Ortho-directed metalation of 3-Carboxy-β-carbolines: Use of the SmI2- cleavable 9-N-(N',N'-dimethylsulfamoyl) blocking group for the preparation of 9-N-deprotected 4-amino derivatives via azide introduction or a palladium- catalyzed cross-coupling reaction

Full text of DOI:10.1021/jo971485l

872
J . Org. Chem. 1998, 63, 872-877
Sch em e 1
Or th o-Dir ected Meta la tion of
3-Ca r boxy-â-ca r bolin es: Use of th e
Sm I2-Clea va ble
9-N-(N′,N′-Dim eth ylsu lfa m oyl) Block in g
Gr ou p for th e P r ep a r a tion of
9-N-Dep r otected 4-Am in o Der iva tives via
Azid e In tr od u ction or a
P a lla d iu m -Ca ta lyzed Cr oss-Cou p lin g
Rea ction
Alexandre Batch and Robert H. Dodd*
Institut de Chimie des Substances Naturelles,
Centre National de la Recherche Scientifique,
91198 Gif-sur-Yvette Cedex, France
Received August 11, 1997
â-Carboline-3-carboxylic esters and amides (1, X ) O
or NH, R ) alkyl group) are a pharmacologically impor-
tant class of compounds, displaying a wide range of
activities by virtue of their high-affinity interactions with
the benzodiazepine receptors of the central nervous
to have a particularly powerful influence on the phar-
macological profiles of these compounds with respect to
the benzodiazepine receptor,2 the synthesis of a 4-amino-
3-carboxy-â-carboline derivative appeared to us to be a
worthwhile goal. In this regard, we recently described
the first synthesis of a 4-amino derivative of a â-carbo-
line-3-carboxamide via treatment of the 4-carboxylic acid
with diphenyl phosphorazidate.7 Unfortunately, the low
yield of this Curtius-type rearrangement together with
the large number of steps necessary to obtain the starting
carboxylic acid (based on Neef and co-workers’ methodol-
ogy for preparing 4-substituted 3-carboxy-â-carbolines)5
made the pharmacological and synthetic exploitation of
this 4-amino derivative unrealizable. These difficulties
motivated our investigation of ortho-directed lithiation
techniques8 as a general method of directly introducing
substituents at C-4 of 3-carboxy-â-carbolines.
As also previously described by us (Scheme 1),9 the
anion of â-carboline 2 (in which the N-benzylcarboxamide
at C-3 is the ortho-directing group) can be selectively
generated at C-4 using methyllithium as the metalating
agent and reacted with an electrophile such as p-
anisaldehyde to give the 4-substituted â-carboline deriva-
tive 3 in high yield. In these preliminary model studies,
the free 9-NH was protected by a methyl group for
system.1 These activities (anxiolytic, hypnotic, mnesic,
anticonvulsant) are intrinsically dependent on, and highly
modulable by, the type of substituents incorporated at
the 4 and 5 or 6 positions of the â-carboline nucleus.2 In
the search for molecules having a narrower range of
activities and, especially, devoid of the undesirable side
effects encountered in the clinical use of most current
benzodiazepine receptor ligands (notably: tolerance,
physical dependence, ataxia, and amnesia),3 the incor-
poration of functional groups on the 3-carboxy-â-carboline
nucleus is a major objective. In addition to the modula-
tion of biological properties which such groups may
themselves confer to these compounds, they provide
handles by which a large number of derivatives may be
prepared and studied pharmacologically.
It is with these objectives in mind that, in recent years,
efforts have been made to introduce the amine function
onto the 3-carboxy-â-carboline nucleus. Thus, 5-, 6-, and
7-amino-â-carboline-3-carboxylic esters have been pre-
pared by reduction of the corresponding nitro-â-carbo-
lines, the latter being synthesized either from the ap-
propriate nitroindole or by direct electrophilic nitration
of the â-carboline ring.4-6 Because substituents at the
C-4 position of 3-carboxy-â-carbolines have been shown
(5) Neef, G.; Eder, U.; Huth, A.; Rahtz, D.; Schmiechen, R.; Seidel-
mann, D. Heterocycles 1983, 20, 1295.
(6) Derivatives of 4-amino-3-carboxy-R-carboline have been recently
prepared for the same purpose: Forbes, I. T.; J ohnson, C. N.;
Thompson, M. J . Chem. Soc., Perkin Trans. 1 1992, 275.
(7) Dorey, G.; Dubois, L.; Prado de Carvalho, L.; Potier, P.; Dodd,
R. H. J . Med. Chem. 1995, 38, 189.
(8) For reviews concerning ortho-directed metalation, see: (a) Que-
guiner, G.; Marsais, F.; Snieckus, V.; Epsztajn, J . Adv. Heterocycl.
Chem. 1991, 52, 187. (b) Snieckus, V. Chem. Rev. (Washington, D.C.)
1990, 90, 879.
(1) Braestrup, C.; Nielsen, M.; Olsen, C. E. Proc. Natl. Acad. Sci.
U.S.A. 1980, 77, 2288.
(2) For reviews, see: (a) Gardner, C. R.; Tully, R. W.; Hedgecock, C.
J . R. Prog. Neurobiol. 1993, 40, 1. (b) Gardner, C. R. Prog. Neurobiol.
1988, 31, 425. (c) Dodd, R. H. Eur. Bull. Cogn. Psychol. 1992, 12, 484.
(3) Lader, M. Adv. Biochem. Pharmacol. 1995, 48, 135.
(4) Settimj, G.; Del Giudice, M. R.; Ferretti, R.; Gatta, F. J .
Heterocycl. Chem. 1988, 25, 1391.
(9) Mehta, A.; Dodd, R. H. J . Org. Chem. 1993, 58, 7587.
S0022-3263(97)01485-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/13/1998

Notes
J . Org. Chem., Vol. 63, No. 3, 1998 873
ined.15,16 Amide 6 was thus prepared by the reaction of
trimethylaluminum and aniline with ethyl â-carboline-
3-carboxylate (1, X ) O, R ) Et).2,14 Treatment of 6 in
THF at -78 °C with methyllithium followed by addition
of p-anisaldehyde and acid treatment of the worked-up
reaction mixture (to promote cyclization of the initially
formed alcohol to the lactone)9 gave only poor yields of
the desired ortho-substituted derivative 7 (<10% as
estimated by 1H NMR spectroscopy of the crude product,
the rest being unreacted starting material). Attempts
to increase the yield of the C-4-alkylated product 7 by
varying reaction times, temperature, and/or the number
of equivalents of base were unsuccessful.
