A simple route to new phenanthro- and phenanthroid-fused thiazoles by a PIFA-mediated (hetero)biaryl coupling reaction

Article abstract of DOI:10.1002/1099-0690(200207)2002:13<2126::AID-EJOC2126>3.0.CO;2-A

An application of the PIFA-mediated [PIFA: phenyliodine(III) bis(trifluoroacetate) biaryl coupling reaction is presented and extended to the formation of heterobiaryl connections. A preliminary study of the scope and limitations of this procedure was carried out in the synthesis of phenanthroids 11 from a series of phenethyl-substituted heterocycles 10, It was observed that in some cases a competitive dimerization process took place. It was also found that the coupling step could be efficiently extended to a larger number of examples if an aromatic ring were situated fused to the 1,2-diarylethane skeleton, as in 23 and 30. The synthesis of a series of 4,5-diarylthiazoles 23a-g was therefore carried out to explore the electronic requirements and the regioselectivity of the PIFA-mediated non-phenolic coupling reaction. When the same procedure was applied to aryl-heteroarylthiazoles 30, a series of phenanthroid-fused thiazoles 31 was obtained in good overall yields. To the best of our knowledge, no oxidative aryl-heteroaryl coupling reaction of this type had previously been reported. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200207)2002:13<2126::AID-EJOC2126>3.0.CO;2-A

FULL PAPER
A Simple Route to New Phenanthro- and Phenanthroid-Fused Thiazoles by a
PIFA-Mediated (Hetero)biaryl Coupling Reaction
[a]
[a]
[a]
[a]
´
´
´
Isabel Moreno, Imanol Tellitu,* Esther Domınguez,* and Raul SanMartın
Keywords: Biaryl coupling / Cyclizations / Heterocycles / Hypervalent compounds / Iodine
An application of the PIFA-mediated [PIFA: phenyliodine(III)
bis(trifluoroacetate)] biaryl coupling reaction is presented
and extended to the formation of heterobiaryl connections. A
preliminary study of the scope and limitations of this proced-
ure was carried out in the synthesis of phenanthroids 11 from
a series of phenethyl-substituted heterocycles 10. It was ob-
served that in some cases a competitive dimerization process
took place. It was also found that the coupling step could
be efficiently extended to a larger number of examples if an
aromatic ring were situated fused to the 1,2-diarylethane
diarylthiazoles 23a−g was therefore carried out to explore the
electronic requirements and the regioselectivity of the PIFA-
mediated non-phenolic coupling reaction. When the same
procedure was applied to aryl-heteroarylthiazoles 30, a series
of phenanthroid-fused thiazoles 31 was obtained in good
overall yields. To the best of our knowledge, no oxidative
aryl-heteroaryl coupling reaction of this type had previously
been reported.
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
skeleton, as in 23 and 30. The synthesis of a series of 4,5- 2002)
Introduction
In this context, considerable attention during the last dec-
ade has been devoted to the chemistry of hypervalent iodine
reagents as a powerful tool for synthetic organic chemists.[3]
The easily handled PIFA [phenyliodine(III) bis(trifluo-
roacetate)] and PIDA [(phenyliodine(III) diacetate] reagents
have been used for the production of aryl radical cations by
an SET mechanism,[4] displaying a reactivity similar to
those of other oxidants such as, for example, TlIII, VV, RuIV
and FeIII salts, but with diminished toxicity. By this strategy,
a series of nucleophiles (azides,[4a,5] acetates,[4] dicarbonyl
compounds,[4] thiophenolates[6] and thiocyanates[6b]) has
been introduced onto electron-enriched benzene rings. In
the particular case of aryl rings with high nucleophilic char-
acter (high Nu), this methodology would give rise to a new
biaryl connection in an elegant and simple way[7] (see
Scheme 2, 3 Ǟ 4 Ǟ 6). This methodology has in fact been
employed, by ourselves[8] and by others,[9] for the prepara-
tion of different synthetic and naturally occurring products
containing the biaryl moiety; in our opinion this approach
should be extended in depth. In this paper we therefore
wish to report our synthetic results on the PIFA-mediated
preparation of phenanthrene building blocks.
Biaryl bond construction has been a recurrent theme for
synthetic organic chemists during recent decades. With this
as a goal, different powerful methodologies have been de-
veloped in order to synthesize different natural products of
interest.[1] Some of these methodologies require substrates
bearing suitable functionalization (approach
A
in
Scheme 1) and, in this context, the procedures introduced
by Stille,[2a,2b] Ullmann,[2c] Semmelhack,[2d] Negishi,[2e] Su-
zuki,[2f] Meyers,[2g] Lipshutz[2h] and Kharasch,[2i] among
others, have become classic tools in the organic chemist’s
repertoire. On the other hand, biomimetic (oxidative) ap-
proaches to the synthesis of biaryl moieties have been ex-
ploited[2j] both with phenolic and with non-phenolic com-
pounds, with the advantage that, in these cases, no addi-
tional functionalization on the aromatic rings (approach B
in Scheme 1) is needed.
According to the general proposal shown in Scheme 2,
the stilbene-like substrates of type 3 must fulfil two prelim-
inary conditions in order to be transformed into the corres-
ponding phenanthrenes or phenanthroids 6. Hence, the suc-
cess of the reaction would probably rely firstly on the ease
of formation of the radical cation intermediate located on
one of the rings, and secondly on the nucleophilic character
of the other ring. In the absence of such nucleophilic char-
acter in the aromatic ring (low Nu), dimerization processes
Scheme 1
[a]
´
´
Departamento de Quımica Organica II, Facultad de Ciencias,
´
Universidad del Paıs Vasco Ϫ Euskal Herriko Unibertsitatea,
Apdo. 644, 48080 Bilbao, Spain
Fax: (internat.) ϩ 34-94/601-2748
E-mail: qopdopee@lg.ehu.es
Supporting information for this article is available on the
WWW under http://www.eurjoc.com or from the author.
2126
 WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0713Ϫ2126 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2002, 2126Ϫ2135

A Simple Route to New Phenanthro- and Phenanthroid-Fused Thiazoles
FULL PAPER
Figure 1 compiles the tricyclic compounds obtained. From
these results we were able to deduce that only electron-rich
aromatic rings were able to provide the corresponding fused
systems. Thus, the fully aromatic tetramethoxyphen-
anthrene[17] 11a, the naphthothiophene[18] 11c, and the pyr-
roloisoquinoline[19] 11j, which was not subject to further
dehydrogenation, were prepared in moderate to high yields.
Conversely, in those cases in which the aryl ring was not
nucleophilic enough (as in 10g), the dimeric material 12 was
the only product detected, as a result of a homocoupling
biaryl process.
Scheme 2
may result (see Scheme 2, 3 Ǟ 4 Ǟ 5).[10] Surprisingly, des-
pite its tremendous potential, this methodology has not, as
far as we know, been extended to the action of different
simple heterocycles that would, eventually, give rise to a
series of heteroaromatic phenanthroids of great interest by
a short and efficient route.
Figure 1. Phenanthrenes and phenanthroids 11, and dimers 12 and
13 obtained from 10
Results and Discussion
In order to evaluate the scope and limitations of the pro-
posed strategy, a series of 1,2-diarylethanes of type 10, with
varying nucleophilicity in one of the rings, was prepared
(see Scheme 3).[11] Precursors 10aϪi[12] were obtained by
standard procedures, in two steps by a Wittig reaction with
the corresponding aromatic or heteroaromatic aldehyde[13]
The particular behaviour of pyrrole 10i deserves a more
detailed inspection. In this case, pyrroleϪpyrrole dimeriz-
ation took place, in preference to the geometrically pre-
vented cyclization, through the 5-position to afford dimer
13. The higher nucleophilicity of this site with respect to the
3-position (the one required for the target heterocyclization)
accounted for the experimental result, and it also revealed
that the radical cation intermediate was generated in the
pyrrole ring, with a second pyrrole ring acting as the nucle-
ophilic partner in the reaction. In contrast, the availability
of the 2(ϭ 5)-position in pyrrole 10j allowed the desired
intramolecular cyclization, providing the corresponding
pyrroloisoquinoline 11j. Finally, under the same reaction
conditions, substrates 10b, 10d, 10e, 10f and 10h decom-
posed to give complex mixtures of unidentified com-
pounds.[20]
and
the
(3,4-dimethoxybenzyl)triphenylphosphonium
bromide 7,[14] followed by catalytic hydrogenation of the ob-
tained cis/trans mixtures of stilbenes 8aϪi.[15] On the other
hand, pyrrole 10j was prepared by condensation of the
phenethylamine 9 with 2,5-dimethoxytetrahydrofuran in
acetic acid.[16]
Although, as mentioned, the chemistry of hypervalent
iodine has for the first time been extended through these
experiments to promote oxidative heterobiaryl coupling re-
actions, starting from simple and nonfunctionalized stil-
bene-like precursors, we were not completely satisfied with
the obtained results, since certain limitations (dimer forma-
tion and degradation processes) had arisen. We therefore
decided to have a closer look at the proposed mechanism
of the coupling step (see Scheme 4).
