Palladium-catalyzed domino direct arylation/n-arylation: convenient synthesis of phenanthridines

Full text of DOI:10.1002/anie.200902400

Angewandte
Chemie
DOI: 10.1002/anie.200902400
Domino Reactions
Palladium-Catalyzed Domino Direct Arylation/N-Arylation:
Convenient Synthesis of Phenanthridines**
David A. Candito and Mark Lautens*
The phenanthridine unit represents an important structural
motif found in natural products and biologically relevant
compounds (Scheme 1). Molecules containing this motif are
ical approach relative to traditional metal-catalyzed cross-
coupling reactions.[4] Catellani and co-workers have reported
a powerful strategy involving a sequence of domino ortho
functionalization with subsequent terminal cross-coupling
processes for the synthesis of diversely substituted aromatic
compounds.[5] Our group has employed this strategy in
devising alternative processes for the efficient construction
of heterocyclic compounds.[6]
À
We envisioned applying a C H activation/cross-coupling
approach toward the synthesis of diversely substituted
phenanthridine derivatives, whereby a sequence of ortho ar-
ylation and subsequent N-arylation would provide the desired
compounds in one step (Scheme 1).
Scheme 1. Examples of biologically relevant benzo[c]phenanthridine
and pyrrolophenanthridine alkaloids.
the subject of considerable interest as potent antitumor,
antimicrobial, and antiviral agents.[1] Much effort has been
invested in the synthesis of derivatives of these compounds to
deduce structure-activity relationships and discover new
analogues with improved properties.[1]
Although a number of methods are available for the
synthesis of these phenanthridines, many are limited because
of the lack of generality, limited functional group tolerance,
and lengthy synthetic sequences.[1–3] Palladium-catalyzed
approaches have addressed issues of functional group toler-
ance, however, lengthy synthetic sequences are still associated
with the generation of functionalized coupling partners.
Methods employing direct arylation allow for the use of
simplified starting materials and offer a more atom econom-
The feasibility of this approach was suggested by the
unexpected reactivity observed during our previous inves-
tigations [Eq. (1)].[7a] During these studies a number of
different imine derivatives were investigated and an interest-
ing side-product was observed when N-diphenylphosphinoyl-
imines (N-Dpp imines) were employed. With these imine
derivatives, arylation occurred at the expected a-position
[Eq. (1), a] accompanied by a small amount of an N-arylated
product [Eq. (1), b]. It was reasoned that silylimines would
favor the product of N-arylation because they are nucleo-
philic at the nitrogen atom and the silyl group can be easily
cleaved under the reaction conditions.[8a,9] To test this
hypothesis silylimine 2a (Table 1) was synthesized and
reacted with iodonaphthalene under our previously devel-
oped reaction conditions, smoothly providing the desired
benzo[c]phenanthridine 3a in 72% yield.[7b]
Herein we report our efforts toward the development of a
highly efficient method for the construction of diversely
substituted phenanthridine derivatives employing N-unsub-
stituted and N-silylimines based on this reaction protocol. To
the best of our knowledge this report represents the first
application of these imine derivatives in the metal-mediated
synthesis of heterocycles. Furthermore, we introduce the N-
arylation of N-silylamidines, thereby expanding the range of
[*] D. A. Candito, Prof. M. Lautens
Department of Chemistry, University of Toronto
80 St. George St., Toronto, ON, M5S3H6 (Canada)
Fax: (+1)416-946-8185
E-mail: mlautens@chem.utoronto.ca
[**] We thank the Natural Sciences and Engineering Research Council
(NSERC), the Merck Frosst Centre for Therapeutic Research, and
the University of Toronto for financial support. D.A.C. thanks the
NSERC for a PGS M scholarship. We would also like to thank Dr.
Brian Mariampillai, Dr. Andrew Martins, Robert Webster, Frederic
Menard, and Jane Panteleev for useful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200902400.
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Table 1: Synthesis of 6-H-substituted phenanthridines.[a]
positive effect on the yield of the reaction. It was possible to
find conditions which provided benzo[c]phenanthridine 2a in
85% yield (Table 1, entry 1). With these conditions in hand, a
substrate study was undertaken to investigate the generality
of this transformation.
A range of phenanthridines and benzo[c]phenanthridines
could be formed in moderate to good yields from readily
available N-silylaldimines and aryl iodides. Notably, the aryl
iodides employed are commercially available and the N-
silylaldimines are available from the corresponding aldehyde
in one step.[9c] The ortho-chloro- and ortho-bromo-N-silylal-
dimines could serve as coupling partners, with ortho-chloro-
N-silylaldimines generally demonstrating better performance
(Table 1, entries 1, 2, 6, and 8). Aryl iodides of varying steric
and electronic properties could be successfully employed as
coupling partners. Furthermore, the protocol is readily
scalable; increasing the reaction scale ten-fold did not affect
the yield significantly (Table 1, entry 7).
