Facile preparation of hexahydropyrrolo[3,2-e][1,4]diazepine-2,5-diones and tetrahydrofuro[1H][3,2-e][1,4]diazepine-2,5-diones by rearrangements of cyclopropylketimines and cyclopropylketones

Article abstract of DOI:10.1021/ol0068187

(equation presented) Chlorolactames 2a-f reacted with sodium azide to give the cyclopropylketimines 3a-f (75-89%), and acid hydrolysis of 3c,d yielded the cyclopropylketones 6c,d (61-67%). Compounds 3a-f and 6c,d were transformed by heating (170-240°C, su

Full text of DOI:10.1021/ol0068187

ORGANIC
LETTERS
2000
Vol. 2, No. 26
4249-4251
Facile Preparation of
Hexahydropyrrolo[3,2-e][1,4]diazepine-
2,5-diones and
Tetrahydrofuro[1H][3,2-e][1,4]diazepine-
2,5-diones by Rearrangements of
Cyclopropylketimines and
Cyclopropylketones†
,‡
Christian Funke,‡ Mazen Es−Sayed,§ and Armin de Meijere*
Institut fu¨r Organische Chemie, Georg-August-UniVersita¨t Go¨ttingen,
Tammannstrasse 2, D-37077 Go¨ttingen, Germany, and Bayer AG,
Landwirtschaftszentrum, Alfred-Nobel-Strasse 50, Geb. 6510,
D-40789 Monheim, Germany
Armin.deMeijere@chemie.uni-goettingen.de
Received November 3, 2000
ABSTRACT
Chlorolactames 2a−f reacted with sodium azide to give the cyclopropylketimines 3a−f (75−89%), and acid hydrolysis of 3c,d yielded the
cyclopropylketones 6c,d (61−67%). Compounds 3a−f and 6c,d were transformed by heating (170−240 °C, sublimation) to the air-sensitive
dihydropyrroles 4a−f (51−71%) and dihydrofurans 7c,d (85−91%). Oxidation of the dihydro derivatives 4a−f and 7c,d with DDQ led to novel
types of pyrrolo[3,2-e][1,4]diazepinedione derivatives 5a−f (75−84%) and furo[1H][3,2-e][1,4]diazepinediones 8c,d (91−93%).
A wide range of compounds with the skeleton of tetrahydro-
[1H][1,4]benzodiazepine-2,5-dione 1 are well-known for their
interesting biological activities.
nephrotoxic (+)-iforrestine1 and the antitumor antibiotic oxo-
tomaymycin.2 Synthetic derivatives have shown anxiolytic,3
anticonvulsive,4 antitumor,5 and antithrombotic activities.6
Moreover, they have been found to possess fungicidal and
plant growth regulating activities7 and have been evaluated
for their herbicidal activity.8 Althouth the elaboration of
(1) Colgate, S. M.; Dorling, P. R.; Huxtable, C. R.; Shaw, T. J.; Skelton,
B. W.; Vogel, P.; White, A. H. Aust. J. Chem. 1989, 42, 1249-1255.
(2) Kariyone, K.; Yazawa, H.; Kohsaka, M. Chem. Pharm. Bull. 1971,
19, 2289-2293.
Natural products containing this ring system are the
(3) Wright, W. B.; Brabander, H. J.; Greenbatt, E. N.; Day, I. P.; Hardy,
R. A. J. Med. Chem. 1978, 21, 1087-1089.
† Part 64 in the series “Cyclopropyl Building Blocks for Organic
Synthesis”. For Part 63 see: Pohlmann, T.; de Meijere, A. Org. Lett. 2000,
2, 3877-3879.
(4) De Martino, G.; Massa,S.; Corelli, F.; Pantaleoni, G.; Fanini, D.;
Palumbo, G. Eur. J. Med. Chem. Chim. Ther. 1983, 18, 347-350.
(5) Jones, G. B.; Davey, C. L.; Jenkins, T. C.; Kamal, A.; Kneale, G.
G.; Neidle, S.; Webster, G. D.; Thurston, D. E. Anti-Cancer Drug Des.
1990, 5, 249-264.
‡ Georg-August-Universita¨t Go¨ttingen.
§ Bayer AG.
10.1021/ol0068187 CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/29/2000

