A novel 1,5-benzoheteroazepine synthesis via a one-pot coupling - Isomerization - Cyclocondensation sequence

Article abstract of DOI:10.1021/ol006721k

(equation presented) Ar¹ = electron deficient (hetero)aryl Ar² = aryl X = NH, O, S 2,4-Di(hetero)aryl substituted 2,3-dihydro 1,5-benzoheteroazepines (hetero = NH, O, S) can be readily sythesized in a one-pot process initiated by a coupling-isomerization sequence of an electron poor (hetero)aryl halide and a terminal propargyl alcohol subsequently followed by a cyclocondensation with 2-amino, 2-hydroxy, or 2-mercapto anilines. In addition, the structures were established unambiguously by an X-ray structure analysis of 7a.

Full text of DOI:10.1021/ol006721k

ORGANIC
LETTERS
2000
Vol. 2, No. 26
4181-4184
A Novel 1,5-Benzoheteroazepine
Synthesis via a One-Pot
Coupling−Isomerization−Cyclocondensation
Sequence§
Roland U. Braun, Kirsten Zeitler,† and Thomas J. J. Mu1ller*
Department Chemie, Ludwig-Maximilians-UniVersita¨t Mu¨nchen, Butenandtstr.
5-13 (Haus F), D-81377 Mu¨nchen, Germany
tom@cup.uni-muenchen.de
Received October 11, 2000
ABSTRACT
2,4-Di(hetero)aryl substituted 2,3-dihydro 1,5-benzoheteroazepines (hetero ) NH, O, S) can be readily sythesized in a one-pot process initiated
by a coupling−isomerization sequence of an electron poor (hetero)aryl halide and a terminal propargyl alcohol subsequently followed by a
cyclocondensation with 2-amino, 2-hydroxy, or 2-mercapto anilines. In addition, the structures were established unambiguously by an X-ray
structure analysis of 7a.
Benzodiazepines (1 and 2) constitute an important class of
psychopharmaca.1 In particular, derivatives of 1,5-benzodi-
azepines 2 have aroused considerable interest as CNS active
anticonvulsant drugs2 and also as in vitro nonnucleoside
inhibitors of HIV-1 reverse transcriptase3 (Figure 1).
§ Dedicated to Prof. Richard R. Schmidt on the occasion of his 65th
birthday.
† X-ray crystal structure analysis.
(1) For reviews, see: (a) Archer, G. A.; Sternbach, L. H. Chem. ReV.
Figure 1.
1968, 68, 747. (b) Popp, F. D.; Noble, A. C. AdV. Heterocycl. Chem. 1967,
8, 21. (c) Sternbach, L. H. Angew. Chem., Int. Ed. Engl. 1971, 10, 34. (d)
Vanderheyden, J. L.; Vanderheyden, J. E. J. Pharm. Belg. 1981, 36, 354.
(e) Jones, G. R.; Singer, P. P. AdV. Anal. Toxicol. 1989, 2, 1. (f) Newkome,
Besides these only nitrogen containing benzoannealed
G. R. In ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees,
C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford, New York,
Toronto, Sydney, Paris, Frankfurt, 1996; Vol. 9, p 181.
seven-membered heterocycles, their oxaza and thiaza ana-
logues 3 have become increasingly interesting since 1,5-
benzothiazepines show antifungal, antibacterial,4 antifeedant,5
antiinflammatory, analgesic,6 and anticonvulsant7 activity.
(2) For synthetic and pharmacological studies, see: (a) Zellou, A.;
Cherrah, Y.; Hassar, M.; Essassi, E.-M. Ann. Pharm. Fr. 1998, 56, 169.
(b) Savelli, F.; Boido, A.; Mule, A.; Piu, L.; Alamanni, M. C.; Pirisino, G.;
Satta, M.; Peana, A. Farmaco 1989, 44, 125. (c) Nawojski, A.; Nawrocka,
W.; Liszkiewicz, H. Pol. J. Pharmacol. Pharm. 1985, 37, 69. (d)
Wilimowski, M.; Orzechowsa-Juzwenko, K.; Barczynska, J.; Kedzierska-
Gozdzik, L.; Witkowska, M.; Wojewodzki, W.; Dus, E.; Plawiak, T.;
Gryska, J.; Maska, H. Pol. J. Pharmacol. Pharm. 1983, 35, 89. (e)
Srivastava, V. K.; Satsangi, R. K.; Kishore, K. Arzneim.-Forsch. 1982, 32,
1512.
(3) For synthetic and pharmacological studies, see: (a) Parker, K. A.;
Dermatakis, A. J. Org. Chem. 1997, 62, 4164. (b) Hargrave, K. D.; Schmidt,
G.; Engel, W.; Austel, V. Patent Application: U.S. 91-650141 19910204.
Patent Priority: U.S. 89-340937 19890420; U.S. 89-372728 19890628; U.S.
89-438922 19891117; U.S. 90-600554 19901019.
10.1021/ol006721k CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/28/2000

