A domino annulation reaction under Willgerodt-Kindler conditions

Article abstract of DOI:10.1021/jo8005705

(Chemical Equation Presented) Butanone side chains at arenes and hetarenes, efficiently introduced by a Heck-type reaction, are transformed to annulated thieno[3,2-b]thiophenes in a domino redox process under Willgerodt-Kindler conditions. A nucleophilic aromatic substitution with an intermediary thioenolate is a reasonable key step of this process.

Full text of DOI:10.1021/jo8005705

A Domino Annulation Reaction under Willgerodt-Kindler
Conditions
Daniel Kadzimirsz,† Daniel Kramer,† Lertnarong Sripanom,† Iris M. Oppel,†
Pawel Rodziewicz,‡ Nikos L. Doltsinis,‡,§ and Gerald Dyker*,†
Faculty of Chemistry & Biochemistry, Ruhr-UniVersita¨t Bochum, UniVersita¨tsstrasse 150,
D-44780 Bochum, Germany, Lehrstuhl fu¨r Theoretische Chemie, Ruhr-UniVersita¨t Bochum,
D-44780 Bochum, Germany, and Department of Physics, King’s College London, Strand,
London WC2R 2LS, United Kingdom
gerald.dyker@ruhr-uni-bochum.de
ReceiVed March 20, 2008
Butanone side chains at arenes and hetarenes, efficiently introduced by a Heck-type reaction, are
transformed to annulated thieno[3,2-b]thiophenes in a domino redox process under Willgerodt-Kindler
conditions. A nucleophilic aromatic substitution with an intermediary thioenolate is a reasonable key
step of this process.
SCHEME 1. Monoannulation Reaction under
Introduction
Willgerodt-Kindler Conditions According to Neckers et al3
One can hardly imagine an experiment which appears more
alchemy-like than a Willgerodt-Kindler reaction:1 elemental
sulfur is directly applied as reagent, developing hydrogen sulfide
while being heated up in a mixture with the substrate and an
additional amine. On the other hand, the underlying mechanism
is far from being completely understood, certainly representing
an extremely complex redox cascade. Presumably, both radicals
and anionic nucleophiles have to be discussed as reactive
intermediates. We became interested in studying domino
processes under Willgerodt-Kindler conditions as powerful
methods for CH transformation.2,3 Recently, Neckers et al.4
reported a new entry to functionalized benzothiophenes 2
(Scheme 1), which profits from the easy access to the acetyl-
substituted substrates 1. Obviously, the acetyl group undergoes
several redox steps, finally ending up as C2-unit within the
thiophene moiety after an intramolecular nucleophilic aromatic
substitution with an intermediary thiolate as key step.
We wish to report on a related domino annulation reaction,
which oxidatively transforms up to six CH bonds, giving rise
to tri- and tetracyclic ring systems with a thieno[3,2-b]thiophene
moiety.5 This process is both of mechanistic interest and of
preparative importance since the resulting highly functionalized
polyheterocyclic systems with flat and at the same time slightly
curved topology can be regarded as potential DNA intercalators.6
Results and Discussion
The butanone chain of our model compounds is readily
introduced in good to excellent yields by a Heck-type reaction
of aryl iodides 3 with allylic alcohol 4 (Scheme 2),7 providing
† Faculty of Chemistry & Biochemistry, Ruhr-Universita¨t Bochum.
‡ Lehrstuhl fu¨r Theoretische Chemie, Ruhr-Universita¨t Bochum.
§ King’s College London.
(1) (a) Willgerodt, C. Ber. Dtsch. Chem. Ges. 1888, 21, 534–536. (b) Kindler,
K. Liebigs Ann. Chem 1923, 431, 187–207.
(5) Kadzimirsz, D. Ph.D. Thesis, Bochum, 2003.
(6) (a) Audoux, J.; Achelle, S.; Turck, A.; Marsais, F.; Ple, N. J. Heterocycl.
Chem. 2006, 43, 1497–1503. (b) Xu, Y.; Qu, B.; Qian, X.; Li, Y. Bioorg. Med.
Chem. Lett. 2005, 15, 1139–1142.
(2) Handbook of C-H Transfomations; Dyker, G., Ed.; Wiley-VCH:
Weinheim, Germany, 2005.
(3) Dyker, G.; Kadzimirsz, D. Eur. J. Org. Chem. 2003, 3167–3172.
(4) Solovyev, A. Y.; Androsov, D. A.; Neckers, D. C. J. Org. Chem. 2007,
72, 3122–3124.
(7) (a) Dyker, G.; Tho¨ne, A. J. Prakt. Chem. 1999, 341, 138–141. (b) Dyker,
G.; Grundt, P.; Markwitz, H.; Henkel, G. J. Org. Chem. 1998, 63, 6043–6047,
and references cited therein.
