Communications
DOI: 10.1002/anie.200705209
Promazine Synthesis
Palladium-Catalyzed Three-Component Approach to Promazine with
Formation of One Carbon–Sulfur and Two Carbon–Nitrogen Bonds
Troels Dahl, Christian W. Tornøe, Benny Bang-Andersen, Poul Nielsen, and Morten Jørgensen*
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The formation of aromatic carbon–heteroatom bonds has
traditionally been achieved by nucleophilic aromatic substi-
tution or by the copper-mediated Ullman reaction.[1] The
former type of chemistry is generally limited to activated
substrates, whereas the latter often requires prolonged
synthesis would require that either C S or C N bond
formation occur initially with subsequent cyclization to the
phenothiazine nucleus. This disconnection of the promazines
leads to the precursors 2-bromothiophenol (2), primary amine
3, and an appropriately substituted 1-bromo-2-iodobenzene
4a–e.
heating in the presence of excess copper salts. The palla-
[2]
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dium-catalyzed formation of aromatic C N bonds, exten-
From reported literature and our experience with reac-
sively developed by the groups of Hartwig and Buchwald, has
provided a powerful alternative.[3] Whereas aryl amination
has been optimized so that it is even applicable to aryl
chlorides and activated phenols, the analogous formation of
tions involving dppf,[5] binap,[6] dpephos,[7] and xantphos,[8] the
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formation of the C S bond was expected to precede the
amination steps.[9] Indeed, clean formation of diaryl sulfide 6
was observed when a mixture of 2, 3, 4a, and NaOtBu was
treated with [Pd2dba3] and dppf at 608C for 20 minutes, and
1a was formed in high yield after 2 hours at 1608C under
microwave (MW) irradiation. These conditions were mim-
icked in a ligand optimization study using oil-bath heating
(Figure 1).[10]
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C O and C S bonds has attracted less attention. For a
medicinal chemistry project, we have identified conditions
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that enable the formation of C S bonds from thiophenols and
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aryl iodides, and C N bonds from amines and aryl bromides
using the same catalyst in a one-pot reaction. We now report
the application of this discovery to the synthesis of the
promazine class of antipsychotics.[4]
Figure 1 summarizes results obtained with commercially
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available and easily handled ligands reported for C S and C
N coupling reactions. Ferrocene ligands such as dppf gave
mainly the desired product (1a) in addition to the noncyclized
intermediate 7. Significant amounts of aniline 5 were
observed with davephos, x-phos, and binap.[11] Noncyclized
promazine 7 was the major product with dpephos and
xantphos. Trace amounts of the desired product were
formed with PPh3, P(o-tol)3, P(tBu)3,[12,13] or the carbene
ligand.[14] Low conversion of 4a occurred with diaryl sulfide 6
as the only detectable product in the absence of palladium
and ligand, whereas small amounts of 6 and bromobenzene
were formed without the ligand.[15]
Our attention was drawn to the phenothiazine backbone
of the promazine series 1a–e as a suitable model system for
the controlled construction of three carbon–heteroatom
bonds in a single synthetic operation (Scheme 1). This
The reaction appears to proceed in a stepwise fashion
from diaryl sulfide 6 (only product with one equivalent of
NaOtBu), to aniline 7 (only product with two equivalents of
NaOtBu), to 1a (74% yield; Table 1) under MW conditions.
The three-component reaction worked well for the parent
promazines 1a–e with yields of the isolated products ranging
from 50% to 76%, and an average yield of greater than 75%
for each of the three bonds formed (Table 1). The reaction
with allyl amine[16] gave a complexmixture of unidentified
products.[17] Benzyl amines were good substrates and the
scope of the reaction was extended to include anilines;[18] 2,6-
disubstituted anilines participated in the reaction, albeit with
reduced yields as the steric hindrance around the nitrogen
atom increased.
Scheme 1. Retrosynthetic analysis for the promazines.
[*]Dr. C. W. Tornøe, Dr. B. Bang-Andersen, Dr. M. Jørgensen
Medicinal Chemistry Research
H. Lundbeck A/S
9 Ottiliavej, 2500 Valby (Denmark)
Fax : (+45)3643-3965
The microwave method was relatively slow as the reagents
had to be mixed immediately before starting the reactions to
avoid catalyst deactivation. Conveniently, the reaction was
performed with conventional heating, warming from room
temperature to 1608C over approximately 0.5 hours, with
subsequent stirring at 1608C overnight (reaction times have
not been optimized).
E-mail: mojj@lundbeck.com
T. Dahl, Dr. P. Nielsen
Department of Chemistry
University of Southern Denmark
55 Campusvej, 5270 Odense M (Denmark)
Supporting information for this article is available on the WWW
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ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 1726 –1728