One-pot palladium-catalyzed synthesis of selectively substituted phenanthridines by sequential aryl-aryl and heck couplings, aza-michael and retro-mannich reactions

Article abstract of DOI:10.1002/adsc.201000114

A catalytic synthesis of selectively substituted phenanthridines is achieved through a reaction sequence involving palladium/norbornene-catalyzed unsymmetrical aryl-aryl and Heck couplings followed by aza-Michael and retro-Mannich reactions. In spite of the many steps involved the method is very simple and allows the formation of selectively substituted phenanthridines under mild conditions in a straightforward one-pot reaction starting from readily available aryl iodides and bromides.

Full text of DOI:10.1002/adsc.201000114

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DOI: 10.1002/adsc.201000114
One-Pot Palladium-Catalyzed Synthesis of Selectively Substituted
Phenanthridines by Sequential Aryl-Aryl and Heck Couplings,
Aza-Michael and Retro-Mannich Reactions
Nicola Della Ca’,a Elena Motti,a Antonio Mega,a and Marta Catellania,*
a
Dipartimento di Chimica Organica e Industriale and CIRCC, Universitꢀ di Parma, V. le G. P. Usberti, 17A, 43124 Parma,
Italy
Fax : (+39)-0521-905-472; e-mail: marta.catellani@unipr.it
Received: February 11, 2010; Published online: June 8, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000114.
Abstract: A catalytic synthesis of selectively substi-
tuted phenanthridines is achieved through a reac-
tion sequence involving palladium/norbornene-cata-
lyzed unsymmetrical aryl-aryl and Heck couplings
followed by aza-Michael and retro-Mannich reac-
tions. In spite of the many steps involved the
method is very simple and allows the formation of
selectively substituted phenanthridines under mild
conditions in a straightforward one-pot reaction
starting from readily available aryl iodides and bro-
mides.
poor conversion of both aryl halides. For example o-
iodotoluene (1a) reacted with o-bromo-N-trifluoro-
AHCTUNGTREGaNNUN cetanilide (2a) and methyl acrylate (3a), under our
previously reported conditions (Scheme 1), to give the
corresponding unprotected 5,6-dihydrophenanthridine
4a in ca.10% yield together with a small amount (ca.
4%) of phenanthridine 5a.
While formation of the unprotected dihydrophen-
AHCTUNGTREGaNNUN nthridine 4a could be anticipated in view of an easy
hydrolytic cleavage of the N-trifluoroacetyl group,
that of compound 5a was quite unexpected. We hy-
pothesized that phenanthridine 5a derived from a
retro-Mannich reaction (we thank a referee for sug-
gesting the term “retro-Mannich”) taking place on
compound 4a. Subjecting compound 4a to the action
of a DMF solution of an equimolar amount of potas-
sium carbonate at 1058C led indeed to the formation
of compound 5a (70% after 24 h) along with the ex-
pected methyl acetate. Using the tert-butyl ester of
À
À
À
Keywords: C C and C N bond formation; C H ac-
tivation; norbornene; palladium; phenanthridine;
sequential reactions
Phenanthridines are an important group of natural acrylic acid for a better analysis we were able to es-
compounds with a broad range of biological and phar- tablish by GC and GC-MS analysis that tert-butyl ace-
macological activities.[1] Due to these properties they tate was formed in an almost equimolar amount to
represent attractive synthetic targets and much atten- 5a. This means that the retro-Mannich is strongly fa-
tion has been focused to establish simple and efficient
methods for their preparation.[2] Palladium-catalyzed
sequential reactions have proven very useful since
they allow to build up complex structures starting
from simple reagents with high selectivity, in one-pot,
under mild conditions.[3]
We have previously reported a facile and efficient
synthesis of selectively substituted 5-arenesulfonyl-
5,6-dihydrophenanthridine derivatives by reaction of
an ortho-substituted aryl iodide with a sulfonylated o-
bromoaniline and an activated terminal olefin, in the
presence of PdACHTUNGTRENNUNG(OAc)2 and norbornene as catalyst,
K2CO3 and NBu4Br in MeCN.[4] On replacing the sul-
fonylated o-bromoaniline with the trifluoroacetylated
one, the reaction became very sluggish leading to Scheme 1.