Sch em e 2
Due to the free 9-NH of â-carboline 7 obviously having
an adverse effect on proton abstraction at C-4,17 an
appropriate protecting group was sought for the former
position. Recent reports have demonstrated the useful-
ness of the N-tert-butyldimethylsilyl (TBDMS) group for
the protection of indole NH prior to lithiation at either
the C-3 position (via halogen exchange)18 or the C-4
position (via ortho-directed lithiation).19 However, our
attempts to prepare the analogous 9-N TBDMS deriva-
tive of ethyl â-carboline-3-carboxylate (1, X ) O, R ) Et)
under similar conditions (LDA, TBDMS chloride, THF)
met with failure, only starting material being recovered.
Although TLC of the reaction mixture indicated that
some N-silylated product was formed, this product did
not survive standard workup conditions. The N-Si bond
of â-carbolines appears to be extremely labile, probably
due to the additional delocalization of the nitrogen lone
pair compared to indole. Attention was then turned to
more classical N-protecting groups such as tert-butyloxy-
carbonyl, benzyloxycarbonyl, acetyl, and tosyl.20 How-
ever, all these groups were cleaved under the strongly
basic conditions of the metalation reaction.
The N,N-dimethylsulfamoyl group has been shown to
be an excellent N-protecting group for the lithiation of
imidazole, being stable in the presence of alkyllithium
reagents and removable in high yield under acidic
conditions.21 Since a dialkylsulfamoyl moiety can also
be regarded as an ortho-directing group in metalation
reactions (and has, in fact, served such a role in the
imidazole field and elsewhere),21,22 there was some ap-
prehension that, introduced at the 9-N position of the
â-carboline nucleus, this group could favor anion forma-
tion at C-1 and/or C-8. However, molecular models
showed that this possibility was unlikely, the coordinat-
ing oxygen atoms of the sulfamoyl group being too distant
to allow effective anion stabilization at these two posi-
tions.
simplicity.10 However, such a group is known to interfere
with receptor binding11 and, moreover, cannot be easily
removed.12 Following our initial report concerning ortho-
directed metalation of â-carboline-3-carboxamides, Mulz-
er and co-workers presented a similar reaction using a
methoxymethyl blocking group at the 9-N position of the
â-carboline and amidomagnesium chlorides as the meta-
lating species.13 Conversion rates were, however, gener-
ally quite low, and moreover, removal of the methoxy-
methyl blocking groups from the products was not
described. Since, in our experience, efficient removal of
this blocking group can be problematic, we preferred to
find a more appropriate 9-N-protecting group before
proceeding with the preparation, via this route, of
4-substituted (and, particularly, 4-amino) â-carbolines
suitable for pharmacological evaluation. We describe
herein the results of this investigation.
We first studied the effects on ortho-metalation of
having no protecting group whatsoever at the 9-N posi-
tion. Thus, reaction of compound 4 (prepared by analogy
with 2,9,14 from ethyl â-carboline-3-carboxylate (1), tri-
methylaluminum, and benzylamine) with up to 5 equiv
of methyllithium at -78 °C in THF followed by addition
of p-anisaldehyde resulted in the formation of the ben-
zylic alkylation product 5 (Scheme 1) as the only isolable
product. To circumvent this parasitic reaction pathway,15
the possibility of utilizing an N-phenylcarboxamide (as
in 6, Scheme 2) as an ortho-directing group was exam-
The 9-N-(dimethylsulfamoyl)-â-carboline derivative 8
was thus prepared in 93% yield by sequential treatment
of compound 6 with sodium hydride and N,N-dimethyl-
(10) Shortly after our report of the ortho-metalation of 3-carboxy-
â-carbolines (ref 9), Queguiner and co-workers described experiments
using 3-carboxy-R-carbolines as substrates and in which the 9-N
position was similarly methylated: Papamicae¨l, C.; Dupas, G.; Bour-
guignon, J .; Queguiner, G. Tetrahedron Lett. 1994, 35, 4099.
(11) Cain, M.; Weber, R. W.; Guzman, F.; Cook, J . M.; Barker, S.
A.; Rice, K. C.; Crawley, J . N.; Paul, S. M.; Skolnick, P. J . Med. Chem.
1982, 25, 1081.
(16) Epsztajn, J .; Bieniek, A.; Plotka, M. W.; Suwald, K. Tetrahedron
1989, 45, 7469.
(17) A similar observation was made by Mulzer and co-workers, ref
13.
(12) Although we reported (ref 9) that 2 could be demethylated using
sequential treatment with benzoyl peroxide and sodium hydroxide, this
methodology proved incompatible with many of the 4-substituted
â-carbolines synthesized from 2 by the ortho-metalation route.
(13) Schlecker, W.; Huth, A.; Ottow, E.; Mulzer, J . Synthesis 1995,
1225.
(14) Hirabayashi, T.; Itoh, K.; Sakai, S.; Kishi, Y. J . Organomet.
Chem. 1970, 25, 33.
(15) Benzylic alkylation of the benzylamido group has sometimes
been observed in ortho-directed lithiation reactions; see, for example:
Epsztajn, J .; Bieniek, A.; Plotka, M. W. J . Chem. Res., Synop. 1986,
20.
(18) Amat, M.; Hadida, S.; Sathyanarayana, S.; Bosch, J . J . Org.
Chem. 1994, 59, 10.
(19) Griffen, E. J .; Roe, D. G.; Snieckus, V. J . Org. Chem. 1995, 60,
1484.
(20) The N-benzyl group was also considered. However, in view of
the likelihood of benzylic alkylation of this group under the conditions
of the ortho-lithiation reaction (ref 15) and the necessity of utilizing
drastic conditions to remove it (ref 6), this possibility was not pursued.