4644 J. Org. Chem. 2008, 73, 4644–4649
10.1021/jo8005705 CCC: $40.75 2008 American Chemical Society
Published on Web 05/28/2008

A Domino Annulation Reaction
SCHEME 2. Heck-Type Synthesis of 2-Arylbutanones 5a
SCHEME 3. Products from the Transformation of
2-Arylbutanones 5 under Willgerodt-Kindler Reaction
Conditionsa
a Conditions: (a) 5% Pd(OAc)2, LiCl, Et3N, DMF, 3 days at 120 °C.
a C4-unit for the Willgerodt-Kindler redox process. In this
process, the Pd catalyst selectively reacts with the iodoarenes
in the presence of chloro substituents. Obviously, also nitro
groups are tolerated.
In our first attempt for a Willgerodt-Kindler reaction with
an arylbutanone 5, the aryl group remained unaffected; as
anticipated, the 2-chlorophenyl group of 5a was inert toward
nucleophilic aromatic substitution even under the relatively harsh
reaction conditions A (morpholine, sulfur, 6 h at 130 °C without
additional solvent). However, two products were isolated in
satisfactoryyield:thethioamide6aasordinaryWillgerodt-Kindler
product, and the aminothiophene 7a, a type of product frequently
observed earlier (Scheme 3).8 An additional cyano group in the
para-position obviously sufficiently activates: Willgerodt-Kindler
conditions transform benzonitrile 5b to a rather complex product
mixture, from which we were able to isolate the highly
functionalized thieno[3,2-b]benzothiophene 8b as a tricyclic ring
system, resulting from a domino annulation process. Therefore,
we tested related model compounds with acceptor-substituted
aryl chlorides, hoping that this process is generally applicable.
The 4-chloropyridine moiety of 5c is also electrophilic enough
for intramolecularly intercepting thiolate intermediates of the
Willgerodt-Kindler reaction, thus leading to the isomeric
tricyclic arenes 8c and 9c in rather good yields. Both spectro-
scopically characterized regioisomers were distinguished by
NMR spectroscopy: in the HMBC spectrum of the major
regioisomer, the thiophenyl hydrogen is correlated with two
quaternary carbons via two bonds (2J-correlation) and with a
third quaternary carbon via three bonds (3J-correlation), being
in accord with structure 8c. Moreover, for this isomer, a signal
at 162.9 ppm is registered in the 13C NMR spectrum, typical
for the N,S-acetal moiety. Regioisomers analogous to 9c were
a Morpholine, sulfur, 6 h at 130 °C (see Experimental Section: conditions
A, reducing nitro groups!); a: moderate reaction conditions; morpholine,
sulfur, diluted with DMF, shorter reaction time, 12 min at 100 °C (see
Experimental Section: conditions B).
1
also detected in the H NMR spectra of the crude products of
the reactions with substrates 5b and 5e but could not be isolated
as pure samples.
one hydrogen bond might be regarded as ordinary linear— also
typical for pyridine water complexes10— the other one is somewhat
unusual: the OH bond points perpendicularly toward the sp2-hybrid
orbital of the free electron pair of the next quinoline nitrogen.
According to DFT calculations of the infinite periodic crystal, this
arrangement represents at least a local energy minimum, which
allows two positively polarized hydrogen atoms to simultaneously
coordinate to one free electron pair; with fixed positions of the
hetarene atoms, the position of the water molecule does not change
In contrast to a chloride group, the methoxy group of substrate
5d is inert under the reaction conditions. Therefore, no annu-
lation reaction takes place and the usual thioamide 6d is the
result. Consequently, we concentrated on other aryl chlorides
for our test reactions. As anticipated, 4-chloroquinoline 5e was
transformed to the tetracyclic annulation product 8e, which could
be of interest as a potential DNA intercalator.6
We succeeded in growing single crystals of the monohydrate
of 8e. According to the X-ray crystal analysis, the tetracyclic
hetarenes are stacked at a separation of 3.572(5) Å and, in addition,
cramped by hydrogen bonds to the crystal water molecules. While
(9) X-ray crystal structure analysis of 8e: Pale orange prism, 0.32 × 0.28 ×
0.23 mm3, monoclinic, P21/n, a ) 17.056(2), b ) 3.9938(5), c ) 23.829(3) Å,
ꢀ ) 98.49(1)°, V ) 1605.4(3) Å3, Fcalc ) 1.483 gcm-3, 2θmax ) 50.50°, λ )
0.71073 Å, T ) 113 K, 8141 measured reflections, 2892 independent reflections
(Rint ) 0.0368), 2084 observed reflections (I > 2σ(I)), µ ) 0.345 mm-1, 224
parameters, R1 (I > 2σ(I)) ) 0.0354, wR2 (all data) ) 0.0846, max/min residual
(8) (a) Asinger, F.; Saus, A.; Mayer, A. Monatsh. Chem. 1967, 98, 825–
836. (b) Xu, Y.; Qu, B.; Qian, X.; Li, Y. Bioorg. Med. Chem. Lett. 2005, 15,
1139–1142.
electron density 0.301/-0.287 eÅ-3
.
