Synthesis and receptor binding evaluation of clavizepine analogues with no ring D substituents

Article abstract of DOI:10.1021/jo052320c

Assembly of the azepine ring of xantheno[9,1-cd]azepines by electrophilic cyclization of sulfonamide acetals provides access to clavizepine analogues in the form of 2,12b-dihydro or 4-hydroxy-2,3,4,12b-tetrahydro-1H-xantheno[9,1-cd] azepines, in the latte

Full text of DOI:10.1021/jo052320c

as the key intermediate. Synthetic samples of rac-clavizepine
1a, its O-methyl analogue 1b, and a few of their synthetic
precursors have shown promising biological activities, as they
exhibit affinity for several receptors (vide infra). This has
encouraged us to synthesize some new analogues, such as
D-ring-unsubstituted derivatives 10 and 13 for structure-activity
studies. To this end, we selected as the key intermediate the
9-hydroxymethylxanthene derivative 5 (Scheme 1), which the
annulation techniques developed by us in the earlier syntheses
were expected to convert into the final target.
Synthesis and Receptor Binding Evaluation of
Clavizepine Analogues with No Ring D
Substituents†
M. Carmen de la Fuente,‡ Shirley E. Pullan,§
Ilse Biesmans,§ and Domingo Dom´ınguez*,‡
Departamento de Qu´ımica Orga´nica y Unidad Asociada al
CSIC, Facultad de Qu´ımica, UniVersidad de Santiago de
Compostela, 15782 Santiago de Compostela, Spain, and
Psychiatry DiVision, Johnson & Johnson PRD, Turnhoutseweg
30, 2340 Beerse, Belgium
The required hydroxymethylxanthene 5 was prepared on a
large scale in 67% overall yield by anti-Markovnikov hydration
of methylenexanthene 4, which was prepared from xanthone
27 by addition of methylmagnesium chloride followed by
dehydration of the resulting tertiary alcohol 3 (Scheme 2).
Unfortunately, reaction of 5 with N-tosyl aminoacetaldehyde
dimethyl acetal under standard Mitsunobu conditions8 afforded
only a disappointing 30% yield of the desired nitrogenated
product 6a (Scheme 3), the main product being the methylene
derivative 4 (64%). That the yield was lower than the 53%
achieved in the corresponding reaction with the trimethoxy-
substituted analogue of 5 during synthesis of 1b6 indicates that
the dimethoxylated ring somehow favors the intermediate
alkoxyphosphonium salt undergoing substitution rather than
elimination.9 In other cases in which phenethyl alcohols have
undergone elimination, even when the more reactive (Boc)NHTs
or (Cbz)NHTs have been used,10 dehydration has been prevented
by addition of pyridine11 (although other authors have simply
avoided the Mitsunobu reaction, aminating by indirect routes).12
In this work, we tackled the problem by using one of the
alternative kinds of sulfonamide that has been put forward as
potentially more efficient than N-tosyl derivatives,13,14 namely
an N-trifluoromethanesulfonamide; and in the event, N-(dimethox-
yethyl)-trifluoromethanesulfonamide did indeed prove to be very
efficient for amination of hydroxymethylxanthene 5, affording
the triflamide 6b in 80% yield after chromatographic removal
of very minor amounts of the elimination product.
qomingos@usc.es
ReceiVed NoVember 9, 2005
Assembly of the azepine ring of xantheno[9,1-cd]azepines
by electrophilic cyclization of sulfonamide acetals provides
access to clavizepine analogues in the form of 2,12b-dihydro-
or 4-hydroxy-2,3,4,12b-tetrahydro-1H-xantheno[9,1-cd]aze-
pines, in the latter case producing the trans derivative
stereoselectively. Binding assays for clavizepine and ana-
logues at adrenergic, dopaminergic, and serotonergic recep-
tors are reported.
(-)-Clavizepine (1a) is a natural product that was first isolated
from Corydalis claViculata (L.) DC in 19861 and was soon
afterward found in Sarcocapnos crassifolia subsp. speciosa,2
both of which are plants belonging to the Fumariaceae family.