The assumption that weakly nucleophilic rings were not
able to undergo the desired coupling was reflected in the
fact that dimer 12 was formed instead of the target benzo-
Scheme 3. Synthesis of phenethyl derivatives 10aϪj
With compounds 10aϪj in hand, the oxidative biaryl quinoline derivative. In view of the previous results, and in
coupling step was accomplished by use of the commercially order to expand the scope of our strategy to a higher num-
available PIFA in the presence of BF3·OEt2 as the activating ber of examples, it was possible to speculate that the reac-
agent (the cyclization process did not take place when the tion rate might be increased by avoidance of the dimeriz-
reaction was carried out in the absence of the Lewis acid). ation pathway, if an aromatic ring were to be situated fused
Eur. J. Org. Chem. 2002, 2126Ϫ2135
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I. Moreno, I. Tellitu, E. Domınguez, R. SanMartın
FULL PAPER
yield and regioselectivity of such a step might be highly
influenced by the electronic nature and location of the aryl
substituents. In order to study both factors,[8b] the synthesis
of a series of 4,5-diarylthiazoles 23 Ϫ including highly ac-
tivated (23a, 23b, 23g), moderately activated (23c), nonac-
tivated (23e, 23f) and deactivated (23d) aromatic rings Ϫ
was planned. Moreover, the projected approach had to be
amenable to easy extension to the preparation of different
4-aryl-5-heteroarylthiazoles of type 19 (Z ϭ N, O, S) (vide
infra). A schematic representation of the selected synthons
17 and 18 is therefore included in Scheme 5.
The construction of the selected precursors started from
bromo ketones 22aϪf, easily accessible by bromination of
the corresponding deoxybenzoins 17aϪf under standard
conditions. Because of the severe electronic and regioselec-
tive constraints of the FriedelϪCrafts acylation[22] used to
prepare deoxybenzoins 17aϪd, an alternative approach had
to be developed to prepare 17f. Consequently, as shown in
Scheme 6, the anion derived from lithiation of 3-bromoani-
sole was prepared and treated with commercially available
amide 21 to afford deoxybenzoin 17f in acceptable yield.
The transformation of bromo ketones into thiazoles 23aϪf
and 23g was carried out in good to excellent yields
(78Ϫ97%) by use of thioacetamide and thiourea, in DMF
as solvent (see Scheme 7).
Scheme 4. Proposed mechanism for the cyclization step
to the 1,2-diarylethane skeleton in such a way that the re-
sulting benzylic intermediate of type 16 (see Figure 2)
would be formed through a more stabilized transition state.
In addition, the closer proximity of the two rings should
make the biaryl connection more likely to occur. A new
series of 4,5-diarylthiazoles of type 19 (see Scheme 5) was
therefore prepared, in order to be transformed into the cor-
responding phenanthro- and phenanthroid-fused thiazoles.
Figure 2. Proposed intermediates 15 and 16
Scheme 6. Synthesis of deoxybenzoins 17
At this stage of the research, the diarylthiazoles 23aϪg
were submitted to our oxidative coupling conditions, af-
fording the corresponding series of phenanthro-fused thia-
zoles 24 in variable yields. From the obtained results, the
following conclusions can be proposed:
1) activation with electron-donating groups is needed in
at least one of the rings,
2) the reaction takes place in moderate to good yield
(63Ϫ83%), provided that at least two methoxy groups are
present in one of the rings (23a, 23b, 23c, 23d, 23g),
3) if only one methoxy group is present, the yield de-
Scheme 5
We considered two reasons to select and focus on the
thiazole system, aside from the simplicity of its projected creases dramatically (less than 5% for 23f),[23]
preparation. Firstly, since the thiazole moiety is present
4) finally, no regioisomers other than those described,
in a number of important natural products,[21] we should which are the result of a paraϪpara interaction, are de-
reach a series of heterocyclic derivatives with a presumably tected.[24]
high potential pharmacological activity. Secondly, the
behaviour of the thiazole system under oxidative coupling fused thiazoles 24, we moved to a next objective: the pre-
conditions has so far been unknown. paration of phenanthroid-fused thiazoles of type 31. For
Once we had completed the preparation of phenanthro-
As already shown, radical cations have been proposed as this purpose, a new route had to be optimized in order to
intermediates in oxidative coupling reactions,[4] and so the construct the skeleton of the required 4-aryl-5-heteroaryl-
2128
Eur. J. Org. Chem. 2002, 2126Ϫ2135

A Simple Route to New Phenanthro- and Phenanthroid-Fused Thiazoles
FULL PAPER
Figure 3. Trialkyltin-substituted heterocycles 29 employed
fact that the 2-position in furans and thiophenes is more
nucleophilic than the 3-position. On the other hand, all at-
tempts to promote cyclization in substrates 30e and 30f re-
sulted in the recovery of the starting materials completely
unchanged. In order to balance the pyridine ring deactiva-
tion, to our minds the reason for the lack of reactivity in
the thiazoles 30e and 30f, a new derivative bearing a me-
thoxy group located para to the cyclization point was pre-
pared. Pyridine 29g, synthesized from 2-methoxypyridine
by metallation with nBuLi and treatment of the resulting
anion with Me3SnCl in the presence of the lithium salt of
2-(dimethylamino)ethanol,[26] was therefore coupled with
bromothiazole 28. To our delight, the action of PIFA on
the obtained thiazole 30g afforded the desired benzoquino-
line 31g in good yield. Later, we found that thiazole 30h,
which bears a pyridine ring with the electron-donating
group located meta with respect to the cyclization point,
could be also transformed regioselectively into the corres-
ponding benzoquinoline 31h in a similar yield, provided
Scheme 7. Synthesis of phenanthrothiazoles 24
thiazoles 30aϪi. As shown in Scheme 8, bromo ketone 26,
obtained from acetophenone 25, reacted with thioacetam-
ide in DMF, and the obtained 4-arylthiazole 27 was regiose-
lectively brominated to afford bromothiazole 28, which in
turn was coupled under Stille conditions with a series of
commercially available (29a, 29c) or known (29b, 29d, 29e,
29f, 29i, 29g, 29h)[25] trialkylstannyl heterocyclic derivatives
29 (see Figure 3) giving rise to the corresponding 4-aryl-5-
heteroarylthiazoles 30aϪi.
Scheme 8. Synthesis of 4-aryl-5-heteroarylthiazoles 30
When the PIFA-mediated coupling reaction was carried
out on thiazoles 30aϪd, the corresponding phenanthroid-
fused thiazoles 31aϪd were isolated in moderate to high
yields (see Figure 4), as one would expect from such nucleo-
philic heterocycles. In addition, no regioisomers other than
Figure 4. Naphthothiazoles 31aϪd and thiazoloquinolines 31g
those shown were detected. This is in agreement with the and 31h
Eur. J. Org. Chem. 2002, 2126Ϫ2135
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I. Moreno, I. Tellitu, E. Domınguez, R. SanMartın
FULL PAPER
1
that the temperature was raised (refluxing solvent).[27] Fi-
nally, and as the only exception, reductive cleavage of the
pyrrole-substituted thiazole 30i was found to yield derivat-
ive 27 under the typical cyclization conditions.
33% yield as an oil. H NMR (CDCl3): δ ϭ 2.91 (s, 8 H), 3.79 (s,
6 H), 3.83 (s, 6 H), 3.87 (s, 6 H), 6.13 (d, J ϭ 4.8 Hz, 2 H), 6.60
(d, J ϭ 2.0 Hz, 2 H), 6.60 (dd, J ϭ 7.9, 2.0 Hz, 2 H), 6.80 (d, J ϭ
7.9 Hz, 2 H), 7.18Ϫ7.20 (m, 2 H) ppm. 13C NMR (CDCl3): δ ϭ
28.8, 33.2, 34.1, 55.8, 55.9, 109.9, 111.2, 111.4, 120.1, 123.9, 124.6,
132.6, 146.7, 147.6, 148.9 ppm.
Conclusion
Typical Procedure for the Synthesis of Deoxybenzoins 17aϪf. Syn-
thesis of 1-(3,4-Dimethoxyphenyl)-2-(3-methoxyphenyl)ethanone
(17b): Thionyl chloride (1.1 mL, 15.1 mmol) was added to a sus-
pension of 3-methoxyphenylacetic acid (1.0 g, 6.0 mmol) in CH2Cl2
(30 mL). The mixture was heated under reflux for 4 h, and the solv-
ent was removed under reduced pressure. The residue was dissolved
in CH2Cl2 (30 mL), veratrole (913 mg, 6.6 mmol) was added, and
the mixture was cooled on an ice bath. AlCl3 (2.0 g, 15.0 mmol)
was then added, and the solution was heated under reflux for 3 h.