various substitution patterns of 1 is well established,9 only a
limited number of the reported examples of such compounds
contain imidazo, pyrido, or thieno moieties instead of the
more common benzo ring.9t,10 In this communication we wish
to report an approach to new types of pyrrolo- and furo-
condensed perhydro[1,4]diazepine-2,5-diones.
The new synthesis of hexahydropyrrolo[3,2-e][1,4]diazepine-
2,5-diones and tetrahydrofuro[1H][3,2-e][1,4]diazepine-2,5-
diones starts with the chlorolactames 2a-d and (2′S,6′S)-
2e,f ,11 which were cleanly converted in good yields (75-
89%) directly to the imines 3a-f by treatment with sodium
azide in DMSO (Table 1). It was surprising that these
of their spectral data and corroborated by an X-ray crystal
structure analysis of the 2-furfuryl-substituted derivative 3b.13
The Cloke rearrangements14 of the cyclopropylketimines
3 could not be brought about under the usual acid catalysis.
Better results were obtained when 3c was heated in a small
sublimation apparatus at 180 °C for 5 min followed by
sublimation onto the coldfinger under reduced pressure (<5
× 10-5 mbar, 170 f 240 °C). This gave 4c in 62% yield,
and under the same or slightly modified conditions, the other
1-substituted dihydropyrrole derivatives 4a,b,d were also
obtained in good yields (64-71%) (Table 1). Interestingly,
the rearrangement of 3e and 3f did only occur at higher
temperature (220 °C), and gave the 1,3-disubstituted deriva-
tives 4e and 4f as crude products in lower yields (51-59%).
When the air-sensitive compounds 4a-f were treated with
1,2-dichloro-5,6-dicyanobenzoquinone (DDQ) in chloroform
at 40 °C, the 1,2,3,4,5,6-hexahydropyrrolo[3,2-e][1,4]-
diazepine-2,5-diones 5a-f were obtained in good yields
(75-84%),15 and the structure of 5c was unequivocally
proved by X-ray crystal structure analysis13 (Scheme 1). Acid
Table 1. Yields of Imines 3, Dihydropyrrole Derivatives 4,
and Hexahydropyrrolo[3,2-e]-[1,4]diazepine-2,5-diones 5 (see
Scheme 1)
yield (%)
entry
R1
n-pentyl
2-furfuryl
4-MeO(C6H4)CH2
4-Cl(C6H4)CH2
Me
R2
3
4
5
a
b
c
d
e
f
H
H
H
H
89
75
77
82
82
85
71a
69b
62
64b
51a
59a
84
75
80
83
77
82
Scheme 1
CH2CH2SMe
Me
i-Bu
a Crude product. b Contains 5% of starting material 3 according to the
1H NMR spectrum.
nucleophilic substitutions by azide were so easily succeeded
by elimination of nitrogen under the applied conditions.12
The structural assignments of 3a-f were made on the basis
(6) (a) Webb, R. R.; Barker, P. L.; Baier, M.; Reynolds, M. E.; Robarge,
K. D.; Blackburn, B. K.; Tischler, M. H.; Weese, K. J. Tetrahedron Lett.
1994, 35, 2113-2116. (b) McDowell, R. S.; Blackburn, B. K.; Gadek, T.
R.; McGee, L. R.; Rawson, T.; Reynolds, M. E.; Robarge, K. D.; Somers,
T. C.; Thorsett, E. D.; Tischler, M.; Webb, R. R.; Venuti, M. C. J. Am.
Chem. Soc. 1994, 116, 5077-5083. (c) McDowell, R. S.; Gadek, T. R.;
Barker, P. L.; Burdick, D. J.; Chan, K. S.; Quan, C. L.; Skelton, N.; Struble,
M.; Thorsett, E. D.; Tischler, M.; Tom, J. Y. K.; Webb, T. R.; Burnier, J.
P. J. Am. Chem. Soc. 1994, 116, 5069-5076.
hydrolysis of the substituted benzyl derivatives 3c and 3d
yielded the ketones 6c (67%) and 6d (61%). Thermal
rearrangement of the cyclopropylketones 614 using the same
experimental setup at 200 °C afforded the dihydrofuran
derivatives 7c and 7d in very good yields (85-91%).
Compounds 7c,d were found to be more stable than the
(7) Suesse, M.; Schaks, A.; Johne, S. East German Patent Appl. 249,475
(1988); Chem. Abstr. 1988, 108, 131865g.
(8) Karp, G. M. J. Org. Chem. 1995, 60, 5814-5819.
(9) (a) Kaneko, T.; Wong, H.; Doyle, T. W. Tetrahedron Lett. 1983, 24,
5165-5168. (b) Reed, J. N.; Snieckus, V. Tetrahedron Lett. 1984, 25,
5505-5508. (c) Nagasaka, T.; Koseki, Y.; Hamaguchi, F. Tetrahedron Lett.
1989, 30, 1871-1872. (d) Kamal, A.; Thurston, D. E. Tetrahedron Lett.
1989, 30, 6221-6222. (e) Pen˜a, M. R.; Stille, J. K. J. Am. Chem. Soc.
1989, 111, 5417-5424. (f) Gu, Z.-Q.; Wong, G.; Dominguez, C.; de Costa,
B. R.; Rice, K. C.; Skolnick, P. J. Med. Chem. 1993, 36, 1001-1006. (g)
Kaneko, T.; Wong, H.; Doyle, T. W. J. Antibiot. 1984, 37, 300-302. (h)
Carey, F. A.; Giuliano, R. M. J. Org. Chem. 1981, 46, 1366-1371. (i)
Confalone, P. N.; Huie, E. M.; Ko, S. S.; Cole, G. M. J. Org. Chem. 1988,
53, 482-487. (k) Kamal, A. J. Org. Chem. 1991, 56, 2237-2240. (l)
Richter, H.; Winter, K.; Kousy, S. E.; Luckner, M. Pharmazie 1974, 29,
506-510. (m) Ishikura, M.; Mori, M.; Terashima, M.; Ban, Y. J. Chem.
Soc., Chem. Commun. 1982, 741-742. (n) Mori, M.; Uozumi, Y.; Kimura,
M.; Ban, Y. Tetrahedron 1986, 42, 3793-3806. (o) Mori, M.; Kimura,
M.; Uozumi, Y.; Ban, Y. Tetrahedron Lett. 1985, 26, 5947-5950. (p)
Ishikura, M.; Mori, M.; Ikeda, T.; Terashima, M.; Ban, Y. J. Org. Chem.
1982, 47, 2456-2461. (q) Boojamra, C. G.; Burow, K. M.; Ellman, J. A.
J. Org. Chem. 1995, 60, 5742-5743. (r) Goff, D. A.; Zuckermann, R. N.
J. Org. Chem. 1995, 60, 5744-5745. (s) Moroder, L.; Lutz, J.; Grams, F.;
Rudolph-Bo¨hner, S.; O¨ sapay, G.; Goodman, M.; Kolbeck, W. Biopolymers
1996, 38, 295-300. (t) Boojamra, C. G.; Burow, K. M.; Thompson L. A.;
Ellman, J. A. J. Org. Chem. 1997, 62, 1240-1256.
(10) Walser, A.; Fryer, R. I. In The Chemistry of Heterocyclic Com-
pounds; Fryer, R. I., Walser, A., Eds.; Wiley: New York, 1991; pp 947-
1052.
(11) (a) General procedure for the synthesis of these compounds, see:
Belov, V. N.; Funke, C.; Labahn, T.; Es-Sayed, M.; de Meijere, A. Eur. J.
Org. Chem. 1999, 1345-1356. Overall yields from methyl 2-chloro-2-
cyclopropylideneacetate: 2b (55%), 2c (53%), 2d (61%), 2e (20%), 2f
(19%). (b) Better yields of chlorolactames 2 were obtained using NH3/
MeOH instead of NaHCO3 aq/CH2Cl2: Limbach, M.; de Meijere, A.,
unpublished results.
(12) For a previous example of this kind of reaction, see: Makosza, M.;
Sienkiewicz, K.; Wojciechowski, K. Synthesis 1990, 850-852.
(13) The structures were solved by direct methods (SHELXS-93/97) and
refined on F2 by full matrix least-squares techniques (Sheldrick, G. M.;
SHELXL-93/97, Program for Crystal Structure Refinement, Universita¨t
Go¨ttingen, Germany, 1997). Crystallographic data (excluding structure
factors) for the structures reported in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supplementary publication
no. CCDC-141906 for 3b and CCDC-141907 for 5c. Copies of the data
can be obtained free of charge on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, U.K. [Fax: int. code +44(1223) 336-033; E-mail:
deposit@ccdc.cam.ac.uk].
4250
Org. Lett., Vol. 2, No. 26, 2000