(21) Chadwick, D. J .; Ngochindo, R. I. J . Chem. Soc., Perkin Trans.
1 1984, 481.
(22) Marsais, F.; Cronnier, A.; Trecourt, F.; Queguiner, G. J . Org.
Chem. 1987, 52, 1133.

874 J . Org. Chem., Vol. 63, No. 3, 1998
Notes
Sch em e 3
Sch em e 4
10) of trifluoromethanesulfonic acid and trifluoroacetic
acid for 1 h at rt.
There have been a number of recent reports concerning
the deprotection of N-(arylsulfonyl)amines using sa-
marium diiodide.24 We were thus curious to see if the
N,N-dimethylsulfamoyl group could also be cleaved by
this reagent. Compound 10 was thus treated at rt with
excess SmI2 in THF in the presence of 1,3-dimethyl-
3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU). After 1
h, complete deprotection of 10 was observed by TLC, and
the product, compound 7, was isolated in 73% yield. This
represents a very useful and mild alternative to the acidic
cleavage of this protecting group described above.
With these exploratory results in hand, substrate 8 was
then employed for the preparation of a fully deprotected
4-amino-3-carboxy-â-carboline derivative, one of our pri-
mary goals in applying ortho-directed metalation tech-
nology to â-carbolines. Thus, ortho-lithiation of 8 using
our standard conditions (2.5 equiv of methyllithium in
THF, 45 min-1 h at -78 °C) followed by addition of 2,4,6-
triisopropylbenzenesulfonyl azide (trisyl azide, 3 equiv)25,26
gave, after hydrolytic workup, 92% of the 4-azido-â-
carboline derivative 11 (Scheme 4). The presence of an
azide function in 11 was indicated by a sharp band at
sulfamoyl chloride in THF (Scheme 3). Reaction of 8 with
∼3 equiv of methyllithium for 45 min at -78 °C followed
by addition of p-anisaldehyde led to formation of a
mixture of the C-4-substituted â-carboline 9 and its
lactonized derivative 10. Compound 9, not isolated, was
converted into 10 by treatment of the reaction mixture
with sulfuric acid in acetonitrile for 30 min at rt.9 The
yield of 10 resulting from these three operations (lithia-
tion, electrophilic substitution, cyclization) was 90%. It
should be noted that, though the overall yield of ortho-
metalation product 10 is substantially the same as that
obtained in the case of the N-methyl derivative 2,9 the
dimethylsulfamoyl protecting group has a favorable effect
on ortho-metalation in that generation of the C-4 anion
is apparently more rapid in the case of 8 (45 min at -78
°C instead of 2 h at -78 °C followed by 20 min at 0 °C
for 2) and furthermore requires a smaller excess of
methyllithium reagent (3 equiv instead of 5 equiv for 2).
1
2136 cm-1 in the infrared spectrum, while the H NMR
spectrum confirmed the C-4 position of the azide, the
characteristic singlet observed at 9.20 ppm for the proton
at this position in precursor 8 having disappeared. The
4-amino derivative 12 was then obtained in 95% yield
by catalytic hydrogenation of 11 over palladium on
carbon. Treatment of 12 with trifluoromethanesulfonic
acid and trifluoroacetic acid (1:10) for 2 h at rt then
provided the deprotected 4-amino-â-carboline-3-carbox-
amide derivative 13 in 95% yield. Deprotection of 12
using SmI2-DMPU also gave 13 in practically quantita-
tive yield.
Removal of the dimethylsulfamoyl protecting group,
essential to our objective of preparing pharmacologically
relevant â-carboline derivatives, proved initially to be
difficult. Application to 10 of the reaction conditions
shown to achieve complete deprotection of N-(dimethyl-
sulfamoyl)imidazole derivatives (2 M HCl, 4 h reflux)21
led to formation of only traces of deprotected product 7.
Increasing the reflux time or acid concentration led to
product decomposition as did the use of a basic medium
(aqueous LiOH). Finally, on the basis of reaction condi-
tions used to remove N-sulfonyl protecting groups in
peptides,23 complete deprotection of 10, to give 7, was
obtained in excellent yield by the action of a mixture (1:
(23) Yajima, H.; Takeyama, M.; Kanaki, J .; Nishimura, O.; Fujino,
M. Chem. Pharm. Bull. 1978, 26, 3752.
(24) (a) Vedejs, E.; Lin, S. J . Org. Chem. 1994, 59, 1602. (b)
Goulaouic-Dubois, C.; Guggisberg, A.; Hesse, M. J . Org. Chem. 1995,
60, 5969. (c) Knowles, H.; Parsons, A. F.; Pettifer, R. M. Synlett 1997,
271.
(25) (a) Leffler, J . E.; Tsuno, Y. J . Org. Chem. 1963, 28, 902. (b)
Harmon, R. E.; Wellman, G.; Gupta, S. K. J . Org. Chem. 1973, 38, 11.
(26) Trisyl azide has been shown to be a more effective azide-transfer
reagent than the more commonly employed tosyl azide: Evans, D. A.;
Britton, T. C. J . Am. Chem. Soc. 1987, 109, 6881.

Notes
J . Org. Chem., Vol. 63, No. 3, 1998 875
Sch em e 5
4-amino-3-carboxy-â-carboline 13, a derivative of which
has previously been synthesized only by a multistep, low-
yielding pathway.7 Moreover, the success of the combi-
nation of ortho-directed metalation, palladium-catalyzed
cross-coupling, and SmI2-promoted removal of the 9-N-
protecting group suggests that this may be a method of
choice for the preparation of 4-amino-3-carboxy-â-carbo-
line derivatives in particular and 4-substituted deriva-
tives in general. This possibility is presently being
investigated.
Exp er im en ta l Section
Gen er a l.. Melting points are uncorrected. IR spectra of
samples were obtained as KBr pellets. 1H and 13C NMR
chemical shifts are given as δ values. TLC and preparative
chromatography were performed on Merck silica gel 60 plates
with fluorescent indicator. The plates were visualized with UV
light (254 and 366 nm). All column chromatography was
conducted on Merck 60 silica gel (230-240 mesh) at medium
pressure (200 mbar). All solvents were distilled and stored over
4-Å molecular sieves before use. Solutions of methyllithium and
samarium iodide were purchased from Aldrich Chemical Co.