After cooling, the reaction mixture was quenched with HCl (1 ,
30 mL) and decanted, and the aqueous layer was extracted with
CH2Cl2 (3 ϫ 20 mL). The combined organic extracts were dried
with Na2SO4 and the solvent was removed under reduced pressure.
Deoxybenzoin 17b was purified by crystallization of the obtained
oil from MeOH (1.32 g, 77% yield). M.p. 57Ϫ60 °C (MeOH). IR
In summary, new synthetic applications of PIFA-medi-
ated biaryl and aryl-heteroaryl coupling reactions have been
presented. The judicious combination of Stille and oxidat-
ive intramolecular coupling procedures with suitably activ-
ated substrates has allowed us to prepare a series of phena-
nthro- and phenanthroid-fused thiazoles in very good over-
all yields. Apart from mechanistic insights, our investi-
gations should provide preparative approaches to
interesting new and more complex heterocyclic compounds,
a line of research now underway in our group.
Experimental Section
1
(KBr): ν˜ ϭ 1670 cmϪ1. H NMR (CDCl3): δ ϭ 3.74 (s, 3 H), 3.88
General: See ref.[28]
(s, 3 H), 3.89 (s, 3 H), 4.18 (s, 2 H), 6.74Ϫ6.91 (m, 4 H), 7.18Ϫ7.26
(m, 1 H), 7.53 (d, J ϭ 2.0 Hz, 1 H), 7.63 (dd, J ϭ 8.3, 2.0 Hz, 1
H) ppm. 13C NMR (CDCl3): δ ϭ 45.0, 54.9, 55.6, 55.8, 109.7,
110.3, 114.7, 121.4, 123.3, 129.4, 136.3, 148.7, 153.0, 159.5, 195.0
ppm. C17H18O4 (286.32): calcd. C 71.31, H 6.34; found C 71.28,
H 6.31.
Typical Procedure for the Oxidative Coupling Reaction with 1,2-Di-
arylethanes 10. Synthesis of 2,3,6,7-Tetramethoxyphenanthrene
(11a): A solution of PIFA (165 mg, 0.38 mmol) and BF3·OEt2
(0.10 mL, 0.76 mmol) in CH2Cl2 (8 mL) was added at Ϫ20 °C to a
solution of ethane 10a (100 mg, 0.33 mmol) in 5 mL of the same
solvent. The mixture was stirred at the same temperature for
40 min, and the solvent was removed in vacuo to provide, after
crystallisation, 89 mg of pure phenanthrene 10a in 91% yield. M.p.
178Ϫ180 °C (hexanes), m.p. 180Ϫ181 °C (toluene/hexanes, 1:1);
see ref.[29]
1-(3,4-Dimethoxyphenyl)-2-(4-nitrophenyl)ethanone (17d): Deoxyb-
enzoin 17d was obtained by the typical procedure, in 81% yield.
1
M.p. 116Ϫ119 °C (MeOH). IR (KBr): ν˜ ϭ 1676 cmϪ1. H NMR
(CDCl3): δ ϭ 3.85 (s, 3 H), 3.90 (s, 3 H), 4.33 (s, 2 H), 6.87 (d, J ϭ
8.3 Hz, 1 H), 7.37 (d, J ϭ 8.7 Hz, 2 H), 7.48 (d, J ϭ 2.0 Hz, 1 H),
7.61 (dd, J ϭ 8.3, 2.0 Hz, 1 H), 8.09 (d, J ϭ 8.7 Hz, 2 H) ppm.
13C NMR (CDCl3): δ ϭ 44.2, 55.7, 55.9, 109.8, 110.0, 123.1, 123.4,
129.0, 130.3, 142.4, 148.9, 153.5, 194.5 ppm. C16H15NO5 (301.29):
calcd. C 63.78, H 5.02, N 4.65; found C 63.81, H 5.12, N 4.61.
7,8-Dimethoxynaphtho[2,1-b]thiophene (11c): Thiophene 11c was
obtained by the typical procedure, from ethane 10c in 52% yield.
M.p. 127Ϫ129 °C (hexanes). 1H NMR (CDCl3): δ ϭ 4.03 (s, 3 H),
4.08 (s, 3 H), 7.26 (s, 1 H), 7.55 (d, J ϭ 5.5 Hz, 1 H), 7.61 (s, 1 H),
7.63 (d, J ϭ 8.7 Hz, 1 H), 7.77 (d, J ϭ 8.7 Hz, 1 H), 7.86 (d, J ϭ
5.5 Hz, 1 H) ppm. 13C NMR (CDCl3): δ ϭ 55.8, 55.9, 103.2, 107.6,
118.9, 121.5, 123.8, 124.5, 125.4, 126.1, 135.0, 135.9, 148.5, 149.4
ppm. C14H12O2S (244.31): calcd. C 68.83, H 4.95; found C 68.79,
H 4.99.
Synthesis of 1-(3-Methoxyphenyl)-2-phenylethanone (17f): nBuLi
(1.56  in hexane, 5.14 mL) was added at Ϫ78 °C to a solution of
3-bromoanisole (1.0 g, 5.4 mmol) in THF (10 mL). The mixture
was stirred at the same temperature for 20 min, and a solution of
the commercially available amide 21 (320 mg, 1.8 mmol) in THF
(10 mL) was then added. The mixture was stirred for 5 min at Ϫ78
°C and allowed to warm up to room temp. over 30 min. The reac-
tion mixture was quenched with HCl (1 , 10 mL) and decanted,
the organic layer was dried with Na2SO4, and the solvent was re-
moved under reduced pressure. The residue was column chromato-
graphed (hexanes/EtOAc, 95:5) to afford ethanone 17f as a colour-
8,9-Dimethoxypyrrolo[2,1-a]-5,6-dihydroisoquinoline (11j):[19] Iso-
quinoline 11j was obtained by the typical procedure, from pyrrole
10j in 48% yield. M.p. 132Ϫ133 °C (Et2O). 1H NMR (CDCl3): δ ϭ
3.00 (t, J ϭ 6.7 Hz, 2 H), 3.89 (s, 3 H), 3.92 (s, 3 H), 4.02 (t, J ϭ
6.7 Hz, 2 H), 6.20 (dd, J ϭ 3.5, 2.6 Hz, 1 H), 6.39 (dd, J ϭ 3.5,
1.6 Hz, 1 H), 6.65 (dd, J ϭ 2.6, 1.6 Hz, 1 H), 6.70 (s, 1 H), 7.02
(s, 1 H) ppm. 13C NMR (CDCl3): δ ϭ 29.0, 44.2, 55.9, 102.2, 108.2,
111.2, 120.3, 120.5, 122.7, 129.9, 132.5, 147.1, 149.0 ppm.
less oil (301 mg, 74%). IR (neat): ν˜ ϭ 1672 cmϪ1 1H NMR
.
(CDCl3): δ ϭ 3.83 (s, 3 H), 4.28 (s, 2 H), 7.08Ϫ7.63 (m, 9 H) ppm.
13C NMR (CDCl3): δ ϭ 45.4, 55.2, 112.6, 119.5, 121.1, 126.7,
129.3, 129.4, 134.4, 137.7, 159.6, 197.3 ppm. MS (EI): m/z ϭ 226
(9) [Mϩ], 135 (100).
1,1Ј-{2,2Ј-[2-(6-Methoxy-2-pyridyl)ethyl]-4,4Ј,5,5Ј-tetramethoxy}-
biphenyl (12):[30] Biphenyl 12 was obtained by the typical procedure,
1
from pyridine 10g in 89% yield as an oil. H NMR (CDCl3): δ ϭ
Typical Procedure for the Synthesis of 2-Bromoethanones 22aϪf.
Synthesis of 2-Bromo-1,2-bis(3,4-dimethoxyphenyl)ethanone (22a):
Bromine (0.2 mL, 3.8 mmol) was added dropwise to a solution of
ethanone 17a[31] (800 mg, 2.52 mmol) in 10 mL of freshly distilled
CHCl3. The mixture was heated under reflux until conversion was
complete (NMR, 3 h). After the mixture had cooled, the solvent
was evaporated under reduced pressure to provide a residue that
was column-chromatographed (CH2Cl2) to yield pure bromoe-
2.77Ϫ2.82 (m, 8 H), 3.81 (s, 6 H), 3.83 (s, 6 H), 3.86 (s, 6 H), 6.45
(d, J ϭ 6.9 Hz, 2 H), 6.48 (d, J ϭ 8.3 Hz, 2 H), 6.66 (s, 2 H), 6.75
(s, 2 H), 7.36 (dd, J ϭ 8.3, 6.9 Hz, 2 H) ppm. 13C NMR (CDCl3):
δ ϭ 32.7, 39.5, 53.1, 55.8, 55.9, 107.4, 111.9, 113.1, 115.1, 132.1,
132.7, 138.6, 146.4, 147.8, 159.1, 163.5 ppm.