Retrosynthetically, 1,5-benzoheteroazepines are synthe-
sized by cyclocondensation of the corresponding 2-substi-
tuted anilines with suitable enones or 1,3-dicarbonyl com-
pounds (and synthetic equivalents).4-7,8 However, the enones
and, in particular, chalcones (i.e., 1,3-diaryl enones) are
usually prepared by an aldol condensation and have to be
isolated and purified prior to the cyclization step. Therefore,
we set out to develop a novel synthesis of 1,5-benzohet-
eroazepines, preferentially in a straightforward highly con-
vergent manner, that also can be conducted in the sense of
a one-pot process. Here, we wish to communicate a facile
one-pot synthesis of 2,4-di(hetero)aryl substituted 2,3-dihydro
1,5-benzodiazepines, -oxazepines, and -thiazepines (3, R1 )
(het)aryl, R2 ) aryl) based upon a coupling-isomerization
sequence with a subsequent cyclocondensation with 2-amino,
2-hydroxy, or 2-mercapto anilines.
benzoheteroazepines,3-7 retrosynthetically, an extension of
the coupling-isomerization-based methodology to a one-
pot synthesis of 1,5-benzoheteroazepines can be easily
envisioned. Upon cyclocondensing o-phenylene diamine,
2-amino phenol, or 2-amino thiophenol as suitable 1,4-
dinucleophilic components with the initially formed enone
functionality, the benzoannealed seven-membered hetero-
cycles are to be readily formed (Scheme 2). In particular,
Scheme 2. Retrosynthetic Concept for a Three-Component
1,5-Benzoheteroazepine Synthesis
Recently, we found that palladium/copper catalyzed cross-
coupling reactions of electron poor halogen substituted
π-systems and 1-aryl prop-2-yn-1-ols do not furnish the
expected propargyl alcohols but rather the isomeric enone
components.9 Mechanistically, this isomerization, occurring
after the cross-coupling reaction, is purely base catalyzed
and opens a new access to electron deficient propenones.
With this powerful tool for the construction of chalcones
(1,3-diaryl propenones) in hand and considering the mild
reaction conditions for the Sonogashira coupling reaction,
we have developed novel one-pot pyrazoline9 and pyrimi-
dine10 syntheses (Scheme 1).
the mild reaction conditions of Sonogashira couplings11 not
only allow the presence of sensitive functional groups without
tedious protection and deprotection steps but are also
advantageous for base-mediated processes such as cyclo-
condensations. In addition, this strategy could also be
extended to a combinatorial approach to 1,5-benzohet-
eroazepines (3).
Scheme 1. One-Pot Pyrazoline and Pyrimidine Synthesis
Based upon a Coupling-Isomerization Sequence
Thus, we have submitted p-iodo nitrobenzene (4a),
4-bromo pyridine (4b), or p-bromo benzonitrile (4c), aryl
propynols 5,12 and 2-heteroatom substituted anilines 6 to the
reaction conditions of the Sonogashira coupling in a boiling
mixture of triethylamine and THF.13 In all cases the isolated
products were the beige to yellow 1,5-benzoheteroazepines
7 in 32-67% yield (Table 1).14 As already shown for the
one-pot synthesis of pyrazolines and pyrimidines the electron
withdrawing nature of the (hetero)aryl halide 4 is crucial for
the successful coupling-isomerization step.9,10
The proton and carbon NMR spectroscopic data support
the formation of the 1,5-benzoheteroazepine, in particular
in the 1H NMR spectra of 7 by the indicative appearance of
(6) ) Satyanarayana, K.; Rao, M. N. A. Ind. J. Pharm. Sci. 1993, 55,
230.
(7) DeSarro, G.; Chimirri, A.; DeSarro, A.; Gitto, R.; Grasso, S.; Zappala,
M. Eur. J. Med. Chem. 1995, 30, 925.
(8) Lloyd, D.; McNab, H. AdV. Heterocycl. Chem. 1998, 71, 1.
(9) Mu¨ller, T. J. J.; Ansorge, M.; Aktah, D. Angew. Chem., Int. Ed. 2000,
39, 1253.
Since cyclocondensations of 2-heteroatom substituted
anilines with chalcones (1,3-diaryl propenones) give 1,5-
(10) Mu¨ller, T. J. J.; Braun, R.; Ansorge, M. Org. Lett. 2000, 2, 1967.
(11) (a) Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara, N.
Synthesis 1980, 627. (b) Sonogashira, K. In Metal Catalyzed Cross-Coupling
Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998,
p 203.
(12) The propynols 5 were synthesized according to Krause, N.; Seebach,
D. Chem. Ber. 1987, 120, 1845.
(4) (a) Mane, R. A.; Ingle, D. B. Ind. J. Chem., Sect. B 1982, 21B, 973.
(b) Jadhav, K. P.; Ingle, D. B. Ind. J. Chem., Sect. B 1983, 22B, 180. (c)
Attia, A.; Abdel-Salam, O. I.; Abo-Ghalia, M. H.; Amr, A. E. Egypt. J.
Chem. 1995, 38, 543.
(5) Reddy, R. J.; Ashok, D.; Sarma, P. N. Ind. J. Chem., Sect. B 1993,
32B, 404.
4182
Org. Lett., Vol. 2, No. 26, 2000