There have been no further reports of the isolation of this
compound, which to date is the only known alkaloid incorporat-
ing a chromeno-3-benzazepine structure. In the mid 1990s, the
total synthesis of racemic clavizepine was achieved by Ikeda’s3
group and our own,4 and both approaches featured a xanthene-
9-carboxylate as the key intermediate. Shortly afterward, we
reported alternative syntheses of racemic clavizepine5 and its
O-methyl analogue 1b6 that featured a 9-hydroxymethylxanthene
The dimethyl acetals 6a and 6b were cyclized under acidic
conditions (HCl, AcOH, 75-80 °C) to 7a (87%) and 7b (84%),
which by catalytic hydrogenation afforded the azepines 8a
(100%) and 8b (90%) (Scheme 3). Reductive cleavage of the
sulfonamide15 and the triflamide16 gave amine 9 in good yield
(7) Galt, R. H. B.; Horbury, J.; Matusiack, Z. S.; Pearce, R. J.; Shaw, J.
S. J. Med. Chem. 1989, 32, 2357-2362.
(8) (a) Mitsunobu, O. Synthesis 1981, 1-28. (b) Hughes, D. L. Org.
React. 1992, 42, 335-656.
(9) This effect of para- and ortho-substituted aryl rings has been invoked
to explain the observed racemization of homochiral benzylic alcohols during
the Mitsunobu reaction: (a) Iida, H.; Yamazaki, N.; Kibayashi, C.
Tetrahedron Lett. 1985, 26, 3255-3258. (b) Brown, R. F. C.; Jackson, W.
R.; McCarthy, T. D. Tetrahedron 1994, 50, 5469-5488. (c) Kaufman, T.
Tetrahedron Lett. 1996, 37, 5329-5332.
† Dedicated to Prof. R. Suau on the occasion of his 60th birthday.
‡ Universidad de Santiago de Compostela.
§ Johnson & Johnson PRD.
(1) Boente, J. M.; Castedo, L.; Dom´ınguez, D.; Ferro, M. C. Tetrahedron
Lett. 1986, 27, 4077-4078.
(2) Castedo, L.; Lo´pez S.; Rodr´ıguez de Lera, A.; Villaverde, M. C.
Phytochemistry 1988, 28, 251-257.
(10) Zhai, H.; Luo, Sh.; Ye, Ch.; Ma, Y. J. Org. Chem. 2003, 68, 8268-
8271.
(3) (a) Ishibashi, H.; Takagaki, K.; Imada, N.; Ikeda, M. Synlett 1994,
49-50. (b) Ishibashi, H.; Takagaki, K.; Imada, N.; Ikeda, M. Tetrahedron
1994, 50, 10215-10224.
(11) Wovkulich, P. M.; Shankaran, K.; Kiegiel, J.; Uskokovic, M. R. J.
Org. Chem. 1993, 58, 832-839.
(12) Feldman, K. S.; Cutarelli, T. D.; Di Florio, R. J. Org. Chem. 2002,
67, 8528-8537.
(4) Va´zquez, R.; de la Fuente, M. C.; Castedo, L.; Dom´ınguez, D. Synlett
1994, 433-434.
(13) Fukuyama, T.; Cheung, M.; Kan, T. Synlett 1999, 1301-1303.
(14) Edwards, M. L.; Stemerick, D. M.; McCarthy, J. R. Tetrahedron
Lett. 1990, 31, 3417-3420.
(5) de la Fuente, M. C.; Castedo, L.; Dom´ınguez, D. J. Org. Chem. 1996,
61, 5818-5822.
(6) de la Fuente, M. C.; Castedo, L.; Dom´ınguez, D. Tetrahedron 1996,
52, 4917-4924.
(15) Birkinshaw, T. N.; Holmes, A. B. Tetrahedron Lett. 1987, 28, 813-
816.
10.1021/jo052320c CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/20/2006
J. Org. Chem. 2006, 71, 3963-3966
3963

SCHEME 1
SCHEME 4a
a Reagents and conditions: (a) HCl, AcOH, rt, 1 h, 70%; (b) TFA, DCM,
rt, 1 h, 44%; (c) LiOH, THF, rt, 1 h, 93%.
SCHEME 2a
TABLE 1. nOe Data for Trifluoroacetate 12
irradiated proton
observed nOe (%)
H12b,R
H1R
H1â
H12 (7), H1R (4)
H1â (30), H12b,R (8)
1R (30), H3â (4)
H
H3â
H4â
Η
3R (30), H4â (7), H1â (3)
H3R (5), H3â (4), H5 (4)
3
TABLE 2. JH,H Couplings in Trifluoroacetate 12
coupled protons
dihedral (deg)a
calcdb 3JH,HHz
obsd 3JH,H
H
H
Η
Η
12b,R-H1R
12b,R-H1â
-82.5
163.0
75.3
1.4
10.6
0.9
0
a Reagents and conditions: (a) MeMgCl (1.2 equiv), THF, 0 °C to room
temperature (rt), 1 h; (b) EtOAc, AcOH, rt, 5 min; (c) (i) BH3-SMe2 (1.2
equiv), THF, 0 °C to rt, 1 h; (ii) H2O2/NaOH, rt, 1 h, 67% overall yield.
