328 reflections
with E > 1.90 were used to produce a phase set with an absolute
figure of merit of 0.76. All 52 heavy atoms in the structure were
located from the E map calculated using this phase set.
Hydrogen atom positions were located in subsequent difference
fouriers and added to the structure, but their positions were not
refined. The heavy atom parameters including anisotropic tem-
perature factors were refined by full matrix least squares using
893 reflections with intensity greater than three times their stan-
dard deviation. The final unweighted R-factor is 0.089. The
final difference fourier was essentially featureless. The highest
(7,8-Dimethyl-9-oxo-9H-2-oxa-1,3,4,10-tetraazacyclopenta-
[b]fluoren-6-yloxy) Acetic Acid Methyl Ester (20).
A mixture of 19 (1.0 g, 3.7 mmol), cesium carbonate (2.4 g, 7.4
mmol), and 1.0 mL of methyl bromoacetate (1.6 g, 10.5 mmol) in
25 mL of acetonitrile was stirred at reflux for 3 hours. The pre-
cipitated solid was filtered, stirred in 100 mL of 25% methanol in
water, and filtered again. Recrystallization from acetonitrile gave
0.55 g (42%) of 20, mp 230° (dec.); ir: 1723, 1585, 1288, 1224,
-1
1
1146, 1112 cm ; H nmr (TFA-d): δ 2.51 (s, 3H), 2.89 (s, 3H),
-
4.08 (s, 3H), 5.20 (s, 2H), 7.76 (s, 1H); ms: m/z 340 M .
Anal. Calcd. for C
H N O : C, 56.47; H, 3.55; N, 16.46.
16 12 4 5
Found: C, 56.55; H, 3.55; N, 16.50.
(1-Oxo-indan-5-yloxy) Acetic Acid Methyl Ester (22).
A suspension of 21 [15] (16.0 g, 108 mmol), cesium carbonate
(38.7 g, 119 mmol) and 10.8 mL of methyl bromoacetate (17.5 g,
114 mmol) in 700 mL of acetone was stirred at room temperature
for 24 hours. The mixture was filtered, and the filter cake was
washed several times with fresh acetone. The combined filtrates
were evaporated, and the residue was recrystallized from ethyl
acetate/hexane to yield 18.2 g (76%) of 22, mp 116-118°; ir:
3
peak in this map had a height of only 0.48 e/Å .
-1
1
1763, 1692, 1614, 1587, 1270, 1220 cm ; H nmr (deuterochlo-
roform): δ 2.61 (t, J = 5.9 Hz, 2H), 3.03 (t, J = 5.9 Hz, 2H), 3.76
(s, 3H), 4.66 (s, 2H), 6.82 (s, 1H), 6.86 (d, J = 8.6 Hz, 1H), 7.64
X-ray Structure Determination of 24.
Compound 24 crystallized as amber rods from ethanol solu-
tions. X-ray data were collected on an Enraf-Nonius CAD-4 dif-
fractometer using CuK radiation (λ = 1.54184 Å). The cell con-
stants and an orientation matrix for data collection were deter-
+
+
(d, J = 8.5 Hz, 1H); ms: m/z 221 M +1 .
Anal. Calcd. for C
H O : C, 65.45; H, 5.49. Found: C,
12 12 4
65.44; H, 5.51.

Sep-Oct 2001
Preparation of 6-, 7-, and 8-Substituted Derivatives
1111
[2] A. K. Zelenin and M. L. Trudell, J. Heterocyclic Chem.,
34, 1057 (1997).
[3] L. W. Deady, J. Desneves and A. C. Ross, Tetrahedron, 49,
9823 (1993).
[4] F. D. Popp, J. Heterocyclic Chem., 9, 1399 (1972).
[5] A. Schonberg, E. Singer, G. A. Hoyer, and D. Rosenberg,
Chem. Ber., 110, 3954 (1977).
[6] R. J. Heffner and M. M. Joullie, Synth. Commun., 21, 2231
(1991).
[7] J. Tatsugi and Y. Izawa, Synth. Commun., 28, 859 (1998).
[8] N. Sato and J. Adachi, J. Org. Chem., 43, 341 (1978).
[9] E. C. Taylor, S. F. Martin, Y. Maki and G. P. Beardsley, J.
Org. Chem., 38, 2238 (1973).
[10] J. G. Cannon, R. G. Dushin, J. P. Long, M. Ilhan, N. D.
Jones and J. K. Swartzendruber, J. Med. Chem., 28, 515 (1985).
[11] Caution: On a single occasion during a large scale prepa-
ration of 3, an exotherm developed, resulting in a run-away reaction
during the period of heating at 80°. We believe this resulted from
rapid decomposition of the dimethyl sulfoxide solvent due to inade-
quate removal under vacuum of the liberated hydrogen bromide.
Halogenation / oxidation reactions in this solvent should be per-
formed with suitable safety precautions.
mined from the centered angles of 25 reflections. X-ray diffrac-
tion data were collected at 23° C using the omega scan technique
with a variable omega scan rate from 2° to 20° per minute. The
data were collected to a maximum 2θ of 100.0°. A total of 4401
reflections were collected, of which 1924 were unique and not
systematically absent. Lorentz and polarization corrections were
applied to the data as well as an empirical absorption correction
based on a series of psi scans. The crystal structure was deter-
mined by direct methods using SIR-92. Hydrogen atom positions
were located in subsequent difference fouriers and added to the
structure, and their positions were using isotropic thermal para-
meters. The heavy atom parameters including anisotropic tem-
perature factors were refined by full matrix least squares using
1147 reflections with intensity greater than three times their stan-
dard deviation. The final unweighted R-factor is 0.058. The
final difference fourier was essentially featureless. The highest
3
peak in this map had a height of only 0.23 e/Å .
Acknowledgements.
We thank Wen-Song Yue for preparing compound 8.
REFERENCES AND NOTES
[12] H. E. Zaugg, J. Org. Chem., 41, 3419, (1976).
[13] L. A. Kapicak and M. A. Battiste, Synthesis, 153 (1971).
[14] J. L. G. Nilsson, H. Selander, H. Sievertsson and I.
Skanberg, Acta Chem. Scand., 24, 580 (1970).
[15] L. W. L. Woo, N. M. Howarth, A. Purohit, H. A. M. Hejaz,
M. J. Reed and B. V. L. Potter, J. Med. Chem., 41, 1068 (1998).
[1] A. V. Eremeev, V. G. Andrianov and I. P. Piskunova,
Chem. Heterocyclic Comp., 14, 500 (1978). The required use of
acetic acid for the preparation of compound 1 is omitted in the exper-
imental example of the paper.