2,2Ј-Bis[5-(3,4-dimethoxyphenylethyl)-1-methylpyrrole] (13):[30] Pyr-
role 13 was obtained by the typical procedure, from pyrrole 10i in
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Eur. J. Org. Chem. 2002, 2126Ϫ2135

A Simple Route to New Phenanthro- and Phenanthroid-Fused Thiazoles
thanone 22a (935 mg, 94%) as a yellowish solid. M.p. 78Ϫ80 °C. C10H11BrO3 (259.10): calcd. C 46.36, H 4.28; found C 46.21, H
FULL PAPER
1
IR (KBr): ν˜ ϭ 1675 cmϪ1. H NMR (CDCl3): δ ϭ 3.82 (s, 3 H),
3.86 (s, 3 H), 3.93 (s, 6 H), 6.86 (s, 1 H), 6.90Ϫ7.10 (m, 3 H), 7.52
(s, 1 H), 7.62 (s, 1 H), 7.63 (dd, J ϭ 8.2, 0.7 Hz, 1 H) ppm. 13C
NMR (CDCl3): δ ϭ 51.6, 55.9, 56.0, 56.1, 110.2, 110.9, 112.5,
113.6, 115.0, 123.6, 126.6, 127.6, 149.0, 150.1, 189.5 ppm.
C18H19BrO5 (395.24): calcd. C 54.70, H 4.85; found C 54.66, H
4.82.
4.32.
Typical Procedure for the Synthesis of Thiazoles 23aϪg. Synthesis
of 4,5-Bis(3,4-dimethoxyphenyl)-2-methylthiazole (23a): A solution
of bromo ketone 22a (1 g, 2.5 mmol) and thioacetamide (280 mg,
3.0 mmol) [or thiourea for 23g] in 20 mL of DMF was heated at
65 °C until total consumption of the starting material (TLC, 8 h).
After this had cooled, ethyl acetate (40 mL) was added and the
mixture was washed with H2O (3 ϫ 20 mL). The organic extracts
were dried with Na2SO4 and the solvent was removed in vacuo.
Thiazole 23a was purified by crystallization from Et2O (0.86 g,
2-Bromo-1-(3,4-dimethoxyphenyl)-2-(3-methoxyphenyl)ethanone
(22b): Bromoethanone 22b was obtained by the typical procedure,
from ethanone 17b in 91% yield. M.p. 149Ϫ152 °C (CH2Cl2/hex-
1
1
anes, 1:1). IR (KBr): ν˜ ϭ 1680 cmϪ1. H NMR (CDCl3): δ ϭ 3.74
93%). M.p. 67Ϫ69 °C. H NMR (CDCl3): δ ϭ 2.73 (s, 3 H), 3.70
(s, 3 H), 3.73 (s, 3 H), 3.86 (s, 3 H), 3.89 (s, 3 H), 6.75Ϫ6.90 (m, 3
H), 7.04Ϫ7.08 (m, 3 H) ppm. 13C NMR (CDCl3): δ ϭ 19.1, 55.4,
55.6, 56.0, 56.1, 110.6, 111.0, 114.8, 115.4, 115.6, 120.6, 125.2,
127.4, 128.7, 148.2, 148.3, 149.7, 150.5, 164.4 ppm. C20H21NO4S
(371.45): calcd. C 64.67, H 5.70, N 3.77; found C 64.77, H 5.59,
N 3.67.
(s, 3 H), 3.91 (s, 3 H), 3.92 (s, 3 H), 6.71Ϫ6.90 (m, 4 H), 7.10 (d,
J ϭ 3.0 Hz, 1 H), 7.44Ϫ7.51 (m, 2 H), 7.59Ϫ7.63 (m, 1 H) ppm.
13C NMR (CDCl3): δ ϭ 55.3, 55.4, 55.9, 56.0, 110.2, 111.0, 113.3,
115.9, 116.9, 123.6, 126.5, 133.9, 136.9, 149.0, 153.8, 159.4, 189.1
ppm. C17H17BrO4 (365.22): calcd. C 55.91, H 4.69; found C 55.65,
H 4.92.
4-(3,4-Dimethoxyphenyl)-5-(3-methoxyphenyl)-2-methylthiazole
(23b): Thiazole 23b was obtained by the typical procedure, from
bromo ketone 22b in 89% yield. M.p. 149Ϫ152 °C (hexanes/
2-Bromo-1-(3,4-dimethoxyphenyl)-2-phenylethanone (22c): Bromoe-
thanone 22c was obtained by the typical procedure, from ethanone
17c[31] in 97% yield. M.p. 104Ϫ106 °C (MeOH). IR (KBr): ν˜ ϭ
1675 cmϪ1. 1H NMR (CDCl3): δ ϭ 3.90 (s, 3 H), 3.93 (s, 3 H), 6.39
(s, 1 H), 6.85 (d, J ϭ 8.5 Hz, 1 H), 7.33Ϫ7.36 (m, 3 H), 7.51Ϫ7.55
(m, 3 H), 7.61 (dd, J ϭ 8.5, 2.0 Hz, 1 H) ppm. 13C NMR (CDCl3):
δ ϭ 50.9, 55.4, 55.6, 109.7, 110.7, 123.4, 126.4, 128.5, 128.6, 136.0,
148.6, 153.3, 189.2 ppm. C16H15BrO3 (335.19): calcd. C 57.33, H
4.51; found C 57.55, H 4.72.
1
CH2Cl2, 1:1). H NMR (CDCl3): δ ϭ 2.74 (s, 3 H), 3.70 (s, 3 H),
3.72 (s, 3 H), 3.87 (s, 3 H), 6.76Ϫ6.94 (m, 4 H), 7.04 (d, J ϭ 2.0
Hz, 1 H), 7.10 (dd, J ϭ 8.3, 2.0 Hz, 1 H), 7.21(d, J ϭ 7.5 Hz, 1
H) ppm. 13C NMR (CDCl3): δ ϭ 19.1, 55.1, 55.4, 55.7, 110.6,
111.8, 113.5, 114.8, 121.5, 122.0, 127.4, 129.6, 130.9, 133.5, 148.4,
149.1, 159.4, 163.6 ppm. C19H19NO3S (341.43): calcd. C 66.84, H
5.61, N 4.10; found C 66.81, H 5.55, N 4.21.
2-Bromo-1-(3,4-dimethoxyphenyl)-2-(4-nitrophenyl)ethanone (22d):
Bromoethanone 22d was obtained by the typical procedure, from
ethanone 17d in 65% yield. M.p. 48Ϫ51 °C (hexanes). IR (KBr):
4-(3,4-Dimethoxyphenyl)-2-methyl-5-phenylthiazole (23c): Thiazole
23c was obtained by the typical procedure, from bromo ketone 22c
in 92% yield. M.p. 78Ϫ80 °C (hexanes). 1H NMR (CDCl3): δ ϭ
2.74 (s, 3 H), 3.65 (s, 3 H), 3.85 (s, 3 H), 6.77 (d, J ϭ 8.4 Hz, 1 H),
6.99 (d, J ϭ 1.9 Hz, 1 H), 7.10 (dd, J ϭ 8.4, 1.9 Hz, 1 H), 7.28Ϫ7.34
(m, 5 H) ppm. 13C NMR (CDCl3): δ ϭ 18.8, 55.1, 55.4, 110.4,
111.6, 121.2, 127.1, 127.5, 128.2, 130.7, 132.0, 148.0, 148.1, 148.7,
163.2 ppm. C18H17NO2S (311.40): calcd. C 69.43, H 5.50, N 4.50;
found C 69.51, H 5.42, N 4.31.
ν˜ ϭ 1675 cmϪ1 1H NMR (CDCl3): δ ϭ 3.87 (s, 3 H), 3.91 (s, 3
.
H), 6.39 (s, 1 H), 6.86 (d, J ϭ 8.7 Hz, 1 H), 7.51 (d, J ϭ 2.1 Hz, 1
H), 7.62 (dd, J ϭ 8.7, 2.1 Hz, 1 H), 7.70 (d, J ϭ 8.7 Hz, 2 H), 8.16
(d, J ϭ 8.7 Hz, 2 H) ppm. 13C NMR (CDCl3): δ ϭ 46.9, 55.8, 56.0,
110.0, 111.0, 123.6, 126.3, 130.2, 142.9, 147.6, 149.2, 154.1, 188.7
ppm. C16H14BrNO5 (380.19): calcd. C 50.55, H 3.71, N 3.68; found
C 50.51, H 3.68, N 3.65.
