Concise preparation of novel tricyclic chemotypes: Fused hydantoin-benzodiazepines

Article abstract of DOI:10.1016/j.tetlet.2010.06.131

The following article describes a concise synthesis of a collection of 4,5-dihydro-1H-benzo[e][1,4]diazepines fused to a hydantoin ring. Molecular complexity and biological relevance are high and structures are generated in a mere three steps, employing the Ugi reaction to assemble diversity reagents. The protocol represents a novel UDC (Ugi-deprotect-cyclize) strategy employed in the Ugi-5-component CO₂-mediated condensation, followed by further cyclization under basic conditions, to afford the fused hydantoin. Mechanistic caveats, dependent on the aldehydes of choice will be revealed and a facile oxidation of the final products to imidazolidenetriones is briefly discussed.

Full text of DOI:10.1016/j.tetlet.2010.06.131

Tetrahedron Letters 51 (2010) 4689–4692
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Concise preparation of novel tricyclic chemotypes: fused
hydantoin–benzodiazepines
Steven Gunawan a, Gary S. Nichol b, Shashi Chappeta a, Justin Dietrich a, Christopher Hulme a,
*
a The Southwest Comprehensive Center for Drug Discovery and Development, College of Pharmacy, Department of Pharmacology/Toxicology, The University of Arizona,
Tucson, AZ 85721, USA
b Department of Chemistry and Biochemistry, The University of Arizona, Tucson, AZ 85721, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The following article describes a concise synthesis of a collection of 4,5-dihydro-1H-benzo[e][1,4]diaze-
pines fused to a hydantoin ring. Molecular complexity and biological relevance are high and structures
are generated in a mere three steps, employing the Ugi reaction to assemble diversity reagents. The pro-
tocol represents a novel UDC (Ugi-deprotect-cyclize) strategy employed in the Ugi-5-component CO2-
mediated condensation, followed by further cyclization under basic conditions, to afford the fused hydan-
toin. Mechanistic caveats, dependent on the aldehydes of choice will be revealed and a facile oxidation of
the final products to imidazolidenetriones is briefly discussed.
Received 18 June 2010
Revised 26 June 2010
Accepted 28 June 2010
Available online 8 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Operationally friendly protocols to produce libraries of novel
small molecules of high molecular complexity are in huge demand
for the interrogation of biological systems.1 As such, development
of new MCRs (multi-component reactions) and functional group
modification of MCR products have proven fruitful tools in the
quest for new molecular probes and their expedited progression
along the drug discovery value chain.2 Such products with high-
iterative-efficiency potential2 have found their way into numerous
corporate compound collections and examples exist of hit to clinic
campaigns were final drugs resided in the virtual diversity space of
the original hit generation library.3 This communication describes
the development of a concise three step synthesis of novel tricyclic
4,5-dihydro-1H-benzo[e][1,4]diazepines fused to an hydantoin
ring and employs the rarely used 5-component Ugi reaction
(U-5-CR), Scheme 1. Essentially, CO2 in MeOH produces carbonic
acid and the reaction follows the widely accepted classical Ugi
mechanism, even though the condensation product differs in that
a urethane is now encapsulated within the final skeleton 1. Prior
reports on applications of this reaction are scarce4, although our
planned strategy builds on an early report from this laboratory
which employed the amidic NH of U-5-CR as an internal nucleo-
phile to afford fully functionalized libraries of hydantoins in a mere
two steps.4a
was prepared in three steps from the commercially available 2-
aminobenzylamine as portrayed in Scheme 3 according to the ref-
erenced procedure.5 The purified Ugi product is subsequently trea-
ted with trifluoroacetic acid promoting amine deprotection and
C-
R3
N+
N+
R1
-O
O
R3
CHO
NC
NH2
OH
CO2
R1
R3
R2
O
R2
O
N+
H
R2
R1
N
H
O
O
R1
R3
N
H
N
O
O
N
R3
R2
O
R2
R1
N
H
1
Scheme 1. 5-Component CO2 modified Ugi reaction.