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Nicola Della Ca’ et al.
Table 1. Synthesis of phenanthridines.[a]
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vored, as expected in view of the stability of the phen-
anthridine structure. In respect to the conditions
shown in Scheme 1 the increase of the temperature to
1058C and the use of DMF in place of MeCN were
found necessary to obtain the desired results. The pre-
ceding steps of the sequence leading to 4a have also
been optimized. This has not been a simple task, how-
ever, in view of the many competitive steps in-
volved.[5] We found that lowering the amount of nor-
bornene, was beneficial for the overall process. Potas-
sium carbonate proved to be the base of choice allow-
ing higher selectivity towards compound 5a. Addition
of triphenylphosphine also had a positive effect, while
the use of quaternary ammonium salts was found not
to be effective.
Entry
R1
R2
R3
R4
5 Yield [%][b]
1
2
3
4
5
6
7
8
9
Me
Me
Me
i-Pr
s-Bu
H
Me
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
5a, 71
5b, 82
5c, 72
5d, 84
5e, 66
5f, 66
5g, 51
5h, 63
5i, 49
5j, 54
5k, 40
5l, 78
5m, 73
5n, 93
Thus, when we allowed 1.1 equivalents of o-iodoto-
luene (1a) to react with 1.0 equivalent of o-bromo-N-
trifluoroacetanilide (2a) and 4 equivalents of methyl
acrylate (3a) in the presence of 5% of PdACTHNUGTRENUNG(OAc)2,
10% of PPh3, 1 equivalent of norbornene and
2.2 equivalents of K2CO3 in DMF at 1058C for 18 h,
the desired compound 5a was isolated in 50% yield
together with compound 4a in 12% yield. The main
-(CH)4-
H
Me
Me
Me
Me
Me
Me
i-Pr
i-Pr
H
OMe
H
H
H
H
H
H
OMe
OMe
CO2Me
H
H
H
H
by-product (34%) was methyl o-methylcinnamate re- 10[c]
Me
OMe
Cl
Me
Cl
11
sulting from a Heck reaction of o-iodotoluene with
methyl acrylate. When methyl vinyl ketone was em-
ployed in place of methyl acrylate, compound 5a was
obtained in 71% yield (Table 1, entry 1). We thus ex-
amined the scope and limitations of the process using
methyl vinyl ketone as activating olefin. This ketone,
which sacrifices three out of its four carbon atoms as
acetone, appears to be the more efficient and conven-
ient partner. Several selectively substituted phenan-
thridines (5) could be prepared in moderate to satis-
factory yields from readily available ortho-substituted
aryl iodides, ortho-bromo-N-trifluoroacetanilides and
methyl vinyl ketone. As in the example reported
12[c]
13[c]
14[c]
H
H
[a]
Reactions were carried out with aryl iodide (1.1 equiv.),
aryl bromide (1.0 equiv.), methyl vinyl ketone
(2.0 equiv.), norbornene (1.0 equiv.), Pd
PPh3 (10 mol%), K2CO3 (2.2 equiv.) in DMF at 1058C
under N2 for 24 h; 0.2·10À2 mmol Pd
(OAc)2/mL DMF.
Isolated yield based on the charged amount of aryl bro-
mides.
ACHTUNGRTEN(NUNG OAc)2 (5 mol%),
AHCTUNGTRENNUNG
[b]
[c]
Methyl vinyl ketone (4.0 equiv.).
above with methyl acrylate, the main by-products action of ortho-iodotoluene with methyl acrylate re-
constantly resulted from the Heck reaction between ported above, the main by-product (from 7 up to 37%
the aryl iodide and methyl vinyl ketone. Most of the yield) appears to be the one resulting from Heck re-
unreacted aryl bromide is recovered. Our results are action of the aryl iodide with methyl vinyl ketone.
summarized in Table 1.
ortho-Alkyl-substituted aryl iodides such as methyl, present in variable amount.