4-(3,4-Dimethoxyphenyl)-2-methyl-5-(4-nitrophenyl)thiazole (23d):
Thiazole 23d was obtained by the typical procedure, from bromo
ketone 22d as a colourless oil in 78% yield, after purification by
column chromatography (hexanes/EtOAc, 1:1). 1H NMR (CDCl3):
δ ϭ 2.78 (s, 3 H), 3.88 (s, 3 H), 3.90 (s, 3 H), 6.77 (d, J ϭ 8.3 Hz,
1 H), 6.99 (dd, J ϭ 8.3, 2.0 Hz, 1 H), 7.05 (d, J ϭ 2.0 Hz, 1 H),
7.47 (d, J ϭ 9.1 Hz, 2 H), 8.14 (d, J ϭ 9.1 Hz, 2 H) ppm. 13C
NMR (CDCl3): δ ϭ 19.3, 55.7, 55.8, 110.9, 111.9, 121.9, 123.9,
126.6, 128.6, 128.7, 130.0, 139.4, 146.7, 148.8, 149.3, 151.3, 165.6
ppm. MS (EI): m/z ϭ 354 (100) [Mϩ], 339 (12), 311 (12), 265 (23).
2-Bromo-1,2-diphenylethanone (22e): Bromoethanone 22e was ob-
tained by the typical procedure, from commercially available deox-
ybenzoin 17e in 98% yield. M.p. 44Ϫ46 °C (hexanes). IR (KBr):
1
ν˜ ϭ 1682 cmϪ1. H NMR (CDCl3): δ ϭ 6.40 (s, 1 H), 7.35Ϫ7.61
(m, 8 H), 7.91Ϫ8.01 (m, 2 H) ppm. 13C NMR (CDCl3): δ ϭ 51.1,
128.3, 128.5, 128.6, 128.7, 133.3, 135.4, 190.6 ppm. C14H11BrO
(275.14): calcd. C 61.11, H 4.03; found C 61.35, H 4.22.
2-Bromo-1-(3-methoxyphenyl)-2-phenylethanone (22f): Bromoe-
thanone 22f was obtained by the typical procedure, from ethanone
17f in 71% yield as a colourless oil after purification by column
2-Methyl-4,5-diphenylthiazole (23e): Thiazole 23e was obtained by
the typical procedure, from bromo ketone 22e in 97% yield. M.p.
44Ϫ46 °C (Et2O). 1H NMR (CDCl3): δ ϭ 2.76 (s, 3 H), 7.27Ϫ7.40
(m, 8 H), 7.49Ϫ7.53 (m, 2 H) ppm. 13C NMR (CDCl3): δ ϭ 19.1,
127.6, 127.8, 128.2, 128.6, 128.9, 129.5, 132.1, 134.8, 163.8 ppm.
C16H13NS (251.35): calcd. C 76.46, H 5.21, N 5.57; found C 76.41,
H 5.42, N 5.31.
chromatography (hexanes/EtOAc, 6:4). IR (neat): ν˜ ϭ 1685 cmϪ1
.
1H NMR (CDCl3): δ ϭ 3.83 (s, 3 H), 6.37 (s, 1 H), 7.08Ϫ7.12 (m,
1 H), 7.31Ϫ7.41 (m, 4 H), 7.51Ϫ7.56 (m, 4 H) ppm. 13C NMR
(CDCl3): δ ϭ 51.3, 55.6, 113.5, 120.5, 129.0, 129.1, 129.8, 135.3,
135.9, 159.8, 190.8 ppm. MS (EI): m/z ϭ 226 (1), 135 (100).
2-Bromo-1-(3,4-dimethoxyphenyl)ethanone (26): Bromoethanone 26
was obtained by the typical procedure, from commercially available 4-(3-Methoxyphenyl)-2-methyl-5-phenylthiazole (23f): Thiazole 23f
acetophenone 25 in 97% yield. M.p. 45Ϫ47 °C (Et2O). IR (KBr):
was obtained by the typical procedure, from bromo ketone 22f in
ν˜ ϭ 1669 cmϪ1
.
1H NMR (CDCl3): δ ϭ 3.91 (s, 3 H), 3.94 (s, 3 86% yield as a colourless oil, after purification by column chroma-
1
H), 4.38 (s, 2 H), 6.87 (d, J ϭ 8.5 Hz, 1 H), 7.49 (d, J ϭ 2.0 Hz, 1 tography (hexanes/EtOAc, 1:1). H NMR (CDCl3): δ ϭ 2.75 (s, 3
H), 7.57 (dd, J ϭ 8.5, 2.0 Hz, 1 H) ppm. 13C NMR (CDCl3): δ ϭ
H), 3.67 (s, 3 H), 6.79Ϫ6.83 (m, 1 H), 7.04Ϫ7.32 (m, 8 H) ppm.
30.5, 55.5, 55.7, 109.6, 110.2, 123.4, 126.4, 148.7, 153.5, 189.5 ppm.
13C NMR (CDCl3): δ ϭ 19.1, 55.0, 113.6, 114.1, 121.4, 127.9,
Eur. J. Org. Chem. 2002, 2126Ϫ2135
2131

´
´
I. Moreno, I. Tellitu, E. Domınguez, R. SanMartın
FULL PAPER
128.6, 129.2, 129.6, 132.0, 132.5, 149.1, 159.3, 163.8 ppm. MS (EI):
zole 28 and 3-(trimethylstannyl)furan (29b),[25a] in 74% yield as a
colourless oil. H NMR (CDCl3): δ ϭ 2.69 (s, 3 H), 3.80 (s, 3 H),
m/z ϭ 281 (100) [Mϩ], 266 (5).
1
3.88 (s, 3 H), 6.27Ϫ6.28 (m, 1 H), 6.82 (d, J ϭ 8.3 Hz, 1 H),
7.12Ϫ7.16 (m, 2 H), 7.35Ϫ7.36 (m, 1 H), 7.44Ϫ7.46 (m, 1 H) ppm.
13C NMR (CDCl3): δ ϭ 19.0, 55.6, 55.7, 110.6, 110.9, 111.7, 116.9,
121.3, 121.7, 127.5, 140.4, 143.1, 148.4, 148.6, 149.8, 162.9 ppm.
HRMS calcd. for C16H16NO3S 301.0773, found 301.0779.
2-Amino-4,5-bis(3,4-dimethoxyphenyl)thiazole (23g): Thiazole 23g
was obtained by the typical procedure, from bromo ketone 22a in
92% yield. M.p. 164Ϫ166 °C (Et2O). H NMR (CDCl3): δ ϭ 3.68
(s, 3 H), 3.72 (s, 3 H), 3.83 (s, 3 H), 3.88 (s, 3 H), 5.44 (br. s, 2 H),
6.71 (d, J ϭ 8.3 Hz, 1 H), 6.80 (s, 1 H), 6.94Ϫ6.98 (m, 3 H), 7.01
(s, 1 H) ppm. 13C NMR (CDCl3): δ ϭ 55.5, 55.7, 56.0, 56.2, 110.6,
111.0, 115.3, 120.6, 116.2, 125.4, 127.4, 146.5, 148.1, 148.2, 148.3,
149.6, 166.0 ppm. C19H20N2O4S (372.44): calcd. C 61.27, H 5.41,
N 7.52; found C 61.31, H 5.62, N 7.31.
1
4-(3,4-Dimethoxyphenyl)-2-methyl-5-(2-thienyl)thiazole (30c): Thia-
zole 30c was obtained by the typical procedure, from bromothia-
zole 28 and commercially available 2-(tributylstannyl)thiophene
(29c), in 89% yield as a colourless oil. 1H NMR (CDCl3): δ ϭ 2.73
(s, 3 H), 3.75 (s, 3 H), 3.89 (s, 3 H), 6.83 (d, J ϭ 8.3 Hz, 1 H),
6.97Ϫ7.08 (m, 3 H), 7.17 (dd, J ϭ 8.3, 2.0 Hz, 1 H), 7.23Ϫ7.28 (m,
1 H) ppm. 13C NMR (CDCl3): δ ϭ 19.1, 55.5, 55.7, 110.6, 111.8,
121.6, 124.0, 126.5, 127.1, 127.2 127.9, 133.2, 148.3, 148.7, 150.3,
163.8 ppm. HRMS calcd. for C16H15NO2S2 317.0544, found
317.0550.