8.3
1.8
5.2
4â-Η3â
4â-Η3R
-37.4
6.5
SCHEME 3a
a Measured in the minimum energy conformer (Figure 1). b Calculated
with the Haasnoot-Altona equation.18
been followed by esterification to 12 was supported when the
proton NMR spectrum of a sample of 13 subjected to the
cyclization conditions showed the exclusive formation of
trifluoroacetate 12.
Interestingly, in the cyclization of 11 the 1H NMR spectrum
of the reaction mixture showed the major product 12, to be
present as just a single stereoisomer,17 the stereochemistry of
which was elucidated from nOe and 3J proton coupling data as
follows. The mutual nOe enhancements of the signals at 3.10
ppm (H1â) and 3.23 ppm (H3â) (Table 1) imply that these two
protons are both axial, and hence the seven-membered ring has
a half-chair conformation. Together with the other nOe data of
Table 1, this makes H12b axial and trans to equatorial H4. These
conclusions were supported by the coupling data for the two
AMX three-spin systems of the azepine ring (Table 2): the large
a Reagents and conditions: (d) For 6a: N-tosyl aminoacetaldehyde
dimethyl acetal, Ph3P, DEAD, THF, rt, 3 h, 30%; for 6b: N-trifluo-
romethanesulfonyl aminoacetaldehyde dimethyl acetal, Ph3P, DEAD, THF,
rt, 5 h, 80%; (e) HCl, AcOH, 80 °C, 87% for 7a, 84% for 7b; (f) H2 (1
atm), 10% Pd/C, THF, rt, 12 h, 100% for 8a, 90% for 8b; (g) Na/Hg,
Na2HPO4, MeOH, reflux, 12 h, 95%; (h) Red-Al, toluene, reflux, 85%;
(i) cinnamaldehyde, MeOH; (ii) NaCNBH3, 50%.
value of 3J12b,1â ) 8.3 Hz confirms the axial orientation of H12b
,
and the small coupling of H4 with vicinal protons shows its
equatorial orientation. Furthermore, the observed coupling
constants were in keeping with those given by the Haasnoot-
Altona equation18 for the minimum-energy conformation19
calculated by molecular mechanics20 for the proposed stereo-
chemistry (Figure 1).
in both cases. The final cinnamyl derivative 10 was obtained
by reductive amination of trans-cinnamaldehyde with amine 9.
We also prepared the hydroxy derivative 13, for which
purpose the sulfonamido aldehyde 11 was obtained by mild
hydrolysis of acetal 6a at room temperature (Scheme 4). TFA
cyclization of 11 afforded the trifluoroacetylated compound 12,
hydrolysis of which gave the desired product, 13. The suspicion
that in the cyclization reaction the initial formation of 13 had
(17) The low isolated yield was due to partial decomposition of the
1
trifluoroacetate during chromatography. Inspection of the H NMR of the
crude cyclization product did not show the presence of the cis stereoisomer.
(18) Haasnoot, C. A. G.; DeLeeuw, F. A. A. M.; Altona, C. Tetrahedron
1980, 36, 2783-2792. Calculations were performed using software provided
by R. Stenutz at http://www.casper.organ.su.se/.
(19) The alternative distorted half-chair conformation with the trifluo-
roacetate group in a pseudoequatorial position is about 7 kcal/mol higher
in energy.
(16) Hendrickson, J. B.; Bergeron, R.; Sternbach, D. D. Tetrahedron
1975, 31, 2517-2521.
(20) Molecular mechanics calculations were performed using the MM2
package of Chem-3D (CambridgeSoft Corporation, Cambridge, MA).
3964 J. Org. Chem., Vol. 71, No. 10, 2006

the 4-hydroxy clavizepine analogue 13 by cyclization of the
sulfonamido aldehyde 11 took place stereoselectively providing
the trans derivative. The synthetic N-cinnamyl derivative 10
showed a binding profile similar to that of clavizepine (1a),
with higher affinity for the 5-HT7 receptor.