J. Org. Chem. Vol. 73, No. 12, 2008 4645

Kadzimirsz et al.
TABLE 1. Bond Lengths and Angles Characterizing the Bridging
Water Molecule between the Nitrogen Atoms of the Two Tetracyclic
Hetarene Layersa
distance (Å)
R(N· · ·Hr)
R(OHr)
R(O· · ·N)
R(N· · ·Hl)
R(OHl)
1.797
0.980
2.749
1.703
1.000
2.699
R(O· · ·N)
angle (deg)
O-Hr-N
O-Hl-N
Hr-O-Hl
C-N-Hl
C-N-Hr
162.87
173.44
106.45
159.34
113.15
a O refers to the oxygen atom of the H2O molecule, H1 and Hr are its
left and right (in the orientation shown in Figure 1) hydrogen atoms, N
is the hetarene nitrogen site bridged by the H2O molecule, and C is the
carbon atom which lies opposite to N in the hetarene six-membered
ring.
thioamide, we obtained a good yield of the morpholino
thiophene 7f′ in this case. Simultaneously, the nitro group is
reduced, resulting in the aniline function of 7f′ and demonstrat-
ing that Willgerodt-Kindler conditions are both oxidative and
reductive. With the activating para-nitro group of 5g, the
synthesis of the corresponding tricyclic hetarene 8g′ is success-
ful, despite the reduction of the nitro group, which must have
taken place after the nucleophilic cyclization. Indeed, under
moderate reaction conditions (diluted with DMF as solvent and
just 100 °C for 12 min), we were able to isolate the monocy-
clization product 10g with an intact11 nitro group. According
to orientating experiments, this type of acetyl benzothiophenes
can indeed be oxidatively cyclized under the rather harsh
reaction conditions A. Therefore, we regard 10g as an inter-
mediary product on the way to tricycle 8g′.
FIGURE 1. Structure of the monohydrate of 8e in the crystal9 and
calculated electron localization function (ELF). Shown are three periodic
layers of the tetracyclic hetarene bridged by a water molecule whose
position and structure are detailed in Table 1. For further details
concerning the electronic structure, see the text.
qualitatively during geometry optimization. Figure 1 illustrates the
electronic structure of the crystal in terms of the electron localization
function (ELF). Focusing on the water molecule bridging the two
nitrogen hetarene atoms, we can clearly see the two lone pairs on
the water oxygen and the rather diffuse lone pair on nitrogen. In
addition, on each of the water hydrogen atoms, there is a basin of
attraction whose shape is typical of hydrogen bonds. The nitrogen
lone pair is seen to lean toward the closer water hydrogen (at a
calculated distance of R(N· · ·Hl) ) 1.70 Å; for details about the
notation, see Table 1). The corresponding hydrogen bond angle
O-Hl-N is 173.4°, further underlining the strength of this nearly
linear H bond. As a measure for the orientation of the H bond
with respect to the hetarene layer, we use the C-N-H1 angle
between the carbon atom opposite the nitrogen in the six-membered
ring, the nitrogen atom, and the left (in Figure 1) water hydrogen
atom. The value of 159.3° indicates that this stronger hydrogen
bond essentially lies in the plane of the hetarene molecule. The
other hydrogen bond is somewhat longer (the calculated distance
is R(N· · ·Hr) ) 1.80 Å). It is somewhat further from linearity
having a O-Hr-N angle of 162.9° and is oriented nearly
perpendicular to the hetarene layer at a C-N-Hr angle of 113.2°,
explaining its weakness relative to the first H bond. The geometrical
data describing the bridging water molecule shown in Figure 1
are summarized in Table 1.
Our general mechanistic rationale12 is depicted in Scheme
4: a suitable leaving group X and an activating, electron-
withdrawing functional group G are prerequisite for the
domino annulation process to take place. The first sulfur atom
is oxidatively introduced, presumably via intermediary enam-
ines, to give thioketones 12, whose corresponding thioenolate
is prone to cyclize by nucleophilic aromatic substitution, thus
giving rise to acetyl benzothiophenes 13 (or the corresponding
enamine) and explaining the isolation of 10g as result under
moderate reaction conditions. Subsequent studies should test
the reactivity of acetyl benzothiophenes 13 under forcing
Willgerodt-Kindler conditions in detail, trying to verify the
transformation to 14 via thiols 15 and 16 on a preparative
scale, while we could already prove the validity of this
working hypothesis by an orientating small scale test with
the parent acetyl benzothiophene.
In conclusion, we have developed a domino process under
Willgerodt-Kindler conditions, which transforms a simple
butanone side chain of suitable functionalized arenes and
(11) Mayer, R.; Viola, H.; Reichert, J.; Krause, W. J. Prakt. Chem. 1978,
320, 313–323.
