Palladium-catalyzed synthesis of selectively substituted phenanthridine derivatives

Article abstract of DOI:10.1002/adsc.200800512

Selectively substituted phenanthridine derivatives are obtained by a facile reaction of o-alkylated aryl iodides, o-bromoarenesulfonylanilines and activated olefins in the presence of palladium and norbornene as catalysts. The reaction takes place under mild conditions to give the products in satisfactory yields using readily available starting materials.

Full text of DOI:10.1002/adsc.200800512

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DOI: 10.1002/adsc.200800512
Palladium-Catalyzed Synthesis of Selectively Substituted
Phenanthridine Derivatives
Nicola Della Ca’,a Elena Motti,a and Marta Catellania,*
a
Dipartimento di Chimica Organica e Industriale and CIRCC, Universitꢀ di Parma, V. le G. P. Usberti, 17A, 43100 Parma,
Italy
Fax : (+39)-0521-905-472; e-mail: marta.catellani@unipr.it
Received: August 14, 2008; Published online: October 16, 2008
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800512.
Abstract: Selectively substituted phenanthridine de-
rivatives are obtained by a facile reaction of o-alky-
lated aryl iodides, o-bromoarenesulfonylanilines
and activated olefins in the presence of palladium
and norbornene as catalysts. The reaction takes
place under mild conditions to give the products in
satisfactory yields using readily available starting
materials.
the timely involvement of each reagent in the se-
quence of bond formation. We have found that react-
ing an o-alkyl-substituted aryl iodide with an aryl bro-
mide, containing a sulfonylated amino group in the
ortho position, and an activated terminal olefin, in the
presence of PdACHTUNGTRNEUG(N OAc)2, norbornene, K2CO3 and
NBu4Br in MeCN at 808C under nitrogen leads to the
formation of the desired product in satisfactory yields
as shown in Table 1, which reports representative re-
sults.
As shown in Table 1 iodoarenes, containing o-alkyl
substituents and 1-iodonaphthalene, readily reacted
with o-bromo-N-arenesulfonylanilines and methyl ac-
rylate to give the corresponding 5-arenesulfonyl-5,6-
dihydrophenanthridines in satisfactory yields. The
À
Keywords: catalysis; C H activation; norbornene;
palladium; phenanthridines; sequential reactions
Phenanthridine derivatives are a class of natural com- presence of either a methyl or a chloro group (en-
pounds with interesting biological and pharmaceutical tries 6 and 7) in the aniline ring did not appear to in-
activities, and much effort has been devoted to the fluence the outcome of the reaction, the correspond-
development of direct and efficient methods for the ing cyclic compounds 4f and 4g being isolated with
synthesis of these systems.[1]
the same yield (84%) and comparable selectivity (96
Palladium-catalyzed sequential reactions, which and 91%, respectively). The more electron-withdraw-
combine high selectivity with easy accessibility and ing substituent NO2 group (entry 8) gave 4h in lower
use of starting reagents, mild reaction conditions and yield (75%). Substituents in the aromatic ring of the
tolerance to a variety of functional groups, have at- sulfonyl moiety somehow affected the reaction
tracted the attention of several researchers.[2] Here we course, the best results being obtained with o-bromo-
report a facile and efficient catalytic synthesis of se- N-(p-chlorobenzenesulfonyl)aniline[6] (entries 10 and
lectively substituted 5-arenesulfonyl-5,6-dihydrophen- 12; R4 =C6H4-4-Cl) followed by o-bromo-N-(benzene-
ACHTUNGTRENNUNG
anthridines, taking advantage of our methodology for sulfonyl)aniline (entries 9 and 11; R4 =C6H5) and o-
multi-component palladium- and norbornene-cata- bromo-N-(p-methylbenzenesulfonyl)aniline (entries 1
lyzed syntheses.[3] It consists of sequential coupling of and 2; R4 =C6H4-4-Me). Analogously, o-isopropylio-
an o-substituted aryl iodide with a sulfonylated o-bro- dobenzene gave phenanthridines 4m and 4d in 78 and
moaniline, insertion of an activated olefin, and aza- 70% yields, respectively (entries 13 and 4). An elec-
Michael cyclization. The procedure parallels the one tron-withdrawing group in the arenesulfonyl ring ex-
we previously utilized for the synthesis of selectively erted a significant positive effect in the reaction of 1-
substituted 6H-dibenzopyran derivatives by reaction iodonaphthalene: dihydrophenanthridine derivative
of an o-substituted aryl iodide with an o-bromophenol 4n (entry 14) was isolated in an acceptable 62% yield
and an electron-deficient olefin.[4] Replacing an o-bro- using
o-bromo-N-(p-chlorobenzenesulfonyl)aniline,
mophenol derivative with an o-bromoaniline one, re- while compound 4e (entry 5) was obtained only in
quired quite different conditions, however, to allow 31% yield using the N-tosylated o-bromoaniline,
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Nicola Della Ca’ et al.
