Novel syntheses of tetrahydrobenzodiazepines and dihydropyrazines via isocyanide-based multicomponent reactions of diamines

Article abstract of DOI:10.1021/cc900125a

In this work, two novel isocyanide-based mul multicomponent reactions of 1,2-diamine compounds with diketene have been developed as efficient strategies for the synthesis of 2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepine2-carboxamidcs with regiochemical control and 1,6-dihydropyrazinc-2,3-dicarbonitrilcs in good to excellent yields at ambient temperature.

Full text of DOI:10.1021/cc900125a

186
J. Comb. Chem. 2010, 12, 186–190
Novel Syntheses of Tetrahydrobenzodiazepines and Dihydropyrazines
via Isocyanide-Based Multicomponent Reactions of Diamines
Ahmad Shaabani,*,† Ali Maleki,† Fatemeh Hajishaabanha,† Hamid Mofakham,†
Mozhdeh Seyyedhamzeh,† Mojtaba Mahyari,† and Seik Weng Ng‡
Department of Chemistry, Shahid Beheshti UniVersity, 19396-4716, Tehran, Iran, and Department of
Chemistry, UniVersity of Malaya, 50603, Kuala Lumpur, Malaysia
ReceiVed August 15, 2009
In this work, two novel isocyanide-based multicomponent reactions of 1,2-diamine compounds with diketene
have been developed as efficient strategies for the synthesis of 2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-
2-carboxamides with regiochemical control and 1,6-dihydropyrazine-2,3-dicarbonitriles in good to excellent
yields at ambient temperature.
diketene,22 herein, we wish to report two hitherto unknown
Introduction
IMCRs which afford 2,3,4,5-tetrahydro-1H-benzo[b][1,4]-
Benzodiazepines1 and pyrazines2 are widely used in
medicinal chemistry. Benzodiazepines as one of the most
widely prescribed class of psychotropics,3 which have
remarkable central nervous system depressant activity,4 with
various biological interest5 have been extended to various
diseases such as cancer,6 viral infection (HIV),7 and cardio-
vascular disorders.8 Pyrazines, which are biosynthesized from
amino acids, are common units in a wide variety of marine
natural products showing cytostatic and antitumor properties,9
and pyrazinamides10 as well as pyrazinesters11 have been
successfully evaluated in vitro and in vivo for antituberculosis
activity. 2,3-Dicyanopyrazines are very useful starting ma-
terials for subsequent heterocyclization such as azaphthalo-
cyanines,12 tetrazoles,13 and nucleophilic substitutions of a
nitrile and polycyclic quinoxalines.14
Diazepam I is the first marketed drug of benzodiazepine
derivatives possessing anxiolytic, anticonvulsant, hypnotic,
sedative, skeletal muscle relaxant, and amnestic properties.15
The benzodiazepine core is indeed a “privileged scaffold”16
found in compounds active against a variety of target types
including therapeutic and prophylactic agent for diabetes,
diabetic nephropathy, or glomerulosclerosis II17 and peptide
hormones III.18 CB1 Cannabinoid receptor antagonists IV19
are another example of six-membered ring analogs from
pyrazine heterocycles (Figure 1).
diazepine-2-carboxamides 4 with regiochemical control via
a condensation reaction between an isocyanide 1, diketene
2, and an aromatic 1,2-diamine (AD) 3. Alternatively, using
2,3-diaminomaleonitrile (DAMN) 5 instead of AD produces
1,6-dihydropyrazine-2,3-dicarbonitriles 6 in good to excellent
yields at ambient temperature (Scheme 1).
Results and Discussion
In a pilot experiment, o-phenylenediamine, diketene, and
cyclohexyl isocyanide were stirred in acetonitrile at room
temperature. The progress of the reaction was monitored by
TLC until o-phenylenediamine as limiting reactant of the
reaction was consumed after 4 h. However, in the event,
seven-membered ring compound 8a was generated and
nucleophilic attack by isocyanide did not occur. On the other
hand, the predicted mechanism was not observed under the
given reaction conditions, and the isolated product was
4-methyl-1H-benzo[b][1,4]diazepin-2(3H)-one 8a.