Table 1. Three-Component 1,5-Benzoheteroazepine Synthesis Based upon a Coupling-Isomerization-Cyclocondensation Sequencea
a Reaction conditions: 1.0 equiv of the (hetero)aryl halide 4, 1.05 equiv of the propargyl alcohol 5, 0.02 equiv of (Ph3P)2PdCl2, 0.01 equiv of CuI, 1.1
equiv of the 2-hetero aniline 6, THF/NEt3 2:1 (10 mL/mmol halide). b Yields refer to isolated yields of compounds 7 after recrystallization estimated to be
g95% pure as determined by NMR spectroscopy and elemental analysis.
Org. Lett., Vol. 2, No. 26, 2000
4183

the ABM-spin system with the characteristic geminal and
vicinal coupling constants for the methylene group reso-
tron poor (hetero)aryl halides with 1-aryl propargyl alcohols
giving rise to chalcones can be extended to a one-pot three
component synthesis of 2,4-di(hetero)aryl substituted 2,3-
dihydro 1,5-benzodiazepines, -oxazepines, and -thiazepines.
Further studies directed to extend these one-pot heterocycle
syntheses are currently underway.
3
3
nances (2J ) 13.5 Hz, J ) 4.4 Hz, J ) 7.1 Hz) and the
vicinal coupling constants for the methine resonances (3J )
3
4.4 Hz, J ) 7.0 Hz). Furthermore, the structure of 7 was
unambiguously supported by an X-ray crystal structure
analysis (Figure 2) of compound 7a15 (Table 1, entry 1).
Acknowledgment. The financial support of the Fonds
der Chemischen Industrie and the Dr.-Otto-Ro¨hm Geda¨cht-
nisstiftung is gratefully acknowledged. The authors wish to
express their appreciation to Prof. H. Mayr for his generous
support.
Supporting Information Available: Tables of data
collection parameters, bond lengths and angles, positional
and thermal parameter, and least-squares planes for 7a. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL006721K
to reflux temperature for 16 h. After cooling to room temperature 138 mg
(1.10 mmol) of 2-amino thiophenol (6c) was added, and the reaction mixture
was heated to reflux temperature for 8 h. After cooling the solvents were
removed in vacuo, and the residue was dissolved in dichloromethane and
filtered through a short pad of silica gel. The solvents were evaporated in