Other by-products containing norbornene[6] are also
isopropyl and sec-butyl efficiently react with ortho-
The proposed reaction pathway is reported in
bromo-N-trifluoroacetanilide and methyl vinyl ketone Scheme 2. The catalytic cycle is initiated by the oxida-
(entries 1, 4 and 5) to give the corresponding phen- tive addition of the aryl iodide to palladium(0),[7]
anthridine in satisfactory yields. The presence of an formed in situ from PdACTHNUTRGNEUNG(OAc)2. Owing to steric strain
additional methyl group in the aryl iodide (entries 2 release, norbornene insertion into the arylpalladium
and 3) is beneficial or innocuous, while the methoxy bond of complex 7 readily occurs.[8] The cis,exo-aryl-
as well as the methoxycarbonyl groups negatively norbornylpalladium iodide species (8), resulting from
affect the reaction outcome (entries 7–9). Both the stereoselective norbornene insertion, is rather stable
methyl and the methoxy groups in the ring of the tri- towards b-hydrogen elimination but prone to undergo
[9]
À
fluoroacetylated ortho-bromoaniline (entries 10, 11 ring closure, by C H activation, to give palladacycle
and 13) are detrimental to the yield of the reaction, 9.[10] ortho-Bromo-N-trifluoroacetanilide reacts at the
while the joint presence of the chloride substituent in aryl site of palladacycle 9,[11] possibly through the in-
2 and of the isopropyl one in 1 (entries 12 and 14) has termediacy of a palladium(IV) species,[12] to generate
a remarkable positive effect. As in the case of the re- the aryl-aryl bond of complex 10. Likely due to steric
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Adv. Synth. Catal. 2010, 352, 1451 – 1454

One-Pot Palladium-Catalyzed Synthesis of Selectively Substituted Phenanthridines
Scheme 2. Proposed reaction pathway to phenanthridines.
hindrance, norbornene deinsertion then takes place, moaniline with methyl vinyl ketone in the absence of
leading to the formation of the biphenylylpalladium norbornene did not lead to the formation of phen-
intermediate 11[13] which, in its turn, undergoes a anthridine derivatives, but to products resulting from
Heck-type reaction. The organic product 12 and palla- the Heck reaction of the aryl iodides and bromides
dium(0) are thus formed; the latter becomes available with methyl vinyl ketone (97 and 30% yield, respec-
for a new catalytic cycle, while the former undergoes tively). This confirms the key role of norbornene in
further transformation. The open precursor 12 cycliz- directing the aryl-aryl coupling of the two aryl halides,
es through an intramolecular aza-Michael reaction by in agreement with the proposed reaction pathway
attack of the ortho-amido group to the activated shown in Scheme 2.
double bond to give the deprotected 5,6-dihydrophen-
In conclusion we have been able to achieve the syn-
ACHTUNGTRENNUNGanthridine 13. In agreement with the course of the thesis of selectively substituted phenanthridines start-
Michael reaction[14] the cyclization step is catalyzed by ing from readily available reagents. The process in-
the basicity of the medium. On the other side com- volves the palladium/norbornene-catalyzed sequential
pound 13 undergoes a retro-Mannich-type reaction to coupling of an ortho-substituted aryl iodide with an
form phenanthridine 5 and acetone. Formation of N-trifluoroacetylated ortho-bromoaniline, insertion of
phenanthridine 5 must occur very fast since both com- an activated olefin, aza-Michael cyclization and retro-
pounds 12 and 13 could not be isolated using methyl Mannich reaction. The latter step occurs with the sac-
vinyl ketone as activated olefin. As mentioned before, rificial elimination of acetone.
however, compound 4a (analogue of 13) could be iso-
lated employing methyl acrylate in place of methyl
vinyl ketone.
Experimental Section
It is worth noting that compound 13 is not formed
through the corresponding forward reaction, namely
addition of acetone carbanion to 5. On its side 13 re-
sults from a sequence of steps involving an aza-Mi-
chael reaction.