O
O
R3
R3
N
N
N
O
N
A summary of the generic scaffolds 2 and 3 made accessible and
introduced in this article is shown in Figure 1. Thus, construction of
the desired Ugi precursor 6 is achieved via condensation of ortho-
N-Boc benzylamines 4, phenylglyoxaldehydes 5, isonitriles and a
saturated solution of CO2 in methanol, Scheme 2. Note that 4
R1
R1
O
O
R2
N
H
NH
O
R2
2
3
* Corresponding author.
E-mail address: hulme@pharmacy.arizona.edu (C. Hulme).
Figure 1. Generic scaffolds of 4,5-dihydro-1H-benzo[e][1,4]diazepines fused to a
hydantoin ring 2 and imidazolidenetriones 3.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.131

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S. Gunawan et al. / Tetrahedron Letters 51 (2010) 4689–4692
R2
O
O
O
O
O
H
N
O
R3
H
N
H+
KOH
NH2
N
HN R3
N
R1
R2
R3
O
N
R1
O
R1
O
NHBoc
O
O
N
N
H
4
5
R1
BocHN
R3 NC
CO2
MeOH
R2
R2
6
7
8
Scheme 2. Preparation of fused benzodiazepine–hydantoins.
Cbz-Cl, Et3N
DCM
Boc2O, DIPEA
DCM
H2, Pd
MeOH
99%
NH2
NH2
NHCbz
NH2
NHCbz
NHBoc
NH2
NHBoc
90%
96%
4a
4b
4
Scheme 3. Synthesis of Boc-2-aminobenzylamine 4.
cyclization to the 4,5-dihydro-1H-benzo[e][1,4]diazepine, 7 typi-
cally in good yield (>90%). Note that this transformation extends
the repertoire of available chemotypes from UDC (Ugi/DeBoc/Cy-
clize) methodology and libraries of this benzodiazepine should
now be readily accessible. Final ring construction was achieved
by treatment of 7 with KOH, thus promoting cyclization and fusion
of a hydantoin-like ring while simultaneously initiating a 1,3-H
shift to give the tricyclic chemotype 8 in good yield. As such, the
methodology represents an example of a post-condensation Ugi
modification4a that employs two internal nucleophiles in distinct
operations, generating a novel scaffold of high complexity in a suc-
cinct 3 functional operations.
With a satisfactory protocol to the generic structure 8 in place,6
a small collection of these molecules were prepared to demon-
strate the generality of the reaction sequence, Figure 2. Diversifica-
tion was based on the commercial availability of different
isonitriles and substituted phenylglyoxaldehydes. Reported per-
cent yields represent conversions of the two combined steps from
the Ugi product 6 to scaffold 8. In essence, scaffold 7 did not re-
quire purification, thus simplifying the production protocol.
Unequivocal evidence for the structure of this chemotype was pro-
vided by X-ray crystallography for 9, Figure 3.7
Figure 3. X-ray crystal structure of 9.
O
O
O
O
O
N
N
N
N
N
N
N
N
N
N
O
O
O
O
O
N
H
N
H
N
H
N
H
N
H
9, 39%, 79%
10, 36%, 96%
11, 39%, 58%
12, 48%, 72%
13, 52%, 71%
O
O
O
O
N
O
N
N
N
N
N
N
N
O
O
O
N
H
N
H
N
H
N
H
O
CF3
O
F
14, 63%, 78%
15, 52%, 52%
16, 55%, 72%
17, 29%, 76%
Figure 2. Example analogs (x% = Ugi yield, x% = yield of 8 from 6).

S. Gunawan et al. / Tetrahedron Letters 51 (2010) 4689–4692
4691
O
O
O
O
R3
O
R3
O
N
R3
R3
N
N
N
N
N
N
N
CDCl3
CDCl3
R1
R1
R1
R1
2 = ortho-MeO
O
O
O
O
NH
O
NH
O
N
R
N
H
R2 = ortho-MeO
R2
O
R2
O
O
OH
3
16a
16b
8
Scheme 4. Aerobic chemical transformations of 8 on standing in CDCl3.
O
O
O
O
O
N
N
N
N
N
N
N
N
N
N
i
ii
iii
O
H+
O
O
O
N
N
H
N
H
N
H
N
H
O
O
O
O
O
OH
OH
OH2
OH
16
16b
Scheme 5. Proposed mechanism involving (i) aromatic substitution, (ii) tautomerization–rearomatization and (iii) oxidation to the imine.