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Table 1. Synthesis of 5-arenesulfonyl-5,6-dihydrophenanthridines.[a]
Entry
R1, R2
R3
R4
Z
4 Yield [%][b]
1
2
3
4
5
6
7
8
Me, H
H
H
H
H
C6H4-4-Me
C6H4-4-Me
C6H4-4-Me
C6H4-4-Me
C6H4-4-Me
C6H4-4-Me
C6H4-4-Me
C6H4-4-Me
C6H5
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
COMe
CN
4a, 74 (83)[c]
4b, 81 (93)
4c, 84 (94)
4d, 70 (93)
4e, 31 (48)[d]
4f, 84 (96)
4g, 84 (91)
4h, 75 (96)
4i, 76 (95)
4j, 87 (97)
4k, 85 (92)
4l, 89 (94)
4m, 78 (95)
4n, 62 (89)
4o, 82 (96)
4p, 61 (90)
Me, 4-Me
Me, 4-OMe+ 3-Me
i-Pr, H
-(CH)4-
H
Me, 4-Me
Me, 4-Me
Me, 4-Me
Me, H
Me
Cl
NO2
H
H
H
H
H
H
H
9
10
11
12
13
14
15
16
Me, H
C6H4-4-Cl
C6H5
Me, 4-Me
Me, 4-Me
i-Pr, H
-(CH)4-
Me, 4-Me
Me, 4-Me
C6H4-4-Cl
C6H4-4-Cl
C6H4-4-Cl
C6H4-4-Me
C6H4-4-Me
H
[a]
Reaction conditions: aryl iodide (1.1 equiv.), aryl bromide (1.0 equiv.), activated terminal olefin (4 equiv.), norbornene
(10 equiv.), Pd(OAc)2 (5 mol%), K2CO3 (2.2 equiv.), NBu4Br (2.2. equiv.) in MeCN at 808C under N2 for 48 h;
0.2·10À2 mmol Pd
(OAc)2/mL MeCN.
Isolated yield on the charged amount of aryl bromide. Conversion of aryl iodides is complete.
In parentheses isolated yield based on converted aryl bromide.
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
[b]
[c]
[d]
The corresponding carbazole 11-(4-methylbenzenesulfonyl)-11H-benzo[a]carbazole (Scheme 2) was also isolated in 31%
yield.[5]
owing to the competitive formation of the corre- the o-substituent in the aryl ring of palladacycle 7.[3c]
sponding carbazole (see below). Aryl–aryl coupling could possibly involve the inter-
Besides acrylates only electron-poor olefins such as mediacy of the palladium(IV) species reported in
methyl vinyl ketone and acrylonitrile gave acceptable brackets.[11] The steric hindrance, exerted by the two
À
results (entries 15 and 16).
ortho substituents in complex 8, favors C C bond
The proposed reaction pathway is depicted in cleavage with deinsertion of norbornene (which thus
Scheme 1. Oxidative addition of the aryl iodide to acts as a catalyst), to afford the biphenylylpalladium
palladium(0) occurs faster than that of the aryl bro- species 9, able to insert the terminal olefin in a Heck-
mide (contained in the same mixture) to form the ar- type reaction.[3a,c] The resulting vinylbiphenyl deriva-
ylpalladium(II) iodide intermediate 5.[7] In the pres- tive 10 undergoes an intramolecular Michael-type re-
ence of two types of olefins, a strained one such as action by attack of the amido group (NHSO2R4) on
norbornene and one activated by an electron-with- the vinyl group to generate the dihydrophenanthri-
drawing substituent such as the alkoxycarbonyl group, dine derivative 4. The cyclization step, which should
complex 5 preferentially inserts the former (norbor- be catalyzed by the basicity of the medium, must take
nene) to give the cis,exo-arylnorbornylpalladium spe- place quite easily since the open-chain precursor 10
[9]
cies 6.[8] Aromatic C H activation by electrophilic has never been detected.
