Synthesis of chromeno[4,3,2-cd]isoindolin-2-ones and chromeno[4,3,2-de] isoquinolin-3-ones. Electrophilic versus anionic cyclization of carbamates

Article abstract of DOI:10.1016/j.tet.2004.07.089

The total synthesis of chromeno[4,3,2-cd]isoindolin-2-ones 6a-d and chromeno[4,3,2-de]isoquinolin-3-ones 15a-b from 4-methoxy-9H-xanthen-9-one is reported. The construction of the nitrogenated ring was attempted by both intramolecular electrophilic and anionic cyclizations of the corresponding carbamate precursors. Only anionic cyclization was possible for isoindolinones, but for isoquinolinones the electrophilic and anionic routes both afforded excellent yields. Graphical Abstract

Full text of DOI:10.1016/j.tet.2004.07.089

Tetrahedron 60 (2004) 10019–10028
Synthesis of chromeno[4,3,2-cd]isoindolin-2-ones and
chromeno[4,3,2-de]isoquinolin-3-ones. Electrophilic versus
anionic cyclization of carbamates
*
´
M. Carmen de la Fuente and Domingo Domınguez
´ ´ ´
Departamento de Quımica Organica y Unidad Asociada al CSIC, Facultad de Quımica, Universidad de Santiago de Compostela,
15782 Santiago de Compostela, Spain
Received 28 May 2004; revised 26 July 2004; accepted 29 July 2004
Available online 11 September 2004
Abstract—The total synthesis of chromeno[4,3,2-cd]isoindolin-2-ones 6a–d and chromeno[4,3,2-de]isoquinolin-3-ones 15a–b from
4-methoxy-9H-xanthen-9-one is reported. The construction of the nitrogenated ring was attempted by both intramolecular electrophilic and
anionic cyclizations of the corresponding carbamate precursors. Only anionic cyclization was possible for isoindolinones, but for
isoquinolinones the electrophilic and anionic routes both afforded excellent yields.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Xanthenes are among the oldest classical pigments,1 are
used as linkers in solid phase peptide synthesis2 and as
protectors of the 50-OH of nucleosides,3 and in many cases
have interesting biological effects4 such as inhibition of
gastric secretion,5 and antitumoral,6 opiaceous7 or cytotoxic
activity.8 Benzolactams such as isoindolinones9 and iso-
Scheme 1.
quinolinones10 have also been reported to have a broad
arylation of carbamates (Banwell’s cyclization)12 is a well
spectrum of pharmacological activities. In particular, in the
recent patent literature there are claims that unsubstituted
established procedure for the synthesis of isoquinolinones,13
chromeno[4,3,2-cd]isoindolin-1-one and isoquinolin-3-one
but we know of no reports of its use for the synthesis of
are poly(ADP ribose) polymerase inhibitors that are useful
isoindolinones. The required carbamate was prepared
for treating neural and cardiovascular tissue damage.11 In
straightforwardly from starting 4-methoxyxanthone
this paper we report our approach to the synthesis of
(Scheme 2). Reduction of xanthone 17 with zinc powder
chromenoisoindolinones 6a–d and chromenoisoquinoli-
in alkaline ethanol gave a 92% yield of xanthydrol 2,6 which
nones 15a–b by construction of the nitrogenated ring on
was then aminated to the N-xanthen-9-yl derivative 3 with
the skeleton of 4-methoxyxanthone 1 by either electrophilic
ethyl carbamate in acetic acid/ethanol (91%). Alkylation of
or anionic annelating (Scheme 1).
3 by treatment with NaH in DMF followed by addition of
methyl iodide gave the tertiary carbamate 4 in 90% yield.
However, reaction of 4 under Banwell’s conditions12 (with
Tf2O (5 equiv) and DMAP (3 equiv) in CH2Cl2) afforded a
2. Results and discussion
quantitative yield of the dimethylamine pyridinium salt
resulting from nucleophilic displacement of the urethane.
We first planned to synthesize isoindolone 6a by the
classical approach, electrophilic cyclization of the corre-
Other attempts at cyclization included the treatment of 4
sponding carbamate 4 (Scheme 2). The intramolecular
with PPA at 70 8C,14 which led to slow oxidation to the
xanthone 1, or with refluxing POCl3,15 which afforded a
complex mixture with no cyclized compounds.
Keywords: Isoindolin-2-ones; Isoquinolin-1-ones; Electrophilic cycliza-
tion; Carbamates; Anionic cyclization.
* Corresponding author. Tel.: C34-981563100; fax: C34-981595012;
e-mail: qomingos@usc.es
The failure of 4 to undergo cyclization was ascribed to the
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.07.089

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M. C. de la Fuente, D. Domınguez / Tetrahedron 60 (2004) 10019–10028
10020
Scheme 2.
Scheme 3.
instability of the carbamate group at the very reactive
9-position of the xanthene nucleus under the harsh
conditions required for its activation. We therefore, decided
to try to construct the fused five membered lactam ring by
means of the anionic cyclization mechanism that we had
previously used for the synthesis of benzofused
g-lactones,16 and which appears to have been applied to
isoindolinones only in the case of a synthesis of dibenz[cd,
f]indolones described in the patent literature.17 For this we
needed to metalate the aromatic ring para to the methoxy
group in 4 so as to acylate it intramolecularly with the
carbamate.18 To be able to carry out the metalation by
halogen–metal exchange, we treated the carbamate 4 with
bromine in acetic acid in the presence of sodium acetate,
which regioselectively afforded the required brominated
compound 5 in high yield (Scheme 3). Treatment of 5 with
an equimolecular amount of n-BuLi at K78 8C (Method A
in Section 3) then provided the intermediate lithiated
derivative that evolved to a mixture of the desired cyclized
compound 6a (54%) and debrominated 4 (39%). To clarify
whether the latter one was produced by protonation of the
intermediate aryl-lithium derivative during work-up or
previously, we repeated the reaction and quenched it with
methanol-d1 (Method B); the finding that the resulted lactam
6b had deuterium at C10b while the accompanying
compound 4 had none suggests that the isoindolone product
acts as a proton source for the organometallic intermediate.
In keeping with this, the yield of 6 increased to 65% when
2 equiv of n-BuLi were used, and to 80% when the
carbamate was added to a solution of 3 equiv of n-BuLi
(Method C). Adding the carbamate to the base instead of the
other way round favors deprotonation at position 10b of the
isoindolinone by the excess of base, which both forestalls its
deprotonation by the aryl-lithium intermediate (which thus
survives to be cyclized) and prevents nucleophilic addition
of n-BuLi to the carbonyl of the cyclized product.
The applicability of the above cyclization procedure to the
synthesis of 10b-substituted isoindolinones was verified by
preparing 6c and 6d by anionic cyclization of the
9-substituted bromocarbamates 9c and 9d. Although
bromination of the corresponding 9-substituted analogues
of 4 did not occur at position 1 but at position 2, which was
ascribed to steric hindrance by C9 substituents, this problem
was circumvented by brominating the starting xanthone
(Scheme 4): regioselective bromination of 1 to 7 followed
by reaction with phenylmagnesium chloride or ethyl-
magnesium bromide gave the tertiary xanthydrols 8a and
Scheme 4.

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M. C. de la Fuente, D. Domınguez / Tetrahedron 60 (2004) 10019–10028
10021
Scheme 5.
8b in high yields, and reaction of the latter ones with ethyl
carbamate followed by N-methylation as before led to the
required 9-substituted bromocarbamates 9c and 9d. Treat-
ment of these intermediates with an equimolecular amount
of n-BuLi in THF at K78 8C (Method A) led to bromine–
lithium exchange, and the resulting aryl-lithiated derivatives
were successfully trapped by the internal acylating carba-
mate in an anionic cyclization step which proceeded in very
good yield for both 6c and 6d.
cyclization of 14 drastically drops to 14 and 11% when
using 2 or 3 equiv of n-BuLi respectively. The deleterious
effect of excess base, which contrasts with its increasing the
yield of isoindolone 6, is due to the acidity of proton 11b of
the isoquinolinone 15a, abstraction of which by the n-BuLi
promotes the alkylation of this position by n-BuBr formed
during the bromine–lithium exchange (as was deduced from
the isolation of significant amounts of the corresponding
11b-butylisoquinolinone when 2 equiv of n-BuLi were
used); with 3 equiv of n-BuLi this process was followed
by nucleophilic addition to the carbonyl of the lactam,
affording an 3,11b-dibutylisoquinolinium derivative as
major product.