4-(3,4-Dimethoxyphenyl)-2-methylthiazole (27): Thiazole 27 was ob-
tained by the typical procedure, from bromo ketone 26 in 98%
1
yield. M.p. 62Ϫ65 °C (EtOAc). H NMR (CDCl3): δ ϭ 2.71 (s, 3
H), 3.86 (s, 3 H), 3.91 (s, 3 H), 6.85 (d, J ϭ 8.3 Hz, 1 H), 7.14 (s,
1 H), 7.36 (dd, J ϭ 8.3, 1.8 Hz, 1 H), 7.42 (d, J ϭ 1.8 Hz, 1 H)
ppm. 13C NMR (CDCl3): δ ϭ 19.1, 55.7, 55.4, 109.4, 110.7, 110.9,
118.5, 127.6, 148.7, 148.8, 154.7, 165.5 ppm. C12H13NO2S (235.30):
calcd. C 61.26, H 5.57, N 5.95; found C 61.31, H 5.67, N 5.81.
4-(3,4-Dimethoxyphenyl)-2-methyl-5-(3-thienyl)thiazole (30d): Thia-
zole 30d was obtained by the typical procedure, from bromothia-
zole 28 and 3-(trimethylstannyl)thiophene (29d),[25b] in 72% yield
Synthesis of 5-Bromo-4-(3,4-dimethoxyphenyl)-2-methylthiazole
(28): Bromine (0.32 mL, 6.3 mmol) was added dropwise to a solu-
tion of thiazole 27 (1.2 g, 5.25 mmol) in 15 mL of CHCl3. The mix-
ture was heated under reflux until conversion was complete (NMR,
4 h). Then, after cooling, the solvent was removed under reduced
pressure and the crude bromothiazole 28 was purified by crystal-
lization from Et2O (1.6 g, 97%). M.p. 158Ϫ161 °C. 1H NMR
(CDCl3): δ ϭ 2.70 (s, 3 H), 3.92 (s, 3 H), 3.94 (s, 3 H), 6.93 (d, J ϭ
8.3 Hz, 1 H), 7.45 (d, J ϭ 1.8 Hz, 1 H), 7.50 (dd, J ϭ 8.3, 1.8 Hz,
1 H) ppm. 13C NMR (CDCl3): δ ϭ 19.5, 55.8, 100.8, 110.5, 111.4,
121.1, 126.1, 148.9, 151.5, 165.3 ppm. C12H12BrNO2S (314.20):
calcd. C 45.87, H 3.85, N 4.46; found C 45.77, H 3.62, N 4.41.
1
as a colourless oil. H NMR (CDCl3): δ ϭ 2.73 (s, 3 H), 3.74 (s, 3
H), 3.89 (s, 3 H), 6.82 (d, J ϭ 8.3 Hz, 1 H), 6.96 (dd, J ϭ 5.1, 1.6
Hz, 1 H), 7.03 (d, J ϭ 2.0 Hz, 1 H), 7.12 (dd, J ϭ 8.3, 2.0 Hz, 1
H), 7.23Ϫ7.29 (m, 2 H) ppm. 13C NMR (CDCl3): δ ϭ 19.1, 55.5,
55.7, 110.7, 111.6, 121.3, 123.8, 125.8, 125.9, 127.6, 132.1, 128.3,
148.3, 148.5, 163.0 ppm. HRMS calcd. for C16H15NO2S2 317.0544,
found 317.0535.
4-(3,4-Dimethoxyphenyl)-2-methyl-5-(2-pyridyl)thiazole (30e): Thia-
zole 30e was obtained by the typical procedure, from bromothia-
zole 28 and 2-(trimethylstannyl)pyridine (29e),[25c] in 69% yield as
a colourless oil. 1H NMR (CDCl3): δ ϭ 2.74 (s, 3 H), 3.79 (s, 3
H), 3.91 (s, 3 H), 6.85 (d, J ϭ 8.3 Hz, 1 H), 7.05Ϫ7.13 (m, 3 H),
Typical Procedure for the Stille Coupling Reaction. Synthesis of
4-(3,4-Dimethoxyphenyl)-5-(6-methoxypyrid-2-yl)-2-methylthiazole 7.18Ϫ7.22 (m, 1 H), 7.43Ϫ7.50 (m, 1 H), 8.56Ϫ8.59 (m, 1 H) ppm.
(30g): A solution of pyridine 29g[25d] (122 mg, 0.45 mmol) in tolu-
ene (5 mL) was added to a suspension of bromothiazole 28
(100 mg, 0.28 mmol), LiCl (36 mg, 0.84 mmol) and Pd(PPh3)4
(33 mg, 10% mol) in 25 mL of the same solvent, and the mixture
was heated under reflux for 48 h. After this had cooled to room
temp., the solvent was evaporated under reduced pressure and the
residue was column-chromatographed (hexanes/EtOAc, 1:1; this
eluent was used for the purification of all derivatives 30) to afford
thiazole 30g (72 mg, 78%) as an oil that was crystallised from ether.
13C NMR (CDCl3): δ ϭ 19.3, 55.8, 55.9, 111.1, 112.1, 121.8, 121.9,
122.3, 127.8, 136.0, 148.8, 149.1, 149.6, 151.1, 151.8, 166.0 ppm.
HRMS calcd. for C17H16N2O2S 312.0932, found 312.0937.
4-(3,4-Dimethoxyphenyl)-2-methyl-5-(3-pyridyl)thiazole (30f): Thia-
zole 30f was obtained by the typical procedure, from bromothiazole
28 and 3-(trimethylstannyl)pyridine (29f),[25c] in 72% yield. M.p.
1
99Ϫ102 °C (Et2O). H NMR (CDCl3): δ ϭ 2.77 (s, 3 H), 3.73 (s,
3 H), 3.87 (s, 3 H), 6.77 (d, J ϭ 8.5 Hz, 1 H), 6.97Ϫ7.05 (m, 2 H),
7.19Ϫ7.31 (m, 1 H), 7.61 (d, J ϭ 7.9 Hz, 1 H), 8.53Ϫ8.60 (m, 2 H)
ppm. 13C NMR (CDCl3): δ ϭ 19.3, 55.6, 55.8, 110.9, 111.8, 121.6,
123.3, 126.9, 128.4, 128.6, 128.9, 131.1, 132.0, 136.8, 148.8, 150.1,
164.8 ppm. C17H16N2O2S (312.39): calcd. C 65.36, H 5.16, N 8.97;
found C 65.40, H 5.14, N 9.01.
1
M.p. 95Ϫ97 °C (Et2O). H NMR (CDCl3): δ ϭ 2.72 (s, 3 H), 3.80
(s, 3 H), 3.90 (s, 3 H), 3.91 (s, 3 H), 6.55 (dd, J ϭ 8.3, 0.8 Hz, 1
H), 6.80Ϫ6.88 (m, 2 H), 7.07Ϫ7.14 (m, 2 H), 7.31Ϫ7.35 (m, 1 H)
ppm. 13C NMR (CDCl3): δ ϭ 19.2, 53.3, 55.8, 109.0, 111.0, 112.1,
114.6, 121.8, 128.1, 133.5, 138.6, 148.7, 148.8, 149.0, 150.8, 163.3,
165.6 ppm. C18H18N2O3S (342.41): calcd. C 63.14, H 5.30, N 8.18;
found C 63.09, H 5.42, N 8.14.
4-(3,4-Dimethoxyphenyl)-5-(6-methoxypyrid-3-yl)-2-methylthiazole
(30h): Thiazole 30h was obtained by the typical procedure, from
bromothiazole 28 and pyridine 29h,[25e] in 77% yield as a colourless
4-(3,4-Dimethoxyphenyl)-5-(2-furyl)-2-methylthiazole (30a): Thia-
zole 30a was obtained by the typical procedure, from bromothia-
zole 28 and commercially available 2-(tributylstannyl)furan (29a) in
86% yield. M.p. 77Ϫ79 °C (hexanes). 1H NMR (CDCl3): δ ϭ 2.73
(s, 3 H), 3.83 (s, 3 H), 3.91 (s, 3 H), 6.26Ϫ6.27 (m, 1 H), 6.32Ϫ6.34
(m, 1 H), 6.83 (d, J ϭ 8.5 Hz, 1 H), 7.09 (s, 1 H), 7.16 (dd, J ϭ
8.5, 2.0 Hz, 1 H), 7.36 (s, 1 H) ppm. 13C NMR (CDCl3): δ ϭ 19.0,
55.6, 55.7, 108.4, 110.6, 111.4, 111.5, 121.3, 127.4, 142.0, 146.1,
148.4, 148.8, 150.0, 163.8 ppm. C16H15NO3S (301.36): calcd. C
63.77, H 5.02, N 4.65; found C 63.59, H 5.22, N 4.34.
1
oil. H NMR (CDCl3): δ ϭ 2.73 (s, 3 H), 3.74 (s, 3 H), 3.86 (s, 3
H), 3.93 (s, 3 H), 6.67 (d, J ϭ 8.3 Hz, 1 H), 6.77 (d, J ϭ 8.3 Hz, 1
H), 6.98Ϫ7.03 (m, 2 H), 7.46 (dd, J ϭ 8.7, 2.4 Hz, 1 H), 8.15 (d,
J ϭ 1.9 Hz, 1 H) ppm. 13C NMR (CDCl3): δ ϭ 19.2, 53.5, 55.6,
55.7, 110.6, 110.8, 111.8, 121.4, 139.6, 121.5, 127.3, 147.1, 148.5,
148.6, 149.7, 163.4, 163.8 ppm. HRMS calcd. for C18H18N2O3S
342.1038, found 342.1039.