Elemental analyses were performed at the ICSN, CNRS, Gif-
sur-Yvette, France.
3-N-Ben zyl-â-ca r bolin e-3-ca r boxa m id e (4). A solution of
trimethylaluminum in heptane (6.2 mL of a 2.0 M solution, 12.4
mmol) was added dropwise at -10 °C under argon to anhydrous
dichloromethane (40 mL). The solution was stirred for 10 min,
benzylamine (0.68 mL, 6.2 mmol) was added dropwise, and
stirring was continued at -10 °C for 20 min and then at rt for
1 h. A solution of ethyl â-carboline-3-carboxylate (1, X ) O, R
) Et) (1.5 g, 6.2 mmol) in dichloromethane (15 mL) was then
added, and the mixture was refluxed for 24 h. After cooling and
neutralization with 1 M HCl, the reaction mixture was extracted
with dichloromethane and ethanol (200 mL of a 9:1 mixture),
and the organic extract was washed with water (3 × 75 mL).
The organic phase was evaporated to dryness under reduced
pressure, and the residual solid was suspended in methanol and
collected by filtration, affording compound 4 in 82% yield: mp
260 °C; 1H NMR (DMSO-d6, 250 MHz) δ 4.68 (2H, d, J ) 6.4
Hz), 7.35-7.50 (6H, m), 7.71 (1H, t, J ) 8.1 Hz), 7.78 (1H, d, J
) 8.1 Hz), 8.52 (1H, d, J ) 7.8 Hz), 8.99 (1H, s), 9.02 (1H, s),
9.33 (1H, t, J ) 6.4 Hz, exchangeable with D2O), 12.07 (1H, s,
exchangeable with D2O); 13C NMR (DMSO-d6, 75 MHz) δ 42.3,
112.2, 114.0, 119.9, 122.1, 126.6, 127.3, 128.1, 128.2, 128.5, 132.2,
137.1, 139.6, 139.8, 140.9, 164.8; IR (KBr) 3360, 3218, 1653, 1536
cm-1; EIMS m/z 301 (M)+. Anal. Calcd for C19H15N3O: C, 75.75;
H, 4.98; N, 13.95. Found: C, 75.63; H, 5.12; N, 13.88.
Attem p ted Or th o-Meta la tion of Com p ou n d 4. To a
solution of compound 4 (200 mg, 0.66 mmol) in anhydrous THF
(65 mL) held at -78 °C under argon for 30 min was added
dropwise over 10 min a solution of methyllithium in THF (3.3
mL of a 1.0 M solution, 3.3 mmol). The solution was stirred for
2 h at -78 °C and then for 30 min at 0 °C before addition, at 0
°C, of freshly distilled p-anisaldehyde (0.4 mL, 3.3 mmol). After
completion of the addition, the reaction mixture was allowed to
come to rt, and stirring was maintained for 1 h. The solution
was then cooled back to 0 °C, water (20 mL) was added, and the
mixture was extracted with ethyl acetate (3 × 20 mL). The
combined organic extracts were washed with water (2 × 15 mL)
and dried over sodium sulfate, and the solvents were removed
under reduced pressure. The residue was purified by column
chromatography on silica gel (heptane-ethyl acetate, 1:1) af-
fording compound 5 as a white solid in 54% yield: mp 205 °C;
1H NMR (DMSO-d6, 250 MHz) δ 3.80 (3H, s), 5.10 (0.5H, t, J )
3.0 Hz), 5.22 (0.5H, t, J ) 5.4 Hz), 5.28-5.39 (1H, m), 5.84 (0.5H,
d, J ) 4.4 Hz, exchangeable with D2O), 5.96 (0.5H, d, J ) 4.6
Hz, exchangeable with D2O), 6.92 (2H, dd, J ) 8.7, 7.0 Hz), 7.24-
7.44 (6H, m), 7.47 (1H, t, J ) 8.7 Hz), 7.57 (2H, d, J ) 7.6 Hz),
7.70 (1H, t, J ) 8.0 Hz), 7.77 (1H, d, J ) 8.0 Hz), 8.48 (1H, dd,
J ) 7.9 Hz), 8.84 (0.5H, s), 8.89 (0.5H, s), 9.06 (0.5H, s), 9.13
(0.5H, s), 9.25 (1H, t, J ) 7.0 Hz, exchangeable with D2O), 12.13
(1H, s, exchangeable with D2O); 13C NMR (DMSO-d6, 75 MHz)
δ 54.8, 58.5, 58.8, 74.1, 74.6, 112.2, 112.9, 113.1, 113.8, 113.9,
As an obvious means of preparing novel pharmacologi-
cally relevant â-carboline derivatives, we next investi-
gated alkylation of the amine function of 12. Initial
efforts using benzyl bromide as the model alkylating
agent in the presence of bases (NaH, K2CO3, or Et3N)
gave only traces of the N-benzyl derivative 15 (Scheme
5). However, when a solution of 12 in benzyl bromide
was heated at 100 °C for 24 h, compound 15 was obtained
in 62% yield. The same product 15 was formed, though
in lower yield (35%), when 12 was treated with benz-
aldehyde and then with sodium borohydride. The low
nucleophilic character of this aromatic amine, together
with the steric hindrance provided by the 3-anilide group,
is no doubt responsible for this relatively poor reactivity.
An alternative route to 4-(N-alkylamino)-3-carboxy-â-
carboline derivatives was suggested by the recent work
of Buchwald and co-workers.27 These authors have
shown that bromopyridines can be effectively coupled to
primary and secondary alkylamines using a Pd2(dba)3-
BINAP complex as catalyst. As shown in Scheme 5, this
methodology can also be applied to 3-carboxamido-â-
carbolines, as illustrated by the formation of the 4-ben-
zylamino derivative 15. Thus, ortho-metalation of 8 with
methyllithium followed by reaction of the anion with
bromine for 15 min at -78 °C provided the 4-bromo-â-
carboline 14 in quantitative yield. The latter was treated
with Pd2(dba)3 (0.1 equiv), BINAP (0.2 equiv), benzyl-
amine (1.5 equiv), and sodium tert-butoxide in THF at
reflux for 16 h, affording the desired 4-benzylamino
derivative 15 in 52% yield. Finally, compound 15 was
deprotected using SmI2 to give 16 in 89% yield.