(12) (a) Darabi, H. R.; Aghapoor, K. European Symposium on Organic
Chemistry, 13th ed.; Cavtat-Dubrovnik, Croatia, 2003, 25-28. (b) Kanyonyo,
M. R.; Ucar, H.; Isa, M.; Carato, P.; Lesieut, D.; Renard, P.; Poupaert, J. H.
Bull. Soc. Chim. Belg. 1996, 105, 17–22. (c) DeTar, D. F.; Carmack, M. J. Am.
Chem. Soc. 1946, 68, 2025–2029. (d) King, J. A.; McMillan, F. H. J. Am. Chem.
Soc. 1947, 69, 1207–1208. (e) Carmack, M. J. Heterocycl. Chem. 1989, 26,
1319–1323. (f) Asinger, F.; Saus, A.; Mayer, A. Monatsh. Chem. 1967, 98, 825–
836.
With a nitro group in the meta-position to the chloride, such
as in substrate 5f, the nucleophilic aromatic substitution is of
course not favored; however, instead of the usually major
(10) Schluecker, S.; Singh, R. K.; Asthana, B. P.; Popp, J.; Kiefer, W. J.
Phys. Chem. A 2001, 105, 9983–9989.
4646 J. Org. Chem. Vol. 73, No. 12, 2008

A Domino Annulation Reaction
SCHEME 4. Mechanistic Rationale for the Domino
Willgerodt-Kindler Reaction with 4-(2-Chlorophenyl)butan-
2-one (5a). A quantity of 274 mg (1.5 mmol) of butanone 5a was
transformed according to the general procedure (Method A). The
crude product was fractionated by flash chromatography (silica,
methyl tert-butyl ether/petrol ether 1:8): 1st Fraction (Rf ) 0.56):
83 mg (20 %) of N-[5-(2-chlorophenyl)thiophen-2-yl]morpholine
(7a) as colorless oil: IR (KBr) ν˜ ) 2964 cm-1 (m), 2864 (m), 1546
(w), 1492 (s), 1447 (m), 1377 (m), 1264 (m), 1220 (m), 1214 (m),
1032 (m), 895 (m), 756 (s), 617 (m); 1H NMR (400 MHz, CDCl3)
δ ) 3.18 ppm (m, 4H), 3.85 (m, 4H), 6.13 (d, J ) 4.0 Hz, 1H),
7.13 (d, J ) 4.0 Hz, 1H), 7.14 (m, 1H), 7.23 (m, 1H), 7.41 (dd, J
) 8.0, 1.5 Hz, 1H), 7.46 (dd, J ) 7.8, 2.0 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ ) 51.2 ppm (t), 66.4 (t), 105.2 (d), 126.4 (s), 126.9
(d), 127.1 (d), 127.5 (d), 130.5 (d), 130.6 (d), 131.6 (s), 133.4 (s),
159.8 (s); MS (EI, 70 eV) m/z (%) ) 279 (100) [M+], 221 (36),
192 (3), 186 (17), 149 (10), 86 (24); HRMS calcd for C14H14NOSCl
279.04845 g/mol), found 279.01912 g/mol. 2nd Fraction (Rf )
0.35): 248 mg (59 %) of N-(4-(2-chlorophenylthiobutyl)morpholine
(6a) as colorless oil; IR (KBr) ν˜ ) 2968 cm-1 (m), 2860 (m), 1471
(s), 1443 (m), 1281 (s), 1254 (m), 1226 (m), 1115 (s), 1022 (m),
882 (m), 764 (s), 676 (m); 1H NMR (200 MHz, CDCl3) δ )
1.92-2.12 ppm (m, 2H), 2.80-2.94 (m, 4H), 3.61-3.71 (m, 4H),
3.74-3.79 (m, 2H), 4.33 (t, J ) 4.9 Hz, 2H), 7.10-7.22 (m, 3H),
7.28-7.39 (m, 1H); 13C NMR (50 MHz, CDCl3) δ ) 28.9 ppm
(t), 32.9 (t), 49.8 (t), 49.9 (t), 66.4 (2t), 126.9 (d), 127.6 (d), 129.5
(d), 130.5 (d), 133.7 (s), 138.7 (s), 203.0 (s); MS (EI, 70 eV) m/z
(%) ) 283 (22) [M+], 248 (100), 158 (11), 145 (56), 125 (11),
112 (35), 86 (50), 43 (42); HRMS calcd for C14H18NOSCl
283.07976 g/mol, found 283.08055 g/mol.
Willgerodt-Kindler Reaction with 4-Chloro-3-(3-oxobutyl)-
benzonitrile (5b). A quantity of 207 mg (1.00 mmol) of butanone
5b was transformed according to the general procedure (Method
A, 14 h reaction time at 130 °C). The crude product was fractionated
by gradient chromatography (silica, petrol ether/methyl tert-butyl
ether in the ratios of 95:5, 90:10, 80:20, 50:50, 20:80, and 0:100).
