A direct palladium-catalyzed route to selectively substituted carbazoles through sequential C-C and C-N bond formation: Synthesis of carbazomycin A

Article abstract of DOI:10.1002/adsc.200800421

The present paper offers a synthetically simple one-pot procedure for the catalytic preparation of the biologically interesting class of carbazoles. The new procedure is based on the combined catalysis of palladium and norbornene starting from o-substituted iodoarenes and N-sulfonylated or N-acetylated o-bromoanilines. A well-known member of this class, carbazomycin A, has been successfully prepared.

Full text of DOI:10.1002/adsc.200800421

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DOI: 10.1002/adsc.200800421
A Direct Palladium-Catalyzed Route to Selectively Substituted
À
À
Carbazoles through Sequential C C and C N Bond Formation:
Synthesis of Carbazomycin A
Nicola Della Ca’,a Giovanni Sassi,a and Marta Catellania,*
a
Dipartimento di Chimica Organica e Industriale and CIRCC, Università di Parma, V.le G. P. Usberti, 17 A, 43100 Parma,
Italy
Fax : (+39)-0521-905-472; e-mail: marta.catellani@unipr.it
Received: July 7, 2008; Published online: September 24, 2008
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800421.
Abstract: The present paper offers a synthetically
simple one-pot procedure for the catalytic prepara-
tion of the biologically interesting class of carba-
zoles. The new procedure is based on the combined
catalysis of palladium and norbornene starting from
o-substituted iodoarenes and N-sulfonylated or N-
acetylated o-bromoanilines. A well-known member
of this class, carbazomycin A, has been successfully
prepared.
sis of selectively substituted carbazoles in the pres-
ence of a suitably placed amino group.
Our experiments were unsuccessful, however, until
we discovered that use of the benzenesulfonyl or
tosyl-substituted amino group allowed us to carry out
an efficient ring closure to carbazole. The reaction
gave 1-substituted carbazoles in good to excellent
yields (Table 1).
Table 1. Synthesis of carbazoles.[a]
À
Keywords: carbazoles; catalysis; C H activation;
norbornene; palladium
Carbazoles are interesting structures present in a
wide variety of pharmaceuticals and natural products
with useful biological activities.[1] Carbazole deriva-
tives also find applications as organic materials.[2]
Entry R1, R2
R3 R4
Time
[h]
3 Yield
[%][b]
1
Me, H
H
H
H
Ts
Ts
Ts
48
60
120
3a, 93
3b, 91
3c, 98
2
Me, 4-Me
Me, 4-OMe+3-
Me
We describe here a one-pot catalytic procedure and
its application to the synthesis of antibiotic carbazo-
mycin A.[3]
3[c]
4
5
6
7
8
9
Et, H
H
H
H
Ts
Ts
Ts
48
65
72
72
48
3d, 94
3e, 82
3f, 87
3g, 94
3h, 90
3i, 92
Recently reported methods to prepare these com-
pounds are based on the N-arylation of aniline deriva-
i-Pr, H
-(CH)4-
Me, H
Me, H
Me, H
tives[4] followed by ring closure through either C H
À
Me Ts
Cl Ts
activation via metallacycles[5] or oxidative biaryl cou-
pling[6] in the presence of a Pd catalyst. Buchwald
et al. reported a different approach based on the abili-
ty of 2-acetaminobiphenyl and Pd to achieve sequen-
H
SO2Ph 96
[a]
Reaction conditions: aryl iodide (1.1 equiv.), aryl bromide
(1.0 equiv.), norbornene (0.25 equiv.), Pd(OAc)2 (5
AHCTREUNG
À
À
tial C H activation and intramolecular C N bond for-
mation.[7] A significant alternative to these strategies
is offered by the combination of intermolecular aryl-
aryl with intramolecular N-aryl coupling.[8] With this
in mind we wondered whether our Pd-catalyzed
cross-coupling method of o-substituted aryl iodides
with aryl bromides[9] could be utilized for the synthe-
mol%), K2CO3 (2.2 equiv.) in DMF at 1058C under N2
for the time needed for Pd black precipitation;
0.2·10À2 mmol Pd
(OAc)2/mL DMF.
Isolated yield based on the charged amount of aryl bro-
mides. Conversion of aryl iodides is over 99% and that
of aryl bromides ranges from 87 to 99%.
A
[b]
[c]
0.5 equiv. of norbornene.
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Nicola Della Ca’ et al.