It is interesting to note that compound 8a in the presence
of p-TsOH · H2O was reacted with isocyanide and produced
the compound 4a (Scheme 2).
To evaluate the use of this interesting approach, a variety
of ADs carrying electron-releasing groups such as CH3
(4d-j), electron-withdrawing groups such as COPh (4k) and
halogenated diamines (4l-n), and aliphatic, alicyclic, and
aromatic isocyanides were reacted under similar circum-
stances. The results are summarized in Table 1. The two-
step reaction proceeded very efficiently under mild conditions
at room temperature to produce the corresponding 2,3,4,5-
tetrahydro-1H-benzo[b][1,4]diazepine-2-carboxamide deriva-
tives 4a-n in high yields. The structures of compounds
Recently, benzodiazepines have been the object of intense
investigations in organic synthesis and medicinal chemistry
and several approaches have been reported for the synthesis
of this heterocyclic compounds.20 However, the development
of new synthetic routes for the preparation of pyrazine and
benzodiazepine derivatives acquired relevance in recent
years.
4a-n were deduced from their IR, mass, 1H NMR, and 13
C
In view of our current studies on isocyanide-based
multicomponent reactions (IMCRs) of diamines21 and
NMR spectral data.
The first step of this reaction was highly regioselective. It
may be explained that the selectivity is due to the electronic
effect of the electron-releasing groups such as CH3 at the
para position is activated exclusively, and product 8A (not
* Corresponding author. E-mail: a-shaabani@cc.sbu.ac.ir.
† Shahid Beheshti University.
‡ University of Malaya.
10.1021/cc900125a  2010 American Chemical Society
Published on Web 11/23/2009

Syntheses via Multicomponent Reactions of Diamines
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 187
Figure 1. Examples of medicinal benzodiazepine and pyrazine derivatives.
Scheme 1. Synthesis of 2,3,4,5-Tetrahydro-1H-benzo[b][1,4]diazepine-2-carboxamides 4 and 1,6-Dihydropyrazine-
2,3-dicarbonitriles 6
Scheme 2. Synthesis of Compound 4a
Table 1. Synthesis of 2,3,4,5-Tetrahydro-1H-benzo[b][1,4]diazepine-2-carboxamides 4a-n
entry
isocyanide
diamine
product
time (h)
yielda (%)
1
2
3
4
5
6
7
8
cyclohexyl isocyanide
tert-butyl isocyanide
1,1,3,3-tetramethylbutyl isocyanide
cyclohexyl isocyanide
tert-butyl isocyanide
1,1,3,3-tetramethylbutyl isocyanide
2,6-(Me)2phenyl isocyanide
benzyl isocyanide
cyclohexyl isocyanide
benzyl isocyanide
o-phenylenediamine
o-phenylenediamine
o-phenylenediamine
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
5
6
6
4
4
5
5
5
5
6
7
7
7
7
90
82
80
92
88
80
86
85
90
85
75
87
80
80
4,5-dimethyl-o-phenylenediamine
4,5-dimethyl-o-phenylenediamine
4,5-dimethyl-o-phenylenediamine
4,5-dimethyl-o-phenylenediamine
4,5-dimethyl-o-phenylenediamine
4-methyl-o-phenylenediamine
4-methyl-o-phenylenediamine
3,4-diaminobenzophenone
9
10
11
12
13
14
cyclohexyl isocyanide
cyclohexyl isocyanide
1,1,3,3-tetramethylbutyl isocyanide
benzyl isocyanide
4,5-dichloro-o-phenylenediamine
4,5-dichloro-o-phenylenediamine
4,5-dichloro-o-phenylenediamine
a Isolated yield.