We next addressed the preparation of six-membered
lactams. The carbamate necessary for electrophilic cycliza-
tion, 13, was prepared starting from xanthydrol 2 by
cyanation with TMSCN, followed by reduction with borane
to the aminomethyl xanthene 11, which was then reacted
with ethyl chloroformate and finally N-methylated
(Scheme 5). Gratifyingly, submitting carbamate 13 to
electrophilic cyclization conditions (treatment with Tf2O
and DMAP) provided the desired isoquinolinone 15a in
excellent yield. This result contrasts sharply with the
failure of this procedure in the case of the lower
homologue 4; it seems likely that carbamate 13 is more
stable, surviving the reactions conditions without
decomposition.
Thus both cyclization procedures are effective for the
synthesis of chromenoisoquinolinone 15a, although the
electrophilic mechanism provides the shorter and higher
yielding route.
As in the case of isoindolinones, we also synthetized the
11b-phenylated analogue (Scheme 6). Carbamate 20 was
prepared from 9-phenylxanthydrol 16 by conversion of the
latter to cyanide 17 (by treatment with TMSCN and ZnI2),
reduction of 17 to amine 18 (best achieved by NaBH4/NiCl2
in EtOH), carboxylation of 18 to carbamate 19, and final
N-methylation. Upon treatment with triflic anhydride and
DMAP the electrophilic cyclization of 20 to 15b occurred in
an excellent 95% yield. Carbamate 24, required for the
anionic cyclization, was prepared from bromophenyl-
xanthydrol 8a, regioselectivity problems precluding its
preparation by direct bromination of 20. Compound 8a
was converted to the cyanide 21, following which reduction
with borane, acylation and N-methylation gave the required
bromocarbamate 24. Finally, addition of an equimolar
amount of n-BuLi promoted anionic cyclization, affording
15b in 80% yield.
The alternative anionic cyclization also proved successful.
The first ones to apply this method to the synthesis of
d-benzolactams were Comins et al., who after considerable
experimentation obtained a 26% optimized yield in the
assembly of the 6-membered lactam ring of the proto-
berberine alkaloid (K)-xylopinine.19 Recent findings by
Orito et al. suggest that these low yields are due to the
organometallic reagent reacting with the benzolactam
product faster than with the substrate.20 Thus, for this
cyclization to be successful it would appear that the
substrate must be such that bromine–lithium exchange and
subsequent entrapment by the carbamate group are so fast
that no organometallic is left when the lactam is formed by
internal acylation. Fortunately this proved to be the case
with the bromocarbamate 14, which was prepared straight-
forwardly by almost quantitative bromination of 13
(Scheme 5). Upon treatment of 14 with an equimolecular
amount of n-BuLi the isoquinolinone 15a was formed in
74%. In contrast with the lower homolog 6, the yield of
In summary, we have evaluated both electrophilic and
anionic cyclization protocols for the annelation of lactams
in xantheno derivatives. The more classical electrophilic
cyclization of carbamates was only useful for the synthesis
of isoquinolinones, while the less known anionic cyclization
proved to be efficient for the assembling of both five and six-
membered lactams.

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10022
Scheme 6.
3. Experimental
(C), 129.8 (CH), 129.5 (CH), 124.0 (CH), 123.4 (CH), 122.5
(C), 121.5 (C), 121.2 (CH), 117.2 (CH), 111.3 (CH), 61.5
(OCH2), 56.5 (OCH3), 46.2 (CH), 15.0 (CH3). EI-MS: m/z
(%) 299 (MC, 49), 270 (74), 211 (100). HRMS: Calcd for
C17H17NO4: 299.115758; found: 299.115593.
3.1. General procedures
The solvent for NMR was CDCl3 (unless otherwise stated),
with TMS as internal reference. Coupling constants (J) are
in Hertz. Most of the 1H (250.13 MHz) and 13C NMR
(62.83 MHz) signals of the tertiary carbamates are doubled
as a consequence of their existence as mixtures of rotamers.
All new compounds were determined to be more than 95%
3.2.3. N-(4-Methoxy-9H-xanthen-9-yl)-N-methylcarba-
mic acid ethyl ester (4). Sodium hydride (1.19 g, 80% in
mineral oil, 39.6 mmol) was washed twice with THF, DMF
(3 mL) was added and this suspension was first deoxy-
genated by passing a stream of argon through it, and then
cooled to 0 8C before a solution of carbamate 3 (3.94 g,
13.1 mmol) in deoxygenated DMF (24 mL) was added.
After 30 min at 0 8C, methyl iodide (1.64 mL, 26 mmol)
was added, and after a further 30 min at rt water was added,
the mixture was extracted with CH2Cl2, the organic extract
was washed with saturated aqueous NaCl solution (3!
100 mL), dried with Na2SO4 and filtered, and the solvent
was removed under reduced pressure. The residue was
purified by flash chromatography (1:4 EtOAc/hexane),
giving 4 as a colourless oil (3.94 g, 90%). IR (NaCl):
1
pure by H and 13C NMR. All chemicals were purchased
from Aldrich.
3.2. Synthesis of chromeno[4,3,2-cd]isoindolin-2-ones
(6a–d)
3.2.1. 4-Methoxy-9H-xanthen-9-ol (2). A suspension of
4-methoxy-9H-xanthen-9-one (1)7 (20 g, 0.088 mol), Zn
(8.68 g, 0.133 mol) and NaOH (21.2 g, 0.53 mol) in 96%
ethanol (220 mL) was heated at 90 8C for 2 h. The solid was
removed by filtration, associated product was recovered by
washing with ethanol, and the pooled washings and filtrate
condensed to dryness. Water was added to the residue and
the precipitated 4-methoxy-9H-xanthen-9-ol was filtered
out and washed with more water affording a white solid
(18.6 g, 92%). Mp 124 8C; lit.6 125–128 8C. 1H NMR: 7.60
(dd, JZ7.6, 1.6 Hz, 1H), 7.35–7.08 (m, 5H), 6.92 (dd, JZ
7.9, 1.6 Hz, 1H), 5.82 (d, JZ8.6 Hz, 1H), 3.94 (s, 3H), 2.15
(d, JZ8.6 Hz, 1H).
1
1695 (CO) cmK1. H NMR: 7.40–7.22 (m, 3H), 7.14–6.86
(m, 4H), 6.82 and 6.63 (both s, 1H), 4.35 and 4.26 (both q,
JZ7.1 Hz, 2H), 3.93 (s, 3H), 2.45 and 2.40 (both s, 3H),
1.39 and 1.31 (both t, JZ7.1 Hz, 3H). 13C/DEPT: 157.9
(CO), 156.6 (CO), 152.2 (C), 151.9 (C), 148.1 (C), 148.0
(C), 142.2 (C), 142.0 (C), 129.6 (CH), 129.5 (CH), 129.1
(CH), 124.1 (CH), 123.4 (CH), 121.0 (CH), 120.5 (CH),
120.4 (CH), 120.1 (CH), 119.4 (C), 119.1 (C), 117.3 (CH),
117.2 (CH), 111.3 (CH), 62.1 (OCH2), 62.0 (OCH2), 56.4
(OCH3), 50.8 (CH), 50.6 (CH), 29.4 (NCH3), 28.9 (NCH3),
15.3 (CH3), 15.1 (CH3). EI-MS: m/z (%) 313 (MC, 12), 211
(100). HRMS: Calcd for C18H19NO4: 313.131408; found:
313.131961.
3.2.2. N-(4-Methoxy-9H-xanthen-9-yl)carbamic acid
ethyl ester (3). A solution of urethane (1.56 g,
17.5 mmol) in acetic acid/ethanol (5 mL/5 mL) was added
to
a solution of 4-methoxy-9H-xanthen-9-ol (4 g,
17.5 mmol) in acetic acid (7 mL) and ethanol (7 mL).
After stirring for 12 h at rt, water was added and a white
solid was filtered out and washed with water and cold
methanol (4.7 g, 91%). Mp 142 8C. IR (KBr): 3308 (NH),
1681 (CO) cmK1. 1H NMR: 7.53 (d, JZ7.4 Hz, 1H), 7.31–
7.22 (m, 2H), 7.16–7.03 (m, 3H), 6.89 (dd, JZ7.7, 1.7 Hz,
1H), 6.20 (d, JZ9.6 Hz, 1H), 5.33 (d, JZ9.6 Hz, 1H), 4.19
(q, JZ7.1 Hz, 2H), 3.95 (s, 3H, OMe), 1.26 (t, JZ7.1 Hz,
3H). 13C/DEPT: 156.7 (CO), 151.2 (C), 148.0 (C), 141.2
3.2.4. N-(1-Bromo-4-methoxy-9H-xanthen-9-yl)-N-
methylcarbamic acid ethyl ester (5). The carbamate 4
(3.2 g, 10.3 mmol) and NaOAc (1.26 g, 15.4 mmol) were
dissolved in AcOH (30 mL), bromine (0.63 mL, 12.2 mmol)
was added, and the solution was stirred for 12 h. Sodium
thiosulphate solution was added and the mixture was
extracted with CH2Cl2, the organic layer washed with
aqueous NaCl, dried with Na2SO4 and filtered, and the

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M. C. de la Fuente, D. Domınguez / Tetrahedron 60 (2004) 10019–10028
10023
solvent was removed under reduced pressure. The residue
was purified by flash chromatography (3:1 CH2Cl2/hexane),
affording 3.6 g (90%) of 5, which was recrystallized from
0.25 mmol) in THF (4 mL) was added to n-BuLi (478 mL
1.6 M, 0.76 mmol) in THF (1 mL) at K80 8C. After 30 min,
aqueous NH4Cl was added to the cooled reaction mixture
and the solvent was removed under reduced pressure. The
residue was extracted with CH2Cl2, and the extract was
washed with water, dried over Na2SO4 and concentrated.