Typical Procedure; Synthesis of 7-Methylphenan-
thridine (5a)
A Schlenk-type flask was charged with Pd
0.044 mmol), PPh3 (22 mg, 0.088 mmol), norbornene (82 mg,
ACHTUNGRTENUN(NG OAc)2 (10 mg,
Under the conditions of Table 1, the reaction of
ortho-iodotoluene and N-trifluoroacetyl-ortho-bro- 0.88 mmol), ortho-iodotoluene (1, 209 mg, 0.96 mmol),
Adv. Synth. Catal. 2010, 352, 1451 – 1454
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Nicola Della Ca’ et al.
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ortho-bromo-N-trifluoroacetylaniline (2, 235 mg, 0.88 mmol)
and methyl vinyl ketone (123 mg, 1.76 mmol) in DMF
(20 mL). K2CO3 (276 mg, 2.0 mmol) was then added as a
solid powder and the resulting mixture was stirred at 1058C
for 24 h. After cooling to room temperature, EtOAc
(60 mL) was added and the mixture was treated with brine
(3ꢂ50 mL). The organic layer was dried with Na2SO4 and
concentrated under reduced pressure. GC, GC-MS and
1H NMR analysis of the crude material revealed the pres-
ence of compound 5a, (E)-4-(2-methylphenyl)but-3-en-2-
one and traces of products containing norbornene together
with unreacted ortho-bromo-N-trifluoroacetylaniline (19%
by 1H NMR). The residue was purified by flash silica gel
chromatography using a 95:5 mixture of hexane-EtOAc as
eluent to obtain 7-methylphenanthridine 5a as a pale yellow
solid (yield: 120 mg, 71%) and (E)-4-(2-methylphenyl)but-3-
en-2-one as a colorless oil (yield: 28 mg, 20%).
7-Methylphenanthridine (5a): mp (hexane) 83–848C;
1H NMR: d=9.53 (1H, s), 8.57 (1H, dd, J=8.1, 1.5 Hz),
8.46 (1H, d, J=8.3 Hz), 8.19 (1H, d further split, J=
8.0 Hz), 7.78–7.63 (3H, m), 7.48 (1H, d further split, J=
7.2 Hz), 2.85 (3H, s); 13C NMR: d=150.0, 143.7, 136.5,
132.8, 130.8, 129.7, 128.8, 128.5, 127.0, 124.7, 124.2, 122.3,
119.9, 18.8; IR (KBr): n=3049, 2950, 1605, 1592, 1518, 1454,
1383, 1239, 927, 894, 808, 749 cmÀ1; MS: m/z=193 (100)
(M+), 192 (39), 165 (19); anal. calcd. for C14H11N: C 87.01,
H 5.74; found: C 87.17, H 5.69.
[3] a) L. F. Tietze, G. Brasche, K. M. Gericke, Domino Re-
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(E)-4-(2-Methylphenyl)but-3-en-2-one: 1H NMR: d=7.84
(1H, d, J=16.0 Hz), 7.58 (1H, d, J=7.6 Hz), 7.31 (1H, t,
J=7.6 Hz), 7.27–7.20 (2H, m), 6.67 (1H, d, J=16.0 Hz),
2.47 (3H, s), 2.41 (3H, s); 13C NMR: d=198.2, 140.8, 137.8,
133.3, 130.8, 130.2, 128.0, 126.4, 126.3, 27.7, 19.7; IR (neat):
n=1692, 1670 cmÀ1; MS: m/z=160 (8) (M+), 145 (100), 117
(26), 116 (22), 115 (68), 91 (27); anal. calcd. for C11H12O: C
82.46, H 7.55; found: C 82.61, H 7.59.
Acknowledgements
This work was supported by MIUR and University of Parma.
NMR facilities were provided by Centro Interdipartimentale
dell’Universitꢀ di Parma.
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Adv. Synth. Catal. 2010, 352, 1451 – 1454