Interestingly, the tri-cyclic scaffolds 8 underwent a chemical
oxidative transformation to the pharmacologically relevant imi-
dazolidinetriones8 3 (Scheme 4) on standing in CDCl3. One partic-
ular example 9 showed 75% conversion to its imidazolidinetrione
congener after 10 days in CDCl3. Oxidative carbon–carbon double
bond cleavage of similar hydantoin derivatives has been previously
reported9 and compound 9 was successfully proven to undergo
such oxidation upon treatment with KMnO4.10 Encouragingly for
future screening efforts the fused hydantoin compounds are stable
in DMSO and other solvents, with no oxidation detected over pro-
longed periods in solution. As supported by a previous study,11 this
finding exemplifies the phenomenon of air oxidation in chloro-
form, suggested to be far more facile than in other regularly used
solvents. Oxidative rate acceleration of 9 by light suggests a singlet
oxygen mechanism may be involved in this process.
References and notes
1. (a) Hulme, C. Multicomponent React. 2005, 311–341; (b) Bienayme, H.; Hulme,
C.; Oddon, G.; Schmitt, P. Chem. Eur. J. 2000, 6, 3321.
2. (a) Dolle, R. E.; La Bourdonnec, B.; Goodman, A. J.; Morales, G. A.; Thomas, C. J.;
}
Zhang, W. J. Comb. Chem. 2009, 11, 739–790; (b) Domling, A. Chem. Rev. 2006,
106, 17–89; (c) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51–80; (d) Hulme,
C.; Lee, Y. S. Mol. Div. 2008, 12, 1–15; (e) Hulme, C.; Nixey, T. Curr. Opin. Drug
Discovery Dev. 2003, 6, 921–929.
3. (a) Hulme, C.; Peng, J.; Tang, S. Y.; Burns, C. J.; Morize, I.; Labaudiniere, R. J. Org.
Chem. 1998, 63, 8021–8023; (b) Nixey, T.; Hulme, C. Tetrahedron Lett. 2002, 43,
6833–6835; (c) Habashita, H.; Kokubo, M.; Hamano, S. I.; Hamanaka, N.; Toda,
M.; Shibayama, S.; Tada, H.; Sagawa, K.; Fukushima, D.; Maeda, K.; Mitsuya, H. J.
Med. Chem. 2006, 49, 4140–4152; (d) Nishizawa, R.; Nishiyama, T.; Hisaichi, K.;
Matsunaga, N.; Minamoto, C.; Habashita, H.; Takaoka, Y.; Toda, M.; Shibayama,
S.; Tada, H.; Sagawa, K.; Fukushima, D.; Maeda, K.; Mitsuya, H. Bioorg. Med.
Chem. Lett. 2007, 17, 727–731.
4. (a) Hulme, C.; Ma, L.; Romano, J.; Morton, G.; Tang, S.; Cherrier, M.; Choi, S.;
Salvino, J.; Labaudiniere, R. Tetrahedron Lett. 2000, 41, 1889–1893; (b) Keating,
T. A.; Armstrong, R. W. J. Org. Chem. 1998, 63, 867–871.
Note an exception was found with compound 16, an analog
5. For the preparation of 4:
derived from 2-methoxyphenylglyoxaldehyde. Interestingly,
a
2-Aminobenzyl-Cbz-amine (4a): To a solution of 2-aminobenzylamine (5.70 g,
46.7 mmol) in anhydrous dichloromethane (150 ml) was added DIPEA
(16.30 ml, 93.0 mmol). Next, benzyl chloroformate (6.66 ml, 46.7 mmol) in
anhydrous dichloromethane (45 ml) was added drop-wise via syringe. The
second product was also observed during exposure to CDCl3
(16a:16b = 1:4.5). Tentatively, the following mechanism,
Scheme 5, is proposed that involves aromatic substitution with
water, tautomerization/rearomatization, and oxidation to the
imine, 16b. Evidence for this structure was provided by detailed
NMR studies.
In summary, a concise three-step synthesis of a collection of
fused 4,5-dihydro-1H-benzo[e][1,4]diazepines-hydantoins has
been successfully developed that utilizes the scarcely employed
5-component CO2-modified Ugi reaction as the diversity generat-
ing event followed by two subsequent cyclization transformations.