Flash chromatography (99:1 CH2Cl2/MeOH) afforded solid
6a (54 mg, 80%).
CH2Cl2/hexane. Mp 130 8C. IR (NaCl): 1696 (CO) cmK1
.
1H NMR: 7.68 and 7.31 (both d, JZ7.1, 8.7 Hz, 1H), 7.27–
7.12 (m, 4H), 6.83 and 6.63 (both s, 1H), 6.79 (d, JZ5.7 Hz,
1H), 4.36–4.19 (m, 2H), 3.95 (s, 3H), 2.37 and 2.35 (both s,
3H), 1.43 and 1.27 (both t, JZ7.1 Hz, 3H). 13C/DEPT:
156.9 (CO), 156.0 (CO), 151.7 (C), 147.8 (C), 144.4 (C),
144.2 (C), 130.1 (CH), 129.7 (CH), 129.6 (CH), 129.5 (CH),
127.2 (CH), 127.1 (CH), 124.7 (CH), 124.6 (CH), 120.6 (C),
120.1 (C), 119.6 (C), 119.4 (C), 116.8 (CH), 116.6 (CH),
115.0 (C), 114.9 (C), 112.7 (CH), 112.6 (CH), 62.2 (OCH2),
62.0 (OCH2), 56.6 (OCH3), 51.8 (CH), 51.6 (CH), 29.2
(NCH3), 28.8 (NCH3), 15.4 (CH3), 15.2 (CH3). EI-MS: m/z
(%) 393 [(MC2)C, 1], 391 (MC, 1), 312 (MKBr, 87), 291
(MKNMeCO2EtC2, 99), 289 (MKNMeCO2Et, 100).
HRMS: Calcd for C18H18BrNO4: 391.041919; found:
391.041090.
3.3.4. 1-Bromo-4-methoxy-9H-xanthen-9-one (7).
Bromine (1.37 mL, 26.6 mmol) was added to a suspension
of 4-methoxy-9H-xanthen-9-one (1, 4 g, 17.7 mmol) and
sodium acetate (2.9 g, 35.4 mmol) in AcOH (65 mL). The
mixture was heated at 60 8C and another three doses of
bromine (each 0.45 mL, 8.8 mmol) and NaOAc (each
0.73 g, 8.8 mmol) were added over 2 days. H2O (750 mL)
was added and the precipitate (4.75 g) was filtered out,
washed with water, loaded onto SiO2 and purified by flash
chromatography (3:1 CH2Cl2/hexane) affording brominated
xanthone 7 as a solid (4.32 g, 88%). Mp 208 8C. IR (KBr):
1
3.3. Anionic cyclization of carbamate 5
1669 (CO) cmK1. H NMR: 8.31 (dd, JZ7.9, 1.6 Hz, 1H),
7.76–7.70 (m, 1H), 7.54 (d, JZ8.6 Hz, 2H), 7.39 (apparent
t, JZ7.6 Hz, 1H), 7.06 (d, JZ8.6 Hz, 1H), 4.03 (s, 3H). 13C/
DEPT: 176.3 (CO), 155.2 (C), 148.9 (C), 148.4 (C), 135.2
(CH), 129.9 (CH), 127.3 (CH), 124.8 (CH), 122.4 (C), 120.1
(C), 118.2 (CH), 115.6 (CH), 110.8 (C), 56.9 (OCH3). EI-
MS: m/z (%) 306 [(MC2)C, 100], 304 (MC, 100), 291
[(MKMe)C2, 92], 289 (MKMe, 92). HRMS: Calcd for
C14H9BrO3: 303.973503; found: 303.973552.
3.3.1. 5-Methoxy-1-methyl-2,10b-dihydro-1H-chro-
meno[4,3,2cd]isoindolin-2-one (6a). Method A (Quenching
with NH4Cl). A solution of carbamate 5 (100 mg,
0.25 mmol) in THF (4 mL) was cooled to K80 8C and
n-BuLi (175 mL 1.6 M, 0.28 mmol) was added. After
30 min a saturated aqueous NH4Cl solution (0.1 mL) was
added to the cooled solution and the solvent was removed
under reduced pressure. The residue was extracted with
CH2Cl2, and the organic extract was washed with water,
dried over Na2SO4 and concentrated. Separation of the
products by flash chromatography (99:1 CH2Cl2/MeOH)
afforded carbamate 4 (31 mg, 39%) and isoindolinone 6a
(37 mg, 54%). Mp 118 8C (dec). IR (NaCl): 1693 (CO). 1H
NMR: 7.59–7.54 (m, 1H), 7.54 (d, JZ8.1 Hz, 1H), 7.38–
7.19 (m, 3H), 7.02 (d, JZ8.1 Hz, 1H), 5.24 (s, 1H), 4.02 (s,
3H), 3.52 (s, 3H). 13C/DEPT (DMSO-d6): 169.6 (CO), 153.2
(C), 150.4 (C), 138.6 (C), 131.6 (C), 129.1 (CH), 126.1
(CH), 125.2 (CH), 123.6 (C), 122.8 (C), 119.9 (CH), 118.2
(CH), 114.1 (CH), 56.9 (OCH3), 54.5 (CH), 31.8 (CH3). EI-
MS: m/z (%) 267 (MC, 41), 266 (100). HRMS: Calcd for
C16H13NO3: 267.089543; found: 267.088436.
3.3.5. 1-Bromo-4-methoxy-9-phenyl-9H-xanthen-9-ol
(8a). A suspension of 7 (2 g, 6.55 mmol) in THF (40 mL)
was cooled to 0 8C, phenylmagnesium chloride (3.93 mL
2 M, 7.86 mmol) was added and the solution was stirred for
2 h at rt. Aqueous NH4Cl was added, and the solvent was
removed under reduced pressure. The residue was parti-
tioned between CH2Cl2 and water, the organic layer was
washed with water and dried, and the solvent was
evaporated. The crude was taken into ether/hexane and 8a
(2.23 g, 89%) was filtered out. Mp 229 8C (dec). IR (KBr):
3481, 1600 cmK1. 1H NMR: 7.73 (d, JZ7.8 Hz, 1H), 7.38–
7.17 (m, 8H), 7.07–7.01 (m, 1H), 6.83 (d, JZ8.7 Hz, 1H),
4.15 (s, 1H, OH), 3.99 (s, 3H, OMe). 13C/DEPT: 148.2 (C),
147.7 (C), 146.9 (C), 141.5 (C), 129.1 (CH), 128.7 (CH),
128.4 (CH), 128.1 (2!CH), 126.6 (CH), 125.8 (2!CH),
125.3 (C), 124.7 (C), 123.8 (CH), 116.3 (CH), 112.7 (C),
111.9 (CH), 71.8 (C), 56.4 (OCH3). EI-MS: m/z (%) 384
[(MC2)C, 3], 382 (MC, 3), 307 [(MKPh)C2, 99], 305
(MKPh, 100). HRMS: Calcd for C20H15BrO3: 382.020456;
found: 382.020758.
3.3.2. 10b-Deutero-5-methoxy-1-methyl-2,10b-dihydro-
1H-chromeno[4,3,2-c,d]isoindolin-2-one (6b). Method B
(Quenching with MeOD). Carbamate
5 (100 mg,
0.25 mmol) was treated as before except that MeOD
(0.1 mL) was added for quenching instead of aqueous
NH4Cl. Work-up as before afforded carbamate 4 (27 mg,
34%) and deuterated 6b (35 mg, 52%): IR (KBr): 1694
1
(CO) cmK1. H NMR: 7.59–7.54 (m. 1H), 7.56 (d, JZ
3.3.6. 1-Bromo-9-ethyl-4-methoxy-9H-xanthen-9-ol (8b).
