2-Benzyliden-2H-thieto[3,2-b]quinoline: A new heterocycle and its rearrangement to 2-phenylthieno[3,2-b]quinoline

Article abstract of DOI:10.1016/j.tetlet.2010.10.039

Synthesis of the strained 2H-thieto[3,2-b]quinoline ring system is reported for the first time. Treatment of (Z)-2-benzyliden-2H-thieto[3,2-b]quinoline derivatives of this heterocycle with base, at reflux in ethanol, causes a novel rearrangement to 2-phen

Full text of DOI:10.1016/j.tetlet.2010.10.039

Tetrahedron Letters 51 (2010) 6687–6689
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2-Benzyliden-2H-thieto[3,2-b]quinoline: a new heterocycle
and its rearrangement to 2-phenylthieno[3,2-b]quinoline
Makhluf J. Haddadin a, , Claudia El-Nachef a, Hawraa Kisserwani a, Yara Chaaban a, Mark J. Kurth b,
⇑
⇑
,
James C. Fettinger b
a Department of Chemistry, American University of Beirut, Beirut, Lebanon
b Department of Chemistry, University of California, One Shields Avenue, Davis, CA 95616, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of the strained 2H-thieto[3,2-b]quinoline ring system is reported for the first time. Treatment of
(Z)-2-benzyliden-2H-thieto[3,2-b]quinoline derivatives of this heterocycle with base, at reflux in ethanol,
causes a novel rearrangement to 2-phenylthieno[3,2-b]quinolines. Indeed, the one-pot reaction of
2-aminobenzaldehydes and (Z)-2-benzylidenethietan-3-one in refluxing basic ethanol leads directly to
2-phenylthieno[3,2-b]quinolines in good yields.
Received 14 September 2010
Accepted 6 October 2010
Available online 8 November 2010
Keywords:
Ó 2010 Elsevier Ltd. All rights reserved.
Friedländer reaction
Thieto[3,2-b]quinoline
Base-mediated rearrangement
Thieno[3,2-b]quinoline
Cyclobuta[b]naphthalene was first synthesized by Cava in
1960.1 On the other hand, heteroatoms in this tricyclic ring are rare
in the literature. For example, 1,2-dihydrocyclobuta[b] quinolines
1a,b, 1,2-dihydrocyclobuta[b]quinoxaline (2a), 6,7-dihydrocyclob-
uta[g]quinoxaline (2b), and naphthothietes 3a,b,c have been
reported as stable isolable compounds.2–4 However, naphthooxetes
4a,b were assumed to be precursors of the corresponding highly
reactive o-quinonemethides5 (Fig. 1).
Y
Y
X
X
Y
X
1a: X = N, Y = CH
1b: X = CH, Y = N
2a: X = N, Y = CH
2b: X = CH, Y = N
S
S
S
To the best of our knowledge, no cyclobutanaphthalene ring
systems with two different heteroatoms are known. We wish to
report, for the first time, the synthesis of the new heterocycle
2-benzyliden-2H-thieto[3,2-b]quinoline and some of its deriva-
tives which contain sulfur and nitrogen as the heteroatoms.
A Friedländer reaction between 2-aminobenzaldehyde (5a) and
thietanone 6 in 10% KOH in ethanol at room temperature gave the
desired (Z)-2-benzyliden-2H-thieto[3,2-b]quinoline (7a) as an
off-white solid in 75% yield (Fig. 2). The structure of 7a was estab-
lished by 1H NMR, 13C NMR, and mass spectrometry and this was
confirmed by X-ray crystallography (Fig. 3a; see experimental
details for all new compounds6).
3a
3b
3c
O
O
4a
4b
Figure 1. Reported cyclobutanaphthalene heteroanalogs.
Friedländer product 7a was heated at reflux in 10% KOH/ethanol.
The structure of 8a was established by 1H NMR, 13C NMR, and mass
spectrometry and confirmed by X-ray crystallography (Fig. 3b).
Similarly, Friedländer reactions of 6 with aminobenzaldehydes
5b and 5c delivered thieno[3,2-b]quinolines 7b and 7c in 69% and
35% yields, respectively (Fig. 4). Attempts to prepare thieno[3,2-
b]quinoline 7d (ꢀ10% crude yield) were foiled by the instability of
2-amino-4,5-dimethoxybenzaldehyde (5d) and the difficulty in iso-
lating 7d from the multicomponent, intractable mixture. The direct,
one-pot Friedländer reaction/base-mediate rearrangement of 5b + 6
When the Friedländer reaction of 5a with 6 was conducted
under the same basic conditions, but at reflux temperature, the
product was shown to be 2-phenylthieno[3,2-b]quinoline (8a).
This novel rearrangement product was also obtained in 94% when
⇑
Corresponding authors. Tel.: +961 1 340460x3987 (M.J.H.); +1 530 554 2145
(M.J.K.).
E-mail addresses: haddadin@aub.edu.lb (M.J. Haddadin), mjkurth@ucdavis.edu
(M.J. Kurth).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.039