Experimental Section
N-(2,2-Dimethoxyethyl), N-Trifluoromethanesulfonyl-9-ami-
nomethyl-4-methoxy-9H-xanthene (6b). Alcohol 5 (0.4 g, 1.65
mmol), N-(2,2-dimethoxyethyl)trifluoromethanesulfonamide (431
mg, 1.82 mmol), and triphenylphosphine (525 mg, 1.98 mmol) were
dissolved in dry THF (5 mL) under Ar and cooled to 0 °C. Diethyl
azodicarboxylate (313 µL, 1.98 mmol) was added dropwise, and
the mixture was stirred for 5 h at room temperature. The THF was
evaporated in vacuo, and the residue was dissolved in CH2Cl2,
washed with 1 M NaOH (2 × 30 mL) and then with brine, and
dried over anhydrous Na2SO4. Evaporation of the solvent in vacuo
afforded a residue that was column chromatographed (silica gel,
1:4 ethyl acetate/hexane) to afford 6b (Rf 0.4, 610 mg, 80%) as a
FIGURE 1. Minimum energy (MM2) conformer of 12.
TABLE 3. Binding Properties (pIC50 Values) for the Reported
Compoundsa
1
foam. IR (NaCl): 2939, 1739. H NMR δ: 7.30-7.28 (m, 3H),
receptors
7.16-7.04 (m, 2H), 6.93-6.87 (m, 2H), 4.38 (t, J ) 7.8 Hz, 1H),
4.29 (t, J ) 5.3 Hz, 1H), 3.95 (s, 3H, OMe), 3.55 (bd, J ) 7.8 Hz,
2H), 3.27 (s, 3H, OMe), 3.26 (s, 3H, OMe), 3.15-2.95 (broad,
2H). 13C NMR δ: 152.8 (s), 148.6 (s), 142.3 (s), 129.2 (d), 129.1
(d), 124.3 (d), 123.9 (d), 123.6 (s), 122.5 (s), 120.8 (d), 120.2 (q,
J ) 323 Hz, SO2CF3), 117.5 (d), 111.5 (d), 103.4 (d, HCOMe2),
56.9 (t), 56.5 (q, OMe), 55.1 (q, OMe), 54.9 (q, OMe), 51.4 (t),
39.9 (d). MS-CI (m/z): 462 (M + H+, 1), 461 (M, 5), 430 (M -
MeOH + H+, 17), 398 (100), 211 (99). HRMS calcd for C20H22-
NSO6F3: 461.1120. Found: 461.1106.
compd
AR2A
AR2B
AR2C
D2L
5-HT1A
5-HT7
1a
1b
1c
1d
7a
7b
8b
10
13
6.81
6.83
6.4
6.81
6.74
6.1
7.01
6.74
6.75
<6b
6.01
<5b
<5b
<5b
5.78
5.31
<5b
<5b
5.8
5.9
5.4
<6b
<6b
<6b
<6b
<6b
<6b
7.05
<6b
c
c
c
c
c
-
-
-
-
-
<7b
<7b
6.2
-
-
< 5b
< 5b
5.54
<5b
-
c
c
c
c
c
c
-
-
-
6.3
6.06
6.12
<7b
<5b
<5b
<5b
7-Methoxy-2-trifluoromethanesulfonyl-2,12b-dihydro-1H-
xantheno[9,1-cd]azepine (7b). Acetal 6b (400 mg, 0.87 mmol),
acetic acid (5 mL), and concentrated HCl (0.6 mL) were heated
under Ar at 80 °C for 1 h and then diluted with water and extracted
with CH2Cl2. The organic extract was washed with 5% K2CO3
solution and then with water, dried over anhydrous Na2SO4 and
concentrated to a residue that was chromatographed (silica gel, 1:4
ethyl acetate/hexane) to afford 7b (Rf 0.4, 289 mg, 84%), which
was recrystallized from CH2Cl2/hexane. Mp: 166 °C. IR (NaCl):
1572, 1495, 1452. 1H NMR δ: 7.42 (d, J ) 7.3 Hz, 1H), 7.29 (dd,
J ) 8.5, 1.1 Hz, 1H), 7.16-6.97 (m, 2H), 6.91 (d, J ) 8.4 Hz,
1H), 6.81 (d, J ) 8.4 Hz, 1H), 6.55 (d, J ) 10.5 Hz, 1H), 5.85 (d,
J ) 10.5 Hz, 1H), 4.74 (d, J ) 13.9 Hz, 1H), 4.31 (d, J ) 7.2 Hz,
1H), 3.93 (s, 3H, OMe), 3.70 (dd, J ) 13.9, 7.2 Hz, 1H). 13C NMR
δ: 150.3 (s), 147.7 (s), 139.4 (s), 129.5 (d), 129.4 (d), 126.1 (s),
125.4 (d), 124.4 (d), 121.7 (s), 121.3 (d), 120.1 (q, J ) 324 Hz,
CF3SO2), 119.2 (s), 117.2 (d), 113.1 (d), 110.9 (d), 59.1 (t), 56.6
(q, OMe), 39.1 (d). MS (m/z): 397 (M+, 32), 264 (M - CF3SO2,
100), 249 (10), 236 (18), 221 (38). HRMS calcd for C18H14F3-
NO4S: 397.0596. Found: 397.0591.