The 90:10 fraction was concentrated, further purified by flash
chromatography (silica, petrol ether/ethyl acetate 5:1, Rf ) 0.16),
and recrystallized (from dichloromethane/pentane 1:3) to give 45
mg (15%) of 2-morpholin-4-ylthieno[3,2-b][1]benzothiophene-7-
carbonitrile (8b) as yellow crystals with mp 205 °C: IR (KBr) ν˜ )
2928 cm-1 (w), 2216 (m), 1521 (s), 1473 (m), 1444 (m), 1381
(w), 1267 (w), 1221 (w), 1113 (m), 924 (w); UV/vis (dichlo-
romethane) λmax (log ε) ) 217 nm (3.43), 232 (3.85), 281 (4.11),
288 (4.12), 333 (4.09); 1H NMR (400 MHz, CDCl3) δ ) 3.25 ppm
(t, J ) 4.8 Hz, 4H), 3.89 (t, J ) 4.8 Hz, 4H), 6.34 (s, 1H), 7.42
(dd, J ) 8.3, 1.5 Hz, 1H), 7.84 (d, J ) 8.3 Hz, 1H), 7.88 (d, J )
1.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ ) 50.7 ppm (t), 66.0
(t), 97.3 (s), 108.03 (s), 119.3 (s), 120.6 (d), 122.7 (d), 124.0 (d),
124.5 (d), 133.5 (s), 139.4 (s), 144.4 (s), 162.9 (s); MS (EI, 70 eV)
m/z (%) ) 301 (19), 300 (100) [M+], 258 (29), 243 (22), 242 (43),
228 (9), 215 (20), 202 (6), 170 (14), 121 (12); HRMS calcd for
C15H12N2OS2 300.03909, found 300.03955.
Annulation Process (Intermediary Enamines Are Omitted)a
a X ) leaving group, G ) functional group activating for nucleophilic
aromatic substitution.
hetarenes into at least tricyclic annulated thieno[3,2-b]-
thiophenes. Mechanistic considerations allow one to identify
other types of substrates as promising candidates for oxidative
heteroannulation reactions, which are currently under investigation.
Experimental Section
General Remarks: Melting points are uncorrected. 1H and 13
C
NMR spectra were recorded by use of CDCl3 as solvent and TMS
as the internal standard. Procedures for the synthesis of arylbu-
tanones 5 by Heck reaction are provided in the Supporting
Information.
Willgerodt-Kindler Reaction with 4-Arylbutan-2-ones (5),
General Procedures. Method A. A mixture of 1.0-1.5 mmol of
the 4-arylbutan-2-one (5; see Supporting Information), 10 mL of
morpholine, and 190 mg (6.0 mmol) of sulfur in a screw-capped
tube was heated under stirring for 6 h at 130 °C. The excess
morpholine was removed in vacuo in the Kugelrohr oven, and the
residue was solubilized in 10 mL of methyl tert-butyl ether to be
filtered through a small pad of silica (3 g). After concentrating in
vacuo at the rotatory evaporator, the residue was fractionated by
flash chromatography. This method usually produces various
amounts of 1-morpholin-4-ylethanthione13 (and related compounds
such as 1,2-dimorpholin-4-ylethane-1,2-dithione14) as solid yellow
1
to orange byproduct: H NMR (200 MHz, CDCl3) δ ) 2.67 ppm
Willgerodt-Kindler Reaction with 4-[4-Chloropyridin-3-
yl]butan-2-one (5c). A quantity of 275 mg (1.5 mmol) of pyridine
derivative 5c was transformed according to the general procedure
(Method A, 6 h at 130° C). The crude product was fractionated by
flash chromatography (silica, methyl tert-butyl ether). 1st Fraction
(Rf ) 0.31): 92 mg (26 %) of 1-morpholin-4-yl-3,8-dithia-5-
azacyclopenta[a]indane (9c) as a yellow solid with mp 144° C; IR
(KBr) ν˜ ) 3112 cm-1 (w), 2927 (s), 2843 (m), 1518 (s), 1451 (m),
1383 (m), 1265 (m), 1117 (s), 814 (w), 717 (m), 675 (w); UV
(acetonitrile) λmax (log ε) ) 347 nm (3.64, br), 307 (4.01), 304
(s, 3H, H-2), 3.75-3.81 (m, 6H), 3.80 (t, J ) 5.3 Hz, 2H); 13C
NMR (50 MHz, CDCl3) δ ) 32.1 ppm (q), 49.6 (t), 50.2 (t), 66.2
(t), 66.4 (t), 199.0 (s). Method B: A mixture of 1.0 mmol of
4-arylbutan-2-one (5), 10 mL of morpholine, 5 mL of DMF, and
190 mg (6.0 mmol) of sulfur was heated under argon for 12 min at
130 °C. The excess morpholine, as well as the solvent DMF, was
removed in vacuo in the Kugelrohr oven. The residue was
solubilized in 10 mL of methyl tert-butyl ether to be filtered through
a small pad of silica (3 g). After concentrating in vacuo at the
rotatory evaporator, the residue was fractionated by flash chro-
matography.