6688
M. J. Haddadin et al. / Tetrahedron Letters 51 (2010) 6687–6689
Br
O
N
NH2
NH2
NH2
S
H
S
6
Cl
CHO
Br
CHO
7a
O
5b
N
5c
r.t. (75%)
10% KOH
in EtOH
5a
6
10% KOH
in EtOH, Δ (94%)
Δ (35%)
Br
O
N
N
S
S
S
Cl
Br
S
7b (69%)
7c (35%)
8a
Figure 2. Friedländer reaction to give (Z)-2-benzyliden-2H-thieto[3,2-b]quinoline
(7a) and its subsequent base-mediated rearrangement to 2-phenylthieno[3,2-b]
quinoline (8a).
5b + 6
5c + 6
Br
N
N
S
S
Cl
Br
8b (74%)
8c (70%
MeO
MeO
N
S
7d
Figure 4. Friedländer reaction to give (Z)-2-benzyliden-2H-thieto[3,2-b]quinoline
(7a).
H
HO
S
OH
N
N
N
N
N
S
7a
Figure 3. (a) X-ray crystallographic structure of 7a (see Supplementary data).
(b) X-ray crystallographic structure of 8a (see Supplementary data).
H
H
HO
S
HO
S
H
and 5c + 6 gave 8b and 8c in 74% and 70% yields, respectively. The
easily effected procedures reported herein constitute an effective
and novel method for the synthesis of thieno[3,2-b]quinolines;
indeed, the literature cites only a few cases of this heterocycle pre-
pared by flash-vacuum pyrolysis (54% yield),9a or nitrene insertion
reaction which gives very low yields (5%).9b,c
We propose the following mechanism (Fig. 5) to explain the
rearrangement of 7a–8a. The driving force for this rearrangement
lies in the fact that 7a has properties of both a potential Michael
acceptor and the inherent strain of a four-membered ring.
In conclusion, we have synthesized the first examples of
thieto[3,2-b]quinoline heterocycles as their 2-benzylidene deriva-
tives which we show to rearrange readily to interesting and rare
thieno[3,2-b]quinolines.
HO
N
-H2O
S
8a
SH
5. Base-mediated
Figure
2H-thieto[3,2-b]quinoline?thieno[3,2-b]quinoline
rearrangement.
References and notes
1. Cava, M. P.; Shirky, R. L. J. Am. Chem. Soc. 1960, 82, 654–656.
Acknowledgments
2. (a) Wilk, M.; Schwab, H.; Rochlitz, J. H. Annalen 1966, 698, 149; (b) Markgraf, J.
H.; Scott, W. L. Chem. Commun. 1967, 296–297; (c) Markgraf, J. H.; Antin, J. H.;
Walker, F. J.; Blatchly, R. A. J. Org. Chem. 1979, 44, 3261–3263.
3. (a) Liu, J.-H.; Wu, A.-T.; Haung, M.-H.; Wu, C.-W.; Chung, W.-S. J. Org. Chem.
2000, 65, 3395–3403; (b) Chung, W.-S.; Liu, J.-H. Chem. Commun. 1997, 205–206;
(c) Chou, T.-S.; Ko, C.-W. Tetrahedron 1994, 50, 10721–10726.
4. (a) Meier, H.; Mayer, A. Synthesis 1996, 327–328; (b) Mayer, A.; Rumpf, N.;
Meier, H. Liebigs Ann. 1995, 2221–2226; (c) Meier, H.; Mayer, A. Tetrahedron Lett.
1994, 2161–2164.
5. Arumugam, S.; Popik, V. V. J. Am. Chem. Soc. 2009, 131, 11892–11899.
6. (a) General procedure for the synthesis of (Z)-2-benzyliden-2H-thieto[2,3-
b]quinolines (7a/b/c). Equivalent amounts of thietanone7 6 (1.07 mmol) and
2-aminobenzaldehyde8 (5a; 1.07 mmol) or its derivatives (5b or 5c) were
We wish to thank Mr. Tharallah Shoker for the spectroscopic
data and the National Science Foundation (CHE-0910870) for
generous financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.10.039.