A suspension of 7 (3 g, 9.83 mmol) in THF (50 mL) was
cooled to 0 8C, ethylmagnesium bromide (4.1 mL 3 M,
12.3 mmol) was added and the solution was stirred at rt for
2 h. After the same work up as for 8a flash chromatography
(1:1 CH2Cl2/hexane) afforded 8b as a colourless oil (1.94 g,
8.1 Hz, 1H), 7.40–7.18 (m, 3H), 7.03 (d, JZ8.1 Hz, 1H),
4.02 (s, 3H), 3.54 (s, 3H). 13C/DEPT: 170.6 (CO), 153.9 (C),
150.9 (C), 139.4 (C), 131.4 (C), 129.1 (CH), 125.6 (CH),
124.9 (CH), 123.5 (C), 123.3 (C), 120.3 (CH), 118.7 (CH),
113.6 (CH), 57.1 (OCH3), 32.2 (NCH3). EI-MS: m/z (%)
268 (MC, 40), 267 (30), 266 (100). HRMS: Calcd for
C16H12DNO3: 268.095820; found: 268.094551.
1
93%). IR (KBr): 3351 (OH), 1621 cmK1. H NMR: 7.73
(dd, JZ8.1, 1.4 Hz, 1H), 7.32–7.18 (m, 3H), 7.32 (d, JZ
8.7 Hz, 1H), 6.78 (d, JZ8.7 Hz, 1H), 3.94 (s, 3H, OMe),
3.67 (s, 1H), 2.69 (dq, JZ15.0, 7.5 Hz, 1H), 1.97 (dq, JZ
15.0, 7.5 Hz, 1H), 0.44 (t, JZ7.5 Hz, 3H). 13C/DEPT: 149.3
(C), 148.1 (C), 142.0 (C), 129.1 (2!CH), 127.3 (CH), 125.6
3.3.3. 5-Methoxy-1-methyl-2,10b-dihydro-1H-chro-
meno[4,3,2-cd]isoindolin-2-one (6a). Method C (Inverse
addition). A solution of the bromocarbamate 5 (100 mg,

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M. C. de la Fuente, D. Domınguez / Tetrahedron 60 (2004) 10019–10028
10024
(C), 124.2 (CH), 123.9 (C), 116.0 (CH), 112.0 (CH), 111.1
(C), 72.3 (C), 56.7 (OCH3), 37.7 (CH2), 9.3 (CH3). EI-MS:
m/z (%) 336 [(MC2)C, 1], 334 (MC, 1), 335 (3), 333 (3),
307 [(MKEt)C2, 100), 305 (MKEt, 98). HRMS: Calcd for
C16H15BrO3: 334.020456; found: 334.020223.
added, and after a further 30 min at rt water was added, the
mixture was extracted with CH2Cl2, the organic extract was
washed with saturated aqueous NaCl solution (3!10 mL),
dried with Na2SO4 and filtered, and the solvent was
removed under reduced pressure. The residue was purified
by flash chromatography (1:4 EtOAc/hexane) giving 9c
(768 mg, 75%) as a solid that was recrystallized from
3.3.7. N-(1-Bromo-4-methoxy-9-phenyl-9H-xanthen-9-
yl)carbamic acid ethyl ester (9a). Phenylxanthydrol 8a
(800 mg, 3.09 mmol), urethane (372 mg, 4.17 mmol) and
AcOH (16 mL) were heated at 110 8C for 15 h. The solvent
was evaporated, the residue was partitioned between
CH2Cl2 and water, and the organic layer was washed with
water, dried and filtered. Flash chromatography (1:9 EtOAc/
hexane) afforded recovered 8a (343 mg, 43%) and 9a
(400 mg, 43%), the latter of which was recrystallized from
CH2Cl2/hexane as a white solid. Mp 181 8C. IR (KBr):
3440, 3419, 1730 cmK1. 1H NMR: 7.37 (d, JZ7.7 Hz, 1H),
7.33–7.12 (m, 8H), 6.93 (m, 1H), 6.78 (m, 2H), 3.97 (s, 3H,
OMe), 3.89 (q, JZ7.0 Hz, 2H), 1.04 (bs, 3H). 13C/DEPT:
155.2 (CO), 148.1 (C), 147.4 (C), 146.4 (C), 142.8 (C),
128.7 (2!CH), 128.2 (CH), 128.1 (CH), 128.0 (CH), 126.9
(CH), 125.5 (2!CH), 124.7 (C), 123.4 (C), 123.3 (CH),
116.1 (CH), 112.5 (C), 111.8 (CH), 60.8 (OCH2), 58.4 (C),
56.3 (OCH3), 14.2 (CH3). EI-MS: m/z (%) 374 (MCKBr,
96), 301 (100). CI-MS: m/z (%) 456 [(MC2)CHC, 5), 455
(MC2, 14), 454 (MCHC, 6), 453 (M, 13). C I-HRMS:
Calcd for C23H21BrNO4: 454.065395; found: 454.063410.
CH2Cl2/hexane. Mp 130 8C. IR (NaCl): 1701 cmK1 1H
.
NMR: 7.44–7.29 (m, 2H), 7.40 (d, JZ8.8 Hz, 1H), 7.24–
7.14 (m, 5H), 7.01–6.97 (m, 2H), 6.74 (d, JZ8.8 Hz, 1H),
3.93–3.88 (m, 5H, OMe, OCH2), 2.87 (s, 3H), 0.88–0.80 (m,
3H). 13C/DEPT: 156.6 (CO), 150.5 (C), 148.7 (C), 142.3
(C), 140.8 (C), 130.1 (CH), 129.5 (CH), 128.8 (CH), 128.7
(CH), 128.4 (CH), 125.8 (CH), 123.7 (CH), 118.9 (C), 117.1
(CH), 111.5 (CH), 110.6 (C), 66.3 (C), 61.7 (OCH2). 56.6
(OCH3), 36.4 (NCH3), 14.6 (CH3). EI-MS m/z (%): 469
[(MC2)C, 1], 467 (MC, 1), 440 [(MKEt)C2, 2), 438
(MKEt, 2), 388 (MKBr, 100), 367 [(MKNMeCO2Et)C2,
74), 365 (MKNMeCO2Et, 74). HRMS: Calcd for
C24H22BrNO4: 467.073220; found: 467.073871.
3.3.10. N-(1-Bromo-9-ethyl-4-methoxy-9H-xanthen-9-
yl)-N-methylcarbamic acid ethyl ester (9d). Sodium
hydride (230 mg, 60% in mineral oil, 5.8 mmol) in DMF
(2 mL), a solution of 9b (781 mg, 1.92 mmol) in DMF
(6 mL) and methyl iodide (239 mL, 3.8 mmol) were used as
described in the preparation of 9c. After work up the residue
was purified by flash chromatography (1:9 EtOAc/hexane)
giving 9d (751 mg, 93%) as a solid that was recrystallized
from ether/hexane. Mp 120 8C. IR(NaCl): 1701,
3.3.8. N-(1-Bromo-9-ethyl-4-methoxy-9H-xanthen-9-
yl)carbamic acid ethyl ester (9b). Sodium hydride
(880 mg, 60% in mineral oil, 22 mmol) was washed twice
with CH2Cl2 and a solution of urethane (1.17 g, 13 mmol) in
methylene chloride (20 mL) was added, The mixture was
stirred for 15 min and cooled to 0 8C. In another flask HClO4
(260 mL, 3 mmol) was added to a solution of 8b (1.0 g,
2.99 mmol) in CH2Cl2 (40 mL). After 1 min this solution
was added over the first, and the mixture was stirred for 1 h
at 0 8C and then extracted with CH2Cl2. The extract was
washed with water, dried with Na2SO4 and filtered, and the
solvent was removed under reduced pressure. The residue
was purified by flash chromatography (1:4 EtOAc/hexane)
giving the secondary carbamate 9b (400 mg, 33%). Mp
169 8C. IR (KBr): 3349 (NH), 1647 (CO) cmK1. 1H NMR:
7.46 (dd, JZ7.8, 1.5 Hz, 1H), 7.29–7.09 (m, 4H), 6.74 (d,
JZ8.6 Hz, 1H), 5.89 (bs, 1H, NH), 3.94–3.92 (bs, 5H,
OCH3 and OCH2), 2.71–2.67 (m, 1H), 1.87–1.75 (m, 1H),
1.33–1.13 (broad, 3H), 0.41 (t, JZ7.4 Hz, 3H). 13C/DEPT:
154.2 (CO), 149.7 (C), 147.5 (C), 142.5 (C), 128.5 (CH),
128.2 (CH), 125.6 (CH), 124.2 (C), 123.5 (CH), 121.5 (C),
115.7 (CH), 111.5 (CH), 110.2 (C), 60.6 (OCH2), 56.6 (C),
56.2 (OCH3), 35.9 (CH2), 14.5 (CH3), 8.1 (CH3). CI-MS:
m/z (%) 407 [(MC2)C, 19], 405 (MC, 19), 378 [(MKEt)C
2, 26], 376 (MKEt, 26), 326 (MKBr, 49), 319 [(MK
NHCO2Et)C2, 97], 317 (MKNHCO2Et, 100). HRMS:
Calcd for C19H20BrNO4: 405.05757; found: 405.056955.