a Binding affinities are shown as pIC50 values calculated from radioligand
binding experiments performed in cell lines expressing human receptors
for adrenergic R2A (AR2A), adrenergic R2B (AR2B), adrenergic R2C (AR2C),
dopamine2 (long) (D2L), serotonin1A (5-HT1A), and serotonin7 (5-HT7).
Briefly, frozen membranes of human receptor-transfected CHO cells (AR2A
,
AR2B, AR2C, D2L, 5-HT7) or L929 cells (5-HT1A) were thawed, briefly
homogenized, and diluted in assay buffer to an appropriate protein
concentration optimized for specific and nonspecific binding. The compound
was incubated with either [3H]-rauwolscine (AR2A, AR2B, AR2C), [3H]-
spiperone (D2L), [3H]-8-OH-DPAT (5-HT1A), or [3H]-serotonin (5-HT7),
with membrane, in the presence and absence of cold excess of appropriate
blank. Membrane-bound activity was collected by filtration method and
measured, and competition binding curves containing at least eight
concentrations were calculated using internal software (Insightful). b No
significant binding was detected at these concentrations. c Not determined.
The biological activity of compounds 1a-d, 7a-b, 8b, 10,
and 13 has been evaluated in a panel of receptor binding assays.
We found that clavizepine (1a) shows affinity at the adrenergic
R
2A, R2B, and R2C, dopaminergic D2, and serotonergic 5-HT1A
and 5-HT7 receptors, as summarized in Table 3. The binding at
the R2-adrenoceptors subtypes is retained in the O-methyl 1b
and N-demethyl 1c5 analogues, while the nonbasic N-tosyl
derivative 1d5 leads to loss of affinity for the receptors tested.
The same behavior was observed within the new series of
D-ring-unsubstituted tosylamides 7a and 13 and triflamides 7b
and 8b, as they did not show any significant binding. However,
the basic cinnamyl derivative 10 showed again moderate
affinities for all three receptors tested, with the higher pIC50
value within the whole series of compounds for the 5-HT7.
In conclusion, we have synthesized new analogues of
clavizepine that have no D-ring substitutents. The very efficient
key amination of an hydroxymethylxanthene intermediate by a
Mitsunobu reaction using trifluoromethanesulfonamide allowed
preparation of the tetracyclic chromeno-3-benzazepine 9 in just
six steps and 38% overall yield. Furthermore, preparation of
7-Methoxy-2-trifluoromethanesulfonyl-2,3,4,12b-tetrahydro-
1H-xantheno[9,1-cd]azepine (8b). Compound 7b (309 mg, 0.78
mmol) and 10% Pd/C (100 mg) were stirred in THF (14 mL) under
1 atm of H2 for 12 h. Filtration through Celite and evaporation of
the solvent in vacuo then afforded sulfonamide 8b (280 mg, 90%),
which was taken into ether/hexane. Mp: 215 °C. IR (NaCl): 1577,
1
1498, 1458, 1376. H NMR δ: 7.43 (d, J ) 7.1 Hz, 1H), 7.29-
7.23 (m, 1H), 7.16-7.10 (m, 2H), 6.83 (d, J ) 8.2 Hz, 1H), 6.77
(d, J ) 8.2 Hz, 1H), 4.49 (d, J ) 9.1 Hz, 1H), 4.30-4.22 (m, 2H),
3.93 (s, 3H, OMe), 3.30 (dd, J ) 14.3, 9.3 Hz, 1H), 3.20 (dd, J )
14.3, 12.1 Hz, 1H), 3.03 (t, J ) 12.7 Hz, 1H), 2.93 (dd, J ) 15.1,
5.5 Hz, 1H). 13C NMR δ: 150.5 (s), 147.4 (s), 140.2 (s), 132.0 (s),
130.0 (d), 129.3 (d), 124.3 (d), 123.8 (d), 122.8 (s), 120.3 (q, J )
323 Hz, SO2CF3), 119.8 (s), 117.2 (d), 110.8 (d), 59.3 (t), 56.6 (q,
OMe), 49.6 (t), 40.4 (d), 37.6 (t). MS (m/z): 399 (M+, 12), 266
(M - CF3SO2, 100), 239 (16), 225 (28), 209 (78). HRMS calcd
for C18H16F3NO4S: 399.0752. Found: 399.0739.