Encouraged by these results we sought to investigate the
possibility of substitution at the 6-position of the phen-
anthridine ring system. Subjecting iodonaphthalene and the
N-silylketimine 2 f to the reaction conditions yielded ben-
zo[c]phenanthridine 3j as the sole product (Table 2, entry 1).
Groups of differing steric and electronic properties such as
alkyl, alkenyl, aryl, and amino groups could be installed
efficiently (Table 2). Significantly, N-silylamidines were dem-
onstrated to be suitable coupling partners and the catalyst
loading could be decreased to 2.5 mol% (Table 2, entry 5).
Varying the substituent at the 6-position was readily
accomplished by employing the desired N-silylketimine or
amidine which was prepared from the reaction between the
corresponding benzonitrile and organolithium reagent.[9d]
Formation of the imine derivatives takes place smoothly
without the formation of many byproducts, although NMR
spectra may be complicated by the presence of tautomers and
geometric isomers with the distribution being a function of
the temperature.[9] Fortunately, subjecting the isomeric mix-
tures of imines to the reaction conditions provided the desired
phenanthridines in consistently high yields. It is likely that the
isomers equilibrate under the reaction conditions.[9] It was
found that the N-silylketimines could be employed without
their prior purification (Table 2, entry 4); however this was
not the case with the N-silylaldimines, where the best yields
were achieved with prior purification of the imine.
Entry Aryl iodide
R, R1, R2
Silylimine
X, R3
Product
Yield
[%][b]
R, R1 =
X=Cl,
R3 =H
2a
1
85
75
2
1a
X=Br,
R3 =H
2b
3a
R=Me,
R1 =R2 =H
1b
3
4
5
6
2a
2a
2a
2a
75
56
86
81
R=Cl,
R1 =R2 =H
1c
R=Me, R1 =Cl,
R2 =H
1d
R=OMe,
R1 =R2 =H
1e
1e
1e
7
8
2a
2b
3e
3e
74[c]
76
X=Cl,
R3 =Cl
2c
9
1a
39
X=Br,
R3 =OMe
2d
10
11
12
1d
1b
39
31
34
X=Br,
R3 =CF3
2e
R=CF3,
R1 =R2 =H
1 f
2b
Two requirements became apparent for the success of this
reaction: a suitable imine derivative must be chosen such that
it possesses a group on the nitrogen atom which can be
cleaved at some point in the catalytic cycle, and only ortho-
substituted aryl iodides were suitable coupling partners under
the developed reaction conditions as complex mixtures were
obtained in the absence of an ortho substituent.
[a] Reaction conditions: Aryl iodide (0.2 mmol, 1.0 equiv), silylimine
(1.1 equiv), Pd(OAc)2 (10 mol%), PPh3 (25 mol%), Cs2CO3 (3.0 equiv),
and norbornene (8.0 equiv) in MeCN (0.05m) were heated in a sealed
tube at 908C for 16–24 h. [b] Yield of isolated product. [c] Reaction scaled
up (2 mmol). TMS=trimethylsilyl.
imine derivatives capable of participating in palladium-
catalyzed cross-coupling processes.[8]
The unsubstituted aldimines are generally not available as
they are often unstable species, however, unsubstituted
ketimines are easily synthesized, isolable compounds. Unsub-
stituted ketimines 2o and 2p were synthesized and subjected
to the reaction conditions. They are indeed suitable substrates
for this transformation, providing the desired products in
comparable yields to the trimethylsilylimines (Table 3,
entries 2 and 3). It is advantageous to utilize such unsubsti-
In examining the reaction parameters, it was found that
solvent, concentration, and the amount of norbornene used
had the greatest influence on the yield. Polar solvents such as
N,N-dimethylformamide, N-methylpyrrolidone, and acetoni-
trile were found to be beneficial for the transformation.
Furthermore, increasing the amount of norbornene had a
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Table 2: Synthesis of 6-substituted phenanthridines.[a]
Table 3: Variation of the imine derivative.
Entry Aryl iodide
R, R1, R2
Silylimine
R3, R4
Product
Yield
[%][b]
Entry
1
Aryl iodide
R, R1, R2
Imine
R3, R4
Product
Yield [%][b]
41
1a
1a
1e
R3 =nBu, R4 =TBDMS
2n
3l
R3 =Me,
R4 =H
2 f
1
2
3
1a
1d
1a
86
91
79
2
3
R3 =nBu, R4 =H
2o
3l
76
60
R3 =iPr,
R4 =H
2g
R3 =Ph, R4 =H
2p
3m
[a] Reaction conditions: see Table 1. [b] Yield of isolated product.