The first transformation occurs under acidic conditions to con-
struct the benzodiazepine ring and is followed by a second cycliza-
tion under basic conditions to afford the fused hydantoin. Because
of the uniqueness of these scaffolds, the desirable drug-like prop-
erties of the molecules generated, and the ease of synthesis, this
methodology represents a viable strategy for future enrichment
of small molecule compound libraries.
reaction proceeded for 2 h. Then, reaction mixture was poured into
a
separatory funnel and washed with brine solution (3 Â 80 ml). Organic layer
was dried over MgSO4 and concentrated in vacuo to give yellowish white solid
which was subsequently purified by Teledyne Isco CombiFlash Rf (hexane/
EtOAc 5–50%) to afford 4a (10.82 g, 42.2 mmol, 90%) of yellowish white solid
product. 1H NMR (300 MHz, CDCl3) d 7.47–7.30 (m, 5H), 7.13 (td, J = 7.7, 1.6 Hz,
1H), 7.06 (dd, J = 7.4, 1.3 Hz, 1H), 6.65–6.75 (m, 2H), 5.15 (s, 2H), 5.08 (s, 1H),
4.33 (d, J = 6.2 Hz, 2H), 4.05 (s, 2H). 13C NMR (75 MHz, CDCl3) d 157.34, 145.75,
136.74, 130.68, 129.63, 128.94, 128.59, 128.47, 122.53, 118.48, 116.33, 67.44,
42.92. [M+H]+ = 257.
2-Boc-aminobenzyl-Cbz-amine (4b): To a solution of 4a (10.74 g, 41.9 mmol)
and DIPEA (14.64 ml, 84 mmol) in anhydrous dichloromethane (100 ml) was
added Boc2O (10.97 g, 50.3 mmol). The reaction was then refluxed for 3 days.
The reaction was then concentrated in vacuo and toluene was added to pull out
t-BuOH giving 19.76 g light yellowish white solid which was then purified by
Teledyne Isco CombiFlash Rf (hexane/EtOAc 5–50%) to afford 4b (14.30 g,
40.1 mmol, 96%) of yellowish white solid product. 1H NMR (300 MHz, CDCl3) d
7.86 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.34–7.40 (d, J = 2.6 Hz, 5H), 7.31 (dd,
J = 7.8, 1.7 Hz, 1H), 7.21 (dd, J = 7.5, 1.3 Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H), 5.33 (s,
1H), 5.15 (s, 2H), 4.33 (d, J = 6.4 Hz, 2H), 1.55 (s, 9H). 13C NMR (75 MHz, CDCl3)
d
157.58, 154.23, 137.14, 136.58, 130.47, 129.20, 128.95, 128.65, 128.56,
124.40, 123.22, 80.66, 67.60, 42.35, 28.77. [M+Na]+ = 379.
2-Boc-aminobenzylamine (4): To solution of 4b (14.2 g, 39.8 mmol) in
Acknowledgments
a
methanol (50 ml) was added 0.5 g Pd/C (10%). H2 (g) was flown into glass
reactor at 40 psi. The reaction was then allowed to run at room temperature
over night. Pd/C was removed using Celite then solution was collected using
vacuum filtration to yield 4 (8.80 g, 39.6 mmol, 99%) of yellow sticky product.
1H NMR (300 MHz, CDCl3) d 9.48 (s, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.27 (td, J = 7.7,
1.6 Hz, 1H), 7.11 (dd, J = 7.4, 1.4 Hz, 1H), 6.96 (td, J = 7.4, 1.1 Hz, 1H), 3.97 (s,
We would like to thank the Office of the Director, NIH and the
National Institute of Mental Health for funding (1RC2MH090878-
01). Abbott Laboratories are also thanked for a New Faculty Award
to C.H.