Figure 2. Structure of intermediate products.
Figure 3. ORTEP diagram for 4i.
8A′) is formed. While in the case of electron-withdrawing
groups such as COPh, which deactivate the para amino
group, the reaction is initiated by the meta amino group to
give 8B (not 8B′) as the favored product (Figure 2).
The structure of the product 4i was confirmed unambigu-
ously by single-crystal X-ray analysis (Figure 3).
In addition, three substituents in the products can be varied
to yield diversity of molecules for chemical library. Repre-
sentative examples of this reaction are shown in Figure 4.
The suggested mechanism for the formation of products
4a-n is illustrated in Scheme 3. It is conceivable that, the
initial event is the formation of ꢀ-keto amide 7 from

188 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Shaabani et al.
Figure 4. Structure of 2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-2-carboxamides 4a-n.
Table 2. Synthesis of 1,6-Dihydropyrazine-2,3-dicarbonitrile
Derivatives 6a-e
Scheme 3. Possible Mechanism for the Formation of
Products 4a-n
entry
isocyanide
product
time (h)
yielda (%)
1
2
3
cyclohexyl isocyanide
tert-butyl isocyanide
1,1,3,3-tetramethylbutyl
isocyanide
6a
6b
6c
20
90
24
85
24 (15)b
50 (85)b
4
5
ethyl 2-isocyanoacetate
benzyl isocyanide
6d
6e
24
24
85
85
a Isolated yield. b Under refluxing conditions.
nucleophilic attack of 3 to the carbonyl (lactone) site of 2.
The product 8 was formed by intramolecular nucleophilic
attack of amine to ketone. On the basis of the well-established
chemistry of reaction of isocyanides with imines,23 inter-
mediate 10 was produced by nucleophilic attack of isocya-
nide 1 to activated iminium 9 followed by nucleophilic attack
of an H2O molecule on the nitrilium moiety and production
of compound 11. Finally, tautomerization of intermediate 11
produces 2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-2-
carboxamide derivatives 4a-n.
In order to investigate the scope and limitations of this
reaction, we decided to extend it to 2,3-diaminomaleonitrile
(DAMN) instead of aromatic 1,2-diamines (ADs). In this
regard, DAMN, diketene, and cyclohexyl isocyanide in
acetonitrile were stirred at room temperature. The progress
of the reaction was monitored by TLC. After 20 h, the
reaction was completed and 5-(cyclohexylamino)-6,6-di-
methyl-1,6-dihydropyrazine-2,3-dicarbonitrile 6a was ob-
tained in 90% yield. To evaluate the use of this approach, a
variety of aliphatic, alicyclic, and aromatic isocyanides as a
third component of this reaction was condensed under similar
circumstances. The results are shown in Table 2, and the
structures of the products 1,6-dihydropyrazine-2,3-dicarbo-
nitriles 6a-e are demonstrated in Figure 5.
Figure 5. Structure of 1,6-dihydropyrazine-2,3-dicarbonitriles 6a-e.
This reaction proceeded very cleanly under mild conditions
at room temperature and no undesirable side reactions were
observed. The reaction was compatible with a wide range
of isocyanides. Treatment of tert-butyl-, 2,6-dimethylphenyl-,
and benzyl isocyanides, and ethyl 2-isocyanoacetate with
DAMN in the presence of diketene in acetonitrile at ambient
temperature led to the formation of the corresponding 1,6-
dihydropyrazine-2,3-dicarbonitrile derivatives in high yields.
Only, in the case of 1,1,3,3-tetramethylbutyl isocyanide after
24 h, the reaction yield was 50%. It is important to note
that, when this reaction was performed under reflux condi-
tions in CH3CN, yield of the reaction increased to 85% after
15 h (Table 2, entry 3).