M. J. Haddadin et al. / Tetrahedron Letters 51 (2010) 6687–6689
6689
dissolved in 10% KOH/ethanol (10 mL) and the solution was stirred at room
temperature until completion of the reaction (5 h by TLC). The resulting
precipitate was collected by suction filtration and washed with water and dried
collected by suction filtration and washed with water to give a pure product
(47 mg, 94% yield). 1H NMR: d 8.63 (s, 1H), 8.18 (dd, J1 = 8.6 Hz, J2 = 0.8 Hz, 1H),
7.91 (dd, J1 = 8.2 Hz, J2 = 1.2 Hz, 1H), 7.85–7.79 (m, 2H), 7.75 (dt, J1 = 7.7 Hz,
J2 = 1.5 Hz, 1H), 7.59–7.41 (m, 4H). 13C NMR: d 158.4, 151.8, 147.2, 133.6, 131.6,
129.7, 129.2, 129.18, 129.1, 129.0, 127.4, 126.7, 125.6, 125.3, 119.8. GC–MS
Calcd = 261. Found: M+1 = 262.1.
General procedure for the direct synthesis of 2-phenythieno[3,2-b]quinolines
(8a,b,c). The above general procedure was followed except that the reaction
mixture was heated at reflux temperature until the reaction was complete (4 h
by TLC). Upon cooling, the product precipitated as a white solid.
2-Phenylthieno[3,2-b]quinoline (8a). 35% yield. See above for spectroscopic and
mass spectrometric data.
leading to the corresponding (Z)-2H-thieto[2,3-b]quinoline. All 1H NMR and 13
C
NMR were determined in CDCl3 at 300 MHz and 75 MHz, respectively.
2-Aminobenzaldehydes were prepared according to the literature method.8 In
the cases of 5b/c/d, the reaction mixtures were not steam-distilled as it is for 5a,
but extracted with CH2Cl2 and the extracted residues were purified by silica gel
column chromatography.
(Z)-2-Benzyliden-2H-thieto[3,2-b]quinoline (7a). Cream colored solid, (75% yield).
1H NMR: d 8.02 (d, J = 8.4 Hz, 1H), 7.70 (s, 1H), 7.72–7.65 (m, overlapped doublet
with a singlet, 3H), 7.60 (dt, J1 = 7.7 Hz, J2 = 1.5 Hz, 1H), 7.52–7.65 (m, 6H). 13C
NMR: d 159.0, 146.7, 137.8, 137.6, 134.4, 130.7, 129.5, 129.1, 129.05, 128.8,
128.2, 127.3, 126.6, 124.5, 122.0. GC–MS Calcd = 261.3. Found M+1 = 262.0.
(Z)-6-Chloro-2-benzyliden-2H-thieto[3,2-b]quinoline (7b). Cream colored solid
(69% yield). 1H NMR: d 8.07 (d, J = 8.4 Hz, 1H), 7.94 (s, 1H), 7.71 (s, 1H), 7.68
(s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.54–7.36 (m, 5H). 13C NMR: d 157.7, 138.3,
133.9, 133.0, 131.0, 130.9, 130.4, 129.8, 129.6, 129.2, 129.1, 129.0, 126.2, 125.7,
125.0. GC–MS Calcd = 295/297. Found: M+1 = 296/298.
6-Chloro-2-phenylthieno[3.2-b]quinoline (8b). 74% yield). 1H NMR: d 8.73 (s, 1H),
8.41 (d, J = 9.3 Hz, 1H), 8.10 (s, 1H), 7.75–7.70 (m, 2H), 7.58–7.47 (m, 4H). 13C
NMR: d 157.7, 138.3, 135.0, 133.8, 132.9, 131.0, 130.8, 130.4, 129.7, 129.5, 129.2,
129.1, 129.0, 126.2, 124.9. GC–MS Calcd = 295/297. Found: M+1 = 296/298.
6,8-Dibromo-2-phenylthieno[2,3-b]quinoline (8c). 70% yield). 1H NMR: d 8.48 (s,
1H), 8.12 (d, J = 1.5 Hz, 1H), 8.05 (s, 1H), 7.98 (apparent d, J = 1.8 Hz, 1H), 7.76 (d,
J = 6.0 Hz, 2H), 7.56–7.38 (m, 3H). 13C NMR: d 158.2, 141.6, 136.3, 133.7, 132.8,
130.6, 130.0, 129.4, 129.3, 129.2, 129.0, 127.0, 126.5, 119.4, 118.7. GC–MS
Calcd = 417/419/421. Found: M+1 = 418/420/422.
(Z)-6,8-Dibromo-2-benzyliden-2H-thieto[3,2-b]quinoline (7c). Cream colored solid
(35% yield). 1H NMR: d 7.98 (d, J = 2.1 Hz, 1H), 7.74 (d, J = 1.8 Hz, 1H), 7.47 (s,
1H), 7.44–7.29 (m, 6H). 13C NMR: d 195.9, 142.8, 139.7, 136.8, 134.5, 134.0,
132.4, 130.2, 129.5, 129.2, 128.8, 125.6, 124.1, 123.5, 119.8. GC–MS Calcd = 417/
419/421. Found: M+1 = 418/420/422.
7. Krubsack, A. J.; Higa, T.; Slack, W. E. J. Am. Chem. Soc. 1970, 92, 5258–5259.
8. Smith, L. I.; Opie, J. Org. Synth. 1955, Col. Vol. 3, 56.
9. (a) Fishwick, C. W. G.; Storr, R. C.; Manley, P. W. Chem. Commun. 1984,
1304–1305; (b) Cliff, G. R.; Jones, G.; Woollard, J. M. K. Tetrahedron Lett. 1973,
2401–2404; (c) Cliff, G. R.; Jones, G.; Woollard, J. M. J. Chem. Soc., Perkin 1 1974,
2072–2076.
(b) Rearrangement of 7a–8a.
2-Phenylthieno[3,2-b]quinoline (8a). Intermediate 7a (50 mg, 0.19 mmol) was
dissolved in 10% KOH/ethanol (10 mL) and the mixture was heated at reflux
temperature for 4 h. Upon cooling, 8a precipitated as a white solid which was