À
substitution leads to the palladium(II) metallacycle
The use of N-sulfonylated o-bromoaniline deriva-
7.[10] At this point, unlike what was observed with pal- tives is essential for the success of the reaction, which
ladium(0), the aryl bromide 2 reacts faster with 7 than leads to very poor results, if any, with N-unsubstitut-
the aryl iodide 1, likely as a consequence of the o-bro- ed, monoalkylated, acetylated or trifluoroacetylated
moarenesulfonylaniline chelating effect. Selective ary- o-bromoaniline.
lation at the aromatic site of intermediate 7 to form
Running the reaction with o-iodotoluene, N-tosyl-
species 8 is then promoted by the directing effect of o-bromoaniline and methyl acrylate in the absence of
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Palladium-Catalyzed Synthesis of Selectively Substituted Phenanthridine Derivatives
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Scheme 1. Proposed reaction pathway to 5-arenesulfonyl-5,6-dihydrophenanthridines.
norbornene under the standard conditions of Table 1, probably because it favours bromide dissociation
led to the exclusive formation of methyl o-methylcin- from palladium complex 9. We thus resorted to the
namate in 98% yield; the o-bromotosylanilide was re- less coordinating MeCN as solvent and added
covered unconverted. This result points to the key NBu4Br[13] to retard cyclization of 9 to 11. The result
role played by norbornene in driving the reaction to- was quite satisfactory but the added salts also fav-
wards the formation of palladacycle precursor 6, oured oxidative addition of the starting aryl iodide to
which is then followed by the steps depicted in palladium(0) to form complex 5[14] and its subsequent
Scheme 1, namely cyclopalladation, aryl–aryl coupling reaction with methyl acrylate to give the correspond-
accompanied by norbornene deinsertion, aryl–vinyl ing Heck product, methyl o-methylcinnamate.[15]
coupling in sequence, and final intramolecular Mi- To prevent an early reaction of the activated terminal
chael reaction.[12]
olefin with aryl iodide 1, norbornene was added
The main problem we had to face stemmed from in a large excess (10:1 molar ratio to the aryl halide).
the tendency of complex 9 to form the carbazole ring In this way the course of the initial step was shifted
(11, Scheme 2)[5] rather than allowing Heck coupling towards norbornene insertion and palladacycle
with an activated olefin to give 10 (Scheme 1), prior formation according to Scheme 1. Noteworthy, the
to the final Michael reaction leading to the phen- large amount of norbornene did not appear to coun-
anthridine ring 4.
teract efficiently the deinsertion step from intermedi-
As previously reported,[5] a coordinating solvent, ate 8 to 9, which is caused predominantly by the
such as DMF, promotes carbazole ring formation, steric hindrance exerted by the bulky sulfonylated
aniline.
In conclusion, we have been able to obtain phen-
anthridine derivatives starting from readily available
reagents through an accurate balance of the compet-
ing processes, in particular the one leading to carba-
zoles in place of phenanthridines. The association of
sulfonylated anilines with an ammonium salt and a
large excess of norbornene in MeCN as solvent was
Scheme 2. Carbazole ring formation from intermediate 9.
found to be a prerequisite for the palladium-catalyzed
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Nicola Della Ca’ et al.
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Experimental Section
[6] A similar positive effect was observed by Miura and
co-workers who reported the synthesis of phen-
anthridine derivatives by oxidative cross-coupling of N-
(2’-phenylphenyl)benzenesulfonamides with olefins
using a palladium-copper catalytic system: M. Miura, T.
Tsuda, T. Satoh, S. Pivas-Art, M. Nomura, J. Org.
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General Procedure for the Synthesis of 5-
AreneACHTUNGTRENNUNGsulfonyl-5,6-dihydrophenanthridines
A Schlenk-type flask, equipped with a magnetic stirring bar,
was charged with Pd(OAc)2 (5 mg, 0.022 mmol), norbornene
AHCTUNGTRENNUNG
(413 mg, 4.4 mmol), the desired aryl iodide (0.48 mmol), the
aryl bromide (0.44 mmol), and the activated olefin
(1.76 mmol) in MeCN (10 mL). K2CO3 (138 mg, 1.0 mmol)
and NBu4Br (322 mg, 1.0 mmol) were then added as solid
powder and the resulting reaction mixture was stirred in an
oil bath at 808C for 48 h. After cooling to room tempera-
ture, the solvent was removed under reduced pressure and
the residue was purified by flash chromatography on silica
gel using an 80:17:3 mixture of hexane-AcOEt-CH2Cl2 as
eluent.
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[12] This result also rules out the possibility that the reac-
tion leading to 4 proceeds through an alternative path-
way consisting of methyl o-methylcinnamate formation,
Michael addition of the arenesulfonyl o-bromoaniline
and final intramolecular arylation in sequence. This al-
ternative pathway to 4 was further excluded on the
ground that methyl o-methylcinnamate and o-bromo-
N-tosylaniline did not react under the reaction condi-
tions.
Acknowledgements
We thank MIUR (grant no. 2006031888) and University of
Parma for financial support. NMR facilities were provided
by Centro Interdipartimentale Misure dell’Universitꢀ di
Parma.
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