4-(3,4-Dimethoxyphenyl)-5-(1-methylpyrrol-2-yl)-2-methylthiazole
(30i): Thiazole 30i was obtained by the typical procedure, from
4-(3,4-Dimethoxyphenyl)-5-(3-furyl)-2-methylthiazole (30b): Thia-
bromothiazole 28 and 1-methyl-2-(trimethylstannyl)pyrrole
1
zole 30b was obtained by the typical procedure, from bromothia- (29i),[25f] in 89% yield as a colourless oil. H NMR (CDCl3): 2.74
2132
Eur. J. Org. Chem. 2002, 2126Ϫ2135

A Simple Route to New Phenanthro- and Phenanthroid-Fused Thiazoles
FULL PAPER
(s, 3 H), 3.16 (s, 3 H), 3.67 (s, 3 H), 3.86 (s, 3 H), 6.21 (dd, J ϭ 8,9-Dimethoxy-2-methylfuro[3,2-a]naphtho[4,3-d]thiazole (31a): Thi-
5.3, 2.8 Hz, 1 H), 6.29Ϫ6.31 (m, 1 H), 6.69 (dd, J ϭ 5.3, 2.0 Hz, azole 31a was obtained by the typical procedure, from thiazole 30a
1 H), 6.79 (d, J ϭ 8.3 Hz, 1 H), 6.92 (d, J ϭ 2.0 Hz, 1 H), 7.16 in 64% yield as a colourless oil, after purification by column chro-
(dd, J ϭ 8.3, 2.0 Hz, 1 H) ppm. 13C NMR (CDCl3): δ ϭ 18.9, 33.7, matography (hexanes/EtOAc, 1:1). 1H NMR (CDCl3): δ ϭ 2.97 (s,
55.1, 55.4, 108.0, 109.8, 110.5, 111.2, 120.0, 120.6, 122.1, 123.0, 3 H), 4.09 (s, 3 H), 4.13 (s, 3 H), 7.24 (d, J ϭ 2.0 Hz, 1 H), 7.45
127.5, 148.0, 148.1, 150.6, 164.5 ppm. HRMS calcd. for (s, 1 H), 7.77 (d, J ϭ 2.0 Hz, 1 H), 8.17 (s, 1 H) ppm. 13C NMR
C17H18N2O2S 314.1089, found 314.1094.
(CDCl3): δ ϭ 20.0, 56.0, 56.1, 103.5, 104.7, 106.1, 116.4, 119.6,
120.7, 121.3, 143.8, 145.6, 148.4, 149.5, 163.8 ppm. HRMS calcd.
for C16H13NO2S2 315.0388, found 315.0381.
Typical Procedure for the Oxidative Coupling Reaction. Synthesis of
5,6,9,10-Tetramethoxy-2-methylphenanthro[9,10-d]thiazole (24a): A
solution of PIFA (139 mg, 0.32 mmol) and BF3·OEt2 (0.08 mL,
0.65 mmol) in CH2Cl2 (8 mL) was added at Ϫ20 °C (at room temp.
for 24f and at 40 °C for 31h) to a solution of thiazole 23a (101 mg,
0.28 mmol) in 5 mL of the same solvent. The mixture was stirred
at the same temperature for 40 min, and the solvent was removed
in vacuo to provide, after column chromatography (hexanes/
EtOAc, 1:1), pure phenanthro-thiazole 24a (81 mg, 81%) as a solid.
M.p. Ͼ 300 °C. 1H NMR (CDCl3): δ ϭ 2.94 (s, 3 H), 4.05 (s, 3 H),
4.12 (s, 3 H), 4.13 (s, 3 H), 4.14 (s, 3 H), 7.14 (s, 1 H), 7.76 (s, 1
H), 7.77, (s, 1 H), 8.13 (s, 1 H) ppm. 13C NMR (CDCl3): δ ϭ 20.0,
55.9, 56.0, 103.3, 103.9, 104.7, 105.9, 120.9, 122.1, 122.4, 123.1,
123.4, 148.7, 148.9, 149.0, 163.7 ppm. C20H19NO4S (369.44): calcd.
C 65.02, H 5.18, N 3.79; found C 65.21, H 5.02, N 3.71.
8,9-Dimethoxy-2-methylfuro[2,3-a]naphtho[4,3-d]thiazole (31b): Thi-
azole 31b was obtained by the typical procedure, from thiazole 30b
in 68% yield. M.p. 165Ϫ168 °C (hexanes). 1H NMR (CDCl3): δ ϭ
2.95 (s, 3 H), 4.10 (s, 3 H), 4.13 (s, 3 H), 6.94 (d, J ϭ 2.0 Hz, 1 H),
7.65 (s, 1 H), 7.77 (d, J ϭ 2.0 Hz, 1 H), 8.14 (s, 1 H) ppm. 13C
NMR (CDCl3): δ ϭ 20.0, 56.0, 56.2, 100.2, 104.5, 106.8, 115.3,
115.5, 121.4, 123.2, 143.8, 145.9, 148.4, 149.1, 149.5, 163.3 ppm.
C16H13NO3S (299.35): calcd. C 64.20, H 4.38, N 4.68; found C
64.12, H 4.41, N 4.72.
8,9-Dimethoxy-2-methylthieno[3,2-a]naphtho[4,3-d]thiazole
(31c):
Thiazole 31c was obtained by the typical procedure, from thiazole
30c in 86% yield. M.p. 171Ϫ174 °C (Et2O). 1H NMR (CDCl3): δ ϭ
2.92 (s, 3 H), 4.07 (s, 3 H), 4.12 (s, 3 H), 7.46 (d, J ϭ 5.3 Hz, 1 H),
7.54 (s, 1 H), 7.80 (d, J ϭ 5.3 Hz, 1 H), 8.07 (s, 1 H) ppm. 13C
NMR (CDCl3): δ ϭ 19.9, 55.8, 56.1, 103.8, 104.4, 121.4, 122.3,
122.9, 124.3, 124.7, 128.3, 133.4, 147.3, 148.8, 149.1, 163.4 ppm.
C16H13NO2S2 (315.41): calcd. C 60.93, H 4.15, N 4.44; found C
61.09, H 4.32, N 4.14.
5,6,10-Trimethoxy-2-methylphenanthro[9,10-d]thiazole (24b): Phen-
anthro-thiazole 24b was obtained by the typical procedure, from
thiazole 23b in 77% yield. M.p. 193Ϫ196 °C (hexanes). H NMR
(CD3COCD3): δ ϭ 2.93 (s, 3 H), 3.99 (s, 3 H), 4.03 (s, 3 H), 4.08
(s, 3 H), 7.25 (dd, J ϭ 9.3, 2.4 Hz, 1 H), 7.33 (d, J ϭ 2.4 Hz, 1 H),
8.23 (s, 1 H), 8.15 (s, 1 H), 8.69 (d, J ϭ 9.3 Hz, 1 H) ppm. 13C
NMR (CDCl3): δ ϭ 21.1, 55.4, 55.8, 56.1, 103.3, 104.7, 106.4,
116.1, 121.7, 122.4, 124.7, 127.5, 148.5, 148.9, 149.1, 157.8 ppm.
C19H17NO3S (339.41): calcd. C 67.24, H 5.05, N 4.13; found C
67.44, H 5.00, N 4.21.
1
8,9-Dimethoxy-2-methylthieno[2,3-a]naphtho[4,3-d]thiazole (31d):
Thiazole 31d was obtained by the typical procedure, from thiazole
1
30d in 81% yield. M.p. 156Ϫ159 °C (hexanes). H NMR (CDCl3):
δ ϭ 2.96 (s, 3 H), 4.08 (s, 3 H), 4.13 (s, 3 H), 7.40 (s, 1 H), 7.47 (d,
J ϭ 5.5 Hz, 1 H), 7.53 (d, J ϭ 5.5 Hz, 1 H), 8.14 (s, 1 H) ppm.
13C NMR (CDCl3): δ ϭ 19.9, 56.0, 56.2, 103.7, 104.6, 120.9, 122.5,
123.4, 125.0, 125.6, 129.1, 134.2, 147.2, 149.3, 149.4, 164.0 ppm.
C16H13NO2S2 (315.41): calcd. C 60.93, H 4.15, N 4.44; found C
61.00, H 4.18, N 4.49.