1
(4.01), 300 (4.01); H NMR (400 MHz, CDCl3) δ ) 3.22 ppm (t,
J ) 4.5 Hz, 4H), 3.92 (t, J ) 4.5 Hz, 4H), 6.54 (s, 1H, H-2), 7.78
(d, J ) 5.5 Hz, 1H), 8.48 (d, J ) 5.5 Hz, 1H), 9.14 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ ) 50.8 ppm (t), 66.7 (t), 106.0 (d),
118.5 (d), 129.5 (s), 131.2 (s), 132.3 (s), 142.7 (d), 143.3 (d), 145.4
(s), 149.9 (s); MS (EI, 70 eV) m/z (%) ) 276 (100) [M+], 261 (9),
218 (74), 204 (7), 191 (23), 149 (28), 109 (14), 57 (36); HRMS
(13) (a) Heyde, C.; Zug, I.; Hartmann, H. Eur. J. Org. Chem. 2000, 3273–
3278. (b) Skramstad, J.; Chaudhry, M. S.; Garvang, A. Acta Chem. Scand. 1984,
B38, 509–511. (c) Fjeldstad, P. E.; Heim, K. Acta Chem. Scand. 1976, B30,
375–376.
(14) Hoppe, H.; Hartke, K. Arch. Pharm. 1975, 308, 526–541.
J. Org. Chem. Vol. 73, No. 12, 2008 4647

Kadzimirsz et al.
calcd for C13H12N2OS2 276.03894 g/mol, found 276.03948 g/mol.
2nd Fraction (Rf ) 0.22): 163 mg (46 %) of 2-morpholin-4-yl-
3,8-dithia-5-azacyclopenta[a]indane (8c) as yellow solid with mp
182 °C; IR (KBr) ν˜ ) 3112 cm-1 (w), 2927 (s), 2843 (m), 1518
(s), 1451 (m), 1383 (m), 1265 (m), 1117 (s), 814 (w), 717 (m),
675 (w); UV (acetonitrile) λmax (log ε) ) 358 nm (4.21, br), 306
(EI, 70 eV) m/z (%) ) 294 (100) [M+], 279 (10), 236 (67), 164
(13). Anal. Calcd for C14H15ClN2OS (294.80) +1 H2O: C, 53.76;
H, 5.48; N, 8.96. Found: C, 54.42; H, 5.06; N, 8.72 (a slight
deviation because the water content of this sensitive hygroscopic
oil is not exactly 1 equiv).
Willgerodt-Kindler Reaction with 4-(2-Chloro-5-nitrophe-
nyl)butan-2-one (5g). A quantity of 227 mg (1.00 mmol) of
butanone 5g was transformed according to the general procedure
(Method A, 6 h reaction time at 130 °C). The crude product was
fractionated by gradient chromatography (silica, dichloromethane/
methyl tert-butyl ether in the ratios of 100:0, 90:10, 80:20, 50:50,
20:80, 0:100, 100 mL of each). The 90:10 fraction was purified
once again by flash chromatography (TLC: silica, petrol ether/
methyl tert-butyl ether, 1:1; Rf ) 0.11). After evaporation of the
solvent, the residue was recrystallized twice (from dichloromethane/
pentane 1:3) to give 63 mg (22%) of 7-amino-2-(morpholin-4-
yl)thieno[3,2-b][1]benzothiophene (8g′) as yellow crystals with mp
205 °C: IR (KBr) ν˜ ) 3418 cm-1 (s), 3354(s), 2826 (m), 1617
(w), 1593 (m), 1523 (s), 1485 (w), 1444 (w), 1428 (m), 1215 (w),
1116 (m); UV/vis (dichloromethane) λmax (log ε) ) 215 nm (3.59),
232 (3.96), 259 (4.09), 327 (4.15); 1H NMR (200 MHz, CDCl3, 25
°C) δ ) 1.53 ppm (s, 2H), 3.18 (t, J ) 4.9 Hz, 4H), 3.85 (t, J )
4.9 Hz, 4H), 6.29 (s, 1H), 6.62 (dd, J ) 8.6, 2.3 Hz, 1H), 6.90 (d,
J ) 2.0 Hz, 1H), 7.50 (d, J ) 8.6 Hz, 1H); MS (EI, 70 eV) m/z
(%) ) 290 (100) [M+], 232 (27), 205 (11), 116 (12); HRMS calcd
for C14H14N2OS2 290.0547, found 290.05515. Alternative Method
B: A quantity of 227 mg (1.00 mmol) of butanone 5g was
transformed according to the general procedure (Method B, 12 min
reaction time at 100 °C). The crude product was fractionated by
flash chromatography (silica, petrol ether/methyl tert-butyl ether,
1:1; Rf ) 0.35, 0.10 (1-morpholinoethanethione13). The fraction
with Rf ) 0.35 was isolated: 50 mg (23%) of 1-(5-nitrobenzo[b-
]thiophen-2-yl)ethanone (10g) as yellow crystals with mp 175-177
°C; IR (KBr) ν˜ ) 3100 cm-1 (w), 1669 (s), 1523 (w), 1505 (m),
1340 (s), 1270 (w), 825 (w), 742 (w); UV/vis (dichloromethane):
λmax (log ε) ) 218 nm (3.10), 222 (3.12), 225 (3.12), 280 (4.01);
1H NMR (200 MHz, CDCl3, 25 °C) δ ) 2.77 ppm (s, 3H), 8.00
(d, J ) 9.1 Hz, 1H), 8.06 (s, 1H), 8.30 (dd, J ) 9.1, 2.3 Hz, 1H),
8.80 (d, J ) 2.3 Hz, 1H); 13C NMR (50 MHz, CDCl3, 25 °C) δ )
26.9 ppm (s), 121.4 (d), 121.6 (d), 123.9 (d), 129.5 (d), 138.9 (s),
145.9 (s), 147.6 (s), 147.8 (s), 191.7 (s); MS (EI, 70 eV) m/z (%)
) 221 (61) [M+], 206 (100), 160 (57), 132 (18), 43 (16); HRMS
calcd for C10H7NO3S 221.01464, found 221.01566.