J. Org. Chem, Vol. 71, No. 10, 2006 3965

7-Methoxy-2,3,4,12b-tetrahydro-1H-xantheno[9,1-cd]aze-
pine (9). Method B. Triflamide 8b (50 mg, 0.12 mmol) was
dissolved in dry THF (7 mL) under Ar, Red-Al solution (65% in
toluene, 195 µL, 0.62 mmol) was added, and the mixture was heated
at 100 °C for 1 h. The resulting solution was cooled to 0 °C, NH4-
Cl solution was added, the THF was removed in vacuo, and the
residue was dissolved in CH2Cl2. This solution was washed with
water and dried over anhydrous Na2SO4, and evaporation of the
solvent in vacuo then afforded a residue that when column
chromatographed (silica gel, 94:6 CH2Cl2/MeOH) afforded amine
9 (Rf 0.3, 28 mg, 85%). IR (NaCl): 3338 (NH), 1578, 1493, 1449.
1H NMR δ: 7.29 (d, J ) 7.5 Hz, 1H), 7.23-7.12 (m, 2H), 7.03
(td, J ) 7.5, 1.8 Hz, 1H), 6.75 (d, J ) 8.2 Hz, 1H), 6.69 (d, J )
8.2 Hz, 1H), 4.32 (d, J ) 8.0 Hz, 1H), 3.89 (s, 3H, OMe), 3.43-
3.20 (m, 2H), 3.12-3.08 (m, 1H), 2.98 (dd, J ) 13.2, 1.6 Hz, 1H),
2.75-2.60 (m, 2H), 2.73 (bs, NH). 13C NMR δ: 150.5 (s), 146.7
(s), 140.0 (s), 134.5 (s), 129.7 (d), 128.3 (d), 124.4 (s), 123.6 (d),
123.0 (d), 122.5 (s), 116.9 (d), 110.0 (d), 59.9 (t), 56.5 (q), 48.3
(t), 41.5 (d), 39.0 (t). MS (m/z): 267 (M+, 39), 237 (52), 225 (100),
209 (28). HRMS calcd for C17H17NO2: 267.1260. Found: 267.1256.
7-Methoxy-2-[(E)-3-phenylprop-2-enyl]-2,3,4,12b-tetrahydro-
1H-xantheno[9,1-cd]azepine (10). Cinnamaldehyde (92 µL, 0.72
mmol) was added to a solution of amine 9 (190 mg, 0.71 mmol) in
dry MeOH (25 mL) followed after 30 min by sodium cyanoboro-
hydride (142 mg, 2.1 mmol). After 14 h of being stirred at room
temperature, some drops of NH4Cl solution were added. The solvent
was evaporated, the residue was dissolved in CH2Cl2, and this
solution was washed with water and dried with anhydrous
Na2SO4. Evaporation of the solvent in vacuo afforded a residue
that was purified by column chromatography (silica gel, 200:1 CH2-
Cl2/MeOH) affording amine 10 (Rf 0.2, 136 mg, 50%), which was
recrystallized from CH2Cl2/hexane. Mp: 125 °C. IR (NaCl): 1579.