1
1689 cmK1. H NMR (345 K): 7.26–7.02 (m, 5H), 6.71
(d, JZ8.7 Hz, 1H), 3.90 (s, 3H, OMe), 3.76 (broad, 2H),
3.30 (broad, 3H), 2.87–2.74 (m, 1H), 2.13 (broad, 1H), 0.80
(broad, 3H), 0.46–0.40 (m, 3H). 13C/DEPT: 156.7 (CO),
155.9 (CO), 149.9 (C), 149.4 (C), 147.5 (C), 142.5 (C),
142.2 (C), 128.7 (CH), 128.5 (CH), 127.7 (C), 125.5 (C),
124.8 (CH), 124.0 (CH), 123.6 (C), 122.9 (C), 116.2 (C),
115.8 (CH), 115.5 (CH), 111.5 (C), 111.4 (CH), 110.2 (C),
61.3 (OCH2), 56.7 (OCH3), 56.5 (O CH3), 37.7 (C), 34.2
(NCH3), 34.0 (CH2), 33.6 (C), 15.1 (CH3), 13.7 (CH3), 9.5
(CH3). EI-MS m/z (%): 340 (MKBr, 42), 319 [(MK
NMeCO2Et)C2, 100], 317 (MKNMeCO2Et, 100). FAB-
MS: 422 [(MC2)CHC, 6], 421 (9), 420 (MCHC, 7), 419
(8). HRMS: Calcd for C20H22BrNO4: 419.073220, found:
419.073112.
3.3.11. 5-Methoxy-1-methyl-10b-phenyl-2,10b-dihydro-
1H-chromeno[4,3,2-cd]isoindolin-2-one (6c). A solution
of carbamate 9c (100 mg, 0.21 mmol) in THF (4 mL) was
cooled to K80 8C and treated with n-BuLi (133 mL,
0.21 mmol) (Method A). After 30 min, work-up, purifi-
cation by flash chromatography (1:4 EtOAc/hexane) and
stirring with hexane afforded isoindolinone 6c as a solid
(68 mg, 93%). Mp 213 8C. IR (KBr): 1686 cmK1. 1H NMR:
7.68–7.64 (m, 1H), 7.64 (d, JZ8.0 Hz, 1H), 7.43–7.16 (m,
6H), 7.02 (d, JZ8.0 Hz, 1H), 6.72–6.67 (m, 2H), 3.97 (s,
3H), 3.16 (s, 3H). 13C/DEPT: 170.6 (CO), 155.5 (C), 151.4
(C), 139.9 (C), 139.6 (C), 137.2 (C), 129.6 (CH), 129.3 (2!
CH), 128.6 (CH), 127.4 (2!CH), 126.5 (CH), 125.9 (C),
125.3 (CH), 122.7 (C), 120.6 (CH), 118.8 (CH), 113.6 (CH),
64.7 (C), 57.3 (OCH3), 30.0 (CH3). EI-MS: m/z (%) 343
(MC, 10), 266 (MKPh, 100). HRMS: Calcd for
C22H17NO3: 343.120844; found: 343.121832.
3.3.9. N-(1-Bromo-4-methoxy-9-phenyl-9H-xanthen-9-
yl)-N-methylcarbamic acid ethyl ester (9c). Sodium
hydride (274 mg, 60% in mineral oil, 6.9 mmol) was
washed twice with THF, and DMF (3 mL) was added.
The resulting suspension was cooled to 0 8C and a solution
of 9a (1.0 g, 2.2 mmol) in DMF (12 mL) was added. After
30 min at 0 8C methyl iodide (274 mL, 4.4 mmol) was

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10025
3.3.12. 10b-Ethyl-5-methoxy-1-methyl-2,10b-dihydro-
1H-chromeno[4,3,2-cd]isoindolin-2-one (6d). A solution
of carbamate 9d (100 mg, 0.24 mmol) in THF (2 mL) was
cooled to K80 8C and treated with n-BuLi (149 mL,
0.24 mmol) (Method A). After 30 min, work-up and
purification by flash chromatography (1:4 EtOAc/hexane)
afforded isoindolinone 6d as a solid (62 mg, 89%), that was
recrystallized from ether/hexane. Mp 143 8C. IR (NaCl):
1693 (CO) cmK1. 1H NMR: 7.57 (d, JZ8.1 Hz, 1H), 7.51–
7.30 (m, 3H), 7.19 (dt, JZ7.6, 1.2 Hz, 1H), 7.02 (d, JZ
8.1 Hz, 1H), 4.03 (s, 3H, OMe), 3.41 (s, 3H, NMe), 2.05 (dq,
JZ14.6, 7.3 Hz, 1H), 1.86 (dq, JZ14.6, 7.3 Hz, 1H), 0.48
(t, JZ7.3 Hz, 3H), 13C/DEPT: 169.8 (CO), 153.8 (C), 150.8
(C), 139.2 (C), 134.8 (C), 128.7 (CH), 125.0 (CH), 124.5
(CH), 123.7 (C), 119.9 (CH), 118.6 (CH), 113.0 (CH), 62.1
(C), 57.1 (OCH3), 33.4 (CH2), 28.8 (NCH3), 7.9 (CH3). EI-
MS: m/z (%) 266 (MCKEt, 100). CI-MS: m/z (%) 296
(MCHC, 100). CI-HRMS: Calcd for C18H18NO3:
296.128669; found: 296.129638.
acid ethyl ester (12). Na2CO3 (880 mg, 8.3 mmol) and
ethyl chloroformate (0.48 mL, 5 mmol) were added to a
solution of the amine 11 (1.0 g, 4.15 mmol) in THF (14 mL)
and the mixture was stirred at rt for 1 h. A pH 7 aqueous
solution of KH2PO4 (50 mL 0.1 M) and NaOH (29 mL
0.1 M) was added, the mixture was extracted with CH2Cl2,
and the organic extract was washed with water, dried with
Na2SO4, filtered, concentrated in vacuo and purified by flash
chromatography (2:3 EtOAc/hexane) affording carbamate
12 as a foam (1.20 g, 93%). IR (NaCl): 3345 (NH), 1706
1
(CO) cmK1. H NMR: 7.32–7.22 (m, 3H), 7.14–7.01 (m,
2H), 6.94–6.85 (m, 2H), 4.68 (broad, 1H, NH), 4.18–4.00
(m, 3H, C9-H and OCH2), 3.94 (s, 3H, OMe), 3.39–3.37 (m,
2H), 1.27–1.19 (m, 3H). 13C/DEPT: 156.9 (CO), 152.3 (C),
148.3 (C), 141.9 (C), 129.3 (CH), 128.5 (CH), 124.1 (C),
123.8 (CH), 123.4 (CH), 123.0 (C), 120.9 (CH), 117.1 (CH),
110.9 (CH), 61.1 (OCH2), 56.3 (OCH3), 49.3 (CH2), 39.7
(CH), 15.0 (CH3). CI-MS: m/z (%) 314 (MCHC, 37), 268
(MKOEt, 22), 225 (MKNHCO2Et, 12). CI-HRMS: Calcd
for C18H20NO4: 314.139233; found: 314.140003.
3.4. Synthesis of chromeno[4,3,2-de]isoquinolin-3-ones
(15a–b)
3.4.4.
N-[(4-Methoxy-9H-xanthen-9-yl)methyl]-N-
methylcarbamic acid ethyl ester (13). Sodium hydride
(268 mg, 60% in mineral oil, 6.7 mmol) in DMF (1 mL), a
solution of 12 (700 mg, 2.23 mmol) in deoxygenated DMF
(7 mL) and methyl iodide (278 mL, 4.34 mmol) were used
as described in the preparation of 4. After work-up the
residue was purified by flash chromatography (1:4 EtOAc/
hexane) giving 13 as an oil (673 mg, 92%). IR (NaCl): 1697
3.4.1. 4-Methoxy-9H-xanthene-9-carbonitrile (10). Zinc
iodide (350 mg, 1 mmol) and trimethylsilyl cyanide
(7.7 mL, 59.6 mmol) in dry CH2Cl2 (20 mL) were cooled
to 0 8C and a solution of xanthydrol 2 (7.0 g, 30.7 mmol) in
CH2Cl2 (90 mL) was added dropwise over 2 h. After 1 h
aqueous NaHCO3 was added, the mixture was extracted
with CH2Cl2, the extract was washed with water, dried with
Na2SO4 and filtered, and the solvent was removed under
reduced pressure. The crude was recrystallized in CH2Cl2/
hexane, affording cyanide 10 (6.48 g, 89%). Mp 140 8C. IR
(KBr): 2237 (CN) cmK1. 1H NMR: 7.50 (d, JZ7.7 Hz, 1H),
7.41–7.01 (m, 5H), 6.95 (dd, JZ7.1 Hz, 2.2, 1H), 5.38 (s,
1H), 3.96 (s, 3H, OMe). 13C/DEPT: 150.9 (C), 148.8 (C),
140.9 (C), 130.5 (CH), 128.8 (CH), 124.6 (CH), 124.1 (CH),
120.2 (CH), 119.3 (C), 118.0 (CH), 115.7 (C), 114.8 (C),
112.5 (CH), 56.7 (OCH3), 30.7 (CH). EI-MS: m/z (%) 237
(MC, 100). HRMS: Calcd for C15H11NO2: 237.078979;
found: 237.078912.