vacuo and the residue was recrystallized from dichloromethane/pentane to
give 228 mg (67%) of analytically pure 7g as yellow needles. Mp 180-
181 °C. 1H NMR (CDCl3, 300 MHz): δ 3.03 (t, J ) 12.8, 1 H), 3.30 (dd,
J ) 4.9 Hz, J ) 12.9 Hz, 1 H), 4.97 (dd, J ) 7.7 Hz, J ) 12.6 Hz, 1 H),
7.16 (dt, J ) 7.5 Hz, J ) 1.4 Hz, 1 H), 7.32 (dd, J ) 7.8, J ) 1.9, 1 H),
7.41 (d, J ) 8.3 Hz, 2 H), 7.61-7.46 (m, 7 H), 8.04 (dd, J ) 7.6, J ) 1.4,
2 H). 13C NMR (CDCl3, 300 MHz): δ 36.7 (CH2), 59.4 (CH), 111.3 (Cquat.),
118.3 (Cquat.), 121.6 (Cquat.), 125.2 (CH), 125.3 (CH), 126.6 (CH), 127.1
(CH), 128.6 (CH), 130.0 (CH), 131.0 (CH), 132.4 (CH), 134.7 (CH), 137.1
(Cquat.), 148.6 (Cquat.), 152.2 (Cquat.), 168.1 (Cquat.). MS (70 eV, m/z (%)):
Figure 2. ORTEP plot of compound 7a.
340 (M+, 8), 211 (M+ - NCC6H4CHdCH2, 100). IR (KBr): V˜ 2229 cm-1
,
1609, 1574, 1452. UV/vis (CHCl3): λmax (ꢀ) 244 nm (28700). Anal. Calcd
for C22H16N2S (340.45): C, 77.62; H, 4.74; N, 8.23; S, 9.42. Found: C,
77.48; H, 4.76; N, 8.26; S, 9.52.
In conclusion, we could show that the mild reaction
conditions of the coupling-isomerization sequence of elec-
(14) All compounds have been characterized spectroscopically and by
correct elemental analysis.
(13) Typical Procedure (7g, entry 7). To a magnetically stirred solution
of 0.25 g (1.00 mmol) of 4-bromo benzonitrile (4c), 22 mg (0.02 mmol) of
Pd(PPh3)2Cl2, and 2 mg (0.01 mmol) of CuI in a degassed mixture of 6
mL of THF and 3.5 mL of triethylamine under nitrogen was added dropwise
a solution of 139 mg (1.05 mmol) of 1-phenyl propyn-1-ol (5a) in 6 mL of
THF at room temperature over a period of 30 min. The mixture was heated
(15) Crystallographic data (excluding structure factors) for the structure
reported in this paper have been deposited with the Cambridge Crystal-
lographic Data Centre as supplementary publication no. CCDC-149968 (7a).
Copies of the data can be obtained free of charge on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, U.K. (Fax: + 44-1223/336-033;
e-mail: deposit@ccdc.cam.ac.uk).
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Org. Lett., Vol. 2, No. 26, 2000