The possible mechanism for the formation of products
6a-e is shown in Scheme 4. It is very interesting that the
initial event is the formation of acetoacetic acid 12 from the
reaction of diketene 2 with trace water of the reaction
media.24 Then, the intermediate 13 was produced from the
nucleophilic attack of DAMN 5 to the ketone site of 12.

Syntheses via Multicomponent Reactions of Diamines
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 189
Scheme 4. Possible Mechanism for the Formation of
Products 6a-e
5.34 (1H, br s, NH), 6.85 (2H, br s, H-Ar), 6.95 (2H, br s,
H-Ar), 7.64 (1H, br s, NH-CO), 9.55 (1H, br s, NH-CO).
13C NMR (75.47 MHz, DMSO-d6) δ: 24.9, 25.0, 25.6, 26.6,
32.6, 32.8, 43.4, 48.2, 67.7, 121.9, 122.0, 122.6, 125.0, 131.3,
138.7, 170.4, 173.2. MS m/z: 302 (M+ + 1, 30), 175 (100),
133 (85), 55 (14), 41 (23). Anal. Calcd for C17H23N3O2: C,
67.75; H, 7.69; N, 13.94; found C, 67.65; H, 7.74; N, 13.84.
Typical Procedure for the Synthesis of 5-(Cyclohexyl-
amino)-6,6-dimethyl-1,6-dihydropyrazine-2,3-dicarboni-
trile (6a). A solution of DAMN (0.108 g, 1 mmol), diketene
(0.084 g, 1 mmol), and cyclohexyl isocyanide (0.109 g, 1
mmol) in 3 mL of CH3CN was stirred for 20 h at ambient
temperature. After completion of the reaction, as indicated
by TLC (ethyl acetate/n-hexane, 3/1), the precipitate was
filtered off, and then crystallized from acetone to give 6a as
colorless crystals. mp 252-254 °C. IR (KBr) cm-1: 3343,
3081, 2931, 2852, 2217, 1579, 1539, 1451, 1391. 1H NMR
(300.13 MHz, DMSO-d6) δ: 1.00-2.10 (16H, m, 5CH2 of
cyclohexyl and 2CH3), 3.69 (1H, m, CH of cyclohexyl), 6.86
(1H, d, J ) 7.6 Hz, NH), 7.12 (1H, br s, NH). 13C NMR
(75.47 MHz, DMSO-d6) δ: 24.3, 25.2, 25.7, 31.9, 49.6, 50.0,
110.2, 110.8, 114.9, 118.4, 155.8. MS m/z: 257 (M+, 20),
242 (25), 175 (25), 160 (100), 133 (22), 57 (45), 41 (75).
Anal. calcd for C14H19N5: C, 65.34; H, 7.44; N, 27.22; found
C, 65.28; H, 7.33; N, 27.20.
Imine 14 was obtained through decarboxylation of 13.24 On
the basis of the well established chemistry of the reaction of
isocyanides with imines,23 intermediate 15 was produced by
nucleophilic attack of isocyanide 1 to imine 14, followed
by an intramolecular nucleophilic attack by the NH2 group
on the activated nitrile moiety, intermediate 16 is produced.
Finally, imine-enamine tautomerization of intermediate 16
produces 1,6-dihydropyrazine-2,3-dicarbonitrile derivatives
6a-e.
Conclusions
Acknowledgment. We gratefully acknowledge financial
support from the Research Council of Shahid Beheshti
University.
In summary, we have developed a novel one-pot two-step
protocol for the synthesis of 2,3,4,5-tetrahydro-1H-
benzo[b][1,4]diazepine-2-carboxamide derivatives with re-
giochemical control and a novel one-pot IMCR for the
synthesis of 1,6-dihydropyrazine-2,3-dicarbonitrile deriva-
tives from condensation reactions between diketene, various
isocyanides, and aromatic 1,2-diamines or 2,3-diaminoma-
leonitrile, respectively. We showed that diketene participates
in two different ways in reactions with diamines and
isocyanides. These two novel reactions can be regarded as
efficient approaches for the preparation of pharmaceutically
relevant tetrahydrobenzodiazepine and dihydropyrazine de-
rivatives in good to excellent yields at ambient temperature.