1
(CO) cmK1. H NMR: 7.22–6.69 (m, 7H), 4.36–4.04 (m,
2H, OCH2), 3.88 (s, 3H, OMe), 3.90–3.82 (m, 1H), 3.38–
3.23 (m, 2H), 2.73 and 2.44 (both s, 3H, NCH3), 1.29 and
1.02 (both t, 3H). 13C/DEPT: 156.8 (CO), 156.6 (CO), 152.4
(C), 148.3 (C), 142.0 (C), 129.3 (CH), 129.0 (CH), 128.4
(CH), 127.1 (C), 126.3 (C), 124.8 (CH), 124.4 (C), 123.8
(CH), 123.4 (CH), 121.0 (CH), 120.8 (CH), 116.9 (CH),
110.9 (CH), 61.5 (OCH2), 60.6 (OCH2), 58.4 (CH2), 57.1
(CH2), 56.3 (OCH3), 38.9 (CH), 38.5 (CH), 36.8 (NCH3),
35.9 (NCH3), 15.2 (CH3), 14.8 (CH3). MS-FAB: m/z (%)
328 (MCHC, 97). HRMS: Calcd for C19H22NO4:
328.154883; found: 328.154347.
3.4.2. (4-Methoxy-9H-xanthen-9-yl)methylamine (11).
Borane dimethylsulphide (3.3 mL, 34.79 mmol) was
added to a solution of 10 (4.0 g, 16.9 mmol) in THF
(40 mL) and the mixture was refluxed for 2 h. The solution
was cooled to 0 8C, water (13 mL) and 20% KOH (13 mL)
were added, and refluxing was continued for a further 2 h.
The solvents were evaporated, the residue was partitioned
between CH2Cl2 and water, and the organic layer was
washed with water, dried with Na2SO4, filtered and
concentrated. Purification by flash chromatography (95:5
CH2Cl2/MeOH) gave the amine as a solid (2.23 g, 55%).
3.4.5.
N-[(1-Bromo-4-methoxy-9H-xanthen-9-yl)-
methyl]-N-methylcarbamic acid ethyl ester (14).
Bromine in AcOH (1.5 mL 1 M, 1.46 mmol) was added to
a solution of 13 (400 mg, 1.22 mmol) and NaOAc (200 mg,
2.44 mmol) in AcOH (6 mL). After 3 h, work-up as in the
preparation of 5 led to a residue that upon flash
chromatography (1:4 EtOAc/hexane) afforded carbamate
14 (482 mg, 97%), which was recrystallized from ether/
hexane. Mp 91 8C. IR (NaCl): 1700 (CO) cmK1. 1H NMR:
7.36–7.05 (m, 5H), 6.69 (d, JZ8.8 Hz, 1H), 4.60–4.35 (m,
1H), 4.12–3.62 (m, 2H, OCH2), 3.87 (s, 3H, OMe), 3.46–
3.25 (m, 2H), 2.79 and 2.53 (both s, 3H, NMe), 1.22 and
0.87 (both t, JZ7.0 Hz, 3H). 13C/DEPT: 156.6 (CO), 152.4
(C), 152.2 (C), 148.0 (C), 143.4 (C), 131.0 (C), 129.1 (CH),
128.6 (CH), 126.8 (CH), 124.7 (C), 124.1 (CH), 123.5 (C),
123.2 (C), 116.5 (CH), 113.9 (C), 113.7 (C), 112.0 (CH),
61.4 (OCH2), 56.5 (OCH3), 55.4 (CH2), 54.1 (CH2), 39.2
(CH), 39.1 (CH), 36.0 (NCH3), 35.5 (NCH3), 15.2 (CH3),
14.7 (CH3). CI-MS: m/z (%) 408 [(MC2)CHC, 22), 406
(MCHC, 22). CI-HRMS: Calcd for C19H21BrNO4:
406.065395; found: 406.064411.
1
Mp 89 8C. IR (NaCl): 1579 cmK1. H NMR 7.25–6.83 (m,
7H), 3.99 (t, JZ5.2 Hz, 1H), 3.95 (s, 3H, OMe), 2.96 (d, JZ
5.1 Hz, 2H), 1.31 (broad, 2H, NH2). 13C/DEPT: 152.6 (C),
148.3 (C), 142.3 (C), 128.9 (CH), 128.4 (CH), 124.3 (C),
123.9 (CH), 123.4 (CH), 123.2 (C), 120.7 (CH), 117.2 (CH),
110.8 (CH), 56.5 (OCH3), 51.3 (CH2), 43.9 (CH).CI-MS:
m/z (%) 242 (MCHC, 71). HRMS: Calcd for C15H16NO2:
242.118104; found: 242.118175.
3.4.3. N-[(4-Methoxy-9H-xanthen-9-yl)methyl]carbamic

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M. C. de la Fuente, D. Domınguez / Tetrahedron 60 (2004) 10019–10028
10026
3.4.6. Isoquinolinone 15a by electrophilic cyclization.
Triflic anhydride (1.05 mL, 6.12 mmol) was added to a
solution of carbamate 13 (400 mg, 1.22 mmol) and DMAP
(453 mg, 3.67 mmol) in methylene chloride (20 mL) at
0 8C. After 4 h. of stirring at 0 8C, 15 mL of 1 M NaOH was
added and the mixture was extracted with CH2Cl2. The
extract was washed with water, dried with Na2SO4 and
filtered, and the solvent was removed under reduced
pressure. Purification by flash chromatography (1:1
EtOAc/hexane) gave 6-methoxy-2-methyl-1,2,3,11b-tetra-
hydrochromeno[4,3,2-de]isoquinolin-3-one (15a, 303 mg,
88%), which was recrystallized from ether/hexane. Mp
171 8C. IR (NaCl): 1649 (CO) cmK1. 1H NMR: 7.82 (d, JZ
8.6 Hz, 1H), 7.32–7.20 (m, 3H), 7.12 (td, JZ8.0, 1.7 Hz,
1H), 6.93 (d, JZ8.6 Hz, 1H), 4.50 (dd, JZ12.7, 5.7 Hz,
1H), 3.99 (s, 3H, OMe), 3.96 (dd, JZ11.9, 5.7 Hz, 1H), 3.79
(apparent t, JZ12.3 Hz, 1H), 3.25 (s, 3H, NMe). 13C/DEPT:
164.7 (CO), 151.7 (C), 150.7 (C), 139.0 (C), 129.1 (CH),
126.1 (CH), 124.1 (CH), 124.0 (CH), 122.4 (C), 121.3 (C),
120.0 (C), 117.8 (CH), 110.7 (CH), 56.5 (OCH3), 52.9
(CH2), 35.8 (CH), 30.2 (NCH3). EI-MS: m/z (%) 281 (MC,
15), 238 (38), 210 (100). HRMS: Calcd for C17H15NO3:
281.105194; found: 281.104917.
(OCH3), 46.3 (C). EI-MS: m/z (%) 313 (MC, 23), 236 (MK
Ph, 100). HRMS: Calcd for C21H15NO2: 313.110279;
found: 313.109484.
3.4.10. (4-Methoxy-9-phenyl-9H-xanthen-9-yl)methyl-
amine (18). A mixture of 17 (400 mg, 1.28 mmol) and
NiCl2 (170 mg, 1.29 mmol) in ethanol (45 mL) was heated
at 60 8C and NaBH4 (230 mg, 5.9 mmol) was added. After
3 h the mixture was filtered through celite, the solvent was
evaporated, the residue was partitioned between CH2Cl2
and water, and the organic phase was washed with water,
dried with Na2SO4, filtered and concentrated. The product
was purified by flash chromatography (97:3 CH2Cl2/MeOH)
and recrystallized from ether/hexane (332 mg, 82%). Mp
1
134 8C. IR (NaCl): 3382 and 3350 (NH2), 1573 cmK1. H
NMR: 7.28–7.15 (m, 7H), 6.97–6.77 (m, 4H), 6.41 (dd, JZ
7.8, 1.6 Hz, 1H), 3.94 (s, 3H, OMe), 3.47 (s, 2H), 0.80 (bs,
2H, NH2). 13C/DEPT: 151.9 (C), 148.4 (C), 148.2 (C), 142.1
(C), 129.9 (C), 129.6 (2!CH), 128.9 (2!CH), 128.6 (CH),
127.4 (C), 127.2 (CH), 126.4 (C), 124.2 (CH), 123.4 (CH),
121.4 (CH), 117.2 (CH), 110.5 (CH), 56.8 (OCH3), 54.3
(CH2), 50.7 (C). MS-FAB: m/z (%) 318 (MCHC, 100).