In conclusion, the introduction of the N,N-dimethyl-
sulfamoyl moiety as a stable but easily removed blocking
group for the 9-N position of 3-carboxy-â-carbolines now
permits preparation, via ortho-directed metalation tech-
niques, of 4-substituted derivatives directly amenable to
pharmacological evaluation. The value of this procedure
is exemplified by the highly efficient preparation of the
(27) Wagaw, S.; Buchwald, S. L. J . Org. Chem. 1996, 61, 7240.

876 J . Org. Chem., Vol. 63, No. 3, 1998
Notes
120.0, 120.8, 122.2, 126.6, 127.0, 127.3, 127.4, 127.7, 127.9, 128.1,
128.6, 132.4, 132.6, 134.3, 135.4, 137.2, 139.2, 139.4, 140.1, 141.0,
for C22H19N3O5S: C, 60.39; H, 4.38; N, 9.60; S, 7.32. Found: C,
60.31; H, 4.54; N, 9.60; S, 7.14.
142.1, 158.1, 163.6, 164.0; IR (KBr) 3370, 3272, 1625, 1532 cm-1
;
(R,S)-10-(4-Meth oxyph en yl)fu r o[3,4-c]-â-car bolin -2(10H)-
on e (7). A solution of compound 10 (124 mg, 0.28 mmol) in
trifluoromethanesulfonic acid and trifluoroacetic acid (5 mL of
a 1:10 mixture) was stirred for 1 h at rt and then neutralized
by addition of aqueous sodium hydroxide (4 N), resulting in
formation of a precipitate. After addition of water (10 mL), the
mixture was filtered, and the precipitate was washed succes-
sively with water, methanol, and ethyl acetate, providing
compound 7 as a white solid in 89% yield: mp >300 °C; 1H NMR
(DMSO-d6, 250 MHz) δ 3.85 (3H, s), 7.07 (2H, d, J ) 8.6 Hz),
7.26 (1H, t, J ) 7.4 Hz), 7.29 (1H, s), 7.44 (2H, d, J ) 8.6 Hz),
7.49 (1H, d, J ) 7.4 Hz), 7.67 (1H, t, J ) 8.1 Hz), 7.83 (1H, d, J
) 8.1 Hz), 9.33 (1H, s), 12.67 (1H, s, exchangeable with D2O);
13C NMR (DMSO-d6, 75 MHz) δ 55.1, 79.4, 112.7, 114.4, 118.8,
120.7, 123.2, 127.3, 128.7, 130.0, 132.7, 137.5, 138.7, 160.1; IR
(KBr) 1760 cm-1; EIMS m/z 330 (M)+. Anal. Calcd for
CIMS m/z 438 (MH)+. Anal. Calcd for C27H23N3O3‚0.65H2O:
C, 72.19; H, 5.45; N, 9.32. Found: C, 72.14; H, 5.62; N, 9.33.
3-N-P h en yl-â-ca r bolin e-3-ca r boxa m id e (6). Using the
procedure employed for the preparation of benzylamide 4,
reaction of trimethylaluminum (5 mL of a 2.0 M solution in
hexane, 10 mmol) with aniline (0.38 mL, 4.2 mmol) and then
with 1 (X ) O, R ) Et) (1.20 g, 5 mmol) afforded compound 6 in
80% yield: mp 285 °C; 1H NMR (DMSO-d6, 250 MHz) δ 7.23
(1H, t, J ) 7.4 Hz), 7.44 (1H, t, J ) 7.8 Hz), 7.50 (2H, d, J ) 7.6
Hz), 7.73 (1H, t, J ) 8.4 Hz), 7.80 (1H, d, J ) 8.4 Hz), 8.07 (2H,
d, J ) 7.8 Hz), 8.56 (1H, d, J ) 7.8 Hz), 9.11 (2H, s), 10.72 (1H,
s, exchangeable with D2O), 12.16 (1H, s, exchangeable with D2O);
13C NMR (DMSO-d6, 75 MHz) δ 112.3, 114.5, 119.8, 120.0, 120.8,
122.3, 123.3, 128.4, 128.6, 128.7, 132.2, 137.3, 138.7, 139.2, 141.1,
163.2; IR (KBr) 3307, 3212, 1648, 1540 cm-1; EIMS m/z 287 (M)+,
195 (M - NHC6H5)+. Anal. Calcd for C18H13N3O‚0.25H2O: C,
74.08; H, 4.66; N, 14.40. Found: C, 74.13; H, 4.62; N, 14.34.
C
20H14N2O3‚1.2H2O: C, 68.25; H, 4.70; N, 7.96. Found: C, 68.31;
H, 4.59; N, 7.97.
4-Azid o-9-(N,N-d im eth ylsu lfa m oyl)-3-N-p h en yl-â-ca r bo-
lin e-3-ca r boxa m id e (11). A solution of compound 8 (271 mg,
0.69 mmol) in anhydrous THF (100 mL) was held at -78 °C
under argon for 30 min before dropwise addition of methyl-
lithium (1.72 mL of a 1.0 M solution in THF, 1.72 mmol) over
10 min. The violet-colored reaction mixture was stirred for 1 h
at -78 °C, and a solution of trisyl azide (635 mg, 2.1 mmol) in
THF (3 mL) was added dropwise over 5 min. The reaction
mixture was stirred for a further 30 min at -78 °C, the cooling
bath was removed, and stirring was continued for 2 h. At the
end of this period, the reaction mixture was cooled to 0 °C and
the reaction quenched by successive addition of acetic acid (560
µL), sodium acetate (167 mg), and methanol (1.6 mL). After 30
min, the solution was concentrated to one-half volume under
reduced pressure, ethyl acetate (100 mL) was added, and the
resulting solution was washed successively with water (30 mL),
saturated aqueous sodium hydrogen carbonate (30 mL), and
water (30 mL). The organic phase was dried over sodium sulfate
and concentrated under reduced pressure leading to precipita-
tion of compound 11 which was collected by filtration and
washed with heptane (92% yield). Obtained as a white solid,
compound 11 gradually turned bright yellow on contact with
9-(N,N-Dim et h ylsu lfa m oyl)-3-N-p h en yl-â-ca r b olin e-3-
ca r boxa m id e (8). A solution of compound 6 (170 mg, 0.59
mmol) in anhydrous THF (20 mL) was treated at 0 °C under
argon with sodium hydride (71 mg of a 50% dispersion in oil,
1.48 mmol). The mixture was stirred for 30 min at 0 °C, and
N,N-dimethylsulfamoyl chloride (191 µL, 1.78 mmol) was then
added. The reaction mixture was allowed to come to rt and
stirred for a further 3 h. The solution was concentrated under
reduced pressure, ethyl acetate (30 mL) was added to the
residue, and the mixture was washed with water (3 × 15 mL).