Supporting Information Available. Experimental pro-
1
cedures, Mass, IR, H NMR, and 13C NMR spectra for
compounds 4a-n, 6a-e, and 8d-h, and crystallographic
data for 4f and 4i (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
References and Notes
(1) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003,
103, 893–930.
(2) (a) Dembitsky, V. M.; Gloriozova, T. A.; Poroikov, V. V.
Mini-ReV. Med. Chem. 2005, 5, 319–336. (b) Gryszkiewicz-
Wojtkielewicz, A.; Jastrzebska, I.; Morzycki, J. W.; Ro-
manowska, D. B. Curr. Org. Chem. 2003, 7, 1257–1277. (c)
Buron, F.; Ple, N.; Turck, A.; Queguiner, G. J. Org. Chem.
2005, 70, 2616–2621. (d) Elmaaty, T. A.; Castle, L. W. Org.
Lett. 2005, 7, 5529–5530. (e) Bonde, C. G.; Gaikwad, N. J.
Bioorg. Med. Chem. 2004, 12, 2151–1254. (f) Gohlke, H.;
Gundisch, D.; Schwarz, S.; Seitz, G.; Tilotta, M. C.; Wegge,
T. J. Med. Chem. 2002, 45, 1064–1072.
Experimental Section
Typical Procedure for the Synthesis of N-Cyclohexyl-2-
methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-
2-carboxamide (4a). A solution of o-phenylenediamine
(0.108 g, 1 mmol) and diketene (0.084 g, 1 mmol) was stirred
in 3 mL of CH3CN for 4 h at ambient temperature. After
completion of the reaction, as indicated by TLC (ethyl
acetate/n-hexane, 2/1), cyclohexyl isocyanide (0.109 g, 1
mmol) and p-TsOH · H2O (0.195 g, 1 mmol) were added to
the mixture. After completion of the reaction, as indicated
by TLC (ethyl acetate/n-hexane, 3/1) after 1 h, the compound
4a was produced. After that, the precipitate was filtered off
and washed with water, and then crystallized from acetone
to give 4a as colorless crystals. mp 263-265 °C. IR (KBr)
cm-1: 3347, 3295, 3200, 3139, 3087, 2926, 2851, 1675,
(3) Michelini, S.; Cassano, G. B.; Frare, F.; Perugi, G. Pharma-
copsychiatry 1996, 29, 127–134.
(4) (a) Archer, G. A.; Sternbach, L. H. Chem. ReV. 1968, 68, 747–
784. (b) Hamor, T. A.; MartinI. L. In Progress in Medicinal
Chemistry; Ellis, G. P., West, G. B., Eds.; Elsevier Science
Publishers: Amsterdam, 1983; Vol. 20. (c) Langnickel, R.;
Bluth, R.; Ott, T. Pharmazie 1986, 41, 689–693. (d) Parola,
A. L.; Yamamura, H. I.; Laird, H. E. Life Sci. 1993, 52, 1329–
1342.
(5) (a) Knabe, J.; Buech, H. P.; Bender, S. Arch. Pharm. 1995,
328, 59–66. (b) Brogden, R. N.; Heel, R. C.; Speight, T. M.;
Avery, G. S. Drugs 1980, 20, 161–178.
1
1634, 1597, 1526, 1449, 1376. H NMR (300.13 MHz,
DMSO-d6) δ: 1.00-1.70 (13H, m, 5CH2 of cyclohexyl and
CH3), 2.39 (2H, br s, CH2), 3.52 (1H, m, CH of cyclohexyl),
(6) Atwal, K. S.; Bergey, J. L.; Hedberg, A.; Moreland, S. J. Med.
Chem. 1987, 30, 635–640.