HRMS-FAB: Calcd for C21H20NO2: 318.149404, found:
318.149563.
3.4.7. Isoquinolinone 15a by anionic cyclization. A
solution of bromocarbamate 14 (50 mg, 0.12 mmol) in
THF (3 mL) and n-BuLi (81 mL 1.6 M, 0.13 mmol) were
used as described in Method A. The product was purified by
flash chromatography, affording 15a (25 mg, 74%).
3.4.11. N-[(4-Methoxy-9-phenyl-9H-xanthen-9-yl)-
methyl]carbamic acid ethyl ester (19). Na2CO3 (215 mg,
2 mmol) and ethyl chloroformate (117 mL, 1.2 mmol) were
added to a solution of amine 18 (320 mg, 1 mmol) in THF
(8 mL) and the mixture was stirred at rt for 30 min. Work up
as described for 12 gave a residue of carbamate 19, which
was recrystallized from CH2Cl2/hexane (353 mg, 90%). Mp
160 8C. IR (NaCl): 3440 (NH), 1720 (CO) cmK1. 1H NMR:
7.35–7.18 (m, 7H), 7.01–6.80 (m, 4H), 6.50 (d, JZ7.5 Hz,
1H), 4.46 (broad, 1H, NH), 4.10 (d, JZ6.0 Hz, 2H), 3.95 (s,
3H, OMe), 3.91 (q, JZ7.1 Hz, 2H, OCH2), 1.06 (t, JZ
7.1 Hz, 3H). 13C/DEPT: 156.7 (CO), 151.4 (C), 148.0 (C),
146.9 (C), 141.6 (C), 129.6 (CH), 128.9 (2!CH), 128.7
(2!CH), 128.6 (CH), 127.1 (CH), 126.6 (C), 125.5 (C),
123.9 (CH), 123.2 (CH), 121.2 (CH), 117.0 (CH), 110.6
(CH), 61.2 (OCH2), 56.6 (OCH3), 51.2 (NCH2), 48.1 (C),
14.8 (CH3). MS-FAB: m/z (%) 390 (MCHC, 28). HRMS-
FAB: Calcd for C24H24NO4: 390.170534; found:
390.170889.
3.4.8. 4-Methoxy-9-phenyl-9H-xanthen-9-ol (16). Phenyl-
magnesium bromide (7.1 mL 2 M, 14.2 mmol) was added to
a suspension of xanthone 1 (3 g, 13.2 mmol) in THF
(90 mL) at 0 8C and the solution was stirred for 2 h. After
work up as for 8a, the residue was purified by stirring in
ether/hexane (3.75 g, 93%). Mp 167 8C. IR (KBr): 3488
1
(OH), 1576 cmK1. H NMR: 7.41–6.93 (m, 10H), 7.17 (t,
JZ7.2 Hz, 1H), 6.87 (dd, JZ7.3, 2.1 Hz, 1H), 3.98 (s, 3H,
OMe), 2.63 (s, 1H, OH). 13C/DEPT: 149.8 (C), 148.4 (C),
147.9 (C), 140.1 (C), 129.4 (CH), 129.3 (CH), 128.3 (2!
CH), 127.3 (C), 127.1 (CH), 126.6 (2!CH), 124.1 (CH),
123.4 (CH), 120.7 (CH), 117.1 (CH), 111.0 (CH), 70.7 (C),
56.6 (OCH3). EI-MS: m/z (%) 304 (MC, 10), 227 (MKPh,
100). HRMS: Calcd for C20H16O3: 304.10994; found:
304.109937.
3.4.12. N-[(4-Methoxy-9-phenyl-9H-xanthen-9-yl)-
methyl]-N-methylcarbamic acid ethyl ester (20). Sodium
hydride (123 mg, 60% in mineral oil, 3 mmol) in DMF
(0.5 mL), a solution of 19 (300 mg, 0.77 mmol) in DMF
(2.5 mL) and methyl iodide (96 mL, 1.54 mmol) were used
as described in the preparation of 9c. After work-up the
residue was purified by flash chromatography (1:3 EtOAc/
hexane), giving carbamate 20 as a foam (286 mg, 92%). IR
3.4.9. 4-Methoxy-9-phenyl-9H-xanthene-9-carbonitrile
(17). A solution of 4-methoxy-9-phenyl-9H-xanthen-9-ol
(16, 2 g, 6.58 mmol) in CH2Cl2 (50 mL) was added
dropwise over 2 h to a suspension of zinc iodide (70 mg,
0.22 mmol) and trimethylsilyl cyanide (1.2 mL, 9.59 mmol)
in dry CH2Cl2 (10 mL) at 0 8C. After 1 h aqueous NaHCO3
was added, the mixture was extracted with CH2Cl2, the
extract was washed with water, dried with Na2SO4 and
filtered, and the solvent was removed under reduced
pressure. Compound 17 was recrystallized from CH2Cl2/
hexane (1.84 g, 90%). Mp 147 8C. IR (NaCl): 2238 (CN),
(KBr): 1700 (CO) cmK1 1H NMR: 7.31–7.12 (m, 7H),
.
6.90–6.75 (m, 4H), 6.47–6.38 (m, 1H), 4.30 and 4.24 (both
s, 2H), 3.92 (s, 3H, OMe), 3.82 and 3.55 (both m, 2H,
OCH2), 2.23 (s, 3H, NMe), 0.99–0.93 (m, 3H). 13C/DEPT:
156.5 (CO), 156.4 (CO), 151.1 (C), 148.1 (2!C), 147.3 (C),
147.0 (C), 141.5 (C), 141.3 (C), 130.5 (CH), 130.3 (CH),
128.6 (2!CH), 128.0 (2!CH), 127.7 (CH), 126.6 (C),
126.3 (CH), 125.5 (C), 122.8 (CH), 122.1 (CH), 121.9 (CH),
116.3 (CH), 115.9 (CH), 109.8 (CH), 109.6 (CH), 60.9
(CH2), 60.8 (CH2), 56.0 (OCH3), 47.6 (C), 36.0 (NCH3),
1
1602 cmK1. H NMR: 7.39–7.21 (m, 8H), 7.14–7.09 (m,
1H), 7.05 (t, JZ8.0 Hz, 1H), 6.97–6.90 (m, 2H), 3.97 (s, 3H,
OMe). 13C/DEPT: 149.7 (C), 148.6 (C), 143.4 (C), 139.9
(C), 130.4 (CH), 129.6 (CH), 129.4 (2!CH), 128.4 (CH),
126.8 (2!CH), 124.8 (CH), 124.2 (CH), 121.7 (C), 121.1
(C), 120.9 (CH), 120.7 (C), 117.9 (CH), 112.0 (CH), 56.7

´
M. C. de la Fuente, D. Domınguez / Tetrahedron 60 (2004) 10019–10028
10027
35.4 (NCH3), 14.3 (CH3), 14.2 (CH3). CI-MS: m/z (%) 404
(MCHC, 100). CI-HRMS: Calcd for C25H26NO4:
404.186184; found: 404.188140.
(OCH3), 49.5 (CH2), 49.4 (C), 14.8 (CH3). MS-FAB: m/z
470 [(MC2)CHC, 37), 468 (MCHC, 37). HRMS-FAB:
Calcd for C24H23BrNO4: 468.081045; found: 468.079173.
3.4.16. N-[(1-Bromo-4-methoxy-9-phenyl-9H-xanthen-9-
yl)methyl]-N-methylcarbamic acid ethyl ester (24).