4692
S. Gunawan et al. / Tetrahedron Letters 51 (2010) 4689–4692
2H), 1.74 (s, 2H), 1.54 (s, 9H). 13C NMR (75 MHz, CDCl3) d 153.86, 139.46,
J = 8.1, 1.3 Hz, 1H), 7.06 (t, J = 7.2 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 5.95 (s, 1H),
4.98 (s, 2H), 3.49 (t, J = 7.4 Hz, 2H), 1.56 (m, 2H), 1.39–1.17 (m, 2H), 0.88 (t,
J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3) d 161.85, 153.72, 142.48, 135.43,
134.61, 130.66, 130.55, 129.71, 129.59, 129.11, 126.44, 123.92, 120.73, 109.36,
45.74, 39.01, 30.71, 20.47, 14.06. MS FT-ICR calcd for C21H22N3O2 [M+H]+:
348.1707, found: 348.1707.
129.37, 129.00, 128.66, 122.73, 120.72, 80.17, 45.91, 28.83. [M+H]+ = 223.
6. For the standard preparation of generic structures 8: CO2 gas was bubbled
through a stirring solution of MeOH for 25 min to generate methyl carbonic
acid. In a separate 25 ml flask, phenyl glyoxal 5 (226 mg, 1.687 mmol) was
added to boc-2-aminobenyzlamine 4 (250 mg 1.125 mmol). Methyl carbonic
acid (10 ml) and N-butyl isonitrile (0.237 ml, 2.252 mmol) were then added to
the latter flask. The reaction was stirred at room temperature under an
atmosphere of CO2 for 16 h. The solvent was evaporated in vacuo and the crude
product purified with a Biotage Isolera4™ system (hexane/EtOAc 10–30%) to
afford the Ugi product (218 mg, 0.438 mmol, 39%) as a yellow oil. Ugi product
7. Nichol, G. S.; Gunawan, S.; Dietrich, J.; Hulme, C. Acta Crystallogr., Sect. E 2010,
66, o625.
8. (a) Kerwin, R. Ex. Opin. Investig. Drugs 2006, 15, 1487–1495; (b) Ishii, A;
Yamakawa, M; Toyomaki Y, U.S. Patent 4,985,453, 1991.
9. Kuninobu, Y.; Kikuchi, K.; Takai, K. Chem. Lett. 2008, 37, 740–741.
(135 mg, 0.270 mmol) was treated with
a
5 ml 10% TFA solution in 1,2-
10. A thirty mmol batch of the reagent was prepared by combining KMnO4
dichloroethane which was irradiated in a Biotage Initiator™ at 80 °C for 20 min.
The resulting orange solution was washed with 1 M NaHCO3 (4 Â 2.5 ml) and
the organic layer dried (Na2SO4), filtered, and evaporated in vacuo. MeOH
(1.50 ml), THF (0.75 ml), H2O (0.50 ml) were added to the crude product
(102 mg, 0.269 mmol) followed by a 1 g/1 ml solution of KOH in H2O (0.03 ml).
The solution was irradiated at 100 °C for 20 min and the resultant orange
solution partitioned between EtOAc (5 ml) and 1 M NaHCO3 (5 ml). The organic
layer was dried (Na2SO4), filtered, and evaporated in vacuo. The final crude
product was purified with a Biotage Isolera4™ (hexane/EtOAc 30%) to afford
the final product 9 (74 mg, 0.214 mmol, 79%) as a yellow solid. 1H NMR
(300 MHz, CDCl3) d 7.59–7.44 (m, 5H), 7.35 (d, J = 7.5 Hz, 1H), 7.32–7.25 (td,
(3 mmol, 0.474 g, finely ground) and alumina (Al2O3, neutral, 575 mg) in a
mortar and pestle and grinding together until a free, homogeneous, purple
powder is obtained (5–10 min). 9 (52 mg, 0.15 mmol) was dissolved in acetone
and the KMnO4/Al2O3 powder (66.50 mg supported reagent, 0.20 mmol
KMnO4) was added. After 15 min of vigorous stirring, the reaction mixture
was filtered and the acetone filtrate condensed. The residue was taken up into
hexane/EtOAc 30%, washed with 0.1 M HCl, dried over MgSO4, and the solvent
was evaporated in vacuo to give the crude material which was then purified by
Biotage Isolera Four (hexane/EtOAc 10–30%) to afford the oxidized product
(21 mg, 0.055 mmol, 27%) of white solid.
11. Sideris, T. D.; Ioannou, P. V. Phosphorus, Sulfur, Silicon 2006, 181, 751–762.