Scheme 2
Table 2. Yields of Ketones 6, Dihydrofuran Derivatives 7, and
Tetrahydrofuro[1H][3,2-e][1,4]diazepine-2,5-diones 8 (see
Scheme 2)
yield (%)
entry
R
6
7
8
c
d
4-MeO(C6H4)CH2
4-Cl(C6H4)CH2
67
61
91
85
91
93
Acknowledgment. This work was supported by the
Deutsche Forschungsgemeinschaft (SFB 416, project A3) and
by the Bayer AG. C.F. is particularly grateful to the Bayer
AG for a 2 month stay in their Agricultural Research Station.
We thank Dr. M. Noltemeyer, Institut fu¨r Anorganische
Chemie, Universita¨t Go¨ttingen, for the X-ray crystal structure
analyses, and we are grateful to Dr. B. Knieriem for his
careful reading of the final manuscript.
corresponding dihydropyrroles 4a-f, and oxidation with
DDQ occurred more slowly in refluxing chloroform, afford-
ing 2,3,4,5-tetrahydrofuro[1H][3,2-e][1,4]diazepine-2,5-di-
ones 8c (91%) and 8d (93%)15 (Scheme 2, Table 2).
Supporting Information Available: Experimental details
and full characterization of all new compounds 3-8. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Reviews: (a) Hudlicky, T.; Kutchan, T. M.; Naqvi, S. M. Org. React.
1985, 33, 247-335. (b) Hudlicky, T.; Rulin, F.; Lovelace, T. C.; Reed, J.
W. In Studies in Natural Products Chemistry, StereoselectiVe Synthesis (Part
B); Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1989; Vol. 3, pp 3-72.
(c) Hudlicky, T.; Reed, J. W. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 5, pp 899-970.
(d) Hudlicky, T.: Becker, D. A.; Fan, R. L.; Kozhushkov, S. I. In Methods
of Organic Chemistry (Houben Weyl); de Meijere, A., Ed.; Thieme:
Stuttgart, 1997; Vol. E 17c, pp 2538-2563.
OL0068187
(15) These compounds are being tested for biological activity.
Org. Lett., Vol. 2, No. 26, 2000
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