Sodium hydride (183 mg, 60% in mineral oil, 4.58 mmol)
in DMF (0.2 mL), a solution of 23 (700 mg, 1.49 mmol) in
DMF (8 mL) and methyl iodide (180 mL, 2.89 mmol) were
used as described in the preparation of 9c. After work-up,
flash chromatography of the residue (1:4 EtOAc/hexane)
gave carbamate 24 (286 mg, 92%), which was recrystallized
from ether/hexane. Mp 120 8C. IR (NaCl): 1697
3.4.13. 1-Bromo-4-methoxy-9-phenyl-9H-xanthene-9-
carbonitrile (21). A solution of xanthydrol 8a (1.5 g,
3.9 mmol) in CH2Cl2 (90 mL) was added dropwise over 2 h
to a suspension of zinc iodide (100 mg, 0.31 mmol) and
trimethylsilyl cyanide (0.98 mL, 7.8 mmol) in dry CH2Cl2
(10 mL) at 0 8C. After 1 h aqueous NaHCO3 was added, the
mixture was extracted with CH2Cl2, the organic layer was
washed with water, dried with Na2SO4 and filtered, and the
solvent was removed under reduced pressure, leaving a
residue that was stirred with ether/hexane (1.48 g, 96%). Mp
1
(CO) cmK1. H NMR: 7.31–6.84 (m, 10H), 6.72 (d, JZ
1
245 8C. IR (KBr): 2232 (CN), 1570 cmK1. H: 7.46–7.01
8.7 Hz, 1H), 4.90–4.85 (m, 1H), 4.41–4.18 (m, 1H), 3.91 (s,
3H, OMe), 3.80–3.61 (m, 2H), 2.25 (s, 3H, NMe), 1.00 (t,
JZ7.1 Hz, 3H). 13C/DEPT: 157.3 (CO), 149.4 (C), 148.6
(C), 148.1 (C), 143.9 (C), 131.1 (CH), 129.0 (2!CH), 128.6
(2!CH), 128.3 (CH), 128.1 (CH), 126.5 (CH), 126.3 (C),
124.0 (C), 123.6 (CH), 116.5 (CH), 115.8 (C), 112.1 (CH),
61.6 (OCH2), 57.9 (OCH2), 56.7 (OCH3), 49.5 (C), 36.9
(NCH3), 36.3 (NCH3), 14.9 (CH3). MS-FAB: m/z (%) 484
[(MC2)CHC, 66), 482 (MCHC, 68). HRMS-FAB: Calcd
for C25H25BrNO4: 482.096695; found: 482.095358.
(m, 10H), 6.88 (d, JZ8.8 Hz, 1H), 3.99 (s, 3H, OMe). 13C/
DEPT: 148.3 (C), 146.9 (C), 143.2 (C), 141.7 (C), 130.3
(CH), 130.1 (CH), 129.2 (CH), 129.1 (2!CH), 128.0 (CH),
127.3 (2!CH), 124.9 (CH), 120.8 (C), 120.2 (C), 118.5 (C),
117.5 (CH), 114.8 (C), 113.6 (CH), 58.6 (OCH3), 46.9 (C).
EI-MS: m/z (%) 393 [(MC2)C, 36], 391 (MC, 36), 316
[(MKPh)C2, 100], 314 (MKPh, 99). HRMS: Calcd for
C21H14BrNO2: 391.020790; found: 391.019766.
3.4.14. (1-Bromo-4-methoxy-9-phenyl-9H-xanthen-9-
yl)methylamine (22). Borane dimethylsulphide (0.7 mL,
7.38 mmol) was added to a solution of nitrile 21 (1.48 g,
3.78 mmol) in THF (80 mL) and the mixture was refluxed
for 2 h. The solution was cooled to 0 8C, water (13 mL) and
20% KOH (13 mL) were added, and refluxing was
continued for a further 2 h. The solvents were evaporated,
the residue was partitioned between CH2Cl2 and water, and
the organic layer was washed with water, dried with
Na2SO4, filtered and concentrated. Purification by flash
chromatography (96:4 CH2Cl2/MeOH) gave the amine as a
solid (900 mg, 60%). Mp 184 8C. IR (NaCl): 3387 (NH),
3.4.17. Isoquinolinone 15b by electrophilic cyclization.
Triflic anhydride (213 mL, 1.24 mmol) was added to a
solution of carbamate 20 (100 mg, 0.25 mmol) and DMAP
(92 mg, 0.76 mmol) in methylene chloride (5 mL) at 0 8C.
After 4 h of stirring at 0 8C, 5 mL of 1 M NaOH was added,
the mixture was extracted with CH2Cl2, the organic phase
was washed with water, dried with Na2SO4 and filtered, and
the solvent was removed under reduced pressure. Purifi-
cation by flash chromatography (1:1 EtOAc/hexane) gave
6-methoxy-2-methyl-11b-phenyl-1,2,3,11b-tetrahydro-
chromeno[4,3,2-de]isoquinolin-3-one (15b, 84 mg, 95%),
which was recrystallized from ether/hexane. Mp 219 8C. IR
1
1570 cmK1. H NMR: 7.29–6.86 (m, 10H), 6.76 (d, JZ
1
(NaCl): 1649 (CO) cmK1. H NMR: 7.92 (d, JZ8.6 Hz,
8.7 Hz, 1H), 4.20 (d, JZ12.9 Hz, 1H), 3.97 (s, 3H, OMe),
3.54 (d, JZ12.9 Hz, 1H). 13C/DEPT: 149.4 (C), 148.4 (C),
147.9 (C), 143.8 (C), 129.8 (CH), 129.5 (CH), 129.2 (2!
CH), 128.5 (2!CH), 128.0 (CH), 126.4 (CH), 126.0 (C),
124.2 (CH), 123.5 (C), 116.3 (CH), 114.0 (C), 112.0 (CH),
56.6 (OCH3), 51.8 (C), 51.1 (CH2). MS-FAB: m/z (%) 398
[(MC2)CHC, 23], 396 (MCHC, 24). HRMS-FAB: Calcd
for C21H19BrNO2: 396.059915; found: 396.059797.
1H), 7.42 (d, JZ8.6 Hz, 1H), 7.25–7.02 (m, 9H), 4.36 (d,
JZ12.4 Hz, 1H), 4.28 (d, JZ12.4 Hz, 1H), 4.03 (s, 3H,
OMe), 3.10 (s, 3H, NMe). 13C/DEPT: 164.3 (CO), 151.7
(C), 151.1 (C), 144.0 (C), 140.3 (C), 129.1 (2!CH), 128.9
(CH), 127.3 (CH), 126.4 (2!CH), 126.3 (C), 126.1 (C),
125.6 (CH), 124.7 (CH), 124.5 (CH), 121.5 (C), 118.1 (CH),
111.1 (CH), 57.9 (CH2), 56.6 (OCH3), 40.8 (C), 35.9
(NCH3). EI-MS: m/z (%) 357 (MC, 8), 314 (100), 299 (89).
HRMS: Calcd for C23H19NO3: 357.136494; found:
357.137727.
3.4.15. N-[(1-Bromo-4-methoxy-9-phenyl-9H-xanthen-9-
yl)methyl]carbamic acid ethyl ester (23). Na2CO3
(429 mg, 4 mmol) and ethyl chloroformate (0.23 mL,
2.43 mmol) were added to a solution of amine 22
(800 mg, 2 mmol) in THF (55 mL), and the mixture was
stirred at rt for 1 h. After work-up as described for 12 the
residue was purified by flash chromatography (1:3 EtOAc/
hexane) affording carbamate 23 (756 mg, 80%). Mp 147 8C.
3.5. Isoquinolinone 15b by anionic cyclization
A solution of bromocarbamate 24 (100 mg, 0.20 mmol) in
THF (5 mL) and n-BuLi (130 mL 1.6 M, 0.20 mmol) were
used as described in Method A. The product was purified by
flash chromatography, affording 15b (59 mg, 80%).
1
IR(KBr): 3332 (NH), 1720, 1693 cmK1. H NMR: 7.30–
7.08 (m, 8H), 6.89–6.90 (m, 2H), 6.73 (d, JZ8.7 Hz, 1H),
4.78 (dd, JZ12.7, 5.8 Hz, 1H), 4.33 (dd, JZ6.5, 5.8 Hz,
1H, NH), 4.22 (dd, JZ12.7, 6.5 Hz, 1H), 3.93 (s, 3H, OMe),
3.85 (q, JZ7.0 Hz, 2H), 1.01 (t, JZ7.0 Hz, 3H). 13C/DEPT:
156.7 (CO), 148.9 (C), 147.9 (C), 147.6 (C), 143.4 (C),
130.2 (CH), 129.5 (CH), 128.9 (2!CH), 128.7 (2!CH),
128.3 (CH), 126.7 (CH), 125.3 (C), 124.1 (CH), 122.9 (C),
116.3 (CH), 114.6 (C), 112.3 (CH), 61.1 (OCH2), 56.7
Acknowledgements
We thank the Spanish Ministries of Education and Culture
(project PB-98-0606) and Science and Technology
(BQU2002-01176), and also Johnson & Johnson Pharma-
ceutical Research and Development, for financial support.

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M. C. de la Fuente, D. Domınguez / Tetrahedron 60 (2004) 10019–10028
10028
10. Biological properties of isoquinolinones: (a) NK1 (sustance P)
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