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Aryl iodides bearing either a single o-methyl group exerted by the two ortho substituents, norbornene is
or an additional one in the para position (entries 1 expelled, thus becoming available for a new catalytic
and 2) reacted with o-bromo-N-tosylaniline to afford cycle, and the biphenylylpalladium intermediate 8 is
the desired carbazoles 3a and 3b in excellent yields. formed, where the amido group (NHR4) is in an ap-
An even better result was attained using 2,3-dimeth- propriate position for an intramolecular amidation re-
yl-4-methoxyiodobenzene with the same o-bromo-N- action leading to compound 3 and Pd(0).
tosylaniline, the corresponding carbazole 3c being iso-
It is worth noting that the aryl bromide 2 wins the
lated in 98% yield. It is worth noting that compound competition with the aryl iodide 1 for reaction with
3c is the sulfonylated 4-deoxycarbazomycin B, a deg- palladacycle 6. This preference may be due to a chela-
radation product of the natural alkaloid carbazomycin tion effect.
B.[1] Replacing the o-methyl group with an ethyl or an
The amount of norbornene is crucial for the success
isopropyl one led to compounds 3d and 3e in 94 and of the reaction since a high concentration favors its
82% yields, respectively (entries 4 and 5). 1-Iodo- insertion but at the same time prevents its deinser-
naphthalene behaved well and gave compound 3f in tion. We were pleased to find that, contrary to what is
87% yield (entry 6). When o-iodotoluene was allowed usually observed for other Pd/norbornene-catalyzed
to react with o-bromo-N-tosylaniline, containing coupling reactions,[15] the yield of carbazoles 3 im-
either a p-methyl or p-chloro substituent, the expect- proved on decreasing the amount of norbornene,
ed carbazoles 3g and 3h were isolated in 94 and 90% good results being obtained even with 0.10 equiv. The
yields, respectively (entries 7 and 8). o-Bromo-N-ben- reaction became slower, however, and longer reaction
zenesulfonylaniline in place of o-bromo-N-tosylani- times were required (120 h to obtain compound 3a in
line coupled with o-iodotoluene to give compound 3i 88% yield).
in 92% yield (entry 9). Under the standard conditions
Certain substituted substrates were found to be
the reaction did not proceed in the absence of norbor- rather reluctant to undergo the reaction and the addi-
nene and no carbazole was obtained, thus confirming tion of triphenylphosphine (TPP) was needed to
that, according to the reaction pathway proposed in obtain acceptable results (Table 2). Thus o-trifluoro-
Scheme 1, C C bond formation takes place before methyliodobenzene (R1 =CF3) and o-bromo-N-tosyl-
À
À
formation of the C N bond.
A
The key intermediate palladacycle 6 is formed by ence of TPP to give 3j in 65% yield together with
oxidative addition of the aryl iodide to Pd(0)[10] fol- 10% of the corresponding deprotected carbazole 3k,
lowed by stereoselective insertion of norbornene to desulfonylation occurring under the reaction condi-
give the cis,exo-arylnorbornylpalladium complex 5.[11] tions.[16] Analogously o-bromo-p-nitro-N-tosylaniline
This species undergoes ring closure to metallacycle (R3 =NO2) reacted with o-iodotoluene under similar
6[12] by electrophilic aromatic substitution involving conditions giving the deprotected carbazole 3l in 58%
[13]
À
C H activation.
o-Bromo-N-tosylaniline 2 then yield (entry 2). Apparently the p-nitro group nega-
reacts with 6, likely through the Pd(IV) species shown tively affects the reactivity of the amido group to-
in brackets,[14] to afford 7, which results from selective wards ring closure. TPP (with 1 equiv. of norbornene)
attack of the aryl group of 2 onto the aromatic site of was also required when the acetamide (R4 =Ac) was
palladacycle 6. At this point, owing to the steric effect used in place of the sulfonamide, leading to the de-
Scheme 1. Proposed reaction pathway.
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Adv. Synth. Catal. 2008, 350, 2179 – 2182