5,6-Dimethoxy-2-methylphenanthro[9,10-d]thiazole (24c): Phen-
anthro-thiazole 24c was obtained by the typical procedure, from
thiazole 23c in 74% yield. M.p. 171Ϫ174 °C (hexanes). H NMR
(CDCl3): δ ϭ 2.95 (s, 3 H), 4.13 (s, 3 H), 4.15 (s, 3 H), 7.52Ϫ7.63
(m, 2 H), 7.92 (dd, J ϭ 7.0, 1.7 Hz, 1 H), 7.99 (s, 1 H), 8.16 (s, 1
H), 8.54 (dd, J ϭ 8.5, 1.0 Hz, 1 H) ppm. 13C NMR (CDCl3): δ ϭ
20.0, 55.9, 56.1, 103.7, 104.7, 122.9, 123.0, 125.9, 123.9, 126.2,
126.3, 128.1, 129.0, 148.1, 149.0, 149.6, 165.1 ppm. C18H15NO2S
(309.38): calcd. C 69.88, H 4.89, N 4.53; found C 69.81, H 4.72,
N 4.29.
1
5,9,10-Trimethoxy-2-methylbenzo[f]thiazolo[4,5-h]quinoline (31g):
Benzoquinoline 31g was obtained by the typical procedure, from
thiazole 30g as an oil, in 78% yield after purification by column
chromatography (hexanes/EtOAc, 1:1). 1H NMR (CDCl3): δ ϭ
2.98 (s, 3 H), 4.12 (s, 3 H), 4.13 (s, 3 H), 4.14 (s, 3 H), 7.02 (d, J ϭ
8.9 Hz, 1 H), 7.82 (s, 1 H), 8.12 (s, 1 H), 8.68 (d, J ϭ 8.9 Hz, 1 H)
ppm. 13C NMR (CDCl3): δ ϭ 20.3, 53.6, 56.0, 56.2, 103.0, 104.6,
110.8, 118.2, 121.7, 123.7, 134.0, 141.1, 149.2, 149.5, 162.2, 168.1
ppm. HRMS calcd. for C18H16N2O3S 340.0882, found 340.0893.
5,6-Dimethoxy-2-methyl-9-nitrophenanthro[9,10-d]thiazole
(24d):
Phenanthro-thiazole 24d was obtained by the typical procedure,
from thiazole 23d in 63% yield. M.p. 244Ϫ247 °C (hexanes). 1H
NMR (CDCl3): δ ϭ 3.00 (s, 3 H), 4.17 (s, 3 H), 4.19 (s, 3 H), 7.96
(s, 1 H), 7.98 (d, J ϭ 9.0 Hz, 1 H), 8.17 (s, 1 H), 8.34 (d, J ϭ 9.0
Hz, 1 H), 9.40 (s, 1 H) ppm. 13C NMR (CDCl3): δ ϭ 20.3, 53.4,
56.3, 103.8, 105.1, 114.0, 119.7, 120.1, 123.6, 124.2, 127.5, 127.8,
145.3, 150.8, 163.4, 172.7 ppm. C18H14N2O4S (354.38): calcd. C
61.01, H 3.98, N 7.91; found C 61.11, H 3.82, N 7.81.
6,9,10-Trimethoxy-2-methylbenzo[h]thiazolo[5,4-f]quinoline (31h):
Benzoquinoline 31h was obtained by the typical procedure, from
thiazole 30h in 86% yield. M.p. 203Ϫ206 °C (Et2O). 1H NMR
(CDCl3): δ ϭ 2.94 (s, 3 H), 4.13 (s, 3 H), 4.15 (s, 3 H), 4.18 (s, 3
H), 6.95 (d, J ϭ 8.7 Hz, 1 H), 8.02 (d, J ϭ 8.7 Hz, 1 H), 8.06 (s, 1
H), 8.52 (s, 1 H) ppm. 13C NMR (CDCl3): δ ϭ 20.1, 53.3, 55.8,
56.2, 103.9, 104.9, 111.2, 116.2, 124.4, 124.7, 136.1, 142.0, 146.4,
148.9, 150.7, 161.6, 164.4 ppm. C18H16N2O3S (340.40): calcd. C
63.51, H 4.74, N 8.23; found C 63.41, H 4.67, N 8.21.
2-Amino-5,6,9,10-tetramethoxyphenanthro[9,10-d]thiazole
(24g):
Phenanthro-thiazole 24g was obtained by the typical procedure,
from thiazole 23g in 83% yield. M.p. 95Ϫ97 °C (hexanes). 1H
NMR (CDCl3): δ ϭ 4.05 (s, 3 H), 4.11 (s, 3 H), 4.12 (s, 3 H), 4.13
(s, 3 H), 5.25 (br. s, 2 H), 6.99 (s, 1 H), 7.79 (s, 1 H), 7.81, (s, 1 H),
7.92 (s, 1 H) ppm. 13C NMR (CDCl3): δ ϭ 56.0, 56.1, 103.4, 104.2,
104.7, 104.9, 121.4, 121.5, 123.6, 147.9, 148.8, 148.9, 149.1, 164.8
ppm. C19H18N2O4S (370.42): calcd. C 61.61, H 4.90, N 7.56; found
C 61.51, H 4.68, N 7.41.
Acknowledgments
Financial support from the University of the Basque Country
(UPV 170.310-G37/98) and the Basque Government (PI 53/96) is
´
gratefully acknowledged. The Ministerio de Educacion y Cultura
Eur. J. Org. Chem. 2002, 2126Ϫ2135
2133

´
´
I. Moreno, I. Tellitu, E. Domınguez, R. SanMartın
FULL PAPER
R. Hamada, H. Tohma, T. Takada, J. Org. Chem. 1998, 63,
(Spain) is also acknowledged for a fellowship granted to I. M. and
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Eur. J. Org. Chem. 2002, 2126Ϫ2135

A Simple Route to New Phenanthro- and Phenanthroid-Fused Thiazoles
FULL PAPER
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[23]
Compound 24f was detected by MS, but not isolated. The ac-
tual structure (a priori, two regioisomers can be formed) could
not be fully established. Compound 24f is represented as the
isomer resulting from a para interaction.
Perkin Trans. 1 1997, 3071Ϫ3080.
[27]
In contrast, a radical approach to methoxybenzoquinolines
from styrylpyridines resulted in the formation of a 1:1 mixture
of regioisomers: D. C. Harrowven, M. I. T. Nunn, Tetrahedron
Lett. 1998, 39, 5875Ϫ5876. An improvement of this methodo-
logy has recently been published: D. C. Harrowven, M. I. T.
Nunn, N. J. Blumire, D. R. Fenwick, Tetrahedron Lett. 2000,
41, 6681Ϫ6683.
[24] [24a]
The regioselectivity obtained is in agreement with electron
density calculations from data provided by the ESR spectra of
various methoxylated benzenes, see: A. Zweig, W. G. Hodgson,
W. H . Ju ra , J. Am. Chem. Soc. 1964, 86, 4124Ϫ4129; A. Zweig,
[28]
[29]
J. E. Lehnsen, M. A. Murray, J. Am. Chem. Soc. 1963, 85,
For General Procedures see ref.[8d]
[24b]
´
3933Ϫ3936.
A steric contribution to the control of the re-
A. Ronlan, O. Hammerich, V. D. Parker, J. Am. Chem. Soc.
gioselectivity in this type of reaction has also been proposed.
1973, 95, 7132Ϫ7138.
[30]
See ref.[4a]
The mass spectrometry data (low or high resolution) for dimers
12 and 13 were impossible to collect under a variety of column
conditions. The dimeric nature of the structures has been pro-
posed on the basis of NMR studies. We have isolated, fully
characterized and published similar dimers in a related work
(ref.[8a]), observing completely analogous behaviour.
[25] [25a]
For the synthesis of 29b see: F. K. Sheffy, J. P. Godschalx,
[25b]
J. K. Stille, J. Am. Chem. Soc. 1984, 106, 4833Ϫ4840.
For
the synthesis of 29d see: M. S. Cooper, R. A. Fairhurst, H.
[25c]
Heany, R. F. Wilkins, Tetrahedron 1989, 45, 1155Ϫ1166.
For the synthesis of 29e and 29f see: Y. Yamamoto, A. Yanagi,
[25d]
[31]
´ ´
E. Domınguez, E. Martınez de Marigorta, R. Olivera, R. San-
´
Martın, Synlett 1995, 955Ϫ956.
Chem. Pharm. Bull. 1982, 30, 1731Ϫ1737.
For the syn-
thesis of 29g see: E. V. Dehmlov, A. Sleegers, Liebigs Ann.
[25e]
Chem. 1992, 953Ϫ959.
For the synthesis of 29h see: M. P.
Received January 29, 2002
[O02001]
Maguirre, K. R. Sheets, K. Mcvety, A. P. Spada, J. Med. Chem.
Eur. J. Org. Chem. 2002, 2126Ϫ2135
2135