The combined aqueous washings were extracted with ethyl
acetate (2 × 10 mL); the organic extracts were combined and
dried over sodium sulfate. The crude reaction product remaining
after removal of the solvents under reduced pressure was
purified by column chromatography on silica gel (dichloro-
methane), affording compound 8 as a colorless solid (93%) which
could be further purified by crystallization from dichloro-
methane-hexane: mp 192 °C; 1H NMR (DMSO-d6, 250 MHz) δ
3.01 (6H, s), 7.25 (1H, t, J ) 7.7 Hz), 7.51 (2H, t, J ) 8.5 Hz),
7.69 (1H, t, J ) 7.8 Hz), 7.90 (1H, t, J ) 8.3 Hz), 8.08 (2H, d, J
) 8.2 Hz), 8.29 (1H, d, J ) 8.5 Hz), 8.73 (1H, d, J ) 7.8 Hz),
9.20 (1H, s), 9.53 (1H, s), 10.85 (1H, s, exchangeable with D2O);
13C NMR (DMSO-d6, 75 MHz) δ 38.1, 114.4, 114.5, 120.1, 122.8,
123.7, 124.0, 128.6, 130.5, 134.2, 136.4, 138.4, 143.6, 162.4; IR
(KBr) 3337, 1677, 1529, 1170 cm-1; EIMS m/z 394 (M)+, 302 (M
1
air: mp 195 °C; H NMR (DMSO-d6, 250 MHz) δ 2.99 (6H, s),
7.26 (1H, t, J ) 7.7 Hz), 7.51 (2H, t, J ) 7.7 Hz), 7.70 (1H, t, J
) 7.6 Hz), 7.89 (1H, t, J ) 8.2 Hz), 8.00 (1H, d, J ) 7.9 Hz),
8.30 (1H, d, J ) 8.2 Hz), 8.79 (1H, d, J ) 7.6 Hz), 9.34 (1H, s),
10.94 (1H, s, exchangeable with D2O); 13C NMR (DMSO-d6, 75
MHz) δ 38.1, 114.2, 120.0, 121.7, 123.9, 124.0, 124.3, 124.5,
128.7, 130.2, 130.5, 131.2, 136.4, 138.4, 139.0, 163.0; IR (KBr)
-
NHC6H5)+, 286 (M SO2NMe2)+. Anal. Calcd for
-
C20H18N4O3S: C, 60.90; H, 4.60; N, 14.20; S, 8.13. Found: C,
60.86; H, 4.58; N, 14.16; S, 8.42.
3340, 2136, 1681, 1525, 1171 cm-1
; HREIMS calcd for
(R ,S )-5-(N ,N -D i m e t h y ls u lfa m o y l)-10-(4-m e t h o x y -
p h en yl)fu r o[3,4-c]-â-ca r bolin -2(10H)-on e (10). A solution of
compound 8 (180 mg, 0.45 mmol) in anhydrous THF (40 mL)
was treated dropwise at -78 °C under argon with a solution of
methyllithium in THF (1.13 mL of a 1.0 M solution, 1.13 mmol).
The reaction mixture was stirred for 45 min at -78 °C, and
freshly distilled p-anisaldehyde (166 µL, 1.37 mmol) was then
added dropwise over 5 min. Stirring was continued at -78 °C
for 30 min and then for 2 h at rt. At the end of the reaction
period, the solution was cooled to 0 °C, water (10 mL) was added,
and the mixture was extracted with ethyl acetate (3 × 20 mL).
The combined organic extracts were evaporated to dryness under
reduced pressure, the residue was dissolved in acetonitrile (15
mL), and concentrated sulfuric acid (0.5 mL) was added. After
30 min of stirring, the solution was diluted with ethyl acetate
(50 mL) and washed successively with aqueous sodium hydrox-
ide (20 mL of a 10% solution), saturated aqueous sodium chloride
solution (20 mL), and water (20 mL). The organic phase was
dried (Na2SO4), the solvents were removed under reduced
pressure, and the residue was purified by column chromatog-
raphy on silica gel (ethyl acetate-heptane, 1:3) affording
compound 10 as a white powder (90%): mp 233 °C; 1H NMR
(DMSO-d6, 250 MHz) δ 3.05 (6H, s), 3.86 (3H, s), 7.08 (2H, d, J
) 8.4, 1.6 Hz), 7.39 (1H, s), 7.45-7.56 (4H, m), 7.83 (1H, t, J )
8.6 Hz), 8.31 (1H, d, J ) 8.6 Hz), 9.79 (1H, s); 13C NMR (DMSO-
d6, 75 MHz) δ 38.1, 55.1, 79.6, 114.5, 114.6, 120.4, 123.8, 124.0,
125.2, 126.5, 130.2, 130.6, 136.6, 137.4, 139.0, 139.4, 160.3, 167.6;
IR (KBr) 1770, 1175 cm-1; CIMS m/z 438 (MH)+. Anal. Calcd
C20H17N7O3S [M]+ m/z 435.1113, found m/z 435.1101.