1H NMR δ: 7.60-7.09 (m, 8H), 7.03 (td, J ) 8.0, 1.5 Hz, 1H),
6.78 (d, J ) 8.2 Hz, 1H), 6.72 (d, J ) 8.2 Hz, 1H), 6.53 (d, J )
15.8 Hz, 1H), 6.33 (dt, J ) 15.8, 6.6 Hz, 1H), 4.48 (d, J ) 9.2 Hz,
1H), 3.92 (s, 3H, OMe), 3.36 (d, J ) 6.6 Hz, 2H), 3.17-3.15 (m,
3H), 2.72 (dd, J ) 14.8, 6.2 Hz, 1H), 2.64 (dd, J ) 12.5, 9.6 Hz,
1H), 2.24 (t, J ) 12.0 Hz, 1H). 13C NMR δ: 150.4 (s), 146.3 (s),
139.6 (s), 136.8 (s), 134.3 (s), 133.2 (d), 129.6 (d), 128.6 (d), 127.9
(d), 127.5 (d), 126.6 (d), 126.3 (d), 124.2 (s), 123.3 (d), 122.4 (s),
122.3 (d), 116.5 (d), 109.7 (d), 66.7 (t), 61.3 (t), 56.2 (q, OMe),
55.0 (t), 37.5 (d), 35.3 (t). MS (m/z): 383 (M+, 26), 266 (M -
CH2CHdCHPh, 100), 237 (40), 225 (42), 209 (90). HRMS calcd
for C26H25NO2: 383.1885. Found: 383.1882.
(4S*,12bS*)-2,3,4,12b-Tetrahydro-4-trifluoroacetoxy-7-meth-
oxy-2-tosyl-1H-xantheno[9,1-cd]azepine (12). TFA (1.5 mL) was
added to a solution of aldehyde 11 (225 mg, 0.51 mmol) in
CH2Cl2 (4 mL), and the mixture was stirred at room temperature
for 1 h, cooled to 0 °C, and treated with a saturated aqueous solution
of NaHCO3. The aqueous phase was separated and extracted with
CH2Cl2, the combined organic phases were washed with brine and
then dried over anhydrous Na2SO4, the CH2Cl2 was removed in
vacuo, and the residue was rapidly column chromatographed (silica
gel, 8:1 CH2Cl2/hexane), which afforded 12 (Rf 0.7, 121 mg, 44%)
as an amorphous solid. IR (NaCl): 2932, 1782 (CO), 1576, 1494.
1H NMR δ: 7.63 (d, J ) 8.3 Hz, 2H), 7.45 (d, J ) 7.0 Hz, 1H),
7.27-7.25 (m, 3H), 7.15-7.12 (m, 2H), 6.98 (d, J ) 8.3 Hz, 1H),
6.75 (d, J ) 8.3 Hz, 1H), 6.00 (dd, J ) 5.2, 1.8 Hz, 1H), 4.84 (d,
J ) 8.3, Hz, 1H), 4.40 (dd, J ) 14.6, 5.2 Hz, 1H), 4.13 (d, J )
13.8 Hz, 1H), 3.92 (s, 3H, OMe), 3.23 (dd, J ) 14.6, 1.8 Hz, 1H),
3.10 (dd, J ) 13.8, 8.3 Hz, 1H). 13C NMR δ: 157.0 (q, J ) 43
Hz, CO2CF3), 150.0 (s), 149.8 (s), 144.0 (s), 140.4 (s), 136.9 (s),
130.3 (d), 129.9 (d), 129.1 (d), 127.2 (d), 126.4 (s), 126.3 (d), 124.3
(d), 123.1 (s), 119.9 (s), 117.0 (d), 114.9 (q, J ) 286 Hz, CF3),
110.0 (d), 79.8 (d), 58.2 (t), 56.5 (q, OMe), 49.2 (t), 37.8 (d), 21.8
(q, Me). MS (FAB) (m/z): 534 (M + H+, 28), 420 (M - OCOCF3,
100). HRMS calcd for C26H23F3NO6S: 534.1198. Found: 534.1188.