TBDMS=tert-butyldimethylsilyl.
R3 =nBu,
R4 =H
2h
4
5
1a
1a
2h
2h
3l
3l
82[c]
69[d]
R3 =Ph,
R4 =H
2i
6
7
1e
68
91
R3 =
R=Me, R1 =F,
R2 =H
1g
R3 =
R=Me, R1 =NHAc,
8
9
R2 =H
98
58
1h
R3 =NEt2,
R4 =H
2l
1a
1h
R3 =
10
76
Scheme 2. Proposed catalytic cycle.
[a] Reaction conditions: see Table 1. [b] Yield of isolated product.
[c] Silylimine not isolated. [d] Pd(OAc)2 (2.5 mol%), MeCN (0.27m)
used.
undergo carbopalladation with norbornene to yield the
intermediate II. Electrophilic metalation followed by depro-
tonation can generate the palladacyclic intermediate III.
Reaction of the imine with the intermediate III would result
in arylation of the ortho-position of the aryl iodide. The
arylation may be proceeding through a palladium(IV)
intermediate, in analogy to what has been observed for
ortho alkylation.[5d] Subsequent decarbopalladation then pro-
tuted imines as the production of waste is minimized. Other
trialklysilylimine derivatives could be employed (Table 3,
entry 1), however, a lower yield was observed, which may be a
result of the enhanced stability of the TDBMS group.
À
À
A simplified catalytic cycle can be proposed on the basis
of the mechanistic work carried out independently by
Catellani et al.,[5] Hartwig et. al.,[8c] and Barluenga et al.[8a]
(Scheme 2). Oxidative addition of the aryl iodide would yield
the aryl–palladium intermediate I which can subsequently
vides the intermediate IV. Cleavage of the N H or N Si bond
can result in the formation of the palladium–imido inter-
mediate V, and subsequent reductive elimination from this
intermediate, releases the product, regenerating palladium(0)
which goes on to continue the cycle.
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Communications
Hashimoto, R. Tokizane, Y. Miwa, H. Minami, K. Yanada, M.
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In conclusion, we have developed a practical and efficient
method for the preparation of diversely substituted phenan-
thridines and benzo[c]phenanthridines from readily available
precursors. This methodology will surely aid in the effort to
generate more interesting structures for use in biological
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reactions and broadened the range of imine derivatives
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Experimental Section
Typical procedure for domino direct arylation/N-arylation:
A 5 mL microwave vial equipped with a magnetic stirring bar and
septum was flame-dried and then cooled under a stream of argon by
venting through a needle in the septum. The vial was then charged
with palladium acetate (10 mol%), triphenylphosphine (25 mol%),
cesium carbonate (3 equiv), and norbornene (8 equiv). The vial was
then sealed and flushed with argon for 1 min. Dry acetonitrile was
added (0.05m, based on aryl iodide) and the solution was stirred at
room temperature for 10 min. The imine (1.1 equiv) and aryl iodide
(1.0 equiv, 0.2 mmol scale) were then added sequentially via syringe
(alternatively, if one of the components was a solid it was weighed
along with the other solids, or transferred to the reaction mixture as a
solution in acetonitrile). The reaction vessel was then immersed in an
oil bath, which was preheated at 908C, for 16–24 h. After this time the
reaction mixture was cooled to room temperature and then filtered
through a short pad of silica with ethyl acetate washings (ca. 60 mL).
Concentration of the filtrate by rotary evaporation provided a residue
which was purified by column chromatography.
[4] For reviews on this subject, see: a) D. Alberico, M. E. Scott, M.
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Satoh, Top. Organomet. Chem. 2005, 14, 55 – 83; d) Handbook of
À
C H Transformations (Ed.: G. Dyker), Wiley-VCH, Weinheim,
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the following reaction conditions: Aryl iodide (0.2 mmol,
1.0 equiv), silylimine (1.1 equiv), Pd(OAc)2 (10 mol%), PPh3
(20 mol%), Cs2CO3 (3.0 equiv), norbornene (3.0 equiv) in
MeCN (0.05m) were heated in a sealed tube which was placed
in an oil bath (908C) for 16–24 h.
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Received: May 6, 2009
Published online: July 31, 2009
À
Keywords: C H activation · domino reactions · imines ·
N-arylation · palladium
.
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