190 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Shaabani et al.
(7) (a) Merluzzi, V.; Hargrave, K. D.; Labadia, M.; Grozinger,
K.; Skoog, M.; Wu, J. C.; Shih, C.-K.; Eckner, K.; Hattox,
S.; Adams, J.; Rosenthal, A. S.; Faanes, R.; Eckner, R. J.;
Koup, R. A.; Sullivan, J. L. Science 1990, 250, 1411–1413.
(b) Di Braccio, M.; Grossi, G.; Roma, G.; Vargiu, L.; Mura,
M.; Marongiu, M. E. Eur. J. Med. Chem. 2001, 36, 935–
949.
benzodiazepine deriVatiVes haVing CCK and/or gastrin an-
tagonistic actiVity. U.S. Patent 5,585,376, 1996.
(18) Tranquillini, M. E.; Cassara, P. G.; Corsi, M.; Curotto, G.;
Donati, D.; Finizia, G.; Pentassuglia, G.; Polinelli, S.; Tarzia,
G.; Ursini, A.; Van Amsterdam, F. T. M. Arch. Pharm. 1997,
330, 353–357.
(19) Barth, F. Annu. Rep. Med. Chem. 2005, 40, 103–118.
(20) (a) Kruse, H. Drug DeV. Res. 1982, 2, 145–151. (b) Ursini,
A.; Capelli, A. M.; Carr, R. A. E.; Cassara, P.; Corsi, M.;
Curcuruto, O.; Curotto, G.; Cin, M. D.; Davalli, S.; Donati,
D.; Feriani, A.; Finch, H.; Finizia, G.; Gaviraghi, G.; Marien,
M.; Pentassuglia, G.; Polinelli, S.; Ratti, E.; Reggiani, A.;
Tarzia, G.; Tedesco, G.; Tranquillini, M. E.; Trist, D. G.; Van
Amsterdam, F. T. M. J. Med. Chem. 2000, 43, 3596–3613.
(c) Herpin, T. F.; Van Kirk, K. G.; Salvino, J. M.; Yu, S. T.;
Labaudiniere, R. F. J. Comb. Chem. 2000, 2, 513–521. (d)
Cepanec, I.; Litvic, M.; Pogorelic, I. Org. Process Res. DeV.
2006, 10, 1192–1198. (e) Zhao, H. Y.; Liu, G. J. Comb. Chem.
2007, 9, 1164–1176. (f) De Silva, R. A.; Santra, S.; Andreana,
P. R. Org. Lett. 2008, 10, 4541–4544. (g) Butini, S.; Gabellieri,
E.; Huleatt, P. B.; Campiani, G.; Franceschini, S.; Brindisi,
M.; Ros, S.; Coccone, S. S.; Fiorini, I.; Novellino, E.; Giorgi,
G.; Gemma, S. J. Org. Chem. 2008, 73, 8458–8468. (h) Reid,
W.; Stahlofen, P. Chem. Ber. 1957, 90, 825–828.
(21) (a) Shaabani, A.; Maleki, A.; Moghimi-Rad, J. J. Org. Chem.
2007, 72, 6309–6311. (b) Shaabani, A.; Maleki, A.; Mofa-
kham, H.; Khavasi, H. R. J. Comb. Chem. 2008, 10, 323–
326. (c) Shaabani, A.; Maleki, A.; Mofakham, H.; Moghimi-
Rad, J. J. Org. Chem. 2008, 73, 3925–3927. (d) Shaabani,
A.; Maleki, A.; Mofakham, H. J. Comb. Chem. 2008, 10, 595–
598. (e) Shaabani, A.; Rezayan, A. H.; Keshipour, S.; Sarvary,
A.; Ng, S. W. Org. Lett. 2009, 11, 3342–3345.