4-Am in o-9-(N,N-d im et h ylsu lfa m oyl)-3-N-p h en yl-â-ca r -
bolin e-3-ca r boxa m id e (12). A solution of compound 11 (250
mg, 0.57 mmol) in acetone and ethanol (40 mL of a 1:1 mixture)
was hydrogenated for 45 min at atmospheric pressure in the
presence of 10% palladium on carbon (150 mg). The reaction
mixture was filtered through Celite, and the filtrate was
evaporated under reduced pressure affording compound 12 as
a white powder (95%) which could be crystallized in methanol:
1
mp 216 °C; H NMR (DMSO-d6, 300 MHz) δ 2.98 (6H, s), 7.22
(1H, t, J ) 7.5 Hz), 7.48 (1H, t, J ) 7.8 Hz), 7.66 (1H, t, J ) 7.8
Hz), 7.80 (2H, t, J ) 8.2 Hz), 7.99 (2H, d, J ) 8.2 Hz), 8.30 (1H,
d, J ) 8.4 Hz), 8.68 (1H, d, J ) 7.9 Hz), 8.87 (1H, s), 10.70 (1H,
s, exchangeable with D2O); 13C NMR (DMSO-d6, 75 MHz) δ 38.1,
114.1, 116.7, 120.0, 122.6, 122.7, 122.9, 123.4, 123.7, 128.1, 128.6,
137.2, 137.9, 138.3, 142.5, 166.2; IR (KBr) 3485, 3334, 1662, 1524
cm-1; CIMS m/z 410 (MH)+. Anal. Calcd for C20H19N5O3S: C,
58.67; H, 4.68; N, 17.10; S, 7.83. Found: C, 58.64; H, 4.71; N,
16.91; S, 7.82.
4-Am in o-3-N-p h en yl-â-ca r bolin e-3-ca r boxa m id e (13). A
solution of compound 12 (160 mg, 0.39 mmol) in trifluoro-
methanesulfonic acid and trifluoroacetic acid (3.3 mL of a 1:10
mixture) was stirred for 2 h at rt. The reaction mixture was
neutralized by the addition of 4 N sodium hydroxide solution.
Water (15 mL) was then added, and the mixture was extracted
with ethyl acetate (40 mL). The organic phase was washed with
water (15 mL) and dried over sodium sulfate, and the solvent

Notes
J . Org. Chem., Vol. 63, No. 3, 1998 877
was removed under reduced pressure, affording compound 13
as a light-yellow powder in 95% yield: mp 292 °C; 1H NMR
(DMSO-d6, 300 MHz) δ 7.19 (1H, t, J ) 7.6 Hz), 7.42 (1H, t, J )
7.4 Hz), 7.49 (2H, t, J ) 7.7 Hz), 7.64 (1H, t, J ) 7.7 Hz), 7.75
(1H, d, J ) 7.8 Hz), 7.97 (2H, d, J ) 7.8 Hz), 8.42 (1H, s), 8.60
(1H, d, J ) 7.8 Hz), 10.57 (1H, s, exchangeable with D2O), 12.07
(1H, s, exchangeable with D2O); 13C NMR (DMSO-d6, 75 MHz)
δ 111.4, 118.5, 119.2, 119.5, 120.6, 121.8, 122.0, 122.6, 125.9,
128.3, 137.8, 138.4, 139.0, 143.0, 166.5; IR (KBr) 3496, 3341,
3297, 1642, 1513 cm-1; CIMS m/z 303 (MH)+. Anal. Calcd for
mixture was allowed to come to rt, and stirring was maintained
overnight at which time water (1 mL) was added followed by
ethyl acetate (20 mL). The aqueous layer was removed, and the
organic phase was washed with water (10 mL) and then with
saturated aqueous sodium chloride (10 mL). The organic phase
was dried (Na2SO4), the solvents were removed under reduced
pressure, and the residue was purified by chromatography on
silica gel (ethyl acetate-heptane, 1:3) affording compound 15
as a white solid (35%), identical in all respects with the
compound obtained from 12 and benzyl bromide (above).
C
18H14N4O‚0.35H2O: C, 70.05; H, 4.80; N, 18.15. Found: C,
F r om th e 4-Br om o Der iva tive 14: A mixture of compound
14 (37 mg, 0.08 mmol), benzylamine (13 µL, 0.12 mmol), tris-
(dibenzylideneacetone)dipalladium(0) chloroform adduct (10 mg,
0.008 mmol), BINAP (10 mg, 0.016 mmol), and sodium tert-
butoxide (19 mg, 0.2 mmol) in anhydrous THF (10 mL) was
degassed by bubbling in argon for 5 min and then refluxed for
16 h. The reaction mixture was cooled to rt, diluted with
dichloromethane (10 mL), and washed with saturated aqueous
sodium chloride (10 mL) and water (10 mL). The organic phase
was dried over sodium sulfate, the solvents were removed under
reduced pressure, and the residue was purified by column
chromatography on silica gel (ethyl acetate-heptane, 1:3),
affording compound 15 in 52% yield, identical in all respects with
the compound obtained from 12 (above).
Gen er a l P r oced u r e for t h e R em ova l of t h e N,N-Di-
m eth ylsu lfa m oyl Block in g Gr ou p Usin g Sm I2. A solution
of the dimethylsulfamoyl derivative (10, 12, or 15; 0.1 mmol)
and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.8
mmol) in anhydrous THF (10 mL) was treated dropwise, at rt
under argon, with a solution of SmI2 in THF (5 mL of a 0.1 M
solution, 0.5 mmol). At the end of the reaction period (0.5-1 h,
as indicated by TLC), 5% HCl solution (2 mL) was added, the
solution was concentrated to one-half volume under reduced
pressure, and ethyl acetate (20 mL) was added. The mixture
was washed with water (10 mL) and saturated aqueous sodium
chloride (10 mL). The organic phase was dried over sodium
sulfate, the solvents were removed under reduced pressure, and
the residue was purified as indicated. Prepared by this method
were the following compounds.
7: 73% yield from 10 after suspension of the residue in
dichloromethane and filtration; identical in all respects to the
compound obtained by acid hydrolysis of 10 (above).
13: 97% yield from 12 after chromatography of the residue
on silica gel (ethyl acetate-heptane, 1:2); identical in all respects
to the compound obtained from acid hydrolysis of 12 (above).