1
(4.46), 301 (4.45), 299 (4.34), 296 (4.45); H NMR (400 MHz,
CDCl3) δ ) 3.24 ppm (t, J ) 4.8 Hz, 4H), 3.88 (t, J ) 4.8 Hz,
4H), 6.36 (s, 1H), 7.71 (d, J ) 5.5 Hz, 1H), 8.36 (d, J ) 5.5 Hz,
1H), 8.93 (s, 1H); 13C NMR (100 MHz, CDCl3) δ ) 51.1 ppm (t),
66.2 (t), 97.7 (d), 118.3 (d), 119.5 (s), 130.2 (s), 138.1 (s), 141.0
(d), 141.6 (d), 148.2 (s), 162.9 (s); MS (EI, 70 eV) m/z (%) ) 276
(100) [M+], 260 (20), 218 (50), 204 (11), 86 (42); HRMS calcd
for C13H12N2OS2 276.03894 g/mol, found 276.03948 g/mol.
Willgerodt-Kindler Reaction with 4-[4-Methoxypyridin-3-
yl]butan-2-one (5d). A quantity of 270 mg (1.5 mmol) of butanone
5d was transformed according to the general procedure (Method
A). The crude product was purified by flash chromatography (silica,
ethyl acetate/triethylamine 97:3, Rf ) 0.35): 193 mg (46%) of N-(4-
(4-methoxy-pyridin-3-yl)thiobutyl)morpholine (6d) as slightly yel-
low oil; IR (KBr) ν˜ ) 2975 cm-1 (m), 2927 (m), 2862 (m), 1586
(s), 1488 (s), 1448 (m), 1284 (s), 1237 (m), 1192 (m), 1114 (s),
1
1021 (s), 829 (m), 782 (w); H NMR (400 MHz, CDCl3) δ )
1.97-2.05 ppm (m, 2H), 2.70 (t, J ) 7.6 Hz, 2H), 2.86 (m, 2H),
3.64-3.71 (m, 4H), 3.76 (m, 2H), 3.87 (s, 3H), 4.33 (t, J ) 5.0
Hz, 2H), 6.77 (d, J ) 5.5 Hz, 1H), 8.25 (s, 1H), 8.37 (d, J ) 5.5
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ ) 27.2 ppm (t), 28.6 (t),
42.8 (t), 49.9 (t), 50.0 (t), 55.2 (q), 66.4 (t), 66.5 (t), 105.9 (d),
125.3 (s), 149.7 (d), 150.3 (d), 163.8 (s), 203.3 (s); MS (EI, 70
eV) m/z (%) ) 280 (23) [M+], 265 (3), 238 (3), 136 (100), 86
(15), 43 (16); HRMS calcd for C14H20N2O2S 280.12455 g/mol,
found 280.12505 g/mol.
Willgerodt-Kindler Reaction with 4-(4-Chloro-2-methylquin-
olin-3-yl)butan-2-one (5e). A quantity of 250 mg (1.00 mmol) of
butanone 5e was transformed according to the general procedure
(Method A). The crude product was purified by gradient chroma-
tography (silica, dichloromethane/methyl tert-butyl ether in the
ratios of 100:0, 90:10, 80:20, 50:50, 20:80, 0:100; TLC: silica,
methyl tert-butyl ether, Rf ) 0.23): 84 mg (24%) of 10-methyl-2-
N-morpholinothieno[2′,3′:4,5]thieno[2,3-c]quinoline hydrate (8e) as
a yellow solid with mp 201 °C; IR (KBr) ν˜ ) 2964 cm-1 (w),
2877 (w), 1726 (m), 1523 (s), 1440 (s), 1381 (w), 1262 (m), 1155
1
(m), 1119 (m), 1036 (w), 869 (m), 761 (w); H NMR (400 MHz,
CDCl3) δ ) 2.93 ppm (s, 3H), 3.25 (t, J ) 6.0 Hz, 4H), 3.85 (t, J
Computational Method. Density functional theory calculations
of the infinite periodic crystal structure were carried out with the
CPMD package15 using the experimentally determined lattice
parameters together with periodic boundary conditions. The struc-
tures and positions of the water molecules were optimized using
the PBE exchange and correlation functional in conjunction with
Vanderbilt ultrasoft pseudopotentials16 and a plane wave basis set
truncated at 30 Ry. During geometry optimization, all atoms in the
unit cell except for the water molecules were kept fixed at their
experimentally determined positions. The electronic structure
analysis, including ELF calculations,17,18 at optimized geometry
was performed using normconserving Goedecker pseudopotentials19,20
and a 120 Ry plane wave cutoff.