(22) (a) Shaabani, A.; Seyyedhamzeh, M.; Maleki, A.; Rezazadeh,
F.; Behnam, M. J. Comb. Chem. 2009, 11, 375–377. (b)
Shaabani, A.; Seyyedhamzeh, M.; Maleki, A.; Behnam, M.;
Rezazadeh, F. Tetrahedron Lett. 2009, 50, 2911–2913. (c)
Shaabani, A.; Seyyedhamzeh, M.; Maleki, A.; Behnam, M.
Tetrahedron Lett. 2009, 50, 6355–6357.
(23) (a) Do¨mling, A.; Ugi, I. Angew. Chem., Intl. Ed. 2000, 39,
3168–3210. (b) Do¨mling, A. Chem. ReV. 2006, 106, 17–89.
(c) El Kaim, L.; Grimaud, L. Tetrahedron 2009, 65, 2153–
2171. (d) Ganem, B. Acc. Chem. Res. 2009, 42, 463–472.
(24) Clemens, R. J. Chem. ReV. 1986, 86, 241–318.
(8) (a) Werner, W.; Baumgart, J.; Burckhardt, G.; Fleck, W. F.;
Geller, K.; Gutsche, W.; Hanschmann, H.; Messerschmidt,
A.; Roemer, W. Biophys. Chem. 1990, 35, 271–285. (b)
Claremon, D. A.; Liverton, N.; Selnick, H. G.; Smith, G. R.
Novel
(N-(1-alkyl-5-phenyl-2,3,4,5-tetrahydro-1H-
benzo[b][1,4]diazepin-3yl)-acetamides. PCT Int. Appl. WO
9640653, 1996.
(9) (a) Betancor, C.; Freire, R.; Perez-Martin, I.; Prange, T.;
Suarez, E. Tetrahedron 2005, 61, 2803–2814. (b) Li, W.;
Fuchs, P. L. Org. Lett. 2003, 5, 2849–2852. (c) LaCour, T. G.;
Guo, C.; Boyd, M. R.; Fuchs, P. L. Org. Lett. 2000, 2, 33–
36.
(10) (a) Fukuwatari, T.; Sugimoto, E.; Shibata, K. Biosc. Biotech.
Biochem. 2002, 66, 1435–1441. (b) Suzuki, Y.; Suzuki, A.;
Tamaru, A.; Katsukawa, C.; Oda, H. J. Clin. Microbiol. 2002,
40, 501–507.
(11) (a) Cynamon, M. H.; Speirs, R. J.; Welch, J. T. Antimicrob.
Agents Chemother. 1998, 42, 462–463. (b) Bergmann, K. E.;
Cynamon, M. H.; Welch, J. T. J. Med. Chem. 1996, 39, 3394–
3400.
(12) Zimcik, P.; Miletin, M.; Musil, Z.; Kopecky, K.; Slajsova,
D. Dyes Pigments 2008, 77, 281–287.
(13) Guillou, S.; Jacob, G.; Terrier, F.; Goumont, R. Tetrahedron
2009, 65, 8891–8895.
(14) Ahmad, A. R.; Mehta, L. K.; Parrick, J. J. Chem. Soc., Perkin
Trans. 1 1996, 2443–2449.
(15) Mandrioli, R.; Mercolini, L.; Raggi, M. A. Curr. Drug Metab.
2008, 9, 827–44.
(16) (a) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.;
Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber,
D. F.; Anderson, P. S. J. Med. Chem. 1988, 31, 2235–2246.
(b) Herpin, T. F.; Van Kirk, K. G.; Salvino, J. M.; Yu,
S. T.; Labaudiniere, R. F. J. Comb. Chem. 2000, 5, 513–
521.
(17) (a) Ohtake, Y.; Fukaya, Y. E. 2,3,4,5-Tetrahydro-1H-1,5-
benzodiazepine derivative and medicinal composition. Patent
1820799A1, 2007. (b) Finch, H.; Shah, P.; Carr, R. A. E. 1,5-
CC900125A