4-(N -Be n zyla m in o)-3-N -p h e n yl-â-ca r b olin e -3-ca r b ox-
a m id e (16): 89% yield from 15 after chromatography of the
residue on silica gel (dichloromethane); mp 162 °C (MeOH); 1H
NMR (DMSO-d6, 250 MHz) δ 4.77 (2H, d, J ) 6.9 Hz), 7.20 (1H,
t, J ) 6.9 Hz), 7.23-7.49 (8H, m), 7.69 (1H, t, J ) 8.1 Hz), 7.81
(1H, d, J ) 8.1 Hz), 7.93 (2H, d, J ) 8.0 Hz), 8.22 (1H, d, J )
7.9 Hz), 8.66 (1H, s), 8.75 (1H, t, J ) 6.9 Hz, exchangeable with
D2O), 10.72 (1H, s, exchangeable with D2O), 12.24 (1H, s,
exchangeable with D2O); 13C NMR (DMSO-d6, 75 MHz) δ 51.0,
112.2, 120.0, 120.2, 120.5, 123.3, 123.4, 125.2, 127.0, 127.1, 128.4,
128.6, 138.3, 138.9, 139.7, 140.1, 145.4, 166.5; IR (KBr) 3414,
3317, 3298, 1636, 1529 cm-1; CIMS m/z 393 (MH)+. Anal. Calcd
for C25H20N4O‚0.25H2O: C, 75.64; H, 5.21; N, 14.11. Found: C,
75.71; H, 5.36; N, 14.12.
70.05; H, 4.84; N, 18.11.
4-Br om o-9-(N,N-d im et h ylsu lfa m oyl)-3-N-p h en yl-â-ca r -
bolin e-3-ca r boxa m id e (14). A solution of compound 8 (200
mg, 0.51 mmol) in THF (40 mL) was treated dropwise at -78
°C under argon with a solution of methyllithium in THF (1.1
mL of a 1 M solution, 1.1 mmol). The reaction mixture was
stirred for 1 h at -78 °C, bromine (57 µL, 1.1 mmol) was added
dropwise, and stirring was continued for 15 min. After addition
of water (10 mL), the solution was allowed to come to rt, and it
was then evaporated to one-half volume and diluted with ethyl
acetate (50 mL). The solution was washed with saturated
aqueous ammonium chloride (20 mL) and water (20 mL). The
organic phase was dried over sodium sulfate and evaporated to
dryness under reduced pressure. The residual solid was sus-
pended in methanol (5 mL) and collected by filtration, affording
compound 14 as a white powder in quantitative yield: mp 220
1
°C; H NMR (DMSO-d6, 300 MHz) δ 3.02 (6H, s), 7.26 (1H, t, J
) 7.5 Hz), 7.51 (2H, t, J ) 7.7 Hz), 7.76 (1H, t, J ) 7.5 Hz), 7.91
(2H, d, J ) 7.7 Hz), 7.98 (1H, t, J ) 8.5 Hz), 8.37 (1H, d, J ) 8.5
Hz), 9.04 (1H, d, J ) 7.9 Hz), 9.50 (1H, s), 10.84 (1H, s,
exchangeable with D2O); 13C NMR (DMSO-d6, 75 MHz) δ 37.5,
110.0, 114.1, 119.2, 122.1, 123.0, 123.4, 123.5, 128.4, 129.2, 130.5,
133.1, 135.2, 138.4, 139.1, 146.7, 163.7; IR (KBr) 3325, 1693,
1526, 1172 cm-1; CIMS m/z 475 (MH+, 81Br), 473 (MH+, 79Br).
Anal. Calcd for C20H17BrN4O3S: C, 50.75; H, 3.62; N, 11.84; S,
6.77. Found: C, 51.15; H, 3.82; N, 11.58; S, 6.75.
4-(N-Ben zylam in o)-9-(N,N-dim eth ylsu lfam oyl)-3-N-ph en -
yl-â-ca r bolin e-3-ca r boxa m id e (15). F r om th e 4-Am in o
Der iva tive 12 a n d Ben zyl Br om id e: A solution of compound
12 (20 mg, 0.046 mmol) in benzyl bromide (2 mL) was heated at
100 °C for 24 h. The reaction mixture was cooled to 0 °C,
saturated aqueous sodium hydrogen carbonate (1 mL) was
added, and the mixture was extracted with dichloromethane (10
mL). The organic extract was washed with water (3 mL) and
saturated aqueous sodium chloride (3 mL), dried over sodium
sulfate, and evaporated to dryness under reduced pressure. The
residue was purified by chromatography on silica gel (ethyl
acetate-heptane, 1:3) affording compound 15 as a white solid
(62%): mp 183 °C; 1H NMR (DMSO-d6, 250 MHz) δ 2.99 (6H,
s), 4 0.64 (2H, d, J ) 6.7 Hz), 7.23 (1H, t, J ) 7.5 Hz), 7.35-
7.50 (6H, m), 7.69 (1H, t, J ) 7.5 Hz), 7.86 (1H, t, J ) 8.3 Hz),
7.92 (2H, d, J ) 8.3 Hz), 8.33 (1H, d, J ) 8.3 Hz), 8.35 (1H, d,
J ) 7.6 Hz), 8.44 (1H, t, J ) 6.8 Hz, exchangeable with D2O),
9.10 (1H, s), 10.79 (1H, s, exchangeable with D2O); IR (KBr)
3326, 3262, 1653, 1526, 1169 cm-1; CIMS m/z 500 (MH)+. Anal.
Calcd for C27H25N5O3S: C, 64.91; H, 5.04; N, 14.02; S, 6.42.
Found: C, 64.66; H, 5.28; N, 14.15; S, 6.46.
F r om 12 a n d Ben za ld eh yd e: A solution of compound 12
(50 mg, 0.12 mmol) and benzaldehyde (16 µL, 0.16 mmol) in 95%
ethanol and THF (5 mL of a 5:1 mixture) was heated at 80 °C
overnight. The solution was cooled and concentrated to dryness
under reduced pressure. The residue was dissolved in dichloro-
methane (5 mL), the solution was cooled to 0 °C, and sodium
borohydride (4.5 mg, 0.12 mmol) was added. The reaction
Ack n ow led gm en t. We thank the Fondation pour
la Recherche Me´dicale for a fellowship (A.B.).
J O971485L