A Direct Palladium-Catalyzed Route to Selectively Substituted Carbazoles
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Table 2. Synthesis of carbazoles requiring the addition of
the substitution effect being more favorable than with
two Me groups only in 2 and 5 positions (Table 2,
entry 4).
To the best of our knowledge this compound has
never been obtained by means of Pd catalysis, the
method of choice involving the use of the cyclohexa-
dienyliron tricarbonyl cation.[3e]
TPP.[a]
Entry R1, R2
R3
H
R4
Ts
Time [h] 3 Yield [%][b]
1
CF3, H
65
3j, 65
3k (R4 =H), 10
3l (R4 =H), 58
3m (R4 =H), 67
3n (R4 =H), 50
2
3
4
Me, H
Me, H
2,5-Me
NO2 Ts
H
H
59
Ac 48
Ac 48
In conclusion, we have described a new Pd- and
norbornene-catalyzed sequential synthesis of 1-substi-
[a]
À
À
tuted carbazoles by C C and C N cross coupling
(1.0 equiv.), norbornene (0.25 equiv. in entries 1 and 2; starting from simple and readily available aryl halides.
Reaction conditions: aryl iodide (1.1 equiv.), aryl bromide
1 equiv. in entries 3 and 4), Pd(OAc)2 (5 mol%), TPP (10
A
Beside the mechanistic interest the present procedure
offers a valid complementary alternative to the previ-
ously reported methods. The straightforward and effi-
cient synthesis of carbazomycin A further adds to the
potentiality of the method.
mol%), K2CO3 (2.2 equiv.) in DMF at 120 (entries 1 and
2) and 1058C (entries 3 and 4) under N2 for the time
needed for Pd black precipitation; 0.2·10À2 mmol Pd-
C
Isolated yield on the charged amount of aryl bromides.
Conversion of aryl iodides and bromides is over 99%
and 95%, respectively.
Experimental Section
protected carbazole 3m in 67% yield (entry 3). On General Procedure for the Reaction of an ortho-
the other side, the acetamide was needed with a 5- Substituted Aryl Iodide and an ortho-Bromo-N-
substituted iodide such as 2,5-dimethyliodobenzene arylsulfonyl- or acetylaniline
(entry 4), which gave no reaction with the sulfona-
mide. Carbazole 3n was obtained in modest yield,
however. The coupling reaction between palladacycle
6 and the sulfonylated bromoaniline 2 (Scheme 1)
would indeed be sterically more difficult in the pres-
ence of an R2 substituent (coming from a 5-substitut-
A Schlenk-type flask, equipped with a magnetic stirring bar,
was charged with Pd(OAc)2 (5 mg, 0.022 mmol), norbornene
G
(10 mg, 0.11 mmol), the desired aryl iodide and bromide
(0.48 and 0.44 mmol, respectively) in DMF (10 mL) and
K2CO3 (138 mg, 1.0 mmol). The reaction mixture was stirred
at 105–1208C for the time needed for Pd black precipitation.
When needed TPP (11.5 mg, 0.044) was added. After cool-
ing to room temperature, the organic layer was diluted with
EtOAc (30 mL) and extracted three times with a solution of
NaCl (25 mL). The organic layer was dried over Na2SO4, the
solvent was removed under reduced pressure and the result-
ing residue was purified by flash chromatography on silica
gel using mixtures of hexane-EtOAc as eluent (97:3 for sul-
fonylated carbazoles, 95:5 for unprotected carbazoles 3k,
3m, 3n and 80:20 for 3l).
À
ed aryl iodide) ortho to the Pd C bond of the palla-
dacycle.
Using TPP we could thus make possible the ring
closure to carbazole for some substrates which were
hardly or poorly reactive under the general conditions
we had previously established.
Aryl iodides bearing functional groups such as the
methoxy, amino, mono- and dimethylamino and the
hydroxy ones in the ortho position inhibited the for-
mation of compound 3.
All these observations turned out to be quite useful
for working out an efficient synthesis of the biologi-
cally important antibiotic carbazomycin A[1,3] (11,
Scheme 2). In agreement with what is observed for
the 5-substituted aryl iodides, compound 9 hardly cou-
pled with o-bromo-N-tosylaniline in the presence of
Acknowledgements
Financial support by MIUR (grant no. 2006031888) and Uni-
versity of Parma is gratefully acknowledged. NMR facilities
were provided by Centro Interdipartimentale dell’Università
Pd
A
acetylaniline even at 1058C in the presence of the
same catalyst to give 11 in a satisfactory 70% yield, di Parma.
Scheme 2. Synthesis of carbazomycin A.
Adv. Synth. Catal. 2008, 350, 2179 – 2182
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Adv. Synth. Catal. 2008, 350, 2179 – 2182