(4S*,12bS*)-2,3,4,12b-Tetrahydro-7-methoxy-2-tosyl-1H-xan-
theno[9,1-cd]azepin-4-ol (13). Trifluoroacetate 12 (119 mg, 0.22
mmol) was dissolved in THF (6 mL), a solution of LiOH‚H2O (130
mg, 3.1 mmol) in H2O (2 mL) was added, and the mixture was
vigorously stirred for 1 h. The THF was evaporated in vacuo, and
the residue was dissolved in CH2Cl2. This solution was washed
with 10% aqueous HCl, the aqueous phase was separated and
extracted with CH2Cl2, the combined organic phases were washed
with water and then dried over anhydrous Na2SO4, and the CH2-
Cl2 was removed in vacuo. Column chromatography of the residue
(CH2Cl2) afforded 13 (Rf 0.2, 98 mg, 93%), which was recrystallized
from ether/hexane. Mp 163 °C (dec). IR (NaCl): 3470 (OH), 1577,
1493. 1H NMR δ: 7.66 (d, J ) 8.3 Hz, 2H), 7.04 (d, J ) 7.0 Hz,
1H), 7.28-7.21 (m, 3H), 7.14-6.91 (m, 2H), 6.84 (d, J ) 8.2 Hz,
1H), 6.71 (d, J ) 8.2 Hz, 1H), 5.09 (d, J ) 9.5 Hz, 1H), 4.86 (dd,
J ) 4.8, 3.1 Hz, 1H), 4.26 (d, J ) 13.5 Hz, 1H), 4.29-4.22 (m,
1H), 3.90 (s, 3H, OMe), 2.97 (d, J ) 14.0 Hz, 1H), 2.96 (dd, J )
13.5, 9.5 Hz, 1H), 2.80 (d, J ) 3.1 Hz, 1H, OH), 2.39 (s, 3H). 13
C
NMR δ: 150.2 (s), 148.5 (s), 143.9 (s), 140.2 (s), 136.6 (s), 132.6
(s), 130.2 (d), 130.1 (d), 128.8 (d), 127.3 (d), 124.2 (d), 124.1 (d),
122.5 (s), 120.6 (s), 116.9 (d), 109.8 (d), 74.7 (d), 58.7 (t), 56.4 (q,
OMe), 52.2 (t), 37.3 (d), 21.9 (q). MS (FAB) (m/z): 438 (M +
H+, 24), 437 (M, 19), 420 (M - H2O + H+, 100). HRMS calcd
forC24H23NO5S: 437.1297. Found: 437.1304.
N-(Formylmethyl), N-Tosyl-9-aminomethyl-4-methoxy-9H-
xanthene (11). A mixture of acetal 6a (370 mg, 0.77 mmol), glacial
acetic acid (6 mL), water (6 mL), and concentrated HCl (2 mL)
was stirred at room temperature under Ar for 1 h, diluted with water,
and extracted with CH2Cl2. The organic extract was washed with
5% K2CO3 solution and then with water, dried over anhydrous
Na2SO4, and concentrated to dryness. Chromatography of the
residue (silica gel, 3:7 ethyl acetate/hexane) afforded aldehyde 11
as a foam (Rf 0.4, 234 mg, 70%). IR (NaCl): 1730 (CHO), 1575,
Acknowledgment. Support of this work by the Spanish
Ministries of Science and Technology (Project BQU2002-
01176) and Education and Science (Project CTQ2005-02338),
in collaboration with ERDF, and by Johnson & Johnson
Pharmaceutical Research and Development is gratefully ac-
knowledged. M.C.F. thanks Xunta de Galicia for a Parga Pondal
contract.
1
1484. H NMR δ: 9.15 (s, 1H, CHO), 7.64 (d, J ) 8.3 Hz, 2H),
7.38-7.21 (m, 4H), 7.16-7.04 (m, 3H), 6.97 (dd, J ) 7.7, 1.5 Hz,
1H), 6.88 (dd, J ) 7.8, 1.5 Hz, 1H), 4.42 (t, J ) 7.4 Hz, 1H), 3.93
(s, 3H, OMe), 3.34 (s, 2H, CH2CHO), 3.21 (d, J ) 7.4 Hz, 2H),
2.41 (s, 3H, Me). 13C NMR δ: 197.8 (d), 152.5 (s), 148.5 (s), 144.5
(s), 142.0 (s), 135.4 (s), 130.3 (d), 129.6 (d), 128.9 (d), 127.9 (d),
124.2 (d), 123.9 (d), 123.8 (s), 122.7 (s), 121.2 (d), 117.2 (d), 111.4
(d), 59.9 (t), 57.8 (t), 56.4 (q, OMe), 40.7 (d), 21.9 (q, Me). MS
(FAB) (m/z): 438 (M + H+, 3), 355 (6), 309 (17), 238 (24), 231
(64). HRMS calcd for C24H24NO5S: 438.1375. Found: 438.1368.
Supporting Information Available: Experimental procedures
and characterization data for 5, 6a, 7a, 8a, 9 (Method A) and N-(2,2-
dimethoxyethyl)trifluoromethanesulfonamide. Copies of the 1H
NMR and 13C NMR spectra for compounds 3, 4, 5, 6a, 6b, 7a, 7b,
8a, 8b, 9, 10, 11, 12, and 13. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO052320C
3966 J. Org. Chem., Vol. 71, No. 10, 2006