) 6.0 Hz, 4H), 6.41 (s, 1H), 7.51 (t, J ) 7 Hz, 1H), 7.61 (t, J )
7 Hz, 1H), 7.95 (d, J ) 8.0 Hz, 1H), 8.10 (d, J ) 8.0 Hz, 1H); 13
C
NMR (100 MHz, CDCl3) δ ) 22.5 (s), 49.5 (d), 64.5 (d), 96.5 (t),
120.6 (q), 120.7 (q), 122.5 (t), 124.6 (t), 125.8 (q), 126.0 (t), 127.7
(t), 135.3 (q), 141.5 (q), 142.9 (q), 150.0 (q), 161.0 (q); MS (FAB)
m/z (%) 340.069 (100) [M+]. Anal. Calcd for C18H16N2OS2 (340.46)
+1.5 H2O: C, 58.83; H, 5.21; N, 7.62. Found: C, 58.89; H, 4.89;
N, 7.81. HRMS calcd for C18H16N2OS2: 340.0704 g/mol, found
340.0696 g/mol.
Willgerodt-Kindler Reaction with 4-[2-Chloro-4-nitrophen-
3-yl]butan-2-one (5f). A quantity of 270 mg (1.5 mmol) of
butanone 5f was transformed according to the general procedure
(Method A). The crude product was purified by flash chromatog-
raphy with all fractions kept under argon (silica, methyl tert-butyl
ether/petrol ether 1:8, Rf ) 0.20): 261 mg (59%) of N-(5-(2-chloro-
4-aminophenyl)thiophen-2-yl)morpholine (7f′) as slightly yellow
oil; IR (KBr) ν˜ ) 3364 cm-1 (m), 2966 (m), 2859 (m), 1621 (s),
1557 (m), 1504 (s), 1451 (m), 1298 (s), 1258 (m), 1201 (m), 1117
Acknowledgment. This work was supported by the Fonds
der Chemischen Industrie. N.L.D. and P.R. gratefully acknowl-
edge financial support by DFG within FOR 618 and computer
time at Rechnerverbund NRW.
1
(m), 903 (m), 859 (m), 817 (m), 729 (m); H NMR (400 MHz,
CDCl3) δ ) 3.11 ppm (t, J ) 5.8 Hz, 4H), 3.85 (t, J ) 5.8 Hz,
4H), 3.86 (s, br, 2H), 6.19 (d, J ) 1.5 Hz, 1H), 6.56 (dd, J ) 8.3
Hz, 2.5, 1H), 6.76 (d, J ) 2.5 Hz, 1H), 7.02 (d, J ) 1.5 Hz, 1H),
7.26 (d, J ) 8.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ ) 50.7
ppm (t), 66.7 (t), 100.5 (d), 113.6 (d), 116.1 (d), 119.5 (d), 123.4
(s), 132.0 (d), 133.0 (s), 140.5 (s), 147.0 (s), 151.7 (s, C-2); MS
(15) Hutter, J., CPMD; see www.cpmd.org.
(16) Vanderbilt, D. Phys. ReV. B 1990, 41, 7892–7895.
(17) Becke, A. D.; Edgecombe, K. E. J. Chem. Phys. 1990, 92, 5397–5403.
(18) Rousseau, R.; Marx, D. Chem.—Eur. J. 2000, 6, 2982–2993.
(19) Goedecker, S.; Teter, M.; Hutter, J. Phys. ReV. B 1996, 54, 1703–1710.
(20) Hartwigsen, C.; Goedecker, S.; Hutter, J. Phys. ReV. B 1998, 58, 3641–
3662.
4648 J. Org. Chem. Vol. 73, No. 12, 2008

A Domino Annulation Reaction
Supporting Information Available: General experimental
methods; proton NMR spectra of new compounds; procedures
for the synthesis of arylbutanones 5 by Heck reaction; DFT
optimized atomic coordinates in the unit cell of the monohydrate
of 8e; crystallographic information file for 8e. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO8005705
J. Org. Chem. Vol. 73, No. 12, 2008 4649